Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][C:24]([C:28]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[O:29])=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:36]([O:38]C)=[O:37])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]([N:18]3[C:27]4[C:22](=[CH:23][C:24]([C:28]([N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)=[O:29])=[CH:25][CH:26]=4)[CH2:21][CH2:20][CH2:19]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:36]([OH:38])=[O:37])[CH:14]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(C(=O)N5CCOCC5)ccc43)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(C(=O)N5CCOCC5)ccc43)nc2c1
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of methyl 2-(4-fluorophenyl)-3-[6-[(morpholin-4-yl)carbonyl]-1,2,3,4-tetrahydroquinolin-1-yl]quinoxaline-6-carboxylate (107 mg, 0.20 mmol) in methanol (30 ml) and water (2.0 ml) was added sodium hydroxide (32 mg, 0.8 mmol) with stifling overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 ml) and adjusted to pH 4 with hydrogen chloride (3 N). The solids were collected by filtration to afford 2-(4-fluorophenyl)-3-[6-[(morpholin-4-yl)carbonyl]-1,2,3,4-tetrahydroquinolin-1-yl]quinoxaline-6-carboxylic acid as a light yellow solid (90 mg, 86%).
Reaction SMILES: [C:1]1([C@@:7]2([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][C@H:8]2[CH2:10][O:11]CC2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(O)C>[OH:11][CH2:10][C@@H:8]1[CH2:9][C@:7]1([CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCC[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC[C@]1(c2ccccc2)C[C@H]1CO
Yield: 91 %

Procedure:
1,1-dimethylethyl [2-((1R,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropyl)ethyl]carbamate (5.9 g, 15.46 mmol), accessed via the method of Preparation 24B was combined with 10% palladium on activated carbon (600 mg) in 100 mL ethyl alcohol and hydrogenated under 1 atm H2(g) for 3 h at ambient temperature. The catalyst was filtered off through celite and the filtrate concentrated to give the title compound (4.1 g, 14.07 mmol, 91%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 7.27-7.12 (m, 5H), 6.59-6.56 (m, 1H), 4.31-4.29 (m, 1H), 3.00-2.94 (m, 1H), 2.87-2.66 (m, 3H), 1.88-1.82 (m, 1H), 1.32-1.25 (m, 10H), 1.11-1.05 (m, 1H), 0.76-0.73 (m, 1H), 0.65-0.63 (m, 1H). ES-LCMS m/z 314.1 (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([OH:19])=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[CH3:20].C([O:23][C:24]([C:26]12[CH2:43][CH:42]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37][CH2:36][N:35]([CH3:44])[C:34](=[O:45])[N:33]1[CH:29]([CH2:30][CH:31](O)[CH2:32]1)[C:28](=[O:47])[NH:27]2)=[O:25])C>>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:19][CH:31]3[CH2:30][CH:29]4[N:33]([C:34](=[O:45])[N:35]([CH3:44])[CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH:41][CH:42]5[C:26]([C:24]([OH:25])=[O:23])([NH:27][C:28]4=[O:47])[CH2:43]5)[CH2:32]3)=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[CH3:20]
Reactant: COc1cc2nc(-c3ccccc3)nc(O)c2cc1C
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)N1CC(O)CC1C(=O)N2
Product: COc1cc2nc(-c3ccccc3)nc(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)c2cc1C
Yield: 11.3 %

Procedure:
Quinazolinol derivative 112 (200 mg, 0.53 mmol) was coupled to compound 51 (268 mg, 0.7 mmol) followed by hydrolysis of the ethyl ester as described in example 52 which gave the title compound (36 mg, 11%). MS (M−H)+ 600.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
2-Chloropyridine-3-carbonyl chloride (18.02 g, 0.102 mol) in CH2Cl2 (100 ml) was added dropwise (via an addition funnel) to a stirred solution of 3-(trifluoromethyl)-aniline (15.00 g, 0.093 mol) and DIEA (24.39 ml, 0.14 mol) in CH2Cl2 (500 ml) at 0° C. The mixture gradually was warmed to RT. The reaction continued for 18 h before washing several times with saturated NaHCO3 aqueous solution and brine, respectively. The organic layer was dried over Na2SO4 and evaporated. The resulting oil was purified over silica gel with EtOAc/hexane (2:1) as eluant to leave the amide as a white solid (26.08 g). MS:(ES+) 301 (M+1)+; (ES−):299 (M−1)−. Calc'd for C13H8ClF3N2O:300.03.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[CH3:9][N:10]1[C:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][C:11]1=[O:17]>C1(C)C=CC=CC=1>[I:8][C:5]1[CH:6]=[CH:7][C:2]([CH:12]2[CH2:13][C:14]([CH3:16])([CH3:15])[N:10]([CH3:9])[C:11]2=[O:17])=[N:3][CH:4]=1
Reactant: CN1C(=O)CCC1(C)C
Reactant: Fc1ccc(I)cn1
Solvent: Cc1ccccc1
Product: CN1C(=O)C(c2ccc(I)cn2)CC1(C)C
Temperature: -4 °C
Reaction time: 2 h
Yield: 37.5 %

