Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C3C=CC(S(C)(=O)=O)=CC=3)SC=12.[CH3:65][O:66][C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=1[CH2:73][C:74]([N:76]=[C:77]=[S:78])=[O:75]>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:77]([NH:76][C:74](=[O:75])[CH2:73][C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][C:67]=2[O:66][CH3:65])=[S:78])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12
Reactant: COc1ccccc1CC(=O)N=C=S
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Agent: CS(=O)(=O)c1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)c3s2)cc1
Product: COc1ccccc1CC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4cn(C)cn4)sc23)c(F)c1
Yield: 52 %

Procedure:
Starting from the amine 177, following the procedure described above for the synthesis of compound 50 (scheme 10, example 55) but replacing 2-phenylacetyl isothiocyanate with 2-(2-methoxyphenyl)acetyl isothiocyanate, title compound 179 was obtained in 52% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 12.58 (s, 1H), 11.75 (s, 1H), 8.46 (d, 1H, J=5.5 Hz), 8.72 (dd, 1H, J=12.3/2.2 Hz), 7.86 (d, 1H, J=1.2 Hz), 7.72 (d, 1H, J=0.8 Hz), 7.70 (s, 1H), 7.57-7.49 (m, 2H), 7.30-7.23 (m, 2H), 7.00 (d, 1H, J=7.8 Hz), 6.92 dt, 1H, J=7.3/0.9 Hz), 6.58 (d, 1H, J=5.1 Hz), 3.82 (s, 2H), 3.79 (s, 3H), 3.72 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11](NC(C3CC3)=O)[CH:10]=2)[C:5](=O)[N:4]2[C:22]([C:27]3C=[CH:31][CH:30]=[C:29](F)[CH:28]=3)(C)[NH:23][C:24](=[O:25])[C:3]=12.C(N(CC)CC)C.Cl.[CH3:42][O:43][NH2:44]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:10]=[CH:11][N:12]=[CH:13][N:14]=2)[C:5](=[N:44][O:43][CH3:42])[N:4]2[C:22]3([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[NH:23][C:24](=[O:25])[C:3]=12
Reactant: CON
Reactant: CC1(c2cccc(F)c2)NC(=O)c2c(Cl)cc(Nc3cc(NC(=O)C4CC4)ncn3)c(=O)n21
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CON=c1c(Nc2ccncn2)cc(Cl)c2n1C1(CCCCC1)NC2=O
Temperature: 25 °C

Procedure:
To a solution of 8′-chloro-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (1, 1 g, 2.89 mmol) in chloroform (30 mL) is added triethylamine (1.21 mL, 8.67 mmol) and O-methylhydroxylamine hydrochloride (241 mg, 2.89 mmol). The reaction is stirred at reflux overnight. The resulting mixture is cooled to room temperature and washed with water. The organic layer is dried over magnesium sulfate, filtered and concentrated. The crude is purified via flash column chromatography to afford 8′-chloro-5′-(methoxyimino)-6′-(pyrimidin-4-ylamino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridin]-1′(5′H)-one (Cpd. No. 134).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[C:12]=2[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[O:30]1[CH2:29][CH:28]1[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:25]=[CH:24][CH:23]=[CH:22][C:11]=3[C:12]=2[C:13](=[O:21])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:6][CH:7]=1
Reactant: BrCC1CO1
Reactant: Cc1ccc(C(=O)c2c(-c3ccc(O)cc3)oc3ccccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1ccc(C(=O)c2c(-c3ccc(OCC4CO4)cc3)oc3ccccc23)cc1

Procedure:
A mixture of 2.0 g. (6.1 mmol.) of 2-p-hydroxyphenyl-3-p-methylbenzoylbenzofuran, 2.6 g. (0.019 mol.) of epibromohydrin and 3.0 g. (0.021 mol.) of potassium carbonate in 100 ml. of dry acetone was refluxed for 12 hours. After cooling, the reaction mixture was filtered and the filtrate was concentrated to give 2-[4'-(2,3-epoxypropoxy)phenyl]-3-(4'-methylbenzoyl)benzofuran.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:10](O)[CH2:11][OH:12]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[O:12][CH2:11][CH2:10][O:5]1
Reactant: O=Cc1ccccc1Br
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Brc1ccccc1C1OCCO1
Yield: 94.9 %

