Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[CH:11]=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.[OH-].[Na+].Cl>CO>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:13]=[C:12]([O:14][CH:15]([F:16])[F:17])[CH:11]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: COC(=O)c1cc(OC(F)F)cc(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1cc(OC(F)F)cc(C(=O)O)c1

Procedure:
Treat a solution of 5-difluoromethoxy-isophthalic acid dimethyl ester (2.7 g, 10.4 mmol) in methanol (35 mL) with 2 N NaOH (5.2 mL, 10.4 mmol) at room temperature for 12 h. Acidify to about pH=3 using 5 N HCl. Extract with ethyl acetate, wash the organic layer with water, saturated aqueous sodium chloride, dry (sodium sulfate) and concentrate to give the crude title product which is used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:23][C:24]1[CH:36]=[CH:35][C:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)(O)[C:26]=2[CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C([Br:48])(=O)C>C(Cl)(Cl)Cl>[CH2:1]([O:23][C:24]1[CH:36]=[CH:35][C:34]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)([Br:48])[C:26]=2[CH:25]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCCOc1ccc2c(c1)C(O)(c1ccc(Cl)cc1)c1ccccc1-2
Reactant: CC(=O)Br
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCCCCCOc1ccc2c(c1)C(Br)(c1ccc(Cl)cc1)c1ccccc1-2
Reaction time: 1 h

Procedure:
2-Docosyloxy-9-(4-chlorophenyl)-9-fluorenol (200 mg, 0.33 mmol) prepared in the above-mentioned 1-2 was dissolved in chloroform (2 ml), acetyl bromide (48 μl, 0.65 mmol) was added dropwise and the mixture was stirred for 1 hour. After completion of the reaction, the solvent was evaporated, and the residue was precipitated with acetonitrile (2 ml) to give 2-docosyloxy-9-(4-chlorophenyl)-9-bromofluorene (209 mg, 0.31 mmol, 95%.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[I:7][C:8]1[CH:9]=C([CH:14]=[CH:15][CH:16]=1)C(O)=O>C(Cl)Cl>[I:7][C:8]1[CH:9]=[C:1]([CH:14]=[CH:15][CH:16]=1)[C:2]([Cl:4])=[O:3]
Reactant: O=C(O)c1cccc(I)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)c1cccc(I)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Oxalyl chloride (2.66 mL, 30.4 mmol) was added dropwise to a suspension of 3-iodobenzoic acid (6.98 g, 27.6 mmol) in DCM (140 mL) under a nitrogen atmosphere at room temperature. The mixture was then stirred at rt for 4 h. After the reaction was complete, solvent was removed in vacuum to yield a residue (3-iodobenzoyl chloride), which was dried in high vacuum and used without further purification. This residue was dissolved in DCM (25 mL) and added slowly to a 0° C., stirred solution of 3,5-diisopropyl-[1,1′-biphenyl]-4-amine (5.0 g, 19.73 mmol) and pyridine (2.71 ml, 33.5 mmol) in DCM (50 mL). The mixture was then warmed up and stirred at rt overnight. After the reaction was complete water was added. Aqueous mixture was extracted with DCM. The DCM layer was separated, washed with water (2×) and brine, and then dried over anhydrous Na2SO4. Filtration and evaporation gave an off-white solid which was recrystallized from 10% hexane in DCM to afford the title compound (5.3 g, 55%).
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]([O:19][CH3:20])=[O:18])[CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[CH:31][C:32]3[O:36][CH:35]=[C:34]([CH3:37])[C:33]=3[CH:38]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:29]2[CH:30]=[CH:31][C:32]3[O:36][CH:35]=[C:34]([CH3:37])[C:33]=3[CH:38]=2)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]([O:19][CH3:20])=[O:18])=[CH:6][CH:5]=2
Reactant: Cc1coc2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COC(=O)c1ccc2nc(Cl)c(N(C)C(C)C)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc2nc(-c3ccc4occ(C)c4c3)c(N(C)C(C)C)nc2c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 78.5 %

