Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C@:8]23[CH2:16][O:15][C@H:14]([C:17]([F:20])([F:19])[F:18])[C@H:13]2[CH2:12][S:11][C:10]([NH:21]C(=O)OC(C)(C)C)=[N:9]3)[CH:7]=1.[CH3:30][C:31]1[N:32]=[CH:33][C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1>>[NH2:21][C:10]1[S:11][CH2:12][C@@H:13]2[C@@H:14]([C:17]([F:19])([F:20])[F:18])[O:15][CH2:16][C@:8]2([C:6]2[CH:7]=[C:2]([NH:1][C:37]([C:34]3[CH:33]=[N:32][C:31]([CH3:30])=[CH:36][N:35]=3)=[O:38])[CH:3]=[CH:4][C:5]=2[F:29])[N:9]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Reactant: Cc1cnc(C(=O)O)cn1
Product: Cc1cnc(C(=O)Nc2ccc(F)c([C@]34CO[C@H](C(F)(F)F)[C@H]3CSC(N)=N4)c2)cn1

Procedure:
Synthesized from tert-butyl [(4aS,5S,7aS)-7a-(5-amino-2-fluorophenyl)-5-trifluoromethyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl]carbamate and 5-methyl-pyrazine-2-carboxylic acid according to the general procedure. 1H NMR (400 MHz, CDCl3) δ ppm 2.72 (s, 3H), 2.88 (dd, J=13.6, 3.8 Hz, 1H), 3.21 (dd, J=13.6, 3.0 Hz, 1H), 3.42-3.49 (m, 1H), 3.94 (d, J=8.3 Hz, 1H), 4.39-4.80 (m, 4H), 7.14 (dd, J=11.9, 8.8 Hz, 1H), 7.62 (dd, J=7.1, 2.8 Hz, 1H), 7.93-7.99 (m, 1H), 8.46 (d, J=1.0 Hz, 1H), 9.39 (d, J=1.3 Hz, 1H), 9.65 (s, 1H)
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:24][CH:25]=[CH2:26])[CH3:23])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([N:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH2:9][CH2:10]2)[CH3:23])[CH:25]=[CH2:26]
Reactant: C=CCN(C)CCCCCc1ccc2c(c1)CCN2C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCN(C)CCCCCc1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
2.45 g (6.8 mmol) 5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester in 5 ml CH2Cl2 were treated with 4 ml TFA at 0° C. The solution was stirred at RT for 0.5 h, and at 40° C. for 1 h. The solution was concentrated, and the residue was dissolved in ether, water. 2M NaOH was added and the inorganic phase was extracted with ether. The combined organic phases were washed with water and dried over Na2SO4 to yield 1.65 g (94%) Allyl-[5-(2,3-dihydro-1H-indol-5-yl)-pentyl]-methyl-amine as light yellow oil, MS: 259 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([O:23]CC)=[O:22])=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>O1CCOCC1.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([C:21]([OH:23])=[O:22])=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(NC(=O)OCc3ccccc3)ccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(Nc1ccc2[nH]c(C(=O)O)cc2c1)OCc1ccccc1

Procedure:
Ethyl 5-Benzyloxycarbonylaminoindole-2-carboxylate, (PREPARATION 56, 0.76 g) is dissolved in 1,4-dioxane (5.6 ml) and water (0.56 ml). Crushed potassium hydroxide (0.23 g) is added and the reaction is heated to 50° for 5 hr. The reaction is neutralized by adding 4.05 ml of 1N aqueous hydrochloric acid. The reaction is extracted with THF/chloroform (10/90, 3 ×), saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title acid, NMR (300 MHz, d4-CD3OD) 7.64, 7.34-7.15, 6.98 and 5.09 δ.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH:11](=O)[CH2:12][CH3:13].N1CCCCC1>C(O)C>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:12]([CH3:13])[CH:11]=[N:1]2)=[CH:6][CH:7]=1
Reactant: CCC=O
Reactant: Nc1cc(Cl)ccc1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cnc2cc(Cl)ccc2c1
Yield: 75 %