Procedure:
2-Bromobenzaldehyde (11.4 g) was dissolved in toluene (150 mL), and thereto were added ethyleneglycol (4.58 g) and p-toluenesulfonic acid monohydrate (135 mg), and the mixture was refluxed for 6 hours with azeotropic distillation. The reaction solution was washed with an aqueous sodium hydrogen carbonate solution, and the solvent was evaporated under reduced pressure to give 2-(2-bromophenyl)-1,3-dioxolane (13.4 g, 95%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4=[N:24][CH:25]=[C:26]([C:28]([OH:30])=O)[CH:27]=[C:22]4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1.C1COCC1.[CH3:36][NH:37][CH3:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH2:18][N:19]3[C:23]4=[N:24][CH:25]=[C:26]([C:28]([N:37]([CH3:38])[CH3:36])=[O:30])[CH:27]=[C:22]4[N:21]=[CH:20]3)[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: CNC
Reactant: O=C(O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
To a stirred mixture of 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (65 mg, 0.153 mmol) from Example 81 and TEA (77 mg, 0.767 mmol) in a mixture of anhydrous THF (1.5 mL) and anhydrous DMF (0.5 mL) at rt was added dimethylamine (2 M solution in MeOH, 383 μL, 0.767 mmol) followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (102 mg, 0.230 mmol). The resulting mixture was stirred at rt for 2 h. The mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-N,N-dimethyl-3H-imidazo[4,5-b]pyridine-6-carboxamide (33 mg, 48%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 8.45 (s, 1H), 8.16 (s, 1H), 7.96 (d, J=7.54 Hz, 1H), 7.68 (s, 1H), 7.20-7.33 (m, 2H), 5.50 (s, 2H), 4.73 (d, J=4.90 Hz, 1H), 3.51 (m, 1H), 3.30 (m, 1H), 2.99 (br. s., 6H), 2.02 (m, 1H), 1.87 (m, 1H), 1.55-1.65 (m, 2H), 1.10-1.30 (m, 4H). LCMS (ESI) m/z 451 (M+H)+.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].C([N:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1)(=O)C1C=CC=CC=1.[CH:26](OCC)=[O:27].Cl>C1COCC1>[CH:26]([CH:23]1[C:22](=[O:25])[CH2:21][CH2:20][NH:19][CH2:24]1)=[O:27]
Reactant: O=C1CCN(C(=O)c2ccccc2)CC1
Reactant: CCOC=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]
Solvent: C1CCOC1
Product: O=CC1CNCCC1=O
Yield: 73 %

Procedure:
The following general procedure was used to synthesize compound IV (R2 ≠H): Into a dried, 3-neck flask fitted with a mechanical stirring device, an addition funnel and a low temperature thermometer was cannulated lithium hexamethyldisilazane (1.0 M in THF, 1.1 molar equiv). The solution was cooled via a dry ice/acetone bath. A solution of N-benzoyl-4piperidone (1.0 equiv) in THF (50 mL) was added dropwise, with stirring, over thirty minutes. The solution was stirred at -72° to -68° C. for thirty minutes. Ethyl formate (2 equiv) was added all at once and the solution stirred at -70° C. for ten minutes, then at room temperature for twenty eight hours. The solution was treated with 1N HCl (200 mL) and extracted (methylene chloride and brine). The extracts were dried (MgSO4) and concentrated to yield 3-formyl-4-piperidone as an orange oil (73%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:23]=[O:24]>CN(C)C=O>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23](=[O:24])[O:12][C:9]1[CH:10]=[C:11]2[C:6]([CH2:5][CH2:4][CH2:3][N:2]2[CH3:1])=[CH:7][CH:8]=1
Reactant: O=C=Nc1ccccc1F
Reactant: CN1CCCc2ccc(O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCc2ccc(OC(=O)Nc3ccccc3F)cc21
Reaction time: 0.5 h

