Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][C:8]3[N:9]2[CH:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1.[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][SH:29])[CH3:22].CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:21]([CH:23]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:24][O:25][C:26](=[O:30])[CH2:27][CH2:28][S:29][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:7][C:8]3[N:9]2[CH:12]=[N:13][N:14]=3)=[CH:4][CH:3]=1)[CH3:22]
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: Ic1ccc2c(-c3ccccc3)cc3nncn3c2c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCCCC(CC)COC(=O)CCSc1ccc2c(-c3ccccc3)cc3nncn3c2c1
Temperature: 60 °C

Procedure:
8-Iodo-5-phenyl-[1,2,4]triazolo[4,3-a]quinoline (900 mg, 3.0 mmol), 3-mercaptopropionic acid 2-ethylhexyl ester (660 mg, 3.0 mmol), iPr2NEt (1.1 mL, 6.3 mmol), Pd2dba3 (69 mg, 0.05 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (87 mg, 0.15 mmol) were dissolved in 1,4-dioxane (15 mL) and degassed for 10 minutes with N2. The reaction was then sealed and heated to 60° C. for 1.5 hours, followed by cooling to room temperature and concentration. The residue was purified by silica gel chromatography (30% EtOAc in hexanes) to give the desired product, 11c.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.C(O)(=O)C.[F:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][CH:27]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.Cl>O1CCCC1.CO>[F:12][C:13]1[CH:14]=[C:15]([CH:25]=[CH:26][CH:27]=1)[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:1])=[CH:20][CH:19]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
0.855 g (8.4 mmol) acetic anhydride is cooled to 0° and 0.475 g (10.3 mmol) acetic acid added dropwise. The reaction mixture is then heated to 55° for 2 hours. After cooling to room temperature the mixture is diluted with 0.5 ml dry tetrahydrofuran. A solution of 0.7 g (3.2 mmol) 4-(3-fluoro-benzyloxy)-phenylamine in 2 ml tetrahydrofuran is added dropwise at room temperature and the resulting mixture is stirred for 3 hours. Evaporation leaves a solid which is dissolved again in 2 ml tetrahydrofuran and cooled to 0°. 0.64 g (8.1 mmol) borane-methyl sulfide complex is slowly added under stirring and cooling. The mixture is stirred 1 h at 0° and 2 h at room temperature. After addition of 5 ml methanol, stirring is pursued for 1 h. The mixture is treated with 10 ml 1M aqueous hydrochloric acid and stirred overnight. The organic solvents are removed under vacuum and the aqueous phase adjusted to pH=10 bei addition of potassium carbonate. Extraction with diethyl ether, drying and evaporation yields 0.57 g (76%) of a colorless solid. MS: m/e=232.2 (M++H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2=[CH:12][NH:13][N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([C:15](O)=[O:16])[C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[CH:5][C:4]=2[N:3]1[CH2:24][C:25]([F:28])([F:27])[F:26].C(=O)(O)[O-].[NH4+:33].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>N1C=CC=CC=1.CCOC(C)=O>[O:1]=[C:2]1[C:11]2=[CH:12][NH:13][N:14]=[C:10]2[C:9]2[CH:8]=[C:7]([C:15]([NH2:33])=[O:16])[C:6]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)=[CH:5][C:4]=2[N:3]1[CH2:24][C:25]([F:27])([F:26])[F:28]
Reactant: [NH4+]
Reactant: O=C(O)c1cc2c3n[nH]cc3c(=O)n(CC(F)(F)F)c2cc1-c1ccncc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: NC(=O)c1cc2c3n[nH]cc3c(=O)n(CC(F)(F)F)c2cc1-c1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 7.9 %

