Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:8][O:9][C:10]=1[CH3:11])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:11][C:10]1[O:9][N:8]=[C:7]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:6]=1[CH2:4][OH:3]
Reactant: CCOC(=O)c1c(C2CCOCC2)noc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(C2CCOCC2)c1CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 33.4 %

Procedure:
To a solution of 5-methyl-3-(tetrahydro-pyran-4-yl)-isoxazole-4-carboxylic acid ethyl ester (4.0 g, 16.7 mmol) in THF (55 mL) at 0° C. was added lithium aluminum hydride (349 mg, 9.0 mmol). And the resulting mixture stirred for 18 h at room temperature. Water (0.5 mL) was added carefully followed by aqueous sodium hydroxide (15%, 1.0 mL) and water (2.2 mL). The resulting suspension was stirred for 15 min at ambient temperature and filtered over Hyflo®. The filtrate was then evaporated and purification by chromatography (silica, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (1.1 g, 34%) as a colourless gum. MS: m/e=198.1 [M+H]+.
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:15]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.[O:17]=[C:18]1[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][CH2:20][N:19]1[CH2:36][C:37](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[C:30]1([C:23]2([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:22][CH2:21][CH2:20][N:19]([CH2:36][C:37]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=4)[N:15]=3)[C:18]2=[O:17])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc(OC(F)(F)F)cc3)no2)CCCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 16 h

Procedure:
(Z)—N-Hydroxy-4-(trifluoromethoxy)benzimidamide (0.125 g, 0.566 mmol), 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (0.175 g, 0.566 mmol; Example 68E) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.163 g, 0.849 mmol) were stirred together in dichloroethane (4 mL) at room temperature for 45 minutes, then heated to 85° C. and stirred for 16 hours. The reaction was cooled and concentrated. Silica gel chromatography using a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) eluting with a gradient of 5% ethyl acetate/hexanes to 35% ethyl acetate/hexanes (Flow=35 mL/minute) over 30 minutes gave the title compound. 1H NMR (300 MHz, CDCl3) δ 8.22-8.08 (m, 2H), 7.43-7.16 (m, 12H), 4.92 (s, 2H), 3.62 (t, J=6.5, 2H), 2.80-2.61 (m, 2H), 2.03-1.80 (m, 2H); MS (ESI+) m/z 494.1 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[C:17]([Cl:19])[N:16]=[N:15][C:14]=3[C:20]([O:22]CC)=O)[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH3:25]>CO>[N:1]1([C:6]2[N:11]=[C:10]([NH:12][C:13]3[CH:18]=[C:17]([Cl:19])[N:16]=[N:15][C:14]=3[C:20]([NH2:25])=[O:22])[CH:9]=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(-n2cccn2)n1
Solvent: CO
Product: NC(=O)c1nnc(Cl)cc1Nc1cccc(-n2cccn2)n1
Temperature: 25 °C
Yield: 55 %

Procedure:
To a solution of ethyl 4-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxylate (107 mg of ˜83% purity, 258 μmol) in methanol (1 mL) was added ammonia in methanol (2.5 mL, 17.5 mmol) and the mixture warmed at 25° C. for 18 h. The mixture was cooled, filtered, and the collected solid dried in vacuo to give 4-(6-(1H-pyrazol-1-yl)pyridin-2-ylamino)-6-chloropyridazine-3-carboxamide (45 mg, 141 μmol, 55%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](OC)=[O:9])[CH:5]=[C:4]([O:12][CH3:13])[N:3]=1.CC(C[AlH]CC(C)C)C.ClCCl>>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[C:4]([O:12][CH3:13])[N:3]=1
Reactant: COC(=O)c1cc(OC)nc(Cl)n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: COc1cc(C=O)nc(Cl)n1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A 25 mL round-bottomed flask was charged with methyl 2-chloro-6-methoxypyrimidine-4-carboxylate [sad105-055 crude] (74 mg, 1 equiv.) under argon. 1M DIBAL-H in dichloromethane (0.73 mL, 2 equiv.) was added over 5 min and the reaction mixture was stirred at −78° C. for 45 min. After 0.5 h, LC-MS showed the reaction was complete. The reaction was quenched at −78° C. with methanol (0.5 mL) and then with 10% NH4Cl (2 mL). The solvents were concentrated under reduced pressure and the residue was diluted with 10% NH4Cl (3 mL). The aqueous layer was extracted with EtOAc (3×10 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure to provide the crude product 2-chloro-6-methoxypyrimidine-4-carbaldehyde as an orange oil (76 mg, 63 mg theoretical, 121%). LC-MS m/z: 205.0: (M+1+MeOH, hemiacetal with methanol). Some over-reduced alcohol was also observed in the crude (2.17 min, M+1=175). The crude aldehyde was used directly in the next step without further purification.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:30]([CH3:32])[CH3:31])[C:27]([OH:29])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(OC)=O)C4=O)=CC=3)=CC=2)=O)CCCCC1>>[CH:2]1([C:1]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([C@@H:26]([CH:30]([CH3:32])[CH3:31])[C:27]([OH:29])=[O:28])[C:22]4=[O:25])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)C4CCCCC4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)C4CCCCC4)cc3)cc2C1=O
Yield: 78 %

