Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:15][CH2:14][CH:13]=[CH:12][O:11]2)=[CH:6][C:5]=1Br.[Br-].[CH2:19]([Zn+])[CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:15][CH2:14][CH:13]=[CH:12][O:11]2)=[CH:6][C:5]=1[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: COC(=O)c1ccc(C2OC=CCO2)cc1Br
Reactant: CCCCC[Zn+]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: C1CCOC1
Product: CCCCCc1cc(C2OC=CCO2)ccc1C(=O)OC
Temperature: 50 °C
Yield: 95.4 %

Procedure:
To a degassed solution of 2-bromo-4-[1,3]dioxin-2-yl-benzoic acid methyl ester (380 mg, 1.3 mmol) in THF (10 mL) are added PdCl2(dppf)2 (108 mg, 0.13 mmol) and n-pentyl zinc bromide (0.5 M in THF, 8.0 mL, 4.0 mmol). The mixture is heated to 50° C. overnight. After cooling to room temperature, the mixture is partitioned between EtOAc (30 mL) and water (30 mL). The organic phase is washed with brine (30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to a residue. The residue is purified by flash chromatography to afford the title compound as syrup (360 mg, 98%). LC-ES/MS m/e 279.3 (M+1).
Reaction SMILES: NCC1C=CC(F)=C(C2CCN(C(C3C4C(=C(F)C=CC=4OC(F)(F)F)N(CCOC)C=3)=O)CC2)C=1.[C:37]([OH:46])(=[O:45])[C@@H:38]([C@H:40]([C:42]([OH:44])=[O:43])[OH:41])[OH:39]>C(#N)C.O>[C:37]([OH:46])(=[O:45])[CH:38]([CH:40]([C:42]([OH:44])=[O:43])[OH:41])[OH:39]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: COCCn1cc(C(=O)N2CCC(c3cc(CN)ccc3F)CC2)c2c(OC(F)(F)F)ccc(F)c21
Solvent: CC#N
Solvent: O
Product: O=C(O)C(O)C(O)C(=O)O
Temperature: 60 °C

Procedure:
[4-(5-aminomethyl-2-fluoro-phenyl)-piperidin-1-yl]-[7-fluoro-1-(2-methoxy-ethyl)-4-trifluoromethoxy-1H-indol-3-yl]-methanone (0.250 g, 0.554 mmol) was weighed in a 20 ml glass vial. A solution of L-(+)-tartaric acid at 2.66 mmol/ml in 5:1 (v/v) acetonitrile/water was prepared, and 0.2084 ml of this solution was added to the weighed solid with stirring and heating to ˜60° C. giving a clear solution. The solution was then evaporated in vacuo on a rotary evaporator leaving a glassy solid which was recrystallized in hot isopropyl acetate to which a minimum amount of isopropanol was added to give a clear solution. Upon cooling the crystalline product was isolated by filtration and dried in vacuo at room temperature.
Reaction SMILES: [Br:1][C:2]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O)(=O)C.[OH-].[Na+]>C(O)C.O.[Fe]>[NH2:10][C:9]1[C:2]([Br:1])=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: N#Cc1cccc([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1cccc(N)c1Br
Temperature: 60 °C
Reaction time: 18 h

Procedure:
2-Bromo-3-nitro-benzonitrile (Compound U1, 678 mg, 2.987 mmol) was dissolved in ethanol (20.9 mL) and water (8.96 mL), added with acetic acid (2.39 mL, 41.81 mmol) and iron (1.17 g, 20.91 mmol), and stirred at 60° C. for 18 hr. The reaction solution was poured into aqueous solution of sodium hydroxide (1 M), extracted with ethyl acetate, washed with water and saturated brine, dried over sodium sulfate, and then filtered. After concentration under reduced pressure, 3-amino-2-bromo-benzonitrile (Compound U2) was obtained as a crude product.
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([Si:14]([CH3:54])([CH3:53])[O:15][CH:16]1[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]2[N:21]=[C:20]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:19]([CH:33]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)O)=[C:18]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[C:47]([F:52])[CH:46]=3)[C:17]1=2)([CH3:13])([CH3:12])[CH3:11]>C1(C)C=CC=CC=1>[Si:14]([O:15][CH:16]1[CH2:25][C:24]([CH3:26])([CH3:27])[CH2:23][C:22]2[N:21]=[C:20]([CH:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[C:19]([CH:33]([F:7])[C:35]3[CH:36]=[CH:37][C:38]([C:41]([F:44])([F:42])[F:43])=[CH:39][CH:40]=3)=[C:18]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[C:47]([F:52])[CH:46]=3)[C:17]1=2)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:54])[CH3:53]
Reactant: CC1(C)Cc2nc(C3CCCC3)c(C(O)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O[Si](C)(C)C(C)(C)C)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: Cc1ccccc1
Product: CC1(C)Cc2nc(C3CCCC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(-c3ccc(F)c(F)c3)c2C(O[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h