Procedure:
A solution of 2-fluoro-5-iodopyridine (260 mg, 1.17 mmol) and 1,5,5-trimethyl-pyrrolidin-2-one (148 mg, 1.17 mmol) in 6 ml of dry toluene was purged with Argon and cooled to −4° C. A 1M solution of sodium hexamethyldisilylamide (NaHMDS) in toluene (2.33 ml, 2.33 mmol) was added dropwise maintaining the temperature below 0° C. The red solution was stirred for 2 h at 0° C., quenched by addition of 5 ml of saturated ammonium chloride solution. After extraction with ethyl acetate/water, drying over sodium sulfate and concentration; the residue (400 mg) was taken up in ethyl acetate, adsorbed onto 5 g of silicagel which was loaded onto a 20 g prepacked flash chromato-graphy column. After elution with a 0% to 75% ethyl acetate in heptane gradient, the fractions containing the desired product were collected to yield 145 mg (38%) of the title compound as a yellow viscous oil, MS: m/e=331.0 (M+H+).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][CH:9]([F:38])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH:35]([CH3:37])[NH:34][CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:20][CH2:19]1.[CH3:39][S:40](Cl)(=[O:42])=[O:41].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[F:38][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH:35]([CH3:37])[N:34]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:19][CH2:20][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:22][CH2:23]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1S(C)(=O)=O

Procedure:
A solution of N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (10 mg, 0.018 mmol), methanesulfonyl chloride (3.1 mg, 0.027 mmol), and DIPEA (7.0 mg, 0.054 mmol) in DCM (181 μL) was stirred at room temperature for 2 h. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (4 mg) as a white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 1.25 (d, J=6.8 Hz, 3H), 1.92-2.03 (m, 2H), 2.09-2.19 (m, 2H), 2.57 (d, J=16.9 Hz, 1H), 2.94 (s, 3H), 3.01 (t, J=10.9 Hz, 2H), 3.14 (dd, J=16.7, 6.3 Hz, 1H), 3.34-3.43 (m, 2H), 3.78 (td, J=14.5, 4.3 Hz, 2H), 4.17-4.25 (m, 1H), 4.43-4.55 (m, 3H), 5.89-6.22 (m, 1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 517.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C:11]([CH2:18][C:19]([CH3:21])=[CH2:20])([C:15]([OH:17])=[O:16])[CH2:10]1.COC1C=C2[C@@]34[C@@H]5C[C@H]6C(CN5CC3)=CCO[C@H]3CC(=O)N([C@H]4[C@@H]63)C2=CC=1OC>CC(O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[N:9]1[C:13](=[O:14])[CH2:12][C@:11]([CH2:18][C:19]([CH3:21])=[CH2:20])([C:15]([OH:17])=[O:16])[CH2:10]1
Reactant: C=C(C)CC1(C(=O)O)CC(=O)N(c2c(C)cccc2C)C1
Agent: COc1cc2c(cc1OC)[C@@]13CCN4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Solvent: CC(C)O
Product: C=C(C)C[C@]1(C(=O)O)CC(=O)N(c2c(C)cccc2C)C1
Temperature: 75 °C