Procedure:
Under nitrogen atmosphere, to a solution of 2-amino-4-chloro-benzaldehyde (467 mg) in ethanol (10 mL) were added propanal (250 μL) and piperidine (50 μl), and the mixture was heated under reflux. Further, to the mixture were added propanal (800 μL) and piperidine (250 μL) in several portions, and the mixture was heated under reflux for total 9 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=6/1) to give 7-chloro-3-methylquinoline (401 mg, 75%).
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.CC(C)([O-])C.[Na+].[Cl:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1.[Cl-].[NH4+]>C1COCC1>[Br:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([Cl:27])[CH:29]=3)(=[O:36])=[O:35])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(N)c23)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Reaction time: 3.5 h
Yield: 49.1 %

Procedure:
To a stirred solution of 2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (213 mg, 0.610 mmol) (Description 17) in THF (5 mL) was added sodium tert-butoxide (234 mg, 2.440 mmol) at RT and the mixture stirred for 15 min before the addition of 3-chlorobenzenesulfonyl chloride (0.172 mL, 1.220 mmol). The mixture was then stirred for 3.5 h. Saturated ammonium chloride solution (20 mL) was added to the mixture which was then extracted with ethyl acetate (2×15 mL). The combined organics were washed with brine (20 mL), dried and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-30% ethyl acetate in cyclohexane, afforded the title compound (157 mg). LCMS (A) m/z: 523/525 [M+1]+, Rt 1.54 min (acidic), Rt 1.83 min (basic).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C:13]2([C:38]([F:41])([F:40])[F:39])[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C:23]3([CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27]3)[NH:22][C:21]4=[O:37])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl>CO>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C:13]2([C:38]([F:39])([F:40])[F:41])[O:17][N:16]=[C:15]([C:18]3[CH:19]=[C:20]4[C:24](=[CH:25][CH:26]=3)[C:23]3([CH2:27][NH:28][CH2:29]3)[NH:22][C:21]4=[O:37])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CC2(C1)NC(=O)c1cc(C3=NOC(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)(C(F)(F)F)C3)ccc12
Agent: Cl
Solvent: CO
Product: O=C1NC2(CNC2)c2ccc(C3=NOC(c4cc(C(F)(F)F)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc21
Temperature: 65 °C
Reaction time: 1 h
Yield: 103.2 %

Procedure:
A 100 mL vial equipped with stir bar was charged with tert-butyl 5′-(5-(3,5-bis(trifluoromethyl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′-oxospiro[azetidine-3,1′-isoindoline]-1-carboxylate (Preparation 21, 240 mg, 0.4 mmol) and anhydrous methanol (25 mL). A methanolic solution of HCl (1 mL of a 1.25M solution) was added and the reaction was heated to 65° C. for 6 hours. The reaction was cooled and concentrated under vacuum. The residue was rinsed with diethyl ether, concentrated under vacuum, and subsequently placed under high vacuum for 1 hour to afford the intermediate (216 mg, 95%) as an HCl salt. m/z (CI) 524 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][CH:27]([O:1][C:2]2[CH:11]=[C:10]([O:12][CH2:13][CH2:14][O:15][CH3:16])[CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: COCCOc1ccc(C(=O)OC)c(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Product: COCCOc1ccc(C(=O)OC)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 89.6 %

Procedure:
Using a procedure similar to that of Example 26-B, methyl 2-hydroxy-4-(2-methoxyethoxy)benzoate (2.72 g, 12.02 mmol) is alkylated with 1-tert-butoxycarbonyl-4-hydroxy-piperidine (2.44 g, 12.02 mmol) to afford methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(2-methoxyethoxy)benzoate (4.41 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:13][C:14]1[CH:15]=[N:16][O:17][C:18]=1[C:19]1[CH:32]=[CH:31][C:22]([CH2:23][S:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])=[CH:21][CH:20]=1)=[O:12])[CH3:9].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11]([NH:13][C:14]1[CH:15]=[N:16][O:17][C:18]=1[C:19]1[CH:32]=[CH:31][C:22]([CH2:23][S:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:21][CH:20]=1)=[O:12])[CH3:9]
Reactant: COC(=O)CCSCc1ccc(-c2oncc2NC(=O)OC(C)c2ccccc2Cl)cc1
Agent: Cl
Solvent: CCO
Product: CC(OC(=O)Nc1cnoc1-c1ccc(CSCCC(=O)O)cc1)c1ccccc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 47.2 %