Procedure:
To a solution of methyl 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (150 mg, 0.36 mmol) in 1,4-dioxane (6 mL) was added 4,4,5,5-tetramethyl-2-(3-methyl-1-benzofuran-5-yl)-1,3,2-dioxaborolane (350 mg, 1.36 mmol), Pd(PPh3)4 (40 mg, 0.034 mmol), K3PO4 (430 mg, 2.04 mmol) and water (5 drops) with stirring for 5 h at 90° C. under an inert atmosphere of nitrogen in an oil bath. The reaction mixture was concentrated under vacuum to give the residue, which was purified via silica gel chromatography (1% to 5% ethyl acetate in petroleum ether) to afford methyl 3-[methyl(propan-2-yl)amino]-2-(3-methyl-1-benzofuran-5-yl)quinoxaline-6-carboxylate as a yellow solid (110 mg, 63%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][NH2:15]>>[CH3:14][NH:15][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: CN
Reactant: O=C1CCC(c2ccccc2)CC1
Product: CN[C@H]1CC[C@H](c2ccccc2)CC1

Procedure:
from 4-phenylcyclohexanone and methylamine. Melting point: 40° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:10]3=[N:9][C:8]=2[C:16]2[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl.Cl.[NH:33]1[CH2:38][CH2:37][CH:36]([C:39]2[N:43]=[C:42]([C:44]3[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=3)[NH:41][N:40]=2)[CH2:35][CH2:34]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)(Cl)Cl>[C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][CH:14]=[N:15][C:10]3=[N:9][C:8]=2[C:16]2[CH:23]=[CH:22][C:19]([CH2:20][N:33]3[CH2:38][CH2:37][CH:36]([C:39]4[N:43]=[C:42]([C:44]5[CH:49]=[CH:48][N:47]=[CH:46][CH:45]=5)[NH:41][N:40]=4)[CH2:35][CH2:34]3)=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1cc(-c2nc(C3CCNCC3)n[nH]2)ccn1
Reactant: O=Cc1ccc(-c2nc3ncccn3c2-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: c1ccc(-c2c(-c3ccc(CN4CCC(c5n[nH]c(-c6ccncc6)n5)CC4)cc3)nc3ncccn23)cc1
Reaction time: 0.08 h

Procedure:
To a solution of 0.094 g (0.314 mM) 4-(3-phenylimidazo[1,2-a]pyrimidin-2-yl)benzaldehyde in 3 mL of THF is added triethylamine (2 eq). The reaction mixture is stirred for 5 minutes. To this solution is added 4-[3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl]pyridine 2HCl (1.5 eq) (Intermediate B) followed by acetic acid (2.5 eq). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH(OAc)3 (6 eq) over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained is taken up in chloroform and washed with water, dried and concentrated. The crude is purified on a flash column chromatography to obtain the desired compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[N:3]=1.[CH3:28][N:29]1[C@@H:33]2[CH2:34][C@H:35]([OH:37])[CH2:36][C@H:30]1[CH2:31][CH2:32]2.BrC1C=C(CO)C=C2C=1CN(CC1C=CC(OC)=CC=1)C(=O)N2C1C(Cl)=CC=CC=1Cl.[H-].[Na+]>>[Cl:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:4]1[N:3]=[C:2]([O:37][CH:35]2[CH2:34][CH:33]3[N:29]([CH3:28])[CH:30]([CH2:31][CH2:32]3)[CH2:36]2)[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:20])[N:9]2[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19]
Reactant: O=c1ccc2c(-c3ccccc3Cl)nc(Br)cc2n1-c1c(Cl)cccc1Cl
Reactant: CN1[C@@H]2CC[C@H]1C[C@H](O)C2
Agent: COc1ccc(CN2Cc3c(Br)cc(CO)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Agent: [H-]
Agent: [Na+]
Product: CN1C2CCC1CC(Oc1cc3c(ccc(=O)n3-c3c(Cl)cccc3Cl)c(-c3ccccc3Cl)n1)C2