Procedure:
The compound of example 118 was prepared analogous to compound of example 98 by hydrolysis of compound of example 117.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[CH2:10][C:11](=O)[CH3:12])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:9](=[O:14])[CH:10]=[C:11]2[CH3:12]
Reactant: CC(=O)CC(=O)Nc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(=O)[nH]c2ccc(Br)cc12

Procedure:
A mixture of 3.00 g (0.0117 moles) of N-(4-bromophenyl)-3-oxobutyramide and 6 ml concentrated sulfuric acid was stirred and heated to 95°-100° C. (H2O bath) for 11/2 hours. The resulting solution was poured onto an ice/H2O mixture to yield a white crystalline product. The crystals were collected and taken up in 200 ml absolute ethanol. The volume was reduced to 150 ml followed by chilling; crystals were isolated (0.71 g 25.6%), mp 292°-299° C. Anal. Calcd. for C10H8BrNO: C, 50.45; H, 3.39; N, 5.88; Br, 33.56. Found: C, 50.28; H, 3.44; N, 5.83; Br, 33.68. A TLC of the product on silica showed Rf 0.18 with ethyl acetate eluent.
Reaction SMILES: Cl.[CH3:2][C:3]([C:6]([O:8][CH3:9])=[O:7])([CH3:5])[NH2:4].C([O-])(=O)C.[K+].[CH3:15][CH:16]([CH3:20])[CH2:17][CH:18]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:2][C:3]([C:6]([O:8][CH3:9])=[O:7])([CH3:5])[NH:4][CH2:18][CH2:17][CH:16]([CH3:20])[CH3:15]
Reactant: CC(C)CC=O
Reactant: COC(=O)C(C)(C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C(C)(C)NCCC(C)C
Temperature: 10 °C

