Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]4[CH2:21][CH2:20][CH:17]([C:18]=3[CH3:19])[NH:16][CH2:15]4)=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23].[O:26]1[CH:30]=[CH:29][C:28]([C:31](O)=[O:32])=[N:27]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C:13]3[CH:14]4[CH2:21][CH2:20][CH:17]([C:18]=3[CH3:19])[N:16]([C:31]([C:28]3[CH:29]=[CH:30][O:26][N:27]=3)=[O:32])[CH2:15]4)=[CH:10][CH:11]=2)[N:6]([CH3:22])[C:5]1=[O:23]
Reactant: O=C(O)c1ccon1
Reactant: CC1=C(c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)C2CCC1NC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC1=C(c2ccc3c(n2)n(C)c(=O)n3CC(C)(C)C)C2CCC1N(C(=O)c1ccon1)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-(2,2-Dimethylpropyl)-3-methyl-5-(6-methyl-2-azabicyclo[2.2.2]oct-5-en-5-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (7-4, 8.6 mg, 0.03 mmol, 1.0 equiv), isoxazole-3-carboxylic acid (2-6, 4.3 mg, 0.04 mmol, 1.5 equiv), DIPEA (13 μL, 0.08 mmol, 3.0 equiv) and HATU (14.4 mg, 0.04 mmol, 1.5 equiv) were added to anhydrous acetonitrile (253 μL). After stirring for 10 min at room temperature, LCMS showed consumption of starting material. Purification by reverse-phase HPLC (10-100% CH3CN:0.1% TFA in H2O) provided 7-5 as a white solid. MS m/z (M+H): calculated=436.2343; observed=436.2351.
Reaction SMILES: [Si]([O:8][C@H:9]1[C@H:13]([CH3:14])[N:12]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[C:17]([Cl:23])[C:16]=2[CH3:24])[C:11](=[O:25])[C:10]1([CH3:27])[CH3:26])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O>C1COCC1>[Cl:23][C:17]1[C:16]([CH3:24])=[C:15]([N:12]2[C@@H:13]([CH3:14])[C@H:9]([OH:8])[C:10]([CH3:27])([CH3:26])[C:11]2=[O:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: Cc1c(N2C(=O)C(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]2C)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(N2C(=O)C(C)(C)[C@@H](O)[C@@H]2C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.9 %

Procedure:
To a solution of rac-4-[(4R,5S)-4-(tert-butyldimethylsilyloxy)-3,3,5-trimethyl-2-oxopyrrolidin-1-yl]-2-chloro-3-methylbenzonitrile (103 mg) in THF (5 mL) was added tetrabutylammonium fluoride-THF solution (1.00 mL, 1 mol/L), and the mixture was stirred at room temperature for 17 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→1/3), and recrystallized from hexane-ethyl acetate to give the title compound as a colorless solid (yield: 41.4 mg, 28.4%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)=O)=[CH:4][CH:3]=1.[NH2:17][C:18]([NH2:20])=[O:19].Cl.C(O)C>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[C:8]3[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=3[NH:20][C:18](=[O:19])[N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1C(=O)c1ccc(F)cc1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=c1nc(-c2ccc(F)cc2)c2c([nH]1)CCCC2
Yield: 61.8 %

Procedure:
A mixture of 2-(4-fluorobenzoyl)cyclohexanone (14 g), urea (7.6 g), conc. hydrochloric acid (8 ml) and ethanol (40 ml) is refluxed for 8 hours. After cooling, the reaction mixture is diluted with water and washed with methylene chloride. The aqueous layer is made alkaline with potassium carbonate, and the precipitated crystal is separated by filtration and recrystallized from N,N-dimethylformamide-ethanol to give the desired compound (9.6 g), m.p. 248°-253° C.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:14][CH2:13][C:12]2[N+:11]([O-])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6]1)=[O:4].[CH2:16]([N:18](CC)CC)C.C[Si](C#N)(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.C(#N)C>[C:16]([C:10]1[CH:9]=[CH:8][C:7]2[CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:14][CH2:13][C:12]=2[N:11]=1)#[N:18]
Reactant: CCN(CC)CC
Reactant: COC(=O)C1CCc2c(ccc[n+]2[O-])C1
Agent: C[Si](C)(C)C#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)C1CCc2nc(C#N)ccc2C1
Temperature: 130 °C
Yield: 23.4 %