Procedure:
A mixture of 4-oxo-7-(pyrid-4-yl)-5-(2,2,2-trifluoroethyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline-8-carboxylic acid [Example 11] (38 mg, 010 mmol), ammonium bicarbonate (46 mg, 0.59 mmol) and di-tert-butyl dicarbonate (47 mg, 0.22 mmol) in 1 mL of pyridine/EtOAc (1/1) is stirred at room temperature under nitrogen for 16 hours and then concentrated to dryness. After purification by preparative HPLC on a C18 reverse phase [eluent A: H2O/0.1M CH3COONH4 (90/10); eluent B: CH3CN/0.1M CH3COONH4 (90/10); gradient A/B: 95/5 to 50/50], 3 mg of a white powder are obtained (8%).
Reaction SMILES: [NH2:1][CH:2]1[CH:11]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[CH:9]=[C:8]([CH2:19][NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[O:26]1[CH2:29][C:28](=O)[CH2:27]1.C[Si]([C:35]#[N:36])(C)C>C(OCC)(=O)C>[CH2:12]([CH:11]1[C:10]2[CH:9]=[C:8]([CH2:19][NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH:1][C:28]1([C:35]#[N:36])[CH2:29][O:26][CH2:27]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1COC1
Reactant: C[Si](C)(C)C#N
Reactant: CCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(N)CC2
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccccc1)C(NC1(C#N)COC1)CC2
Temperature: 210 °C
Yield: 2.4 %

Procedure:
N-((7-Amino-8-benzyl-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)ethanesulfonamide (0.243 g, 0.678 mmol) and 3-oxetanone (0.098 g, 1.356 mmol) were sealed in a vial and heated at 210° C. for 2 minutes. Trimethylsilyl cyanide (0.181 mL, 1.356 mmol) was added, the vial was resealed and the mixture was heated again at 210° C. for 2 minutes. The mixture was diluted with ethyl acetate (40 mL) and washed with 1 N NaOH (1×20 mL) and brine (1×20 mL). The organic extract was collected, dried on MgSO4 and evaporated under reduced pressure to give a brown oil. The residue was purified by preparative HPLC. Product was obtained as a colourless oil (7.2 mg, 0.016 mmol, 2.4%).
Reaction SMILES: C([O-])(=O)C.[Na+].[F:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH2:12])=[CH:9][CH:8]=1.Br[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH2:26][C:27]#[N:28])(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN1CCCC1=O.O.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:6][C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[CH:12]/[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH2:25][CH2:26][C:27]#[N:28])(=[O:23])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1
Reactant: C=Cc1ccc(F)cc1
Reactant: N#CCCS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#CCCS(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Temperature: 135 °C
Yield: 70.1 %

Procedure:
To a suspension of sodium acetate (54 g, 0.66 mol) and 4-fluorostyrene (90 g, 0.74 mol) in 1-methyl-2-pyrrolidinone (500 mL) was added 3-[(4-bromophenyl)sulfonyl]propanenitrile (Step 1, 90 g, 0.33 mol) and palladium (II) acetate (1.4 g, 6.2 mmol). The mixture was plunged into an oil-bath at 100° C. and heated to 135° C. for 20 minutes. The cooled reaction mixture was diluted with water and EtOAc and filtered through Hyflo®. The organic layer of the filtrate was washed with water (×3) then concentrated in vacuo. The residue was triturated with isohexane to give 3-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)propanenitrile (73 g). δH (360 MHz, CDCl3): 7.88 (2H, d, J 8.0), 7.69 (2H, d, J 8.3), 7.51 (2H, dd, J 5.6, 8.3), 7.22 (1H, d, J 15.0), 7.10-7.02 (3H, m), 3.39 (2H, t, J 7.7), 2.83 (2H, t, J 7.7).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[CH:10]([Mg]Br)=[CH2:11].Cl.[OH-].[Na+]>O1CCCC1>[CH:10]([C:3]1([OH:9])[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)=[CH2:11]
Reactant: O=C1CN2CCC1CC2
Reactant: C=C[Mg]Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CC1(O)CN2CCC1CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
Under an argon atmosphere, a solution of 3-quinuclidinone (1.25 g, 10 mmol) in anhydrous tetrahydrofuran (10 mL) was added over 15 minutes to a 1 M solution of vinylmagnesium bromide in tetrahydrofuran (20 mL, 20 mmol) at 0° C. to 5° C., stirred at room temperature for 24 hours, cooled to 0° C., and acidified to pH 1 with 6 M hydrochloric acid. The mixture was stirred for 15 minutes, basified to pH 10 with 25% aqueous sodium hydroxide, extracted with chloroform (4×50 mL) and chloroform/methanol (4:1, 50 mL), combined the organic layers, dried (MgSO4), evaporated under reduced pressure and purified by flash chromatography (eluting with ammoniated chloroform/methanol, 85:15) to obtain the title compound (830 mg, 5.4 mmol, 54%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[C:18]1([C:24]2[N:25]=[C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])N=N[CH:29]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.COCCOCCOC>>[N:12]1([C:10]([C:7]2[CH:8]=[C:9]3[C:4]([C:3]4[CH:29]=[C:24]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:25]=[C:26]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:2]=4[NH:1]3)=[CH:5][CH:6]=2)=[O:11])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1nncc(-c2ccccc2)n1
Reactant: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Solvent: COCCOCCOC
Product: CCOC(=O)c1nc(-c2ccccc2)cc2c1[nH]c1cc(C(=O)N3CCOCC3)ccc12
Temperature: 185 °C