Procedure:
To a mixture of 1-(2,6-dimethylphenyl)-3-(2-methylallyl)-5-oxo-pyrrolidine-3-carboxylic acid (prepared from step b, 9 g, 31.36 mmol) and brucine (12.37 g, 31.35 mmol) was added iPrOH (75 mL) and heated with stirring at 75° C. until it became a clear solution, which was then allowed to cool to room temperature slowly. The resulting white solid was filtered and discarded. The filtrate was then diluted with Et2O (100 mL) and washed with 2 N HCl (2×100 mL), dried (Na2SO4) and concentrated under reduced pressure to obtain (S)-1-(2,6-dimethyl-phenyl)-3-(2-methyl-allyl)-5-oxo-pyrrolidine-3-carboxylic acid (550 mg, enantiomeric ratio: 9:1, with the enantiomeric ratio determined using a RegisWhelk® chiral analytical column and 10% EtOH in hexanes isocratic solvent system, flow rate: 1 mL/min, 30 min run). Further recrystallization of the above carboxylic acid derivative from hot toluene/dioxane (9:1, 14 mL) enriched the enantiomeric ratio to 99.2:0.8 and afforded 430 mg of (S)-1-(2,6-dimethylphenyl)-3-(2-methylallyl)-5-oxo-pyrrolidine-3-carboxylic acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([F:63])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][C:59]([F:62])=[C:58]([F:63])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 91 mg (0.3 mmol) (4-tert-butyl-benzyl)-[2-(3,4-difluoro-phenyl)-ethyl]-amine in 2 ml DMF was added. After stirring for 18 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; EtOAc/heptane 1:6) to give 95 mg light yellow viscous oil (66%). MS (ISP) 447.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OC1CCC(c2ccc(Br)cc2)OC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1CCC(c2ccc(Br)cc2)OC1
Reaction time: 2 h
Yield: 20 %

Procedure:
To a round bottom flask containing 6-(4-bromophenyl)tetrahydro-2H-pyran-3-ol (638 mg, 2.48 mmol) was added DCM (16 ml). The mixture was stirred at room temperature before Dess-Martin Periodonane (1.3 g, 2.98 mmol) was added in several portions. After the addition, the reaction mixture was stirred for 2 hours before being quenched by a solution of saturated NaHCO3. The organic layer was washed with saturated NaHCO3 twice, then brine. The organic portion was dried over sodium sulfate, filtered and concentrated to afford a crude oil. Column purification afforded the title compound as a thick oil after drying (126 mg, 20% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.55 (m, 2H) 7.26-7.32 (m, 2H) 4.75 (dd, J=10.61, 2.78 Hz, 1H) 4.27-4.36 (m, 1H) 4.14-4.22 (m, 1H) 2.59-2.77 (m, 2H) 2.35 (ddt, J=13.74, 6.60, 3.35, 3.35 Hz, 1H) 2.11-2.24 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[F:21][C:22]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:23]=1[NH2:24]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:24][C:23]2[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:22]=2[F:21])=[O:15])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1cc(F)ccc1F
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1cc(F)ccc1F)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carbonyl chloride (120 mg, 0.33 mmol) and 2,5-difluoroaniline (50 mg, 0.39 mmol). The title compound was obtained as a solid (45 mg, 44% yield). 1H NMR (400 MHz, d6-DMSO) δ: 10.62 (1H, m), 9.00 (2H, s), 8.75 (1H, s), 7.50 (1H, m), 7.48 (1H, m), 7.40 (1H, m). MS m/z: 460.05, 462.04 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.OC1C=CC(C(OC)=O)=CC=1.C1(CO)CCC1>>[CH:4]1([CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:18][CH:19]=2)[CH2:2][CH2:3][CH2:1]1
Reactant: O=C(O)CNC(=O)c1ccc(OCCC2CC2)cc1
Agent: COC(=O)c1ccc(O)cc1
Agent: OCC1CCC1
Product: O=C(O)CNC(=O)c1ccc(OCC2CCC2)cc1
Yield: 97 %

Procedure:
The same reactions as in Example 9 (9a) and (9b) were conducted using methyl 4-hydroxybenzoate (3.81 g, 25.0 mmol) and cyclobutylmethanol (2.36 mL, 25.0 mmol) to give 6.41 g of the title compound (colorless oil, yield: 97%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N-]1C=CN=C1.[CH2:16]([C:20]1[C:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[C:36]([CH2:38][CH2:39][CH3:40])[CH:35]=[CH:34][C:33]=3[S:41](=[O:44])(=[O:43])[NH2:42])=[CH:28][C:27]=2[F:45])=[C:23]([C:46]#[N:47])[N:22]([C:48]2[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=2[Cl:57])[N:21]=1)[CH2:17][CH2:18][CH3:19].C1CCN2C(=NCCC2)CC1>>[CH2:16]([C:20]1[C:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[C:36]([CH2:38][CH2:39][CH3:40])[CH:35]=[CH:34][C:33]=3[S:41](=[O:43])(=[O:44])[NH:42][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[CH:28][C:27]=2[F:45])=[C:23]([C:46]#[N:47])[N:22]([C:48]2[CH:53]=[C:52]([N+:54]([O-:56])=[O:55])[CH:51]=[CH:50][C:49]=2[Cl:57])[N:21]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C#N)c1Cc1ccc(-c2cc(CCC)ccc2S(N)(=O)=O)cc1F
Reactant: O=C(O)c1ccccc1F
Agent: c1c[n-]cn1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C#N)c1Cc1ccc(-c2cc(CCC)ccc2S(=O)(=O)NC(=O)c2ccccc2F)cc1F