Procedure:
The title compound was prepared from 100 mg of 7-bromo-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-1,6-naphthyridin-2(1H)-one (COMPOUND HHH2), 147 mg of a ca. 1.4:1 mixture of pseudotropine and tropine (EXAMPLE HHH9, Step A), and 25 mg of NaH by a procedure analogous to that described in COMPOUND HHH6.
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([CH3:23])[C:11]=2[CH3:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C.O>[F:1][C:2]1[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH:13]=[C:12]([CH3:23])[C:11]=2[CH3:24])=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[O:26][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]
Reactant: CCOC(=O)CBr
Reactant: Cc1cc(-c2cccc(F)c2)cc(CNc2c(F)ccc(O)c2F)c1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)cc(C)c2C)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
To a stirred solution of 2,4-difluoro-3-[[5-(3-fluorophenyl)-2,3-dimethyl-phenyl]methylamino]phenol (137 mg, 0.38 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (170 mg, 0.5 mmol, 1.4 eq). The resulting mixture was stirred for 30 min at room temperature, then ethyl 2-bromoacetate (77 mg, 0.46 mmol, 1.2 eq) was added. The mixture was stirred at room temperature for 2.5 h and then diluted in water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give the title compound as an oil (120 mg, 70%).
Reaction SMILES: CC([N:5]=[C:6]([C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]=[CH:13]2)[CH2:7][CH2:8][CH3:9])(C)C.[CH:20]([C:29]([O:31][CH3:32])=[O:30])([C:25](OC)=[O:26])[C:21](OC)=[O:22]>O(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:8]([C:7]1[C:21]([OH:22])=[C:20]([C:29]([O:31][CH3:32])=[O:30])[C:25](=[O:26])[NH:5][C:6]=1[C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]=[CH:13]2)[CH3:9]
Reactant: CCCC(=NC(C)(C)C)c1ccc2c(ccn2C)c1
Reactant: COC(=O)C(C(=O)OC)C(=O)OC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCc1c(-c2ccc3c(ccn3C)c2)[nH]c(=O)c(C(=O)OC)c1O
Temperature: 230 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
To a suspension of 2-methyl-N-(1-(1-methyl-1H-indol-5-yl)butylidene)propan-2-amine (6.70 g, ca. 26.1 mmol), prepared according to procedure described in Example 21 Step 2, in Ph2O (40 mL) was added trimethyl methanetricarboxylate (8.44 g, 44.4 mmol, 1.7 eq). Distillation apparatus was set up then attached to the flask. The reaction was stirred at 230° C. for 10 min then heating was removed. The mixture was cooled to room temperature. The precipitate was collected by filtration then washed with diethyl ether to afford the title compound as a yellow solid (4.85 g, 14.9 mmol, 55%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:15]([C:18]12[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2)=[C:16]=[O:17]>>[C:1]([O:5][C:6]([N:8]1[C:11]2([CH2:12][N:13]([C:16](=[O:17])[NH:15][C:18]34[CH2:19][CH:20]5[CH2:26][CH:24]([CH2:23][CH:22]([CH2:21]5)[CH2:27]3)[CH2:25]4)[CH2:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC12CNC2
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Product: CC(C)(C)OC(=O)N1CCC12CN(C(=O)NC13CC4CC(CC(C4)C1)C3)C2