Procedure:
A suspension of methyl 2-methylalaninate hydrochloride (6.9 g, 45 mmol) in dry dichloromethane (180 mL) was treated with potassium acetate (4.4 g, 45 mmol) and the reaction mixture stirred for ten minutes. The reaction mixture was then cooled to 10° C. and treated with 3-methylbutanal (4.8 g, 56 mmol). This was followed by the addition of sodium triacetoxyborohydride (11.91 g, 56 mmol) in portions over a period of ten minutes. Reaction mixture was stirred at room temperature for 16 h. Then saturated aqueous sodium bicarbonate solution was added to the reaction and resulting mixture was stirred for another 30 minutes. The reaction mixture was further basified with aqueous sodium carbonate to pH=˜10. Dichloromethane layer was separated and the aqueous layer extracted with dichloromethane (3×50 mL). Organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, and evaporated to give titled product as colorless oil which was used as such for the next step. 1HNMR (300 MHz, CDCl3): δ 0.95 (s, 3H), 0.96 (s, 3H), 1.25-1.35 (m, 7H), 1.55-1.65 (m, 1H), 1.80 (s, 1H), 2.40-2.48 (m, 2H), 3.63 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([C:25](=[O:34])[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:36].[H-].[Na+]>C1COCC1>[CH2:1]([N:8]1[CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:12][C:11]([CH3:21])([CH3:20])[N:10]2[N:22]=[CH:23][C:24]([C:25](=[O:34])[CH:26]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)[CH3:36])=[C:9]12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1ccc(CC(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(C(C)C(=O)c2cnn3c2N(Cc2ccccc2)C(c2ccccc2)CC3(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
To 0.64 g (1.42 mmol) of 4 dissolved in 10 mL of THF was added 0.177 mL (2.85 mmol) of iodomethane followed by 0.11 g (2.8 mmol) of sodium hydride (60% dispersion in mineral oil). After stirring at room temperature for 2 h, the reaction was quenched by addition of approximately 2 mL of saturated aqueous ammonium chloride. The reaction was then diluted with AcOEt and dried over sodium sulfate. Filtering the solution through a short plug of silica gel and concentrating in vacuo provided the crude product. Purification by flash chromatography eluting with 90% hexanes/ethyl acetate gave 0.42 g (64%) of the title compound as a cream colored powder. MS Calcd.: 463. Found: 464 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35](Br)=[CH:34][CH:33]=1)([CH3:29])([CH3:28])[CH3:27].C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:26]([O:30][C:31](=[O:39])[C:32]1[CH:37]=[CH:36][C:35]([N:22]2[CH2:23][CH2:24][N:19]([C:16]3[CH:17]=[CH:18][C:13]([C:12](=[O:25])[NH:11][C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=4)=[CH:14][N:15]=3)[CH2:20][CH2:21]2)=[CH:34][CH:33]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCNCC3)nc2)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)OC(=O)c1ccc(N2CCN(c3ccc(C(=O)Nc4cccc(C(C)(C)C)c4)cn3)CC2)cc1

Procedure:
4-{4-[5-(3-tert-Butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid tert-butyl ester was synthesized from N-(3-tert-butyl-phenyl)-6-piperazin-1-yl-nicotinamide and 4-bromo benzoic acid tert-butyl ester in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C31H38N4O3 (m/e) 514, obsd 515 (M+H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([NH:11][C:12]3[C:13]4[CH2:21][CH2:20][N:19]([C:22](=O)[CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:18][C:14]=4[N:15]=[CH:16][N:17]=3)[CH:9]=[CH:10][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[ClH:37]>C1COCC1.C(OCC)C.O>[ClH:37].[F:26][C:24]([F:25])([F:27])[CH2:23][CH2:22][N:19]1[CH2:20][CH2:21][C:13]2[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:2]4[O:1][CH2:6][CH2:5][O:4][C:3]=4[CH:7]=3)=[N:17][CH:16]=[N:15][C:14]=2[CH2:18]1
Reactant: O=C(CC(F)(F)F)N1CCc2c(ncnc2Nc2ccc3c(c2)OCCO3)C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)CCN1CCc2c(ncnc2Nc2ccc3c(c2)OCCO3)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 1-(4-(2,3-dihydrobenzo[b][1,4]dioxin-6-ylamino)-5,6-dihydropyrido[3,4-d]pyrimidin-7(8H)-yl)-3,3,3-trifluoropropan-1-one (0.069 g, 0.17 mmol) in THF (5 mL) was cooled to 0° C. under nitrogen. Lithium aluminum hydride was added (0.85 ml of a 1.0M solution in THF, 0.85 mmol) and the mixture was stirred at 0° C. for one h. The mixture was allowed to gradually warm to r.t. with overnight stirring and then cooled again to 0° C. Water (1 mL) was added dropwise. After five min, 10N NaOH (1 mL) was added and the mixture was allowed to warm to r.t. Water (3 mL) was added. The mixture was then extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with water and brine and dried over sodium sulfate. The solvent was concentrated to leave an oil which was purified by silica gel chromatography (ethyl acetate/hexane gradient). The colorless oil so obtained (0.020 g) was dissolved in diethyl ether and treated with 1.0 M HCl in diethyl ether (0.05 mL) to produce a solid which was triturated with diethyl ether and dried to yield the product (17 mg).
Reaction SMILES: [NH2:1]/[C:2](/[CH3:8])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5].[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[H][H]>CO>[CH3:9][S:10]([OH:13])(=[O:12])=[O:11].[NH2:1][C@H:2]([CH3:8])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: COC(=O)/C=C(/C)N
Agent: CS(=O)(=O)O
Solvent: CO
Product: COC(=O)C[C@@H](C)N
Yield: 61.2 %