Procedure:
A 150 mL pressure vessel was charged with 6-(methoxycarbonyl)-5,6,7,8-tetrahydroquinoline 1-oxide (13.58 g, 65.52 mmol), triethylamine (18 mL, 130 mmol), trimethylsilyl cyanide (26.2 mL, 196 mmol) and acetonitrile (33 mL), and the mixture was heated at 130° C. for 21 h. Slowly quenched reaction into 2M Na2CO3 (250 mL) then diluted with DCM (500 mL). The mixture was filtered through celite and the filter cake washed with DCM (2×200 mL) and water (100 mL). The aqueous layer was extracted with additional DCM (100 mL×2). The combined organics was washed with 1M Na2CO3 (200 mL) and 1 M NaH2PO4 (150 mL×2), dried (Na2SO4), filtered and evaporated. The residue was purified by silica chromatography (100% hexanes to 100% DCM to 20% MeOH in DCM). Additional purification by silica chromatography (0-100% EtOAc in hexanes) yielded a pale yellow solid (3.32 g, 23%). m/z=217.5 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J=7.9 Hz, 1H), 7.47 (d, J=7.9 Hz, 1H), 3.74 (s, 3H), 3.18-2.94 (m, 4H), 2.88-2.78 (m, 1H), 2.35-2.26 (m, 1H), 2.09-1.97 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([N:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2I)[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2I)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl>CC1N(C(N(C)C)=O)C1.[Cu]>[N+:1]([C:4]1[CH:28]=[CH:27][C:7]([C:8]([N:10]2[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]2=3)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N(CCc1ccccc1I)c1ccccc1I
Agent: [Cu]
Agent: CC1CN1C(=O)N(C)C
Agent: Cl
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2-c2ccccc21
Yield: 96.5 %

Procedure:
To a solution of 0.90 g of N-(4-nitrobenzoyl)-N-(2-iodophenyl)-2-iodobenzeneethylamine in 10 ml of N,N-dimethylpropyleneurea (DMPU) is added 1.91 g of "activated" copper bronze. The mixture is stirred and heated at 195° for 2 days, cooled and slowly dropped into 100 ml of 0.5N HCl with stirring. The precipitate is filtered, washed with H2O and air dried (1.0 g of solid). The solid is extracted with ethyl acetate to give 0.50 g of solid. Chromatography on thick layer silica gel plates with ethyl acetate-hexane (1:2) as solvent gives 0.15 g of yellow solid.
Reaction SMILES: [C:1](O)(=O)C.[F:5][C:6]([F:50])([F:49])[C:7]1[CH:8]=[C:9]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:10][N:11]([C@H:18]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:20]2[C:32]([CH3:41])=[C:33]([C:37]([F:40])([F:39])[F:38])[C:34]([CH3:36])=[CH:35][C:19]1=2)[C:12]1[N:13]=[N:14][N:15]([CH3:17])[N:16]=1.C=O.C([BH3-])#N.[Na+]>C(#N)C.ClCCl>[F:48][C:45]([F:46])([F:47])[C:43]1[CH:42]=[C:9]([CH:8]=[C:7]([C:6]([F:5])([F:49])[F:50])[CH:44]=1)[CH2:10][N:11]([C@H:18]1[CH2:24][CH2:23][CH2:22][N:21]([CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([CH3:1])[CH2:30][CH2:31]2)[C:20]2[C:32]([CH3:41])=[C:33]([C:37]([F:38])([F:39])[F:40])[C:34]([CH3:36])=[CH:35][C:19]1=2)[C:12]1[N:13]=[N:14][N:15]([CH3:17])[N:16]=1
Reactant: CC(=O)O
Reactant: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CCNCC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2c(c(C)c1C(F)(F)F)N(CC1CCN(C)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 18 h