Procedure:
At −5° C., 0.06 ml of diethylaminosulphur trifluoride, dissolved in 10.15 ml of toluene, was added dropwise to 200 mg (0.3 mmol) of [5-(tertbutyldimethylsilanyloxy)-2-cyclopentyl-4-(3,4-difluorophenyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-3-yl]-(4-trifluoromethylphenyl)-methanol dissolved in 2 ml of toluene. After 60 minutes, the reaction was quenched with saturated aqueous sodium bicarbonate solution, toluene was added and the organic phase was washed once more with saturated aqueous sodium bicarbonate solution and dried. The solvent was distilled off under reduced pressure and the residue was then purified over a silica gel column This gave a total of 190 mg of a colourless oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:22]=[C:21]3[C:17]([CH:18]=[N:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I:23]I.[OH-].[K+].[O-]S([O-])(=S)=O.[Na+].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]=[C:11]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([I:23])=[N:19][NH:20]3)=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3cn[nH]c3c2)CC1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(I)n[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A solution of 4-(1H-indazol-6-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (9.70 g, 3.24 mmol) in DMF (32 mL) at room temperature was treated with iodine (1.23 g, 4.86 mmol) and KOH (grounded, 454 mg, 8.1 mmol). The resulting mixture was stirred at room temperature for 40 min, then treated with saturated Na2S2O3 aqueous solution. The resulting mixture was then extracted with EtOAc (3×). The combined extracts were washed with brine and dried over Na2SO4. The resulting mixture was filtered and concentration under reduced pressure. The resulting residue was purified by flash chromatography on silica-gel (gradient eluant 10% to 40% EtOAc in heptane) to yield the title compound as white solid.
Reaction SMILES: [CH2:1]1[CH2:18][O:17][C:3]2([CH2:10][C@H:9]3[C@H:5]([CH2:6][C:7](=[O:16])[CH:8]3[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4]2)[O:2]1.C(Cl)(Cl)Cl.[BH4-].[Na+]>C(O)C>[CH2:18]1[CH2:1][O:2][C:3]2([CH2:10][C@H:9]3[C@H:5]([CH2:6][C@@H:7]([OH:16])[C@@H:8]3[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:4]2)[O:17]1
Reactant: CCOC(=O)C1C(=O)C[C@@H]2CC3(C[C@H]12)OCCO3
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)[C@@H]1[C@H]2CC3(C[C@H]2C[C@H]1O)OCCO3
Reaction time: 1 h
Yield: 76 %

Procedure:
To a stirred solution of 2.09 g of (1S,5R)-7,7-ethylenedioxy-2-ethoxycarbonylbicyclo[3.3.0]octan-3-one (I)' having [α]D21 +23.9° (c=2.55, CHCl3) in 21 ml of ethanol was added at -40° C. over 30 minutes 0.17 g of sodium borohydride. The mixture was stirred for 1 hour. After removal of ethanol in vacuo, the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (eluting solution: 20-50% (v/v) diethyl ether/n-hexane) to obtain 1.60 g of the oily title compound.
Reaction SMILES: O.[O:2]=[S:3]1(=O)[C:7](C)(C)[C:6](=[O:10])[N:5]([CH2:11][CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[CH:4]1C>C1COCC1>[F:27][C:24]1[CH:23]=[CH:22][C:21]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][CH2:11][N:5]3[C:6](=[O:10])[CH2:7][S:3](=[O:2])[CH2:4]3)[CH2:16][CH2:17]2)=[CH:26][CH:25]=1
Reactant: CC1N(CCCCN2CCN(c3ccc(F)cc3)CC2)C(=O)C(C)(C)S1(=O)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1CS(=O)CN1CCCCN1CCN(c2ccc(F)cc2)CC1
Yield: 52.5 %

