Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=1N)([O-])=O.[C:16]([CH2:18]C(OCC1C=CC=CC=1)=O)#N.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CN(C=O)C>[F:13][C:12]([F:15])([F:14])[O:11][C:9]1[CH:10]=[C:4]2[C:5]([CH:16]=[CH:18][NH:1]2)=[CH:7][CH:8]=1
Reactant: N#CCC(=O)OCc1ccccc1
Reactant: Nc1ccc(OC(F)(F)F)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc2cc[nH]c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63 %

Procedure:
To a suspension of t-BuONO (8.01 mL, 67.5 mmol) and CuCl2 (7.26 g, 54 mmol) in acetonitrile (50 mL), at 61° C. with gentle stirring, is added 2-nitro-4-trifluoromethoxyaniline (10.0 g, 45.0 mmol) portionwise. The mixture is stirred at this temperature for 2 h after the addition. The solvent is removed on a rotorvap and the residue is treated with HCl (6 N, 200 mL), and extracted with dichloromethane (3×100 mL). The extracts are combined, dried over anhydrous Na2SO4, and passed through a short silica gel pad. The solvent is removed and the residue is added to a suspension of benzyl cyanoacetate (7.88 g, 45 mmol) and K2CO3 (12.42 g, 90 mmol) in DMF (100 mL). This mixture is then stirred at 45° C. overnight and poured into ice-water (700 mL), and extracted with dichloromethane (3×100 mL). The organics are dried over anhydrous Na2SO4 and again passed through a short silica gel pad, eluting with ethyl acetate. The solvent is then replaced with EtOH (160 mL), acetic acid (16 mL) and water (16 mL), and the reaction mixture is hydrogenated over 5% Pd/C (2.80 g) at 50 psi overnight. The mixture is filtered over Celite and the volatiles are removed in vacuo. The residue is dissolved in dichloromethane (200 mL), washed with Na2CO3 (2 M, 2×50 mL), water (2×50 mL), brine (50 mL) and dried over anhydrous Na2SO4. The crude product, obtained after the removal of the solvent, is chromatographed (silica gel, DCM/Hexanes, 1/1) to provide 6-trifluoromethoxyindole (5.70 g, 63% based on 2-nitro-4-trifluoromethoxyaniline).
Reaction SMILES: [C:1]1(=[O:39])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:10][C:11]([F:23])([F:22])[CH2:12][CH2:13][O:14]CC2C=CC=CC=2)[C:4](=[O:34])[C:3]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:2]12.C[Si](I)(C)C.C(N(CC)CC)C>ClCCl.CO>[C:4]1(=[O:34])[N:5]([CH2:6][CH2:7][CH2:8][N:9]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)(=[O:25])=[O:26])[CH2:10][C:11]([F:23])([F:22])[CH2:12][CH2:13][OH:14])[C:1](=[O:39])[C:2]2=[CH:38][CH:37]=[CH:36][CH:35]=[C:3]12
Reactant: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCOCc2ccccc2)cc1
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N(CCCN2C(=O)c3ccccc3C2=O)CC(F)(F)CCO)cc1
Reaction time: 1 h