Procedure:
A solution of 1-methyl-1,2,3,4-tetrahydroquinolin-7-ol (500 mg, 2.09 mM) in dry dimethylformamide (DMF, 5 mL) was added to the stirred solution of sodium hydride in dry DMF at −10° C. during 5 minutes under nitrogen environment. The reaction mixture was stirred for 30 minutes. Then, 2-fluorophenyl isocyanate (352 mg/ml, 3.14 mM) was added to the stirring reaction mixture. The mixture was stirred further for 3 hours during which the temperature was allowed to reach the room temperature (37° C.). The reaction mixture was quenched with water, diluted with water, extracted with ethyl acetate and dried over sodium sulphate. The combined fractions of ethyl acetate were concentrated under vacuum and chromatographed using ethyl acetate:hexane (1:49) to afford the pure compound 8l as oil. Yield: 580 mg, 63.03%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:17])=[CH:4][C:5]2[O:15][C:14](=[O:16])[C:9]3[CH2:10][NH:11][CH2:12][CH2:13][C:8]=3[C:6]=2[CH:7]=1.C(N(CC)CC)C.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:35][CH:34]2[CH2:36][CH2:37][CH:31]([CH2:32][CH2:33]2)[CH2:30]1>>[CH:34]12[CH2:36][CH2:37][CH:31]([CH2:32][CH2:33]1)[CH2:30][N:29]([CH2:28][CH2:27][N:11]1[CH2:12][CH2:13][C:8]3[C:6]4[CH:7]=[C:2]([Cl:1])[C:3]([CH3:17])=[CH:4][C:5]=4[O:15][C:14](=[O:16])[C:9]=3[CH2:10]1)[CH2:35]2
Reactant: ClCCN1CC2CCC(CC2)C1
Reactant: Cc1cc2oc(=O)c3c(c2cc1Cl)CCNC3
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc2oc(=O)c3c(c2cc1Cl)CCN(CCN1CC2CCC(CC2)C1)C3
Yield: 62.4 %

Procedure:
Prepared by the method described for Example 13 from 9-chloro-1,2,3,4-tetrahydro-8-methyl-5H-[1]benzopyrano[3,4-c]pyridin-5-one (2.0 g, 0.008 moles), 0.008 moles), triethylamine (2.3 ml, 0.017 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane hydrochloride (1.8 g, 0.008 moles). Recrystallization from ethanol gave the product (2.0 g) as the hemihydrochloride, mp 255° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=2[C:22]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]2)=[O:23])=[CH:4][CH:3]=1.Cl[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH:45]([CH3:47])[CH3:46])=[CH:39][CH:38]=1>>[CH2:44]([O:43][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=3[C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH:27]([C:31]([O:33][CH3:34])=[O:32])[CH2:26]3)=[O:23])=[CH:4][CH:3]=2)=[CH:42][CH:41]=1)[CH:45]([CH3:47])[CH3:46]
Reactant: CC(C)COc1ccc(CCl)cc1
Reactant: COC(=O)c1ccc(OCCCc2ccc(O)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1
Product: COC(=O)c1ccc(OCCCc2ccc(OCc3ccc(OCC(C)C)cc3)cc2)c(C(=O)NC2CCCC(C(=O)OC)C2)c1

Procedure:
Methyl 4-(3-{4-[(4-isobutoxybenzyl)oxy]phenyl}propoxy)-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate is prepared in analogy to the process described in Example 34 from methyl 4-[3-(4-hydroxyphenyl)propoxy]-3-({[3-(methoxycarbonyl)cyclohexyl]amino}carbonyl)benzoate and 1-(chloromethyl)-4-isobutoxybenzene.
Reaction SMILES: [OH:1][CH:2]([C@@H:11]1[CH2:16][CH2:15][C@H:14]([CH2:17][NH:18]C(=O)OC(C)(C)C)[CH2:13][CH2:12]1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[OH-].[Na+]>O1CCOCC1>[NH2:18][CH2:17][C@@H:14]1[CH2:13][CH2:12][C@H:11]([CH:2]([OH:1])[CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@@H](C(O)CCc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: NC[C@H]1CC[C@@H](C(O)CCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.5 %

Procedure:
To a solution of (±)-tert-butyl {[cis-4-(1-hydroxy-3-phenylpropyl)cyclohexyl]methyl}carbamate (3.63 g, approximately 10 mmol) in dioxane (20 ml) cooled in an ice-bath was added dropwise 4M hydrogen choride in dioxane (20 ml, 80 mmol). The solution was stirred 2 hours at ice-bath temperature, one hour at ambient temperature, then concentrated at reduced pressure. The solid residue was taken up in methylene chloride (200 ml) and 10N sodium hydroxide (1.0 ml, 10 mmol) was added. The mixture was stirred 20 minutes at ambient temperature, dried (sodium carbonate and sodium sulfate), filtered, and the solvent evaporated under reduced pressure to give crude (+−)-1-[cis-4-(aminomethyl)cyclohexyl]-3-phenylpropan-1-ol (2.71 g, theoretical yield 2.47 g) as a yellow gum: 1H NMR (CDCl3) 7.28 (2H, m), 7.18 (3H, m), 3.51 (1H, m), 2.85 (1H, m), 2.64 (3H, m), 1.88 (1H, m), 1.69 (1H, m), 1.54-1.33 (3H, m). MS: 248.3 (M+1).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[OH:7][CH2:8][C:9](=[O:12])[CH2:10][OH:11]>Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:7][CH2:8][C:9](=[O:12])[CH2:10][O:11][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: O=C(CO)CO
Reactant: C1=COCCC1
Agent: Cl
Product: O=C(COC1CCCCO1)COC1CCCCO1
Temperature: 85 °C
Yield: 66.8 %