Procedure:
To a solution (1 ml) of methyl 3-(4-[4-[1-(2-chlorophenyl)ethoxy-carbonylamino]-5-isoxazolyl]benzylsulfanyl)propionate (22 mg, 0.046 mmol) in ethanol was added 2N hydrochloric acid (2 ml), and the mixture was stirred at 50° C. for 4 hours. The solvent was evaporated under reduced pressure, and water was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude product was purified by silica gel chromatography (dichloromethane:methanol=9:1) to give the title compound (10 mg, 47%).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>>[C:28]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:9]4[N:10]=[CH:11][CH:12]=[C:7]5[CH2:6][CH2:5][O:4][C:8]=45)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:37])=[CH:39][CH:40]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1
Agent: Cl
Product: CC(C)(C)c1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4nccc5c4OCC5)CC3)CC2)cc1

Procedure:
The title compound, white solid (106 mg, 86%), MS (ISP) m/z=491.5 [(M+H)+], mp 183° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 4-tert-butyl-benzoic acid.
Reaction SMILES: [C:1]([O-:4])([O-])=O.[Na+].[Na+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9](B(O)O)[CH:8]=1>COCCOC.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>[CH3:12][C:11]1[CH:10]=[CH:9][CH:8]=[C:9]2[C:8]=1[N:7]=[C:12]([C:9]1[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=1)[C:11]([CH:1]=[O:4])=[CH:10]2
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cccc2cc(C=O)c(-c3cccnc3)nc12
Yield: 281.9 %

Procedure:
Prepared according to the procedure described for Intermediate 1, utilising Intermediate 32 (10 g, 48.7 mmol), Na2CO3 (7.74 g, 73 mmol), 3-pyridylboronic acid (5.98 g, 48.7 mmol) and tetrakis(triphenylphosphine)palladium(0) (2.81 g, 2.43 mmol) in DME (150 mL) and water (40 mL). The title compound (11.36 g, 94%) was obtained as a brown solid. δH (CDCl3) 10.20 (s, 1H), 9.02 (dd, J 2.3, 0.8 Hz, 1H), 8.86 (s, 1H), 8.80 (dd, J 4.9, 1.7 Hz, 1H), 8.10 (ddd, J 7.9, 2.3, 1.7 Hz, 1H), 7.90 (d, J 8.3 Hz, 1H), 7.78-7.75 (m, 1H), 7.58 (dd, J 8.1, 7.2 Hz, 1H), 7.53 (ddd, J 7.9, 4.9, 0.8 Hz, 1H), 2.88 (s, 3H). LCMS (ES+) 249 (M+H)+, RT 1.41 minutes.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:10]([O:12][C@@H:13]1[CH2:29][C@@H:28]2[C@@:16]([CH3:39])([C@@H:17]3[C@@H:25]([CH2:26][CH2:27]2)[C@:24]2(O)[C@@:20]([CH3:38])([C@@H:21]([C:31]4[CH:32]=[CH:33][C:34](=[O:37])[O:35][CH:36]=4)[CH2:22][CH2:23]2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:11])=O)(C)(C)C.Cl>CCOC(C)=O>[NH2:8][C@H:9]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:10]([O:12][C@@H:13]1[CH2:29][C@@H:28]2[C@@:16]([CH3:39])([C@@H:17]3[C@@H:25]([CH2:26][CH2:27]2)[C:24]2[C@@:20]([CH3:38])([C@@H:21]([C:31]4[CH:32]=[CH:33][C:34](=[O:37])[O:35][CH:36]=4)[CH2:22][CH:23]=2)[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:11]
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccc(=O)oc4)CC[C@]32O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](N)C(=O)O[C@H]1CC[C@@]2(C)[C@H](CC[C@H]3C4=CC[C@H](c5ccc(=O)oc5)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a solution of (R)-((3S,5R,8R,9S,10S,13R,14S,17R)-14-hydroxy-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)hexadecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-(tert-butoxy carbonylamino)-4-methylpentanoate (16 mg, 0.027 mmol, 1 eq) in EtOAc (3 mL) was added HCl (4 M in EtOAc, 3 mL) in drops at 0° C. The resulting mixture was warmed to room temperature after 30 min and stirred for 2 h. The mixture was quenched with saturated NaHCO3 solution and extracted with EtOAc (20 mL×3). The organic layer was washed with H2O (10 mL×4) and then dried over anhydrous Na2SO4, concentrated under reduced pressure. The crude product was then purified via Prep-TLC(CH2Cl2:MeOH=10:1) to afford the (R)-((3S,5R,8R,9S,10S,13R,17S)-10,13-dimethyl-17-(2-oxo-2H-pyran-5-yl)-2,3,4,5,6,7,8,9,10,11,12,13,16,17-tetradecahydro-1H-cyclopenta[a]phenanthren-3-yl) 2-amino-4-methylpentanoate (8 mg, 62.3%). LCMS (M+H+) m/z 482.6.
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:4]=[CH:3]1>C1CCCCC1.[Rh].[O-2].[Al+3].[O-2].[O-2].[Al+3]>[CH3:1][CH:2]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:4]=[CH:3]1
Reactant: CC1C=NC(c2ccccc2)CC=CCCC=CC1
Agent: [Rh]
Agent: [Al+3]
Agent: [O-2]
Solvent: C1CCCCC1
Product: CC1C=NC(c2ccccc2)CCCCCCCC1
Yield: 94 %