Procedure:
A solution of 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-benzyloxy-4-aza-octane (9.5 g, 17.1 mM) and trimethylsilyl iodide (2.7 mL, 10% excess) in dry dichloromethane is stirred overnight at room temperature under nitrogen. Triethylamine (3 g) is added, and stirring is continued for 1 hour at room temperature. Following the addition of more dichloromethane, the reaction mixture is washed with 1N HCL (twice), aqueous NaHSO3 (twice), brine (twice), and dried (Na2SO4). The solvents are removed by evaporation to yield an oil. This oil is dissolved in methanol and 1 mL of a 9N solution of HCL in methanol is added. The mixture is evaporated and stripped twice with CCl4 to provide an oil, which upon scratching with ether/petroleum ether yields 1-phthalimido-4-p-toluenesulfonyl-6,6-difluoro-8-hydroxy-4-aza-octane as slightly violet crystals: 6.8 g (85%).
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:8]=[C:7]([CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)[S:18][C:14]=3[C:13](=[O:26])[N:12]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:11]2=[O:33])[O:6][N:5]=1)[CH3:3].[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][CH:50]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[CH2:34]([O:36][C:37]1[C:46]([O:47][CH3:48])=[CH:45][C:44]2[C:43]([C:49]3[CH:50]=[CH:51][C:52]([C:53]([N:30]4[CH2:31][CH2:32][CH:27]([N:12]5[C:13](=[O:26])[C:14]6[S:18][C:17]([C:19]7[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=7)=[CH:16][C:15]=6[N:10]([CH2:9][C:7]6[O:6][N:5]=[C:4]([CH2:2][CH3:3])[N:8]=6)[C:11]5=[O:33])[CH2:28][CH2:29]4)=[O:54])=[CH:56][CH:57]=3)=[N:42][C@@H:41]3[CH2:58][CH2:59][S:60][CH2:61][C@@H:40]3[C:39]=2[CH:38]=1)[CH3:35]
Reactant: CCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4)cc32)n1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccc(F)cc6)cc5n(Cc5nc(CC)no5)c4=O)CC3)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
1-[(3-ethyl-1,2,4-oxadiazol-5-yl)methyl]-6-(4-fluorophenyl)-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione hydrochloride (310 mg; compound B87) is reacted with 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (216 mg; compound C10) and HOBt (83 mg) and EDCI (104 mg) in DMF (10 ml) according to the procedure described in example 46 to afford the title compound after purification by flash column chromatography [amino phase silica gel, eluation gradient: DCM/ethanol, 100/0/to 90/10 (v/v)] and by preparative HPLC as a solid.
Reaction SMILES: [C:1]([O:4][CH2:5][C@:6]12[O:13][C@:10]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=4)[CH:15]=3)([O:11][CH2:12]1)[C@H:9]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C@@H:8]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:7]2=[O:47])(=[O:3])[CH3:2].[BH4-].[Na+]>CO.O1CCCC1>[C:1]([O:4][CH2:5][C@:6]12[O:13][C@:10]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=4)[CH:15]=3)([O:11][CH2:12]1)[C@H:9]([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@@H:8]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C@H:7]2[OH:47])(=[O:3])[CH3:2]
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)C(=O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](COC(C)=O)(O3)[C@H](O)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 99.8 %

Procedure:
To a solution of [(1R,3R,4R,5S)-3,4-dibenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-2-oxo-6,8-dioxabicyclo[3.2.1]octan-1-yl]methyl acetate 28h (4.09 g, 6.2 mmol) in an anhydrous methanol/tetrahydrofuran mixture (v/v=3/1, 20 mL) was added sodium borohydride (278 mg, 7.5 mmol) at 0° C. The mixture was stirred at 0° C. for 5 min, then quenched with water at 0° C. and adjusted with saturated aqueous ammonium chloride till pH becomes 7. The mixture was concentrated in vacuo to remove parts of the solvent. The resulting mixture was extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (100 mL×3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 28i as pale yellow oil (4.08 g, 100%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.50 (m, 2H), 7.38 (d, 3H), 7.30 (m, 3H), 7.21 (m, 3H), 7.03 (d, 2H), 6.80 (d, 2H), 6.74 (d, 2H), 5.17 (d, 1H), 4.75 (d, 1H), 4.52 (d, 1H), 4.41 (d, 1H), 4.34 (d, 1H), 4.27 (d, 1H), 4.13 (d, 1H), 3.99 (m, 2H), 3.94 (m, 3H), 3.85 (m, 3H), 3.71 (d, 1H), 2.01 (s, 3H), 1.28 (t, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C:17]([OH:19])=[O:18])=[CH:11][C:10]=2[CH3:20])=[CH:4][C:3]=1[CH:21]([CH3:23])[CH3:22].C([O-])(=[O:26])C.[Na+].CO>C(O)(=O)C.C(OCC)(=O)C.C(Cl)Cl>[CH:21]([C:3]1[C:2](=[O:26])[NH:7][N:6]=[C:5]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][C:17]([OH:19])=[O:18])=[CH:11][C:10]=2[CH3:20])[CH:4]=1)([CH3:23])[CH3:22]
Reactant: CC(=O)[O-]
Reactant: Cc1cc(CC(=O)O)cc(C)c1Oc1cc(C(C)C)c(Cl)nn1
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(CC(=O)O)cc(C)c1Oc1cc(C(C)C)c(=O)[nH]n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A solution of [4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-3,5-dimethyl-phenyl]-acetic acid (9a) (0.10 g, 0.29 mol) in glacial acetic acid (3 mL) was treated with sodium acetate (54 mg, 0.65 mol) at room temperature. The reaction mixture was heated to 100° C. for 24 h. At this time, the reaction mixture was cooled to room temperature and was concentrated under vacuum. The resulting residue was diluted with water (100 mL), made basic by the addition of a 1N aqueous sodium hydroxide solution and was extracted with ethyl acetate (200 mL). The ethyl acetate layer was discarded. The water layer was acidified to pH=4 by the addition of a 1N aqueous hydrochloric acid solution and was extracted with ethyl acetate (2×200 mL). The organic layers were combined, washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, filtered and concentrated under vacuum to afford a solid. The solid was dissolved in ethyl acetate by adding methanol to form a solution and it was absorbed onto silica and concentrated under vacuum. The preabsorbed solid was purified by column chromatography using silica gel eluted with 20% ethyl acetate in hexanes containing 2% glacial acetic acid. The desired fractions were concentrated as several separate batches and placed under high vacuum for 1 h. 1H NMRs were obtained to determine if batches contained only the desired isomer. The best batches were combined, diluted with a 1:1 methylene chloride:hexanes solution. This process was performed three times. The solid was dried under high vacuum overnight and then slurried in acetonitrile and filtered. The resulting solid was dried in the vacuum oven at 60° C. for 24 h to afford [4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-3,5-dimethyl-phenyl]-acetic acid (10a) (61 mg, 65%) as a white solid; EI(+)-HRMS m/z calcd for C17H20N2O4 (M+) 316.1423, found 316.1427. Molecular Weight=316.3599; Exact Mass=316.1423
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[CH:10](=O)[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13].C(OCC)(=O)C>CCCCCC>[OH:13][C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[CH:10]=[N:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(O)ccc1N
Reactant: O=Cc1ccccc1O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(O)ccc1N=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 19 h
Yield: 93 %