Procedure:
A mixture of 236.3 g 3,4-dihydropyran and 90.1 g 1,3-dihydroxy-2-propanone, to which had been added 20 drops of concentrated hydrochloric acid, was heated to 85° C at which temperature, an exothermic reaction began. A cooling bath was applied to maintain the temperature in the range 85°-95° C during the next 15 minutes when heat was again applied to maintain the temperature at 85°-95° C for 2 hours. Excess dihydropyran was removed by warming under reduced pressure and the residue was dissolved in 600 ml of diethyl ether. The ether solution was washed (4 × 200 ml) with 5% aqueous sodium carbonate, then with water (3 × 300 ml) and dried over magnesium sulfate. The dried solution was distilled under reduced pressure to give 172.7 g of 1,3-bis(2-tetrahydropyranyloxy)-2-propanone, b.p. 90°-97°/2 × 10-4 mm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31](O)=[O:32])=[O:22])[C:16]=1[CH3:34].C(N(CC)CC)C.ClC(OCC)=O.[NH2:48][OH:49]>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:12][N:13]=[CH:14][C:15]1[NH:19][C:18]([CH3:20])=[C:17]([C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([NH:48][OH:49])=[O:32])=[O:22])[C:16]=1[CH3:34]
Reactant: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCCCC(=O)O
Reactant: NO
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1[nH]c(C=NN=C2C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCCCCC(=O)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 48.9 %

Procedure:
8-(5-(((5-fluoro-2-oxoindolin-3-ylidene)hydrazono)methyl)-2,4-dimethyl-1H-pyrrole-3-carboxamido)-octanoic acid (469 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (237 mg, 49%) as a red solid. LC-MS (m/z) 485 (M+1).
Reaction SMILES: CO[C:3]1[CH:4]=[CH:5][C:6]2N=[CH:11][CH:10]=[C:9]([C@@H](O)[C@H]3N4C[C@H](C=C)[C@@H](CC4)C3)[C:7]=2[CH:8]=1.C1C=CC=CC=1.[C:31]([O:34]CC)(=[O:33])[CH3:32]>>[C@@H:32]1([C:31]([OH:34])=[O:33])[C:8]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10][CH2:11]1
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccc(OC)cc12
Reactant: CCOC(C)=O
Solvent: c1ccccc1
Product: O=C(O)[C@H]1CCCc2ccccc21

Procedure:
The quinine salt was suspended in 180 mL of ethyl acetate and the suspension was washed with 1N hydrochloric acid (2×92 mL). The mixture was then dried (NaSO4), filtered and concentrated. The residue was dissolved in hexane and crystallized to give (S)-1,2,3,4-tetrahydro-1-naphthoic acid (14.27 g 0.08 mol), m.p. 54°-56° C. α!D -62.76° (c=1.0165, benzene).
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].Cl>O1CCCC1.[OH-].[Li+]>[CH2:31]([O:30][C:28]([NH:27][CH:4]([CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8])[C:3]([OH:38])=[O:2])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: COC(=O)C(CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CN(c2ccccc2)C2(CCN(C(=O)NCC(NC(=O)OCc3ccccc3)C(=O)O)CC2)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of 177 mg (0.34 mmol) of 2-benzyloxycarbonylamino-3-((3-methyl-4-oxo-1-phenyl-1,3,8,-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 4 ml of tetrahydrofuran, 4 ml of 0.1M aqueous lithium hydroxide solution was added, and the resulting mixture was stirred overnight at 0° C. To the reaction mixture, 0.1M hydrochloric acid was added, and the resulting mixture was extracted with ethyl acetate. Organic phases were combined, washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was reprecipitated from ether/chloroform to obtain 143 mg of 2-benzyloxycarbonylamino-3-((3-methyl-4-oxo-1-phenyl-1,3,8,-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid (yield: 83%).
Reaction SMILES: N[C:2]1[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][N:7]2[C@@H:14]1[CH2:16][C@@H:15]1[F:17].N([O-])=[O:25].[Na+].NC(N)=O.C(Cl)(Cl)Cl>S(=O)(=O)(O)O.O.O.O.[N+]([O-])([O-])=O.[Cu+2].[N+]([O-])([O-])=O.[Cu-]=O>[F:12][C:10]1[C:9]([CH3:13])=[C:8]2[C:3]([C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][N:7]2[C@@H:14]2[CH2:16][C@@H:15]2[F:17])=[C:2]([OH:25])[CH:11]=1
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)cc(N)c2c1=O
Reactant: O=N[O-]
Agent: O=[Cu-]
Agent: [Cu+2]
Agent: NC(N)=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(C)c(F)cc(O)c2c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 20.9 %