Procedure:
By the method of Example 1, Step H, 2-fluorobenzoic acid is converted to its imidazolide and reacted with 3-n-butyl-1-(2-chloro-5-nitrophenyl)-4-[(3-fluoro-5'-n-propyl-2'-sulfamoylbiphenyl-4-yl)methyl]-1H-pyrazole-5-carbonitrile (from Step D) in the presence of DBU to give the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][C:37]([N:39]1[CH2:42][CH2:41][C@H:40]1[CH2:43][OH:44])=[O:38])([CH3:35])([CH3:34])[CH3:33].[Cl:45][C:46]1[CH:47]=[C:48](O)[CH:49]=[N:50][C:51]=1[Cl:52]>C1COCC1>[Cl:45][C:46]1[CH:47]=[C:48]([O:44][CH2:43][C@@H:40]2[CH2:41][CH2:42][N:39]2[C:37]([O:36][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:38])[CH:49]=[N:50][C:51]=1[Cl:52]
Reactant: Oc1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cnc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A solution of triphenylphosphine (2.6 g, 9.94 mmol) and diethyl azodicarboxylate (1.6 mL, 9.94 mmol) in THF (16 mL) was stirred at 0° C. for 15 minutes. 1-t-Butyloxycarbonyl-2-(S)-azetidinemethanol (1.55 g, 8.28 mmol, from step 7c above) and 5,6-dichloro-3-pyridinol (1.5 g, 9.1 mmol) were then added. The reaction mixture was allowed to warm slowly to room temperature and stir overnight. The solvent was removed, and the residue was redissolved in methylene chloride. The solution was washed with saturated aqueous K2CO3 and brine, dried over MgSO4 and concentrated. The residue was chromatographed (silica gel; ethyl acetate:hexane, 1:5) to afford the 5,6-dichloro-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)pyridine (1.08 g): MS (CI/NH3) m/z 333 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ1.42 (s, 9H), 2.22-2.42 (m, 2H), 3.85-3.92 (m, 2H), 4.12 (dd, J=2.7, 10.1 Hz, 1H), 4.30-4.40 (m, 1H), 4.48-4.56 (m, 1H), 7.41 (d, J=2.8 Hz, 1H), 7.97 (d, J=2.8 Hz, 1H). To a solution of 5,6-dichloro-3-(1-t-butyloxycarbonyl-2-(S)-azetidinylmethoxy)-pyridine (1.06 g, 3.11 mmol) in CH2Cl2 (10 mL) at 0° C. was added TFA (10 mL). The solution was allowed to warm to room temperature while stirring for 45 minutes. The volatile components were then removed under vacuum. The residue was treated with saturated K2CO3 solution, then extracted with methylene chloride. The organic extract was dried over MgSO4 and concentrated. The residue was chromatographed (silica gel; MeOH/CHCl3/NH4OH, 1:10:0 to 1:10:0.05) to afford the free base of the title compound (475 mg, 64% yield): mp 59-60° C.; MS (CI/NH3) m/z 233 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ2.21-2.44 (m, 2H), 3.45 (m, 1H), 3.73 (dd, J=8.4, 15.8 Hz, 1H), 3.98-4.08 (m, 2H), 4.28 (m, 1H), 7.37 (d, J=2.8 Hz, 1H), 8.01 (d, J=2.8 Hz, 1H). The base (336 mg) was slurried in ether and converted to the hydrochloride salt by treatment with saturated HCl in ether. Recrystallization from methanol/ether gave the title compound (317 mg, 81% yield): mp 181-182° C.; MS (CI/NH3) m/z 233 (M+H)+; 1H NMR (D2O, 300 MHz) δ2.65-2.74 (m, 2H), 4.03-4.21 (m, 2H), 4.44 (d, J=4.4 Hz, 1H), 4.95 (m, 1H), 7.79 (d, J=2.9 Hz, 1H), 8.13 (d, J=2.9 Hz, 1H). Anal. Calcd. for C9H11N2OCl2.1.0 HCl: C, 40.10; H, 4.11; N, 10.39. Found: C, 39.89; H, 4.08; N, 10.25.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[C:23](O)=[O:24].N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:23]([C:14]3[CH:15]=[CH:16][C:17]4[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:13]=3)=[O:24])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1ccc2ccccc2c1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1ccc2ccccc2c1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and 2-naphthoic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.51-7.67 (m, 2H), 7.85-8.07 (m, 4H), 8.46 (s, 1H). MS (DCI/NH3) m/z 308. Anal. Calculated for C20H22N2O.HCl: C, 70.06; H, 6.76; N, 9.14. Found: C, 69.72; H, 6.58; N, 8.03.
Reaction SMILES: OC[C:3]1[CH:4]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:6](=[O:16])[N:7]2[C:12]=1[C:11]1[S:13][CH:14]=[CH:15][C:10]=1[CH2:9][CH2:8]2.[C:23]([O:26][C:27](=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:26][CH2:27][SH:13]1[C:11]2[C:12]3[N:7]([CH2:8][CH2:9][C:10]=2[CH:15]=[CH:14]1)[C:6](=[O:16])[C:5]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[CH:4][CH:3]=3)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1c(-c2ccccc2)cc(CO)c2n1CCc1ccsc1-2
Solvent: c1ccncc1
Product: CC(=O)OC[SH]1C=CC2=C1c1ccc(-c3ccccc3)c(=O)n1CC2