Procedure:
In analogy to the experimental procedure of example 8) 1,6-diaza-spiro[3.3]heptane-1-carboxylic acid tert-butyl ester instead of 1-benzyl-1,6-diaza-spiro[3.3]heptane was converted using 1-isocyanato-adamantane instead of (3-isocyanato-propyl)-benzene into the title compound which was used directly in the next step without further purification.
Reaction SMILES: Cl.[CH:2]1[C:10]2[N:9]3[C:11]([C@@H:14]4[C@H:18]([CH3:19])[CH2:17][C@H:16]([NH2:20])[CH2:15]4)=[CH:12][N:13]=[C:8]3[CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.O.C(=O)([O-])[O-].[K+].[K+].[F:28][C:29]([F:37])([F:36])[CH2:30][CH2:31][S:32](Cl)(=[O:34])=[O:33]>C1COCC1>[CH:2]1[C:10]2[N:9]3[C:11]([C@@H:14]4[C@H:18]([CH3:19])[CH2:17][C@H:16]([NH:20][S:32]([CH2:31][CH2:30][C:29]([F:37])([F:36])[F:28])(=[O:34])=[O:33])[CH2:15]4)=[CH:12][N:13]=[C:8]3[CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: C[C@@H]1C[C@H](N)C[C@@H]1c1cnc2cnc3[nH]ccc3n12
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](NS(=O)(=O)CCC(F)(F)F)C[C@@H]1c1cnc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.7 %

Procedure:
To a 2 L flask (1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentanamine hydrochloride (248.0 g, 733 mmol), water (1240 ml), THF (124 ml) and activated carbon (24.12 g) was added and stirred for about 10 min. The resulting mixture was filtered through celite rinsing with a mixture of water (100 mL) and THF (24 mL). Potassium carbonate (668 g, 4836 mmol) and THF (1736 ml) were added and a solution of 3,3,3-trifluoropropane-1-sulfonyl chloride (315 g, 1524 mmol, Matrix) in THF (620 ml) was added over about 1 hr. After cooling to ambient temperature the layers were separated and the aqueous layer extracted with THF (500 mL). The combined organic layers were washed with aqueous ammonium chloride (3×100 mL) and concentrated to approximately 1 L. Water (1770 mL) was added slowly at about 50° C. and the slurry cooled to about 23° C. The solids were collected by filtration, washed with 35% THF in water (750 mL) and dried in a vacuum oven. The crude material was dissolved in MeOH (4.5 L) and treated with activated carbon (28.3 g). After filtering through celite and rinsing with MeOH (500 mL), the solution was concentrated under reduced pressure to approximately 1 L and water (800 mL) was added slowly at about 50° C. then cooled to 35° C. when additional water (360 mL) was added. The product was collected by filtration, washed with 1:1 MeOH:water (2×350 mL) and dried in a vacuum oven to afford N-((1S,3S,4R)-3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)-4-methylcyclopentyl)-3,3,3-trifluoropropane-1-sulfonamide (215.3 g, 71%) as a white crystalline solid (m.p. 225° C.). 1H NMR (400 MHz, DMSO) δ 11.99 (bs, 1H), 8.30 (s, 1H), 7.40 (bs, 1H), 7.38 (s, 1H), 7.27-7.07 (m, 1H), 6.62 (d, J=3.4 Hz, 1H), 3.75 (dt, J=10.1, 7.8 Hz, 1H), 3.70-3.55 (m, 1H), 3.15-3.02 (m, 2H), 2.61-2.40 (m, 2H), 2.40-2.29 (m, 1H), 2.23 (dd, J=13.3, 6.9 Hz, 1H), 2.16-2.03 (m, 1H), 1.94-1.77 (m, 1H), 1.20-0.99 (m, 1H), 0.17 (d, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([NH:9]C(=O)C(C)(C)C)[CH:3]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl>[NH2:9][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][N:5]=1
Reactant: CC(C)(C)C(=O)Nc1cc(Cl)c(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Nc1cc(Cl)c(Cl)cn1
Yield: 96.6 %