Procedure:
Add glacial acetic acid (0.25 mL) over 25 minutes to a solution of (S)-(3,5-bistrifluoromethylbenzyl)-(7,9-dimethyl-1-piperidin-4-ylmethyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(2-methyl-2H-tetrazol-5-yl)-amine (Example 160) (0.038 g, 0.057 mmol), 37% aqueous formaldehyde (0.014 mL, 0.189 mmol) and sodium cyanoborohydride (0.011 g, 0.172 mmol) in acetonitrile (2.5 mL) at room temperature under an atmosphere of nitrogen and stir for 18 h. Dilute the reaction with dichloromethane (20 mL) and wash with 2 N sodium hydroxide and brine (10 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using flash column chromatography on silica gel, eluting with dichloromethane/methanol/concentrated ammonium hydroxide (90:10:1), to provide the title compound as a white crushable foam (0.028 g, 72%). 1H NMR (CDCl3, 500 MHz) δ 1.15-1.70 (m, 4H), 1.83-2.06 (m, 7H), 2.33-2.35 (m, 9H), 2.76-3.03 (m, 5H), 3.24 (br s, 1H), 4.13 (m, 3H), 4.80-4.87 (m, 1H), 5.14 (br s, 1H), 5.58 (br s, 1H), 6.58 (m, 1H), 7.77-7.78 (m, 3H); ESI MS m/z 678 [C31H36F9N7+H]+.
Reaction SMILES: [Mg].BrCC.[CH2:5]=[C:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:21]([CH2:22][CH2:23][C@:7]12[CH3:8])[C:20]1[CH:19]=[CH:18][C:17]([OH:24])=[CH:16][C:15]=1[CH2:14][CH2:13]3.CN(C)P(=O)(N(C)C)N(C)C.[CH2:36]=[O:37].Cl>C1COCC1.C1C=CC=CC=1>[OH:24][C:17]1[C:18]([CH:36]=[O:37])=[CH:19][C:20]2[C@@H:21]3[C@H:12]([C@H:9]4[C@@:7]([CH2:23][CH2:22]3)([CH3:8])[C:6](=[CH2:5])[CH2:11][CH2:10]4)[CH2:13][CH2:14][C:15]=2[CH:16]=1
Reactant: C=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Reactant: C=O
Agent: Cl
Agent: [Mg]
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CCBr
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(O)c(C=O)cc4[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a suspension of magnesium (0.365 g, 15 mmol) in THF (3.0 mL) was added bromoethane (1.5 mL, 20 mmol) dissolved in THF (3.0 mL) at room temperature. 17-Methyleneestra-1,3,5(10)-trien-3-ol (19, 0.805 g, 3.0 mmol) dissolved in THF (7.5 mL) was added to the reaction mixture, and stirring continued for 30 min. The solvent was removed at reduced pressure, and to the residue were added benzene (35 mL), hexamethylphosphoric triamide (1.4 mL, 7.5 mmol) and paraformaldehyde (0.630 g). Stirring was continued for 6 h at 80° C. After the reaction mixture was cooled to room temperature, 5N HCl (15 mL) was added and the mixture extracted with EtOAc. The combined organic layers were washed with H2O, then with saturated aqueous NaCl, and dried (Na2SO4). The desiccant was filtered and the solvent was evaporated at reduced pressure. The residue was purified by column chromatography (silica gel) using n-hexane:AcOEt (10:1→3:1, v/v) to afford 0.695 g of 23 (78% yield), m.p. 128°-130° C.
Reaction SMILES: Br[C:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[NH:4][C:3]=1[C:15](=[O:18])[CH2:16][CH3:17].C(O)C.[NH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[NH:4][C:3]([C:15](=[O:18])[CH2:16][CH3:17])=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([S:23]([NH2:22])(=[O:25])=[O:24])=[CH:27][CH:28]=3)[C:6]=2[CH3:7])=[CH:9][CH:10]=1
Reactant: CCC(=O)c1[nH]c(-c2ccc(Cl)cc2)c(C)c1Br
Reactant: NS(=O)(=O)c1ccc(B(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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCC(=O)c1[nH]c(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Yield: 6.7 %