Procedure:
253 g (1 mol) of 3-methyl-12-phenyl-1-aza-1,5,9-cyclododecatriene is dissolved in 2 liters of cyclohexane, and the solution is hydrogenated at 20°-25° C. under an initial pressure of 100 bars, in the presence of 40 g of rhodium/aluminium oxide, for 4 hours in a steel autoclave. After distilling off the solvent, there is obtained as the main fraction 242 g (0.94 mol) of 3-methyl-12-phenyl-1-aza-cyclododecene as a cis-trans isomeric mixture; b.p. 112° C./4 Pa.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[C:10]([N+:15]([O-])=O)[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.[NH4+].[Cl-]>CCO.O.[Fe]>[F:1][C:2]1[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cccc2c(Oc3cc(C(F)(F)F)ccc3F)ccnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c(Oc3cc(C(F)(F)F)ccc3F)ccnc12
Yield: 83.9 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-11, step-4 using 4-(2-fluoro-5-(trifluoromethyl)phenoxy)-8-nitroquinoline (432 mg, 1.22 mmol), iron powder (683 mg, 12.2 mmol), and NH4Cl (517 mg, 9.76 mmol) in EtOH (5 mL) and water (2 mL) to afford 330 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.52 (d, J=5.1 Hz, 1H), 7.94 (d, J=6.6 Hz, 1H), 7.79-7.70 (m, 2H), 7.35 (d, J=6.0 Hz, 2H), 6.91 (d, J=3.6 Hz, 1H), 6.63 (d, J=4.2 Hz, 1H), 5.98 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.CN(C)CCCN=C=NCC.Cl.[NH2:33][CH2:34][C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][CH:36]=1.C(N(C(C)C)C(C)C)C>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][C:3]=1[C:4]([NH:33][CH2:34][C:35]1[CH:36]=[CH:37][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:43][CH:44]=1)=[O:6]
Reactant: COC(=O)c1ccc(CN)cc1
Reactant: O=C(O)c1cc(OCc2cccc(Cl)c2)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)c1ccc(CNC(=O)c2cc(OCc3cccc(Cl)c3)ccc2Cl)cc1
Temperature: 40 °C

