Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:44][CH3:45])[C:7]([C:31]2[CH2:32][CH2:33][N:34](C(OC(C)(C)C)=O)[CH2:35][CH:36]=2)=[N:8][C:9]=1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)=[C:13]([CH3:30])[CH:12]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCCl>[CH2:44]([C:6]1[N:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:9]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:18][CH2:19][CH:20]([N:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)[CH2:21][CH2:22]3)=[C:13]([CH3:30])[CH:12]=2)=[N:8][C:7]=1[C:31]1[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=1)[CH3:45]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1C1=CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCC(N4CCN(C)CC4)CC3)c(C)c2)nc1C1=CCNCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
To a mixture of tert-butyl 4-[5-carbamoyl-3-ethyl-6-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)pyrazin-2-yl]-3,6-dihydropyridine-1(2H)-carboxylate (600 mg) and 1,2-dichloroethane (6 mL) was added trifluoroacetic acid (742 μL), followed by stirring at room temperature for 3 hours. The mixture was subjected to liquid separation by the addition of a 5% aqueous potassium carbonate solution and chloroform. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=1:0:0-100:10:1) to obtain 6-ethyl-3-({3-methyl-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}amino)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazine-2-carboxamide (460 mg) as an orange solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH3:23])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH2:19][CH2:20][CH2:21][CH3:22])=[N:14][O:15][C:16]=2[CH2:17][OH:18])[CH:9]=1)=[O:4].[OH-].[Na+]>O1CCOCC1.O>[CH2:19]([C:13]1[C:12]([CH2:11][O:10][C:8]2[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]([CH3:23])[N:7]=2)=[C:16]([CH2:17][OH:18])[O:15][N:14]=1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCc1noc(CO)c1COc1cc(C(=O)OC)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCc1noc(CO)c1COc1cc(C(=O)O)n(C)n1
Temperature: 90 °C
Yield: 99.8 %

Procedure:
To a solution of 5-(3-butyl-5-hydroxymethyl-isoxazol-4-ylmethoxy)-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (260 mg, 0.81 mmol) in dioxane (15 mL) was added aqueous sodium hydroxide (2 M, 7.0 mL, 7.0 mmol). After heating at 90° C. for 1.5 h the solution was cooled to room temperature, diluted with water, extracted with ethyl acetate and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and concentrated to afford the title compound (250 mg, 100%) as a white solid. MS: m/e=308.5 [M−H]−.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[O:9])[CH:4]=1.[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30]>CCOCC.CC(C)=O.CCOCC.O.C(OCC)(=O)C.C(Cl)Cl>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30].[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30].[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:2][C:3]2[O:7][N:6]=[C:5]([C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[O:9])[CH:4]=2)[CH2:22][CH2:21]1
Reactant: OCCN1CCNCC1
Reactant: O=C(c1ccc(F)cc1)c1cc(CBr)on1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(F)cc1)c1cc(CN2CCN(CCO)CC2)on1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
A solution of 5.7 g of (5-bromomethylisoxazol-3-yl)-4-fluorophenylmethanone in 100 ml of Et2O was added to a solution of 6.5 g of N-beta-hydroxyethylpiperazine in 400 ml of 25% acetone/Et2O. The resulting mixture was stirred at room temperature for 24 hours. This mixture was filtered and the solution was concentrated in vacuo to give an oil. The residue was dissolved in 300 ml of H2O and shortly thereafter a precipitate formed. The solid was filtered and dried to give 5.2 g of crude solid. A solution of 4.3 g of the amine in 50 ml of 50% ethyl acetate/CH2Cl2 was added dropwise to a solution of excess maleic acid in 600 ml of Et2O. The precipitated salt was filtered and recrystallized from 160 ml of isopropanol to yield 5.2 g (55%) of crystals, m.p. 139°-140°.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]([CH3:26])[C:11]([N:13]1[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[O:12])=O)(C)(C)C.[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30]>>[F:27][C:28]([F:33])([F:32])[C:29]([OH:31])=[O:30].[NH2:8][CH2:9][CH:10]([CH3:26])[C:11]([N:13]1[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14]1)=[O:12]
Reactant: CC(CNC(=O)OC(C)(C)C)C(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(CN)C(=O)N1Cc2ccccc2C[C@H]1C(=O)O