Procedure:
Under a nitrogen atmosphere, 78.0 mg (0.0869 mmol) of Ru(OCOCH3)2((R)-tol-binap), 1.00 g (8.69 mmol) of methyl 3-aminocrotonate, 0.83 g (8.69 mmol) of methanesulfonic acid and 5 ml of methanol were placed in a stainless steel autoclave, and the mixture was kept at 50° C. under 3 MPa pressure of hydrogen for 15 hours with stirring. After completion of the reaction, the solvent was distilled off, and the residue was recrystallized from methanol/ethyl acetate to give the objective methyl (R)-3-aminobutanoate methanesulfonate (1.135 g, white crystals). The yield was 61.3%.
Reaction SMILES: Br[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[S:11]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12]1.[F-].[Cs+].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.COCCOC.CO>[OH:10][C:5]1[CH:4]=[CH:3][C:2]([C:13]2[CH:14]=[CH:15][S:11][CH:12]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OB(O)c1ccsc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: O=Cc1cc(-c2ccsc2)ccc1O
Temperature: 80 °C

Procedure:
0.15 g of tetrakis(triphenylphosphine)palladium catalyst (1.3 10−4 mol) is added to a solution of 5-bromosalicylaldehyde (0.86 g, 0.0043 mol) and of 3-thiopheneboronic acid (0.6 g, 0.0047 mol) in 10 ml of 1,2-dimethoxyethane and 5 ml of methanol. 1.3 g of cesium fluoride are added and the mixture is heated at 80° C. for 20 hours. The reaction mixture is cooled to room temperature and poured into water. The resulting mixture is extracted with dichloromethane and the organic phase is washed with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The title product is isolated by chromatography on a column of silica (eluent: 88/12 cyclohexane/ethyl acetate. 0.62 g of a pale yellow solid is recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]([C@H:19]2[CH2:23][CH2:22][C@H:21]([CH2:24]Br)[C@H:20]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:5][CH:4]=1.[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][N:8]([C@H:19]2[CH2:23][CH2:22][C@H:21]([CH2:24][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[C@H:20]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:5][CH:4]=1
Reactant: C1CCNC1
Reactant: COc1ccc(CN(C(=O)OCc2ccccc2)[C@H]2CC[C@H](CBr)[C@H]2c2ccc(F)cc2)cc1
Solvent: CC#N
Product: COc1ccc(CN(C(=O)OCc2ccccc2)[C@H]2CC[C@H](CN3CCCC3)[C@H]2c2ccc(F)cc2)cc1
Temperature: 90 °C

Procedure:
To a solution of 500 mg of product from Step C in 3.0 mL of acetonitrile was added 0.40 mL of pyrrolidine. The reaction was heated at 90° C. for 3 days in a sealed vial and then concentrated. The residue was purified by flash chromatography eluting with 0 to 5% methanol in methylene chloride to obtain 483 mg of title compound. Mass spec (NH3 /CI): 517 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][C:17](B2OC(C)(C)C(C)(C)O2)=[CH:16][CH:15]=1>>[CH3:12][NH:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[N:9]3)=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: CNc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Brc1ccc2cccnc2c1
Product: CNc1ccc(-c2ccc3cccnc3c2)cc1

Procedure:
N-Methyl-4-(quinolin-7-yl)aniline T515 was prepared using general procedure A from 7-bromoquinoline (41 mg, 0.2 mmol) and N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (46 mg, 0.2 mmol). T515 was obtained as a yellow wax (18 mg, 38%). 1H NMR (400 MHz, CDCl3): δ 8.90 (dd, J=4.0, 1.2 Hz, 1H), 8.26 (m, 1H), 8.13 (m, 1H), 7.82-7.81 (m, 2H), 7.64 (m, 2H), 7.34 (dd, J=8.4, 4.4 Hz, 1H), 6.73 (m, 2H), 2.90 (s, 3H); MS (ESI): 235 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]([N:18]([CH3:20])[CH3:19])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([N+:21]([O-])=O)[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]([N:18]([CH3:19])[CH3:20])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([NH2:21])[CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CN(C)c1cc(-c2cccc(F)c2)nc2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: CCO
Product: CN(C)c1cc(-c2cccc(F)c2)nc2ccc(N)cc12
Reaction time: 18 h