Procedure:
A solution of 2-chloro-5-{[(3-chlorophenyl)methyl]oxy}benzoic acid (250 mg, 0.84 mmol) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (250 mg, 1.3 mmol) in DCM (3 ml) was stirred at room temperature for 30 min. A solution of methyl 4-(aminomethyl)benzoate hydrochloride (262 mg, 1.3 mmol) in DCM (2 ml) was added followed by N-ethyl-N-(1-methylethyl)-2-propanamine (220 ul, 1.3 mmol). The mixture was heated at 40° C. overnight. The mixture was then diluted with methanol and purified by SCX cartridge eluting with methanol. The fractions were combined and evaporated to give the title compound as a white solid. MS (ES+) m/z 444 [M+H]− (C23H1935Cl2NO4). 1H-NMR (400 MHz, d6-DMSO) δ 3.85 (3H, s), 4.51 (2H, d, J 4), 5.17 (2H, s), 7.12 (2H, d, J 8), 7.42-7.49 (7H, m), 7.95 (2H, d, J 8), 9.06 (1H, s).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Cl.Cl[CH2:21][N:22]1[CH:26]=[CH:25][CH:24]=[N:23]1>O1CCCC1>[C:8]1([P:7]([CH2:21][N:22]2[CH:26]=[CH:25][CH:24]=[N:23]2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: ClCn1cccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1ccc(P(Cn2cccn2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
Diphenylphosphine (2.642 g, 14.2 mmol) is placed into a Schlenk flask with degassed tetrahydrofuran (50 ml). The solution is cooled to −78° C. and n-butyllithium (8.4 ml, 1.6 M in hexanes, 15.0 mmol) is added dropwise. The red solution is stirred at −78° C. for an additional 1 hour then the cooling bath is removed and the solution is stirred for 3 hours. The red solution is cooled to 0° C. and 1-(chloromethyl)pyrazole hydrochloride (0.698 g, 4.56 mmol) is added at once. The ice bath is removed and the reaction is stirred for 11 hours before adding degassed methanol (25 ml) and water (20 ml). The organic phase is separated and the aqueous phase is extracted with diethyl ether (3×10 ml). The organic phase is dried over magnesium sulfate, filtered and concentrated. The crude material is purified by chromatography (SiO2, 10% ethyl acetate/petroleum ether) to give 1-(diphenylphosphinomethyl)pyrazole as a white solid in 47% yield (0.574 g, 2.16 mmol). This material is characterized as follows: 1H NMR (CDCl3, 500 MHz) δ7.49 (dd, J=2.0, 0.5 Hz, 1H), 7.45-7.40 (m, 4H), 7.40-7.35 (m, 6H), 7.25 (dd, J=2.5, 0.5 Hz, 1H), 6.19 (dd, J=2.5, 2.0 Hz, 1H), 4.91 (d, J=4.5 Hz, 2H); 13C{1H} NMR (CDCl3, 125 MHz) δ139.50, 136.04 (d, J=13.4 Hz), 133.18 (d, J=19.3 Hz), 129.34, 129.49, 128.95 (d, J=6.4 Hz), 106.11, 53.01 (d, J=16.0 Hz); 13P{1H} NMR (CDCl3, 80 MHz) δ−14.98.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH:16]([C:20]#[CH:21])[CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:27]=O>C(O)=O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:22])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH3:27])[CH:16]([C:20]#[CH:21])[CH2:15]4)[CH:12]=3)[C:7](=[O:23])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: C=O
Reactant: C#CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1
Solvent: O=CO
Product: C#CC1CN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CCN1C

Procedure:
A mixture of 200 mg of 1-cyclopropyl-7-(3-ethynyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 0.3 ml of 90% formic acid and 0.24 ml of 37% formalin is heated for 2 hours, then evaporated. The residue is diluted with water, nuetralized to pH 7 with 1N sodium hydroxide, the solid collected, and washed with water, ether and dried in vacuo, giving 156 mg of the desired product.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:28]=[C:29]1[CH2:32][CH:31]([C:33]([OH:35])=O)[CH2:30]1.[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:39])=[O:38].C(N(CC)CC)C>CN(C=O)C>[CH3:36][S:37]([N:40]1[CH2:45][CH2:44][N:43]([C:33]([CH:31]2[CH2:30][C:29](=[O:28])[CH2:32]2)=[O:35])[CH2:42][CH2:41]1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=C1CC(C(=O)O)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCN(C(=O)C2CC(=O)C2)CC1
Temperature: 0 °C