Procedure:
To a 500 milliliter round bottom flask equipped with a water condenser, magnetic stirrer and drying tube was added 12.32 grams (0.10 mole) of 4-amino-3-methylphenol, 12.21 grams (0.10 mole) of salicylaldehyde and 250 milliliters of ethyl acetate. The resulting reaction mixture was stirred for 19 hours at room temperature and ambient pressure. After the stirring period, the reaction mixture was washed twice with saturated brine solution and decolorized with activated charcoal. The reaction mixture was then dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a yellow oil which solidified on standing. The resulting solidified material was slurried in hexane, collected by filtration and dried to yield 21.12 grams (0.093 moles) of 4-(2-hydroxybenzylideneamino)-3-methylphenol in the form of a yellow solid having a melting point of 95°-97° C.
Reaction SMILES: [C:1]1([CH:7]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:36])[N:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH2:22][N:23]4[CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[O:18])[CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O>[C:37]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:8]2[CH:9]=[CH:10][C:11](=[O:36])[N:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH2:22][N:23]4[CH2:28][C:29]([OH:31])=[O:30])=[O:18])[CH:13]=2)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)CN1CCc2c(C(=O)NCCn3cc(C(c4ccccc4)c4ccccc4)ccc3=O)cccc21
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CCc2c(C(=O)NCCn3cc(C(c4ccccc4)c4ccccc4)ccc3=O)cccc21
Reaction time: 1 h
Yield: 66.6 %

Procedure:
The mixture of tert-butyl {4-[({2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}amino)carbonyl]-2,3-dihydro-1H-indol-1-yl}acetate (75 mg) in TFA (2.1 mL) was stood at ambient temperature for 1 hour. The resulting mixture was evaporated in vacuo and was added saturated NaHCO3 aqueous solution (5.0 mL). The aqueous solution was extracted with chloroform (10 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to afford {4-[({2-[5-(diphenylmethyl)-2-oxo-1(2H) -pyridinyl]ethyl}amino)carbonyl]-2,3-dihydro-1H-indol-1-yl}acetic acid (45 mg) as an yellow amorphous.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:19][C:20]([CH3:22])=[CH2:21])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4]([C:6]1([CH2:19][CH:20]([CH3:21])[CH3:22])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: C=C(C)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(CC(C)C)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
5% Pd/C (0.3 g, 50% wet) is added to a solution of 4-(2-methylallyl)piperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester (1.0 g, 0.0032 mol) in ethanol (10 mL). The reaction mixture is stirred under the positive pressure of hydrogen gas for 1 hr at room temperature. The reaction mixture is filtered through celite bed and washed with ethanol (15 mL). Combine filtrate is concentrated under reduced pressure to get 4-isobutylpiperidine-1,4-dicarboxylic acid-1-tert-butyl ester-4-ethyl ester.
Reaction SMILES: [F:1][C:2]([F:25])([CH:22]([F:24])[F:23])[C:3]([NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:8][C:7]=1[N+:19]([O-])=[O:20])=[O:4]>[Pd].C(O)C>[OH:20][N:19]1[C:7]2[CH:8]=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=2[NH:5][C:3]1([OH:4])[C:2]([F:25])([F:1])[CH:22]([F:24])[F:23]
Reactant: O=C(Nc1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])C(F)(F)C(F)F
Agent: [Pd]
Solvent: CCO
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc2c1NC(O)(C(F)(F)C(F)F)N2O