Procedure:
A second run using NaIO4 (1.41 g), H2O (13 ml), 1 (2.02 g) and THF (20 ml) was conducted in a similar manner yielding 0.910 g of product.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:16])[CH3:15])=[CH:10][C:9]=1[NH:17][C:18](=[O:30])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[CH:23]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:14]([C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]#[N:29])[CH:23]=3)[CH2:19][C:18](=[O:30])[NH:17][C:9]=2[CH:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(c1)NC(=O)CC(c1ccnc(C#N)c1)=N2

Procedure:
Prepared from {2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-4-isopropyl-phenyl}-carbamic acid tert.-butyl ester (Example K74) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a yellow solid (33 mg).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:18]1[C:19]2[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][C:20]=2[N:21]=[CH:22][N:23]=1>>[C:1]1([S:7]([C:10]2[CH:16]=[CH:15][C:13]([NH:14][C:18]3[C:19]4[CH:27]=[C:26]([Cl:28])[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Clc1cc2c(Cl)ncnc2cn1
Reactant: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Product: O=S(=O)(c1ccccc1)c1ccc(Nc2ncnc3cnc(Cl)cc23)cc1

Procedure:
Prepared according to Procedure A from 4-benzenesulphonylaniline (Helv. Chim. Acta., 1983, 66 (4), 1046) and 4,6-dichloropyrido[3,4-d]pyrimidine; δH [2H6]-DMSO 9.09 (1H,s), 8.80-8.88 (2H,m), 8.19 (2H,d), 7.94-8.09 (4H,m), 7.53-7.20 (3H,m); m/z (M+1)+ 397.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]#[N:21])[CH:14]=3)[N:11]=[C:10]([C:22](O)=[O:23])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)C(C)C)(C)C.ClC1C=C(N2C(C3C=CC=C(OCCO)C=3)=CC(C([N:58]3[CH2:62][C:61](=[O:63])[NH:60][CH2:59]3)=O)=N2)C=CC=1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([C:20]#[N:21])[CH:14]=3)[N:11]=[C:10]([C:22]([N:58]3[CH2:62][C:61](=[O:63])[NH:60][CH2:59]3)=[O:23])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1cc(-n2nc(C(=O)O)cc2-c2cccc(Cl)c2)ccc1F
Reactant: O=C1CN(C(=O)c2cc(-c3cccc(OCCO)c3)n(-c3cccc(Cl)c3)n2)CN1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=CO
Product: N#Cc1cc(-n2nc(C(=O)N3CNC(=O)C3)cc2-c2cccc(Cl)c2)ccc1F

Procedure:
The preparation of the title compound takes place starting from the compound of Example 109A using 3.2 equivalents of N,N-diisopropylethylamine and with the addition of 0.1% formic acid in the preparative HPLC in analogy to the synthesis of the compound of Example 23. 45 mg (77% of theory) of the title compound are obtained.
Reaction SMILES: CN(C)C.[C:5]([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH:14]2[S:18][C:17](=[O:19])[NH:16][C:15]2=[O:20])=[CH:11][CH:10]=1)(=[O:7])[CH3:6].[C:23]1([C:29](Cl)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O>C(Cl)Cl.C(OCC)(=O)C>[C:5]([O:8][C:9]1[CH:22]=[CH:21][C:12]([CH2:13][CH:14]2[S:18][C:17](=[O:19])[N:16]([C:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:15]2=[O:20])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Oc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(CC2SC(=O)N(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.43 g of trimethylamine were added to a solution of 9.0 g of 5-(4-acetoxybenzyl)thiazolidine-2,4-dione [prepared as described in step (b) above] in 70 ml of methylene chloride, and a solution of 9.45 g of triphenylmethyl chloride in 30 ml of methylene chloride was added dropwise to the resulting mixture. The mixture was then stirred at room temperature for 1 hour, after which it was allowed to stand overnight at the same temperature. At the end of this time, the reaction mixture was mixed with water and ethyl acetate, and the organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The crystals which separated out on distilling off the solvent under reduced pressure, were washed with a mixture of hexane and ethyl acetate and dried, to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].CC(O)=O.[O:14]1[CH2:17][C:16](=O)[CH2:15]1.O>CCO>[Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[N:5]=[C:16]1[CH2:17][O:14][CH2:15]1
Reactant: O=C1COC1
Reactant: Nc1cc(F)cc(Br)c1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Fc1cc(Br)cc(N=C2COC2)c1
Yield: 76.8 %