Procedure:
BOP (4.43 g, 10 mmol) was poured some more to a solution of 3-oxo-cyclobutanecarboxylic acid (1.14 g, 10 mmol), intermediate 35, 1-(Methanesulphonyl)piperazine (1.64 g, 10 mmol), and triethylamine (4.1 mL, 30 mmol) in DMF (10 mL) in argon under stirring at 0° C. The mixture was stirred for 20 h, evaporated, and the residue was dried at 0.5 mmHg. The residue was subjected to chromatography on SiO2 (200 g, 40-63 μm, CHCl3/hexane 8:2, 9:1, 9.5:0.5→CHCl3→CHCl3/i-PrOH 99:1→95:5) to give the title compound as white crystals in 2.2 g yield. GCMS data: M+ 260 (Calculated for C10H16N2O4S 260.31), 93.5%, r.t. 14.64 min. 1H-NMR data (dmso-d6): 3.56-3.64 (m, 4H), 3.50 (ddd, 1H, J=7.1 Hz, J=9 Hz, J=15 Hz), 3.20-3.29 (m, 4H), 3.08-3.15 (m, 4H), 2.89 (s, 3H).
Reaction SMILES: [N+](C1C=CC([O:10][C:11]([N:13]2[CH2:19][CH2:18][CH2:17][C:16]([CH3:21])([CH3:20])[C:15]3[CH:22]=[CH:23][C:24]([N+:26]([O-:28])=[O:27])=[CH:25][C:14]2=3)=O)=CC=1)([O-])=O.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1>[CH3:21][C:16]1([CH3:20])[CH2:17][CH2:18][CH2:19][N:13]([C:11]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[O:10])[C:14]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:15]1=2
Reactant: CC1(C)CCCN(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2cc([N+](=O)[O-])ccc21
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: CC1(C)CCCN(C(=O)N2CCCC2)c2cc([N+](=O)[O-])ccc21
Temperature: 60 °C
Yield: 99.7 %

Procedure:
5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid 4-nitro-phenyl ester (0.442 g, 0.00115 mol), pyrrolidine (1.090 mL, 0.013 mol) and anhydrous tetrahydrofuran (10 mL) were combined in a round bottom flask and heated to 60° C. for 23 hours. The reaction was concentrated under reduced pressure, then purified by normal phase chromatography to yield an off-white solid, (5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-pyrrolidin-1-yl-methanone (0.364 g, 78%). LCMS: m/z=318.15 (M+H+), 1H NMR (400 MHz, CDCl3) δ 7.97 (m, 1H), 7.87 (m, 1H), 7.60 (d, 1H, J=8.8 Hz), 3.10 (br s, 4H), 1.89 (br s, 2H), 1.73 (m, 6H), 1.47 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:6]([C:12](=[O:11])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][NH:5]2)=[CH:7][CH:8]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cccc(Cl)c1
Product: CCOC(=O)c1c[nH]c2cc(Cl)ccc2c1=O
Yield: 131.8 %

Procedure:
3-Chloroaniline (5.0 g) and diethyl ethoxymethylenemalonate (10.2 g) were reacted in the same manner as in Experimental Example 1 to obtain 7-chloro-3-ethoxycarbonyl-4(1H)-quinolone (13.0 g). This compound (5.0 g) was hydrolyzed in the same manner as in Experimental Example 2 to obtain a carboxylic acid (4.2 g). This acid derivative (4.2 g) was dissolved in pyridine (40 ml), piperazine (5.2 g) was added to the solution, and the mixture was heated under reflux for 48 hours. The solvent was removed by distillation, and the residue was purified by column chromatography (Wako Gel C-200, 100 g). Elution with a mixed solvent of chloroform (90 parts) and methanol (10 parts) gave 7-piperazinyl-4(1H)-quinolone (compound 67, 3.3 g).