Procedure:
Compound 8 (10 g, 0.04 mol) in 6 N HCl (50 mL) was heated at reflux for 10 h. This solution was neutralized with Na2CO3 (to pH 7 by litmus) and then extracted with EtOAc (3×150 mL). The combined EtOAc extracts were dried over magnesium sulfate, filtered and concentrated to give a solid residue, which, after recrystallization from EtOH, gave 6.3 g (97%) of compound 4 as a white solid (mp 140-141° C.).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C([Li])CCC.[O:23]=[C:24]([CH3:30])[CH2:25][CH2:26][CH2:27][C:28]#[N:29]>O1CCCC1.C(OCC)C>[OH:23][C:24]([C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[CH:10]=1)([CH3:30])[CH2:25][CH2:26][CH2:27][C:28]#[N:29]
Reactant: FC(F)(F)c1ccc(-c2cccc(Br)c2)cc1
Reactant: CC(=O)CCCC#N
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(O)(CCCC#N)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
Under a nitrogen atmosphere a stirred solution of 7.5 grams (0.025 mole) of 3-(4-trifluoromethylphenyl)phenyl bromide in 100 mL of tetrahydrofuran was cooled to about -78 ° C., and 10.0 mL (0.025 mole) of n-butyllithium (2.5 molar in hexane) was added dropwise. Upon completion of addition, the reaction mixture was stirred at -78 ° C. for about one hour. After this time a solution of 2.8 grams (0.025 mole) of 5-oxohexanenitrile in 10 mL of tetrahydrofuran was added dropwise. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature as it stirred for about 18 hours. After this time the reaction mixture was diluted with diethyl ether and partitioned between an aqueous dilute solution of hydrochloric acid and diethyl ether. The organic layer was separated and dried with sodium sulfate. The mixture was filtered and concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using 1:1 ethyl acetate and hexane as the eluant. The product-containing fractions were concentrated under reduced pressure, yielding about 3.0 grams of 5-hydroxy-5-[3-(4-trifluoromethylphenyl)phenyl]hexanenitrile. The NMR spectrum was consistent with the proposed structure. This reaction was repeated.
Reaction SMILES: [NH:1]([C:5]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:6]=1[CH2:7][N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])C(C)=O.[ClH:22].N>C(O)C>[ClH:22].[NH2:1][C:5]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:13][C:6]=1[CH2:7][N:8]([CH2:9][CH3:10])[CH2:11][CH3:12]
Reactant: CCOC(=O)c1ccc(NC(C)=O)c(CN(CC)CC)c1
Agent: Cl
Agent: N
Solvent: CCO
Product: CCOC(=O)c1ccc(N)c(CN(CC)CC)c1

Procedure:
19 gm of 2-acetamino-5-carbethoxy-N,N-diethyl-benzylamine were dissolved in 100 ml of ethanol, and after addition of 60 ml of concentrated hydrochloric acid the mixture was refluxed for 1 hour. Thereafter the mixture was poured over ice, made alkaline with ammonia and extracted three times with chloroform. The combined chloroform extracts were dried over sodium sulfate and evaporated in vacuo, and the residue was purified by chromatography on silica gel (elution agent: ethyl acetate); by addition of isopropanolic hydrochloric acid, 2-amino-5-carbethoxy-N,N-diethyl-benzylamine hydrochloride was obtained, which was recrystallized from ethanol and then had a melting point of 138°-142° C.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[N:15]=[C:14]2[C:9]([C:10](=[O:29])[C:11]([C:26]([OH:28])=[O:27])=[CH:12][N:13]2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=2)=[CH:8][C:7]=1[F:30].[CH3:31]O>>[Cl:5][C:6]1[N:15]=[C:14]2[C:9]([C:10](=[O:29])[C:11]([C:26]([O:28][CH3:31])=[O:27])=[CH:12][N:13]2[C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=2)=[CH:8][C:7]=1[F:30]
Reactant: CO
Reactant: O=C(O)c1cn(-c2ccc(F)c([N+](=O)[O-])c2)c2nc(Cl)c(F)cc2c1=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cn(-c2ccc(F)c([N+](=O)[O-])c2)c2nc(Cl)c(F)cc2c1=O