Procedure:
To a solution of 3-bromo-5-fluoroaniline (CAS 134168-97-1) (3.0 g, 16 mmol) in EtOH (50 mL), was added HOAc (900 mg, 16 mmol), and oxetan-3-one (CAS 6704-31-0) (2.4 g, 32 mmol). The mixture was stirred at reflux for overnight. It was poured into water (100 mL) and extract with EtOAc (100 mL×2). The combined organic layers was dried over Na2SO4 and concentrated in vacuum to give the crude product (3.0 g, 77%).
Reaction SMILES: [CH:1]([O:4][C@H:5]1[CH2:22][C@@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][C:15]2=O)[CH2:7][C@@H:6]1[OH:25])([CH3:3])[CH3:2].[BH3-]C#N.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1.S1(CCCC1)(=O)=O>O.CN(C=O)C>[CH:1]([O:4][C@H:5]1[CH2:22][C@@:21]2([CH3:23])[C@@H:8]([CH2:9][CH2:10][C@@H:11]3[C@@H:20]2[CH2:19][CH2:18][C@@:16]2([CH3:17])[C@H:12]3[CH2:13][CH2:14][CH2:15]2)[CH2:7][C@@H:6]1[OH:25])([CH3:3])[CH3:2]
Reactant: CC(C)O[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C[C@@H]1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Solvent: CN(C)C=O
Product: CC(C)O[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CCC[C@@]4(C)CC[C@@H]32)C[C@@H]1O
Temperature: 110 °C

Procedure:
To a mixture of 2β-isopropoxy-3α-hydroxy-5α-androstan-17-one tosylhydazone (300 mg), NaBH3CN (144 mg) and p-toluenesulfonic acid (30 mg) was added DMF and sulfolane (1:1, 3 mL) and the mixture obtained was heated to 110° C. for 3 h. Then additional amount of NaBH3CN (144 mg) and p-toluenesulfonic acid (30 mg) was added and it was heated for another hour. Water was then added and the mixture was extracted with EtOAc (2×45 mL). The combined extracts were dried over Na2SO4 and the crude product obtained by removal of the solvent was purified by flash chromatography over silica gel to yield the pure 2β-isopropoxy-3α-hydroxy-5α-androstane (37 mg); TLC Rf (EtOAc:hexane 1:9)=0.17.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:17](F)=[C:16]3[C:11]([C:12](=[O:25])[C:13]([C:22]([OH:24])=[O:23])=[CH:14][N:15]3[CH:19]3[CH2:21][CH2:20]3)=[CH:10][C:9]=2[F:26])[CH2:3]1.[CH3:27][O-:28].[Na+]>CS(C)=O>[NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:17]([O:28][CH3:27])=[C:16]3[C:11]([C:12](=[O:25])[C:13]([C:22]([OH:24])=[O:23])=[CH:14][N:15]3[CH:19]3[CH2:20][CH2:21]3)=[CH:10][C:9]=2[F:26])[CH2:3]1
Reactant: C[O-]
Reactant: NC1CCCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1c(N2CCCC(N)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 2 h

Procedure:
A mixture of 7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (1.21 g) obtained as described in Example 1(b), sodium methoxide (1.2 g) and dimethylsulfoxide (40 ml) was stirred for 2 hours at 120°-140° C. The reaction mixture was concentrated in vacuum and water was added to the residue. Neutralization of the mixture with 1N hydrochloric acid followed by evaporation of the solvent and purification by silica gel column chromatography (chloroform:methanol:ammonium hydroxide=100:30:5) gave 7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid. The physical properties of this product wereidentical with those of the compound obtained in Example 6.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[CH:10][CH:9]=[C:8]2[O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20]([C:24](O)=[O:25])=[CH:19][CH:18]=[CH:17]2.[C:29]1([NH2:36])[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35]>>[NH2:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[NH:36][C:24]([C:20]1[C:21]2[C:16](=[CH:15][C:14]([O:13][C:8]3[C:7]4[C:12](=[C:3]([C:2]([F:28])([F:1])[F:27])[CH:4]=[CH:5][CH:6]=4)[N:11]=[CH:10][CH:9]=3)=[CH:23][CH:22]=2)[CH:17]=[CH:18][CH:19]=1)=[O:25]
Reactant: O=C(O)c1cccc2cc(Oc3ccnc4c(C(F)(F)F)cccc34)ccc12
Reactant: Nc1ccccc1N
Product: Nc1ccccc1NC(=O)c1cccc2cc(Oc3ccnc4c(C(F)(F)F)cccc34)ccc12
Yield: 80.9 %