Procedure:
The (3S)-2-[(2RS)-3-tert.butoxycarbonylamino-2-methylpropanoyl]-3-carboxy-1,2,3,4-tetrahydroisoquinoline obtained is treated with trifluoroacetic acid according to the method is Example 1 (Step E), providing (3S)-2-[(2RS)-3-amino-2-methylpropanoyl]-3-carboxy-1,2,3,4-tetrahydroisoquinoline trifluoroacetate, which is transformed into the hydrochloride by being dissolved in an excess of normal HCl and concentrated to dryness.
Reaction SMILES: [CH2:1]([C:3]1OC(=O)[CH:6]=[C:5]([O:10][CH3:11])[CH:4]=1)[CH3:2].[CH3:12][O:13][C:14]([C:16]#[C:17][C:18]([O:20][CH3:21])=[O:19])=[O:15]>ClCCl>[CH3:12][O:13][C:14](=[O:15])[C:16]1[C:17](=[C:3]([CH2:1][CH3:2])[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=1)[C:18]([O:20][CH3:21])=[O:19]
Reactant: CCc1cc(OC)cc(=O)o1
Reactant: COC(=O)C#CC(=O)OC
Solvent: ClCCl
Product: CCc1cc(OC)cc(C(=O)OC)c1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.6 %

Procedure:
The following is based on the procedure described in Tam, T. F. and Coles P., Synthesis, 383 (1988). 6-ethyl-4-methoxy-2H-pyran-2-one (40.5 g, 263 mmol) was placed in a 500 mL round bottom flask and dimethylacetylenedicarboxylate (42 mL, 342 mmol) was added. This mixture was stirred until the solid completely dissolved. The flask was fitted with a water condenser and placed in a preheated oil bath at 180° C. for 3 hours. The reaction was allowed to cool to room temperature, diluted with dichloromethane (75 mL), and was purified by silica gel chromatography using a gradient of 5-20% ethyl acetate in hexanes. The appropriate fractions were collected and concentrated by rotary evaporation to yield compound P (44.16 g, 67%) as a clear oil. 1H NMR CDCl3 δ: 7.30 (d, 1H, J=3 Hz), 6.95 (s, 1H, J=3 Hz), 3.90 (s, 3H), 3.88 (s, 3H), 3.85 (s, 3H), 2.64 (q, 2H, J=8.0 Hz), 1.21 (t, 3H, J=8.0 Hz). ESMS m/z: 221 [M−OCH3]+, 275 [M+Na+].
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23]5[N:24]=[C:25]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:26](C6CCCCO6)[CH:27]=5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Cl.CO>CCO>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([C:23]5[NH:24][C:25]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])=[N:26][CH:27]=5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cn(C4CCCCO4)c(CC(C)(C)O)n3)cc1OCC2
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(-c3cnc(CC(C)(C)O)[nH]3)cc1OCC2
Temperature: 25 °C
Yield: 12 %

Procedure:
To a solution of 1-[4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-1-(tetrahydro-pyran-2-yl)-1H-imidazol-2-yl]-2-methyl-propan-2-ol (735 mg, 1.42 mmol) in EtOH (15 mL) was added a solution of hydrogen chloride in MeOH (7.1 mL, 28.4 mmol). The reaction mixture was heated at reflux for 5 h, cooled to r.t. and concentrated. Saturated NaHCO3 solution was added slowly and the reaction mixture was extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by prep-TLC (DCM:MeOH=8:1) to give 290 as a yellow solid (74 mg, 12%). 1H NMR (CDCl3, 400 MHz): δ 8.44 (d, J=8.4 Hz, 1H), 7.89 (s, 1H), 7.58 (s, 1H), 7.43-7.36 (m, 2H), 7.28 (s, 1H), 5.95-5.91 (m, 1H), 4.45-4.02 (m, 4H), 2.97 (s, 2H), 1.60 (d, J=6.8 Hz, 6H), 1.30 (s, 6H). MS: (ESI, m/z)=434 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:18])[CH:8]=2)[N:3]=1.O.[NH2:20][NH2:21]>>[Br:18][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:20][NH2:21])[CH:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cc(-c2ccccc2)c2cc(Br)ccc2n1
Reactant: NN
Solvent: O
Product: NNc1cc(-c2ccccc2)c2cc(Br)ccc2n1