Procedure:
To the solution of 1-(3-bromo-5-(4-chlorophenyl)-4-methyl-1H-pyrrol-2-yl)propan-1-one (compound 53b, 1.0 g, 3.06 mmol) in a mixture of toluene: ethanol (5:15 ml) was added 4-aminosulfonylbenzene boronic acid (0.67 g, 3.37 mmol) and potassium carbonate (1.26 g, 9.19 mmol) at a temperature of about 25° C. in a sealed tube and a nitrogen gas was bubbled through the resulting reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.17 g, 0.153 mmol) under nitrogen atmosphere and the reaction mixture was heated at about 90° C. to 95° C. for 18 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was washed with 10% methanol in dichloromethane (3×25 ml). The combined filtrate was concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 40% ethyl acetate in hexanes as an eluent to obtain the title compound (0.082 g, 6.65%).
Reaction SMILES: [N:1]1([S:6]([CH2:9][CH2:10][CH2:11][NH2:12])(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[Cl:22][C:23]1[CH:24]=[C:25]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:26][N:27]1[CH2:32][CH2:31][O:30][C@@H:29]([CH2:33][NH:34][C:35](=O)[O:36]C2C=CC([N+]([O-])=O)=CC=2)[CH2:28]1>CN(C)C=O.ClCCl>[Cl:22][C:23]1[CH:24]=[C:25]([CH:47]=[CH:48][C:49]=1[Cl:50])[CH2:26][N:27]1[CH2:32][CH2:31][O:30][C@@H:29]([CH2:33][NH:34][C:35]([NH:12][CH2:11][CH2:10][CH2:9][S:6]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)(=[O:7])=[O:8])=[O:36])[CH2:28]1
Reactant: O=C(NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCS(=O)(=O)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCCS(=O)(=O)N1CCCC1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Temperature: 25 °C
Reaction time: 21 h
Yield: 63 %

Procedure:
A solution of Intermediate 28 (0.027 g) in N,N-dimethylformamide (1 ml) and dichloromethane (2 ml) containing N,N-diisopropylethylamine (0.041 ml) was added to a stirred solution of Intermediate 13 (0.051 g) in dry dichloromethane (2 ml) at room temperature under nitrogen, and the mixture was stirred at room temperature for 21 h. The mixture was applied directly to a sulphonic acid ion exchange cartridge (2 g Isolute SCX) and eluted with methanol (6 column volumes) followed by 10% 880 ammonia in methanol (3 column volumes); evaporation of the methanol/ammonia fractions gave the crude product (0.063 g). Purification by chromatography on silica gel (2 g Varian Bond Elut cartridge), eluting with chloroform, ether, ethyl acetate, acetone, and methanol, gave the title compound as a gum (0.036 g).
Reaction SMILES: [C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[OH:18])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:27][C:28]([CH3:31])([OH:30])[CH3:29].[I-].[Na+].CC1(C)CO1>CN(C=O)C>[C:1]([S:5]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH2:27][C:28]([CH3:31])([OH:30])[CH3:29])[N:14]=[CH:13][CH:12]=[C:11]2[Cl:19])(=[O:6])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)S(=O)(=O)c1cc2c(Cl)ccnc2cc1O
Reactant: CC(C)(O)CCl
Agent: CC1(C)CO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(O)COc1cc2nccc(Cl)c2cc1S(=O)(=O)C(C)(C)C
Reaction time: 0.17 h
Yield: 14.9 %