Procedure:
The title compound (38.3 mg, 81% yield) was prepared as a brown solid from 6-(8-trifluoromethylquinolin-4-yloxy)-1-naphthoic acid (39.8 mg, 0.1 mmol) and o-phenylenediamine (43.2 mg, 0.4 mmol) by an analogous procedure to that described in example 16. 1H NMR (DMSO-d6) δ 4.98 (s, 2H, benzene-NH2), 6.65 (t, J=7.3 Hz, 1H, Ar—H), 6.83 (d, J=7.6 Hz, 1H, Ar—H), 6.89 (d, J=5.2 Hz, 1H, Ar—H), 7.00 (t, J=7.2 Hz, 1H, Ar—H), 7.38 (d, J=7.5 Hz, 1H, Ar—H), 7.62 (dd, J=2.4 and 9.2 Hz, 1H, Ar—H), 7.68 (t, J=7.7 Hz, 1H, Ar—H), 7.83 (t, J=7.9 Hz, 1H, Ar—H), 7.90 (d, J=7.0 Hz, 1H, Ar—H), 7.97 (d, J=2.3 Hz, 1H, Ar—H), 8.10 (d, J=8.3 Hz, 1H, Ar—H), 8.29 (d, J=7.1 Hz, 1H, Ar—H), 8.47 (d, J=9.2 Hz, 1H, Ar—H), 8.70 (d, J=7.8 Hz, 1H, Ar—H), 8.87 (d, J=5.2 Hz, 1H, Ar—H), 9.86 (s, 1H, benzene-NH). LC-MS (m/z) 474 (M+1).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)=[C:9]2[C:4]=1[CH:5]=[CH:6][CH:7]=[N:8]2.Cl.O1CCOCC1>O1CCOCC1>[N:13]1([C:10]2[CH:11]=[CH:12][C:3]([C:2]([F:27])([F:1])[F:26])=[C:4]3[C:9]=2[N:8]=[CH:7][CH:6]=[CH:5]3)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)c3cccnc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(N2CCNCC2)c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
To a solution of tert-butyl 4-[5-(trifluoromethyl)-8-quinolinyl]-1-piperazine-carboxylate (Step 2, 0.85 g) in 5 mL dioxane was added 5 mL of 4 N HCl/dioxane. The mixture was stirred at room temperature overnight. The reaction was concentrated on a rotary evaporator, dissolved in water, neutralized with aqueous sodium hydroxide and extracted with CH2Cl2 The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated on a rotary evaporator to give 0.65 g of the desired product as an off-white solid; MP. 155-157° C.; MS (ES) m/z (relative intensity): 282 (M+H)+ (100).
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:13]=[O:14])=[CH:7]2.[C:15](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[C:11]([O:12][CH3:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:13]=[O:14])=[CH:7]2
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc2c(Br)c(O)ccc2c1
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc2cc(C=O)ccc2c1Br
Yield: 96 %

Procedure:
Step c) A mixture of 5-bromo-6-hydroxy-2-naphthaldehyde (34.0 g, 135.5 mmol), potassium carbonate (18.7 g, 135.5 mmol), dimethyl sulfate (12.8 mL, 135.5 mmol) and acetone (500 mL), was refluxed for 3 hours. The volatiles were removed in vacuo, and the residue was suspended in water. The precipitated solid was filtered and dried, to yield a yellow solid (34.5 g, 96% yield, m.p. 133°-135° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[NH:9][CH:10]=[C:11]([C:16]([O:18]CC)=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2>Cl>[Cl:1][C:2]1[C:3]([F:22])=[CH:4][C:5]2[C:6]([CH:21]=1)=[N:7][C:8]1[NH:9][CH:10]=[C:11]([C:16]([OH:18])=[O:17])[C:12](=[O:15])[C:13]=1[CH:14]=2
Reactant: CCOC(=O)c1c[nH]c2nc3cc(Cl)c(F)cc3cc2c1=O
Agent: Cl
Product: O=C(O)c1c[nH]c2nc3cc(Cl)c(F)cc3cc2c1=O
Temperature: 20 °C
Yield: 58.1 %