Procedure:
A suspension of 1.55 g of-4,5-dihydro-10-(hydroxymethyl )-8-phenyl-7H-thieno[2,3-a ]quinolizin-7-one in 6.7 ml of pyridine was treated with 3.35 ml of acetic anhydride while stirring, whereby a clear solution was obtained after about 15 minutes. After stirring overnight. the precipitated yellow crystals were removed by filtration under suction and washed with ether. The filtrate was evaporated in vacuo and the residue together with the above yellow crystals were recrystallized from methanol. There was obtained pure (4,5-dihydro-7-oxo-8-phenyl-thieno[2,3-a]-quinolizin-1-yl)methyl acetate of m.p. 145°-146°.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:8]([C:23]3[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)c(Cl)c1
Product: O=[N+]([O-])c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1

Procedure:
4-Bromophenylacetic acid (107.5 g, 0.5 mol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole. 2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (38.2 g, 0.1 mol) was treated as described in general procedure B using 1-fluoro-4-nitrobenzene to give 2-(4-bromo-benzyl)-1-(4-nitro-phenyl)-4-(2,4-dichloro-phenyl)-1H-imidazole.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38]>>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@H:2]4[NH:1][CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: COC(=O)CCBr
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)CCN[C@@H]1CCc2c(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)cccc21
Temperature: 80 °C
Yield: 63.6 %

Procedure:
Prepared using General Procedure 6. To the solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (90.0 mg, 0.25 mmol) and K2CO3 (103.5 mg, 0.75 mmol) was added methyl 3-bromopropanoate (41.8 mg, 0.25 mmol). The reaction was heated to 80° C. for 30 min and repeated four time at 80° C. for 30 min with additional methyl 3-bromopropanoate (41.8 mg, 0.25 mmol) added each time. The solvent was evaporated, and the residues partitioned between EA and water. The organic layer was collected, dried over MgSO4, and purified by chromatography (MeOH/DCM with 0.025% TEA) to give 71 mg (63%) of (R)-methyl 3-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)amino)propanoate as a solid. LCMS-ESI (m/z) calculated for C25H26N4O4: 446.5. found 447.2 [M+H]+, tR=2.61 min. 1H NMR (400 MHz, CDCl3) □δ 8.40 (d, J=2.1, 1H), 8.31 (dd, J=8.9, 2.2, 1H), 8.04 (d, J=7.6, 1H), 7.49 (d, J=7.5, 1H), 7.35 (t, J=7.6, 1H), 7.09 (d, J=9.0, 1H), 4.77 (dt, J=12.2, 6.1, 1H), 4.31 (t, J=6.8, 1H), 3.73-3.58 (m, 3H), 3.43 (ddd, J=17.4, 8.7, 4.6, 1H), 3.24-3.08 (m, 1H), 3.04-2.85 (m, 2H), 2.56 (t, J=6.5, 2H), 2.47 (dtd, J=12.8, 8.4, 4.7, 1H), 1.99-1.82 (m, 1H), 1.54-1.32 (m, 6H).