Procedure:
In the manner given in Example 1, 2-chloro-6-bromo-4-phenylquinoline is reacted with hydrazine hydrate at reflux to give 6-bromo-4-phenyl-2-hydrazinoquinoline.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>ClCCl>[CH3:13][S:14]([NH:1][CH2:2][CH2:3][CH2:4][O:5][S:14]([CH3:13])(=[O:16])=[O:15])(=[O:16])=[O:15]
Reactant: NCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCCOS(C)(=O)=O
Yield: 69.8 %

Procedure:
To a solution of 3-amino-1-propanol (11.47 ml, 150 mmoles) and triethylamine (46 ml, 330 mmoles) in dichloromethane (250 ml) was added methylsulfonyl chloride (25.5 ml, 330 mmoles) with stirring under ice-cooling and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed in turn with an aqueous sodium bicarbnonate and water and dried. After the solvent was distilled off, the residue was purified by column chromatography (eluent:ethyl acetate) to obtain 24.22 g of the desired product (69.8%, white crystals).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[N:7][NH:6][N:5]=1)([O-:3])=[O:2].Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:14][CH:10]([F:15])[N:6]1[N:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: O=[N+]([O-])c1cn[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(C(F)F)n1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A 100-mL single-neck round-bottomed flask containing 4-nitro-2H-1,2,3-triazole (500 mg, 4.38 mmol, 1.0 eq.), sodium 2-chloro-2,2-difluoroacetate (1310 mg, 8.76 mmol, 2.0 eq.), K2CO3 (1140 mg, 8.76 mmol, 2.0 eq.), and acetonitrile (20 mL) was stirred at reflux for 5 h. After cooling to room temperature, the reaction mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 4:1 petroleum ether/ethyl acetate to afford 159a (350 mg, 48%) as a brown liquid. 1H NMR (500 MHz, CDCl3) δ 8.38 (s, 1H), 7.39 (t, J=57.5 Hz, 1H).
Reaction SMILES: [Cl:1][SiH:2]([CH3:4])[CH3:3].[CH:5]([Si:7]([CH:12]=[CH2:13])([CH:10]=[CH2:11])[CH:8]=[CH2:9])=[CH2:6]>CC(OC)(C)C>[Si:7]([CH2:12][CH2:13][Si:2]([Cl:1])([CH3:4])[CH3:3])([CH2:10][CH2:11][Si:2]([Cl:1])([CH3:4])[CH3:3])([CH2:8][CH2:9][Si:2]([Cl:1])([CH3:4])[CH3:3])[CH2:5][CH2:6][Si:2]([Cl:1])([CH3:4])[CH3:3]
Reactant: C=C[Si](C=C)(C=C)C=C
Reactant: C[SiH](C)Cl
Solvent: COC(C)(C)C
Product: C[Si](C)(Cl)CC[Si](CC[Si](C)(C)Cl)(CC[Si](C)(C)Cl)CC[Si](C)(C)Cl
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
Under argon, 234.2 g (2.475 mol) chlorodimethyl silane, 500 ml TBME and 1.5 g catalyst 1 were added to 75 g (0.550 mol) tetravinyl silane. The reaction mixture was heated, with vigorous stirring, to 45° C. until an exothermic reaction set in and the temperature rose to 51° C. A mixture comprising 525 g (3.853 mol) tetravinyl silane, 1639.4 g (17.327 mol) chlorodimethyl silane and 940 ml TBME was then added slowly dropwise, wherein care was taken that the reaction temperature did not fall below 50° C. Stirring was then continued for 1.5 hours under reflux, the reaction mixture was cooled to room temperature, the catalyst was filtered off over a frit, and volatile constituents were removed from the colourless solution under vacuum. The product took the form of a white solid. Yield: 2120.8 g (94% of theoretical yield).
Reaction SMILES: [C:1]1([CH2:7][C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([N-:14]CC)[CH3:13].[Li+].BrCC#N>C1COCC1>[C:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:13][C:12]#[N:14])([O:10][CH3:11])=[O:9]
Reactant: COC(=O)Cc1ccccc1
Reactant: CC[N-]CC
Agent: N#CCBr
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CC#N)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of methyl phenylacetate (200 g, 1.33 mol) in THF (300 mL) is added, dropwise, to a −78° C. solution of lithium diethylamide (LDA, 1.4 mol) in THF (2500 mL). After addition is complete, a precipitate forms, and additional THF (200 mL) is added. The resulting mixture is vigorously stirred while a solution of bromoacetonitrile (168 g, 1.4 mol) in THF (400 mL) is slowly added. After 20 minutes the cooling bath is removed and the reaction mixture is quenched with saturated NH4Cl solution (500 mL). After allowing the mixture to slowly warm to ambient temperature any solid material is removed by filtration and the solvent is removed in vacuo. The residue is dissolved in ET2O (1000 mL) and diluted with H2O (1000 mL). The organic phase is then washed with 0.5N HC1 (1×1000 mL), saturated NaCl solution (2×1000 mL) and concentrated in vacuo. The residue is then vacuum distilled (˜1 mm Hg) and the fraction boiling between 125° C. and 145° C. is collected to give β-(carbomethoxy)-β-phenylpropionitrile which solidifies upon standing.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[C:10](OC(=O)C)(=[O:12])[CH3:11]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH:4][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C)c(N)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(C)ccc1C
Reaction time: 4 h