Procedure:
The title compound was prepared by reduction of a nitro group by catalytic hydrogenation as follows. Into a 500 mL Parr shaker bottle was placed 4.0 g of the N-[2-(3-fluorophenyl)-6-nitro-4-quinolinyl]-N,N-dimethylamine along with 150 mg of a catalyst consisting of 5% palladium on calcium carbonate support. To this was added 150 mL of ethanol, followed by application of a 50 psi hydrogen atmosphere. The reaction was shaken for 18 hr then the hydrogen atmosphere was replaced by nitrogen. The catalyst was removed by filtration, and the solution concentrated. The residue was taken up in ethyl acetate, washed with 5% sodium hydroxide solution, then the organic layer was dried over Na2SO4, filtered and concentrated. The extract was recrystallised from methylene chloride and hexane to give 2.8 g (77%) of the product.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:30])[CH2:10][C@@:11]1([C:24]2[S:25][C:26](Br)=[CH:27][CH:28]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13][CH2:12]1.[CH3:31][NH:32][C:33]([NH:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1)=[O:34]>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.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>[OH:7][NH:8][C:9](=[O:30])[CH2:10][C@@:11]1([C:24]2[S:25][C:26]([C:38]3[CH:39]=[CH:40][CH:41]=[C:36]([NH:35][C:33]([NH:32][CH3:31])=[O:34])[CH:37]=3)=[CH:27][CH:28]=2)[S:17](=[O:18])(=[O:19])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:21])=[O:22])[CH2:13][CH2:12]1
Reactant: CNC(=O)Nc1cccc(B(O)O)c1
Reactant: CS(=O)(=O)N1CC[C@](CC(=O)NOC2CCCCO2)(c2ccc(Br)s2)S(=O)(=O)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: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CNC(=O)Nc1cccc(-c2ccc([C@@]3(CC(=O)NO)CCN(S(C)(=O)=O)CCS3(=O)=O)s2)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 13.4 %

Procedure:
A mixture of N-(2-tetrahydropyranyloxy)-2-[(S)-7-(5-bromo-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (230 mg), 3-(methylaminocarbonylamino)phenylboronic acid (123 mg) and tetrakis(triphenylphosphine)palladium(0) (24.4 mg) in a mixture of 1,2-dimethoxyethane (2 ml) and 2M aqueous sodium carbonate solution (0.85 ml) was stirred for 4 hours at 80° C. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue was dissolved in methanol (2 ml) and 10% hydrogen chloride in methanol (0.5 ml) was added thereto. After being stirred for 30 minutes at room temperature, the solution was concentrated in vacuo. The residue was purified with silica gel column chromatography (eluent; 0.5-5% methanol in chloroform) to give N-hydroxy-2-[(S)-7-(5-(3-(methylaminocarbonylamino)-phenyl)-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (30 mg).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:22]=[CH:21][C:13]([C:14]([O:16]C(C)(C)C)=[O:15])=[C:12]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=4[CH3:32])[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1>FC(F)(F)C(O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:22]=[CH:21][C:13]([C:14]([OH:16])=[O:15])=[C:12]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:26]=4[CH3:32])[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1cccc(C(=O)Nc2cc(-c3ccc4c(c3)OCO4)ccc2C(=O)OC(C)(C)C)c1C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(C(=O)Nc2cc(-c3ccc4c(c3)OCO4)ccc2C(=O)O)c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-(benzo[1,3]dioxol-5-yl)-2-(2,3-dimethylbenzamido)benzoate and stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure and methanol was added to the obtained residue and a solid substance was separated by filtration to obtain 31 mg of 4-(benzo[1,3]dioxol-5-yl)-2-(2,3-dimethylbenzamido)benzoic acid as white solid.