Procedure:
To a solution of 6-(tert-butylsulfonyl)-4-chloroquinolin-7-ol (250 mg, 0.834 mmol) in DMF (2756 μl) was added K2CO3 (576 mg, 4.17 mmol) followed by 1-chloro-2-methylpropan-2-ol (209 μl, 2.502 mmol). After 10 min, LCMS showed no product. Heated reaction to 60° C. No reaction after 3 hr at this temperature. Added sodium iodide (375 mg, 2.50 mmol) and 2,2-dimethyloxirane (371 μl, 4.17 mmol) and stirred for 2 days at to 60° C. The crude sample was purified via Biotage normal phase chromatography (25 g SNAP column, 0% -80%, 80%. hex/EtOAc). The pure product containing-fractions were combined and concentrated leading to the product as an off-white solid: 1-((6-(tert-butylsulfonyl)-4-chloroquinolin-7-yl)oxy)-2-methylpropan-2-ol (46 mg, 0.124 mmol, 14.83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (s, 6H) 1.33 (s, 9H) 4.03 (s, 2H) 4.56 (s, 1H) 7.72 (s, 1H) 7.76 (d, J=4.80 Hz, 1H) 8.64 (s, 1H) 8.94 (d, J=4.80 Hz, 1H). MS (m/z) 372.2 (M+H+).
Reaction SMILES: COC([C:5]1([C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=O.[Li+].[Cl-].C([O-])(O)=O.[Na+]>O.CS(C)=O>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][CH:5]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: COC(=O)C1(c2ncnc3cc(F)ccc23)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(F)ccc23)CC1
Temperature: 25 °C

Procedure:
A mixture of 4-(7-fluoro-quinazolin-4-yl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-methyl ester (“6.83 g”), as prepared without further purification in the previous step, LiCl (1.32 g, 31.1 mmol), water (832 μL, 46.2 mmol), and DMSO (6.0 mL) was stirred under air at 150° C. (oil bath) with an efficient condenser (to retain reagent water) for 9.5 h. The dark solution was then allowed to cool to rt, shaken with 1.0 M NaHCO3, and extracted with EtOAc (1×60 mL) and 9:1 DCM/MeOH (2×30 mL). The organic layers were combined, dried (Na2SO4), and concentrated to afford a thick clear amber oil. Flash chromatography of this residue (3:2 hexanes/EtOAc) afforded the title compound as a thick clear yellow syrup that was rubbed to a beige solid (2.37 g, 46% from 4-chloro-7-fluoroquinazoline). 1H-NMR (300 MHz, CDCl3) δ 9.23 (s, 1H), 8.20 (dd, 1H), 7.67 (dd, 1H), 7.42 (ddd, 1H), 4.42-4.25 (br m, 2H), 3.65 (m, 1H), 2.96 (m, 2H), 2.14-1.83 (m, 4H), 1.49 (s, 1H). LC/MS (ESI): calcd mass 331.2, found 332.1 (MH)+ (weak).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N:11]([C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C(N(CC)CC)C.S(Cl)(Cl)=O>ClCCCl.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:8])[CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:15](=[O:22])[N:11]2[CH:12]([CH3:14])[CH3:13])=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(=O)N(c1cc(Br)ccc1C(=O)O)C(C)C
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Product: CCOC(=O)C1C(=O)c2ccc(Br)cc2N(C(C)C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.7 %

Procedure:
To a solution of 4-bromo-2-[(3-ethoxy-3-oxopropanoyl)(propan-2-yl)amino]benzoic acid (6.2 g, 16.7 mmol) in 170 mL of DCE is added triethylamine (3.5 mL, 25.1 mmol), followed by addition of thionyl chloride (1.45 mL, 20.6 mmol) at 0° C. After stirring at room temperature for 3 hours, the reaction medium is diluted with DCM and washed with aqueous HCl solution (1M). The organic phase is washed with saturated aqueous NaHCO3 solution and saturated aqueous NaCl solution, dried over Na2SO4 and concentrated to dryness. The oil obtained is purified by flash chromatography (toluene/EtOAc: 100/0 to 90/10) to give 2,23 g of a white solid (yield: 52%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]3[C:22]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[N:16]([CH3:23])[C:15]4[C:10]=3[C:11]([CH:12]=[CH:13][CH:14]=4)=[C:4]2[CH:3]=1.[C:24]([NH2:28])(=[O:27])[CH:25]=[CH2:26]>>[CH3:23][N:16]1[C:15]2[C:10]3[C:11](=[C:4]4[C:5](=[N:8][C:9]=3[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]1=3)[CH:6]=[CH:7][C:2](/[CH:26]=[CH:25]/[C:24]([NH2:28])=[O:27])=[CH:3]4)[CH:12]=[CH:13][CH:14]=2
Reactant: C=CC(N)=O
Reactant: CN1c2ccccc2-c2nc3ccc(Cl)cc3c3cccc1c23
Product: CN1c2ccccc2-c2nc3ccc(/C=C/C(N)=O)cc3c3cccc1c23
Yield: 91 %