Procedure:
To a stirred solution of 2,5-dimethylaniline (5.30 g) and 4-dimethylaminopyridine (6.41 g) in dichloromethane (90 ml) was added acetic anhydride (4.13 ml) under ice-cooling, and the mixture was stirred for 4 hours. The reaction mixture was washed with 1N hydrochloric acid and a saturated aqueous sodium bicarbonate solution subsequently, and dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 2′,5′-dimethylacetanilide (6.09 g).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([O:10]C(C)C)=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH:22]=[C:21]([CH3:32])[C:20]=1[F:33].[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[C:4]([CH3:16])[C:3]=1[NH:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[CH:26]=2)[CH:22]=[C:21]([CH3:32])[C:20]=1[F:33]
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(OCC(=O)OC(C)C)c2C)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(OCC(=O)O)c2C)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of isopropyl 2-[4-fluoro-3-[[2-fluoro-5-(3-fluorophenyl)-3-methyl-phenyl]methylamino]-2-methyl-phenoxy]acetate (150 mg, 0.33 mmol) in THF (6 mL) was added NaOH (1M aqueous solution, 4.0 mL, 4.0 mmol). The reaction mixture was stirred at room temperature for 2 h, then the THF removed under reduced pressure. The remaining aqueous solution was adjusted to pH 3-4 with diluted HCl and the solid that precipitated collected by filtration, washed with water and dried in vacuo to give the title compound as a white solid (100 mg, 74%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:8]=[CH:7][C:6]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][CH:18]=1)=[O:4].[CH3:26][N:27]1[CH2:32][CH2:31][C:30]2([C:43]3[C:35](=[CH:36][C:37]4[CH2:38][CH2:39][NH:40][C:41]=4[CH:42]=3)[O:34][CH2:33]2)[CH2:29][CH2:28]1>>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:8]=[CH:7][C:6]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:40]2[C:41]3[CH:42]=[C:43]4[C:30]5([CH2:33][O:34][C:35]4=[CH:36][C:37]=3[CH2:38][CH2:39]2)[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]5)=[O:24])=[CH:19][CH:18]=1)=[O:4]
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: COC(=O)c1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)O)cc1
Product: COC(=O)c1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1