Procedure:
A suspension of 5.75 g of 8-chloro-3-ethoxycarbonyl-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine in 60 cm3 of 17.5% hydrochloric acid is heated, with stirring, at a temperature close to 100° C. for 30 minutes. After cooling to about 20° C., the insoluble matter is drained and washed with 3 times 20 cm3 of ethanol and 3 times 20 cm3 of diethyl ether. 3.05 g of 8-chloro-7-fluoro- 4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a beige solid which decomposes at 416° C.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[C:7](=[NH:20])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:22]1[CH:23]=[CH:24][C:25]2[C:31]3([CH:40]=[CH2:41])[CH2:32][CH2:33][C:34]4([CH2:39][CH:30]3[CH2:29][CH2:28][O:27][C:26]=2[CH:42]=1)[O:38][CH2:37][CH2:36][O:35]4>O1CCOCC1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:8]1([C:7]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[N:20][C:22]2[CH:23]=[CH:24][C:25]3[C:31]4([CH:40]=[CH2:41])[CH2:32][CH2:33][C:34]5([CH2:39][CH:30]4[CH2:29][CH2:28][O:27][C:26]=3[CH:42]=2)[O:35][CH2:36][CH2:37][O:38]5)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: C=CC12CCC3(CC1CCOc1cc(Br)ccc12)OCCO3
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=CC12CCC3(CC1CCOc1cc(N=C(c4ccccc4)c4ccccc4)ccc12)OCCO3
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
A 1 L round-bottom flask equipped with an air cooled reflux condenser outfitted with a nitrogen inlet adapter was charged with palladium(II) acetate (0.441 g, 1.97 mmol), Xantphos (1.71 g, 2.95 mmol), Cs2CO3 (22.4 g, 68.8 mmol), evacuated and filled with nitrogen (three cycles), and then 1,4-dioxane (131 mL) was added followed by an additional three cycles of evacuation and nitrogen backfilling. The suspension was stirred at rt for about 15 min and then TEA (0.41 mL, 3.0 mmol) was added. After an additional 15 min of stirring at rt, a solution of benzophenone imine (9.90 mL, 59.0 mmol) and rac-(7aS,11aS)-3-bromo-11a-vinyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolane] (18.0 g, 49.1 mmol) (prepared as described in WO 2012125797) in dioxane (65 mL) was added and the reaction mixture was heated to about 100° C. for about 18 h. The reaction mixture was diluted with EtOAc (300 mL) and filtered. The filtered solid was washed with EtOAc (2×50 mL) and the combined filtrate was concentrated under reduced pressure. The crude material was purified on silica gel (330 g, eluted with 0 to 30% EtOAc in heptane). Collection and concentration of the appropriate fractions gave rac-(7aR,11aR)—N-(diphenylmethylene)-11a-vinyl-7,7a,8,10,11,11a-hexahydro-6H-spiro[dibenzo[b,d]oxepine-9,2′-[1,3]dioxolan]-3-amine (85, R2=Vinyl) (17.8 g, 78%). LC/MS, method 3, 2.98 min, MS m/z 466 (M+H)+. 1H NMR (400 MHz, CDCL3) δ 7.86-7.79 (m, 2H), 7.58-7.50 (m, 1H), 7.49-7.40 (m, 2H), 7.38-7.26 (m, 3H), 7.19-7.13 (m, 2H), 7.10-7.04 (m, 1H), 6.73-6.58 (m, 1H), 6.49-6.44 (m, 1H), 5.97-5.85 (m, 1H), 4.96-4.88 (m, 1H), 4.42-4.32 (m, 1H), 4.08-3.98 (m, 1H), 3.99-3.86 (m, 4H), 3.71-3.59 (m, 1H), 2.41-2.30 (m, 1H), 2.29-2.19 (m, 1H), 2.16-2.08 (m, 1H), 1.88-1.60 (m, 4H), 1.61-1.46 (m, 1H), 1.44-1.35 (m, 1H).