Procedure:
To 25 ml of methanol was added dropwise 1 g of thionyl chloride. To the solution was added 1.1 g of 7-chloro-6-fluoro-1-(4-fluoro-3-nitrophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. The solution was heated at reflux overnight. The reaction solution was allowed to cool down and concentrated in vacua. Diethyl ether was added to the residue. The solid was collected by filtration to give 1.4 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC=CC=3)=[CH:15][CH:14]=2)[C:9]1=[O:27])([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)[C:9]1=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(OCc3ccccc3)cc2)C1=O
Agent: [Pd]
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(O)cc2)C1=O

Procedure:
In an analogous manner to that described in Example 2b), the hydrogenolysis of the (S)-[1-(4-benzyloxy-phenyl)-2-oxo-pyrrolidin-3-yl]-carbamic acid tert-butyl ester [Example 8 b)] using palladium on carbon as the catalyst yields the title compound as a white solid in quantitative yield; MS: m/e=291 (M−H)+.
Reaction SMILES: Br[C:2]1C=C(N[C@@H]2CCCN(C(OC(C)(C)C)=O)C2)C(OC)=N[CH:7]=1.Cl[CH2:25][C:26]([N:28]1CC[CH2:31][C@@H:30]([NH:34][C:35]2[C:40](=[O:41])[NH:39][CH:38]=[C:37]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[CH:36]=2)[CH2:29]1)=[O:27]>>[C:26]([N:28]1[CH2:31][CH:30]([NH:34][C:35]2[C:40](=[O:41])[NH:39][CH:38]=[C:37]([C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)[CH:36]=2)[CH2:29]1)(=[O:27])/[CH:25]=[CH:2]/[CH3:7]
Reactant: O=C(CCl)N1CCC[C@@H](Nc2cc(-c3ccncc3)c[nH]c2=O)C1
Reactant: COc1ncc(Br)cc1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Product: C/C=C/C(=O)N1CC(Nc2cc(-c3ccncc3)c[nH]c2=O)C1

Procedure:
Following Example 1, but using tert-butyl 3-aminoazetidine-1-carboxylate (Example 1 Step 3) and reaction with (E)-but-2-enoyl chloride (Example 1 Step 6) provided the desired compound after purification: 1H NMR (300 MHz, DMSO-d6) 11.83 (br s, 1H), 8.52 (d, J=5.7 Hz, 2H), 7.61 (d, J=5.7 Hz, 2H), 7.25-7.35 (m, 1H), 6.55-6.75 (m, 1H), 6.49 (d, J=2.1 Hz, 1H), 6.26 (d, J=6.6 Hz, 1H), 6.01 (dd, J=15.2, 1.7 Hz, 1H), 4.45-4.65 (m, 1H), 4.20-4.40 (m, 2H), 4.07 (dd, J=8.6, 4.7 Hz, 1H), 3.87 (dd, J=9.9, 4.8 Hz, 1H), 1.82 (dd, J=6.6, 1.5 Hz, 3H); MS (ES) m/z 311 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([S:12](Cl)(=[O:14])=[O:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:16])[CH:3]=1.[CH3:17][NH:18][CH3:19].O>>[CH3:17][N:18]([CH3:19])[S:12]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([CH3:16])[CH:3]=[C:2]2[Cl:1])(=[O:14])=[O:13]
Reactant: CNC
Reactant: Cc1cc(Cl)c2cccc(S(=O)(=O)Cl)c2n1
Solvent: O
Product: Cc1cc(Cl)c2cccc(S(=O)(=O)N(C)C)c2n1

Procedure:
4-Chloro-2-methylquinoline-8-sulfonyl chloride (100 mg, 0.362 mmole) and a 40% solution of dimethylamine in water (408 mg, 3.62 mmole) were stirred at 60° C. for 1 h. The content of the flask was filtered off and a white solid was obtained (103 mg, 100%).