Procedure:
The title compound was prepared from 2'-methoxycarbonyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carboxylic acid (D53) and 1'-methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (D7) following a similar procedure to Example 15 as an off-white powder (66%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][NH2:10])=[C:6]([OH:8])[CH:7]=1.[CH3:11][C:12]1[CH:17]=[CH:16]C(S([O-])(=O)=O)=[CH:14][CH:13]=1.CC(C(=O)C)C(=O)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[C:17]([CH3:16])=[C:12]([CH3:11])[C:13]([CH3:14])=[N:10]2)=[C:6]([OH:8])[CH:7]=1
Reactant: NNc1ccc(Br)cc1O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: CC(=O)C(C)C(C)=O
Product: Cc1nn(-c2ccc(Br)cc2O)c(C)c1C
Yield: 47.3 %

Procedure:
320 mg of the title compound was prepared in a manner similar to Example 54b) by using 5-bromo-2-hydrazinylphenol 4-methylbenzenesulfonate (0.9 g), which was prepared in a manner similar to Example 54a), and 3-methylpentane-2,4-dione (0.9 g).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=[CH:17][C:12]=2[S:11][C:10]=1[C:28]([O:30]CC)=[O:29])(C)(C)C.[OH-].[Na+].CCO.Cl>O.C1COCC1>[C:6]([CH2:7][O:8][C:9]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=3[Cl:27])=[CH:17][C:12]=2[S:11][C:10]=1[C:28]([OH:30])=[O:29])([OH:33])=[O:5]
Reactant: CCOC(=O)c1sc2cc(OCc3ccc(Cl)cc3Cl)ccc2c1OCC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: O=C(O)COc1c(C(=O)O)sc2cc(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 50 °C
Reaction time: 24 h
Yield: 92.5 %

Procedure:
A mixture of ethyl 3-(2-tert-butoxy-2-oxoethoxy)-6-((2,4-dichlorobenzyl)oxy)-1-benzothiophene-2-carboxylate (1.1 g), 1N NaOH (5 mL), EtOH (5 mL) and THF (10 mL) was stirred at 50° C. for 24 h. Water and 1N HCl (5 mL) were added to the mixture and the mixture was extracted with THF-EtOAc. The organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was washed with hexane to give the title compound (0.850 g). The obtained crystals were recrystallized from acetone-water.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][CH:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+].[C:30](O)(=O)[CH3:31]>>[CH2:30]([N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:16])([F:17])[F:18])[O:19][CH2:20][CH:21]1[CH2:23][C:24]([F:25])([F:26])[F:27])[CH3:31]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)NC(CC(F)(F)F)CO3
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OCC1CC(F)(F)F

Procedure:
This compound was prepared by General Method 5 (EXAMPLE 1) from (±)-3,4-dihydro-8-isopropoxy-3-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (0.019 g, 0.05 mmol) and NaBH4 (0.5 pellets, >0.5 mmol) in 2 mL glacial acetic acid to afford (±)-4-ethyl-3,4-dihydro-8-isopropoxy-3-(2,2,2-trifluoroethyl)-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline, of sufficient purity as to be used directly in the next reaction.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:31][CH:30]4[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]5[C:27]([C:33](O)=[O:34])([NH:28][C:29]4=[O:32])[CH2:26]5)[CH2:15]3)[CH:10]=[C:9]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:44]1([S:47]([NH2:50])(=[O:49])=[O:48])[CH2:46][CH2:45]1.CCN=C=NCCCN(C)C.C1CCN2C(=NCCC2)CC1>C(Cl)Cl>[C:1]1([C:7]2[N:12]=[C:11]([O:13][CH:14]3[CH2:31][CH:30]4[CH:16]([C:17](=[O:37])[N:18]([CH3:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]5[C:27]([C:33]([NH:50][S:47]([CH:44]6[CH2:46][CH2:45]6)(=[O:49])=[O:48])=[O:34])([NH:28][C:29]4=[O:32])[CH2:26]5)[CH2:15]3)[CH:10]=[C:9]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CN1CCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3cc(-c4ccccc4)nc(-c4ccccc4)n3)CC2C1=O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)C2CC2)NC(=O)C2CC(Oc3cc(-c4ccccc4)nc(-c4ccccc4)n3)CC2C1=O
Yield: 62.4 %