Procedure:
A mixture of N-(2,2,3,3-tetrafluoropropionyl)-2,6-dinitro-4-(trifluoromethyl)aniline (20 grams), 200 ml. of ethanol, and 1.5 grams of 5 percent palladium on carbon was hydrogenated to 137 lbs. TLC showed three streaks. The solution was left standing for 11/2 hours, after which the expected product streak predominated. The reaction mixture was hydrogenated further (8 more lbs) then left standing another 20 minutes. The reaction mixture was then filtered and evaporated, leaving 17.8 grams of an orange solid. It was dissolved in about 75 ml. of water and 2.1 grams of NaOH, filtered, and acidified with slow dropwise addition of about 10 ml. of acetic acid in about 50 ml. of water. At about pH 5-6, a glob of sticky dark material coagulated onto the stirrer and was removed. The acidification was continued, yielding a flocculant precipitate which was separated by filtration and air dried. It was purified by dissolving it in a small amount of 1 percent NaOH solution and reacidifying with dilute acetic acid, yielding the expected product as a pale yellow solid which on rapid heating melted sharply at about 100° C., resolidified, and melted again at 216°-219° C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:28]([F:31])([F:30])[F:29])=[C:11]([CH2:15][O:16][CH:17]3[CH2:20][N:19]([C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]3)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[N:32]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([C:28]([F:31])([F:30])[F:29])=[C:11]([CH2:15][O:16][CH:17]4[CH2:20][N:19]([C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]4)[CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: C1COCCN1
Reactant: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(CCl)cc3)c2C(F)(F)F)C1
Product: CC(C)(C)NC(=O)N1CC(OCc2cccc(-c3ccc(CN4CCOCC4)cc3)c2C(F)(F)F)C1
Yield: 69.7 %

Procedure:
The benzyl chloride (195) (40 mg, 0.088 mmol) and morpholine (3 mL, 31 mmol) were heated to 50° C. for 18 h. The reaction mixture was cooled, excess amine was removed under reduced pressure and the residue partitioned between ethyl acetate and sodium hydroxide (1M). The organic phase was washed with water (2×20 mL) and brine (20 mL), dried (Na2SO4), filtered and the solvent removed under reduced pressure to afford the crude product. Purification by SCX-2 cartridge afforded the title compound (196) as a white solid (31 mg, 70% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([CH2:15][OH:16])[CH:14]=1)[C:9]([OH:11])=O)=[O:5])[CH3:2].C(Cl)CCl.C(N(C(C)C)CC)(C)C.[CH2:30]([NH:33][CH2:34][CH2:35][CH3:36])[CH2:31][CH3:32]>CN(C=O)C>[CH2:30]([N:33]([CH2:34][CH2:35][CH3:36])[C:9]([C:8]1[CH:7]=[C:6]([CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[CH2:31][CH3:32]
Reactant: CCOC(=O)c1cc(CO)cc(C(=O)O)c1
Reactant: CCCNCCC
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCN(CCC)C(=O)c1cc(CO)cc(C(=O)OCC)c1

Procedure:
A mixture of diethyl 1,3,5-benzenetricarboxylate (5.2 g) and borane methylsulfide complex (6.1 g) is stirred in THF (150 mL) at 20-25 degrees C. overnight. The mixture is then treated with methanol, concentrated to dryness, and chouromatographed (silica gel) to give diethyl 5-(hydroxymethyl)isophthalate. Diethyl 5-(hydroxymethyl)isophthalate (3.4 g) is hydroyzed in ethanol and water with lithium hydroxide monohydrate (0.57 g) at 20-25 degrees C. for 3.5 hours at which time the solvents are removed under reduced pressure. Water (100 mL) is added and the mixture is acidified to pH=4 with concentrated hydrochloric acid. The mixture is extracted with ethyl acetate and dried over magnesium sulfate, filtered, and concentrated to give 3-(ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid, high resolution MS MH+=225.0769. 3-(Ethoxycarbonyl)-5-(hydroxymethyl)benzoic acid (2.3 g), EDC (3.0 g), 1-HOBT (2.1 g), diisopropylethylamine (2.7 mL), dipropyl amine (2.8 mL), and DMF (50 mL) are stirred at 20-25 degrees C. overnight. The mixture is then partitioned between ethyl acetate, water, and saline. The organic phase is separated and dried over magnesium sulfate, filtered, and concentrated. Chromatography (silica gel) gives ethyl 3-[(dipropylamino)carbonyl]-5-(hydroxymethyl)benzoate, NMR (CDCl3) δ 0.77, 1.0, 1.4, 1.6, 1.7, 3.2, 3.5, 4.4, 4.8, 7.6, 8.0 and 8.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:31]([O-])=O)([CH3:4])([CH3:3])[CH3:2].CC(O)C.[H][H]>C1(C)C=CC=CC=1.[Pt]>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[NH2:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Reactant: [H][H]
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reaction time: 4 h
Yield: 108.8 %