Procedure:
Ethyl 5-amino-7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (1.414 g, 4.39 mmol) was suspended in 35% aqueous sulfuric acid solution (15 ml), and while cooling with ice, an aqueous sodium nitrite solution (394 mg, 5.70 mmol/4.5 ml) was dripped therein over a period of 5 minutes. After then stirring at 0° C. for 30 minutes, a small amount of urea was added, and at the same temperature, an aqueous copper (II) nitrate trihydrate solution (17.00, 70.2 mmol/155 ml) was dripped therein over a period of 10 minutes. After stirring at 0° C. for 5 minutes, copper (I) oxide (565 mg, 3.95 mmol) was added while stirring the reaction solution violently. After then stirring at room temperature for 20 minutes, extraction into chloroform (200 ml×2) was performed, and after making the aqueous layer slightly basic with sodium bicarbonate, the aqueous layer was extracted with chloroform (150 ml×3). The combined organic layer was then dried over anhydrous sodium sulfate, and after removing the drying agent bt the filtration, the solvent was evaporated under a reduced pressure. The crude product obtained was then subject to a silica gel chromatography, thereby obtaining 297 mg (21%) of the title compound as a yellow powder from a chloroform:methanol=10:1 eluate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21](F)=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C-:29]#[N:30].[Na+]>CS(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][S:15]([C:18]2[C:27]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:21]([C:29]#[N:30])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(F)c3c2CCCC3)CC1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(C#N)c3c2CCCC3)CC1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-(4-Fluoro-5,6,7,8-tetrahydro-naphthalene-1-sulfonylamino)-piperidine-1-carboxylic acid tert-butyl ester (970 mg, 2.35 mmol) was dissolved in DMSO (10 mL) and sodium cyanide (577 mg, 11.77 mmol) was added. The mixture was heated overnight at 100° C. An additional 5 equivalents of sodium cyanide (577 mg, 11.77 mmol) were added and the reaction was stirred overnight at 100° C. The reaction was cooled to room temperature and diluted with dichloromethane (100 mL). The mixture was charged to a separatory funnel and extracted three times with water, brine and then dried over MgSO4. Filtration and concentration in vacuo afforded a brown color foam that was triturated with EtOAc to afford a tan solid. Wt.: 550 mg (56%) 1H NMR (300 MHz, CDCl3) δ 7.87 (d, 1H), 7.48 (d, 1H), 4.52 (d, 1H), 3.93 (m, 2H), 3.30 (m, 1H), 3.07 (m, 4H), 2.73 (m, 2H), 1.80 (m, 6H), 1.37 (s, 9H), 1.30 (m, 2H); LC/MS m/z 418 (M−H)−.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>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.C1(C)C=CC=CC=1>[CH:4]1[C:3]2[C:2](=[CH:15][CH:10]=[CH:9][CH:8]=2)[CH:6]=[CH:5][C:4]=1[C:3]1[C:2]2[C:11]([CH:10]=[C:9]3[C:8]=1[CH:7]=[CH:7][CH:6]=[CH:5]3)=[CH:12][CH:13]=[CH:14][CH:15]=2
Reactant: Brc1c2ccccc2cc2ccccc12
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: OBO
Solvent: Cc1ccccc1
Product: c1ccc2cc(-c3c4ccccc4cc4ccccc34)ccc2c1
Yield: 173.5 %

Procedure:
22.5 g of 9-bromoanthracene, 15.8 g of 2-naphthelene boronic acid and 2.0 g of tetrakis(triphenylphosphine)palladium were mixed, followed by argon displacement. After adding 150 ml of toluene and 140 ml of 2M sodiumcarbonate aqueous solution thereto, it was refluxed on heating for 7 hours. After standing to cool, the crystal precipitated was filtrated it was washed by ethanol and toluene. The crystal obtained was recrystallized in toluene, followed by filtering and drying, and then 23.1 g of 9-(naphthalene-2-yl)anthracene was obtained (yield: 87%).