Procedure:
The acid 17f (240 mg, 0.41 mmol) was reacted with cyclopropane sulfonamide (63 mg, 0.52 mmol), EDAC (105 mg, 0.55 mmol) and DBU (182 mg, 1.2 mmol) in dry DCM according to the procedure described in Example 13 step f. Purification by column chromatography on silica gel eluted with diethyl ether-ethyl acetate gave the title compound, (175 mg, 62%), (M+H)+684.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[C:18]([OH:20])=O.[NH2:26][C:27]1[CH:28]=[C:29]([NH:34][C:35](=[O:45])[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([N:42]([CH3:44])[CH3:43])[CH:37]=2)[CH:30]=[CH:31][C:32]=1[F:33].CN(C=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.O>[CH3:43][N:42]([CH3:44])[C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=1)[C:35]([NH:34][C:29]1[CH:30]=[CH:31][C:32]([F:33])=[C:27]([NH:26][C:18](=[O:20])[C:17]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:15]([O:14][CH3:13])[CH:16]=2)[CH:28]=1)=[O:45]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: CN(C)c1cccc(C(=O)Nc2ccc(F)c(N)c2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N(C)C)c3)ccc2F)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.12 g) in methylene chloride (5 ml) was added to a stirred mixture of 3,4-dimethoxybenzoic acid (0.91 g), N-(3-amino-4-fluorophenyl)-3-dimethylaminobenzamide (0.14 g), DMF (2 ml) and 4-dimethylaminopyridine (0.004 g). The reaction mixture was stirred at ambient temperature for 18 hours. Water (20 ml) and methylene chloride (10 ml) were added. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, dried (MgSO4) and evaporated. The residual oil was purified by column chromatography on silica gel using a 49:1 mixture of methylene chloride and methanol as eluent. The material so obtained was triturated under diethyl ether. There was thus obtained the title compound (0.084 g) as a colourles solid, m.p. 187-188° C.; NMR Spectrum: (CDCl3) 3.02 (s, 6H), 3.97 (s, 6H), 6.86 (m, 1H), 6.93 (d, 1H), 7.09 (d, 1H), 7.16 (t, 1H), 7.25 (m, 1H), 7.32 (t, 1H), 7.41 (m, 1 H), 7.5 (d, 1H), 7.88 (m, 1H), 7.97 (s, 1H), 8.04 (s, 1H), 8.42 (m, 1H);
Reaction SMILES: C[O-].[Na+].C([C@@H]1CC[C@@H](C)C[C@H]1OC([N:17]1[CH:22]=[CH:21][C:20](=[O:23])[CH2:19][CH:18]1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[CH3:31])=O)(C)C>CO>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C@H:18]2[CH2:19][C:20](=[O:23])[CH:21]=[CH:22][NH:17]2)=[C:25]([CH3:31])[CH:26]=1
Reactant: Cc1cc(F)ccc1C1CC(=O)C=CN1C(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(F)ccc1[C@H]1CC(=O)C=CN1
Yield: 161 %

Procedure:
Sodium methoxide (100 mg) was added to a solution of intermediate 6b (170 mg) in MeOH (15 mL) under a nitrogen atmosphere. The mixture was refluxed for two hours and the solvent was removed in vacuo. The residue was partitioned between water (10 mL) and AcOEt (15 mL). The layers were separated, and the aqueous phase was extracted with further AcOEt (4×10 mL). The combined organic extracts were washed with brine (10 mL), dried and concentrated in vacuo to give the title compound (145 mg) as a light yellow oil.