Procedure:
tert-Butyl[4-(7-benzyloxy-3-nitroquinolin-4-ylamino)butyl]carbamate (20.36 g, 43.6 mmol) was slurried in toluene (450 mL) and added to a Parr vessel charged with 5% platinum on carbon (4.3 g) and a small amount of toluene. 2-Propanol (50 mL) was added, and the vessel was charged with hydrogen (30 psi, 2.1×105 Pa). The hydrogen was replaced three times. After 4 hours, the catalyst was removed by filtration through a layer of CELITE filter aid, and the filter cake was rinsed with toluene (0.5 L), 50% toluene/2-propanol (0.5 L), and 2-propanol (0.25 L). The filtrate was concentrated under reduced pressure, and the residue was mixed with toluene and concentrated under reduced pressure to provide 20.7 g of tert-butyl[4-(3-amino-7-benzyloxyquinolin-4-ylamino)butyl]carbamate as a viscous, black oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N:7]2[CH2:13][CH2:12][CH2:11][C:10]([C:15]([F:18])([F:17])[F:16])([OH:14])[CH2:9][CH2:8]2)=[C:5]([N+:19]([O-])=O)[CH:4]=[N:3]1.C(OC([NH:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43](O)=[O:44])=O)(C)(C)C>>[NH2:29][C:30]1[S:34][C:33]([C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])=[N:32][C:31]=1[C:43]([NH:19][C:5]1[CH:4]=[N:3][N:2]([CH3:1])[C:6]=1[N:7]1[CH2:13][CH2:12][CH2:11][C:10]([OH:14])([C:15]([F:18])([F:17])[F:16])[CH2:9][CH2:8]1)=[O:44]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCCC(O)(C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CCCC(O)(C(F)(F)F)CC1
Yield: 29 %

Procedure:
Following the procedure for Example 101 starting from 1-(1-methyl-4-nitro-1H-pyrazol-5-yl)-4-(trifluoromethyl)azepan-4-ol and 5-(tert-butoxycarbonylamino)-2-(2,6-difluorophenyl)-thiazole-4-carboxylic acid gave 405 as a pale brown solid (53 mg, 29% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.95 (s, 1H), 7.94 (s, 1H), 7.39-7.28 (m, 1H), 7.02 (t, J=8.7 Hz, 2H), 6.21 (s, 2H), 3.73 (s, 3H), 3.46 (ddd, J=13.7, 8.5, 5.0 Hz, 1H), 3.29-3.18 (m, 3H), 2.95 (s, 1H), 2.15-1.97 (m, 5H), 1.87-1.77 (m, 1H). LCMS (ES+) m/z 517 (M+1)
Reaction SMILES: C([O:8][C:9]1([CH3:30])[CH2:18][CH2:17][C:16]2[NH:15][CH:14]=[C:13]3[C:19](=[O:29])[N:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)[N:21]=[C:12]3[C:11]=2[CH2:10]1)C1C=CC=CC=1.[H][H]>CN(C=O)C.CCO.[Pd]>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([N:20]2[C:19](=[O:29])[C:13]3=[CH:14][NH:15][C:16]4[CH2:17][CH2:18][C:9]([OH:8])([CH3:30])[CH2:10][C:11]=4[C:12]3=[N:21]2)=[CH:23][CH:24]=1
Reactant: [H][H]
Reactant: CC1(OCc2ccccc2)CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC1(O)CCc2[nH]cc3c(=O)n(-c4ccc(Cl)cc4)nc-3c2C1

Procedure:
8-Benzyloxy-2-p-chlorophenyl-8-methyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one (4 g) is dissolved in 200 mL of a 1:1 mixture of DMF/EtOH and subjected to catalytic hydrogenation with 5% palladium on carbon (1 g) for 24 hours under 1 atm. of hydrogen. After the reaction is over, the catalyst is filtered off, the filtrate is evaporated, and the dried residue is triturated with EtOH to yield 2-p-chlorophenyl-8-hydroxy-8-methyl-2,3,6,7,8,9-hexahydropyrazolo[4,3-c]quinolin-3(5H)-one.