Procedure:
The general procedure (Method M) applied to 3-chloro-8-methyl-8H-quino[4,3,2-kl]acridine, 28 (100 mg, 0.32 mmol) and acrylamide (46 mg, 2 eq) gave the title compound (102 mg, 0.29 mmol, 91%).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:28][CH3:29])[CH:25]=[C:24]4[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.C(O)(C)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:27]=3[N:26]([CH2:28][CH3:29])[CH:25]=[C:24]4[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1cn(CC)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCn1cc(CCC(=O)O)c2cccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.5 %

Procedure:
Sodium hydroxide (66 mg) was added to a solution of ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-ethyl-1H-indol-3-yl]propanoate (D120) (79 mg) in THF (5 mL), isopropanol (4 mL) and water (2 mL). The reaction mixture was stirred at room temperature overnight. The mixture was neutralized with 2 M HCl till pH ˜6.0. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-ethyl-1H-indol-3-yl]propanoic acid (E26) (42 mg). δH (DMSO-d6, 400 MHz): 1.04 (3H, t), 1.37 (6H, d), 2.62 (2H, t), 2.98 (2H, t), 4.14 (2H, q), 4.89 (1H, m), 7.18 (1H, t), 7.27 (1H, s), 7.45 (2H, t), 7.81 (1H, dd), 8.13 (1H, dd), 8.20 (1H, d), 12.07 (1H, s); MS (ES): C24H24ClN3O4 requires 453; found 454.2 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:15]([O-])=O)=[C:10]([O:13][CH3:14])[N:11]=2)[C:6](=[O:18])[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4]1)[CH3:2].C(O)C>C(O)(=O)C>[NH2:15][C:9]1[CH:8]=[C:7]2[C:12](=[N:11][C:10]=1[O:13][CH3:14])[N:3]([CH2:1][CH3:2])[CH:4]=[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:6]2=[O:18]
Reactant: CCOC(=O)c1cn(CC)c2nc(OC)c([N+](=O)[O-])cc2c1=O
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(CC)c2nc(OC)c(N)cc2c1=O
Temperature: 70 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A suspension of 20 g of ethyl 1-ethyl-1,4-dihydro-7-methoxy-6-nitro-4-oxo-1,8-naphthyridine-3-carboxylate in 400 ml of acetic acid was heated to 70° C. To this suspension was added portionwise 40 g of reduced iron-powder. The mixture was heated at 70° C. for one hour with stirring, and then 500 ml of ethanol was added. The mixture was filtered to remove the insoluble material and the solvent was distilled off under reduced pressure. To the residue was added 500 ml of water and the mixture was allowed to stand overnight in a refrigerator. The resulting precipitate was collected by filtration and recrystallized from ethanol to give 14.8 g of ethyl 6-amino-1-ethyl-1,4-dihydro-7-methoxy-4-oxo-1,8-naphthyridine-3-carboxylate, m.p. 250°-252° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:8])[C@H:5]([NH2:7])[CH3:6].[F:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C(N(CC)CC)C.C(O[BH3-])(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[CH3:2][O:3][C:4](=[O:8])[C@H:5]([NH:7][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([F:9])=[CH:11][CH:12]=1)[CH3:6]
Reactant: COC(=O)[C@@H](C)N
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)[C@@H](C)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of (R)-2-amino-propionic acid methyl ester hydrochloride (25 g, 179 mmol) and 4-fluorobenzaldehyde (23 ml, 215 mmol) in 1,2-dichloroethane (200 ml) was added triethylamine (25 ml, 179 mmol). The resulting mixture was stirred for two hours at ambient temperature followed by addition of sodium acetoxyborohydride (57 g, 268 mmol) in four portions. The resulting mixture was stirred overnight at ambient temperature. The reaction was neutralized with dilute aqueous sodium hydroxide solution and extracted with dichloromethane (2×). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (34.4 g, 91% yield).