Procedure:
(1H-Indol-6-yl)(morpholino)methanone (200 mg, 0.869 mmol), ethyl 5-phenyl-1,2,4-triazine-3-carboxylate (299 mg, 1.303 mmol) and 1-methoxy-2-(2-methoxyethoxy)ethane (556 μL, 3.91 mmol) were mixed in a sealed microwave vial. The mixture was heated in microwave at 185° C. for 8 hrs. The mixture was purified using preparative HPLC to give titled product. MS (ESI) m/z 430.09 (M+H)+. 1H NMR (DMSO-d6) δ ppm 11.82 (s, 1H), 9.13 (s, 1H), 8.47 (d, 1H, J=7.9), 8.27 (d, 2H, J=7.7), 7.81 (s, 1H), 7.56(t, 2H, J=7.6), 7.44 (t, 1H, J=7.3), 7.36 (d, 1H, J=7.9), 4.57 (q, 2H, J=7.1), 3.67-3.45 (bm, 8H), 1.47 (t, 3H, J=7.1). NOE and ghmbc were used to confirm the structure.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][N:4]=1.[ClH:13]>COC(=O)C>[Cl:13][CH2:2][C:3]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1ccnc(CO)c1
Reactant: Cl
Solvent: COC(C)=O
Product: COC(=O)c1ccnc(CCl)c1
Reaction time: 3 h

Procedure:
A solution of the product of stage (ii) in methylacetate (5 ml) was treated with ethereal hydrogen chloride (5 ml). The resulting solid was collected by filtration and added to thionyl chloride (7.5 ml) at 0°-5°. The mixture was stirred at 0°-5° for 3 h and then at ambient temperature for 1 h. Diethyl ether (100 ml) was added and the resulting solid was collected by filtration and washed with diethylether (2×50 ml), to give the title compound as a solid (1.7 g) T.l.c. Silica dichloromethane/methanol/ammonia 75:10:2 Rf 0.8.
Reaction SMILES: BrC1C=CC=C2C=1C=C(O)N=C2.BrC1C=C2C(C=C(O)N=C2)=CC=1.[Br:25][C:26]1[CH:40]=[CH:39][CH:38]=[CH:37][C:27]=1[CH2:28][NH:29][C:30](=[O:36])[CH:31](OC)OC>>[Br:25][C:26]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:27]=1[CH:28]=[N:29][C:30]([OH:36])=[CH:31]2
Reactant: COC(OC)C(=O)NCc1ccccc1Br
Agent: Oc1cc2c(Br)cccc2cn1
Agent: Oc1cc2ccc(Br)cc2cn1
Product: Oc1cc2cccc(Br)c2cn1

Procedure:
The title compounds was obtained as a yellow solid following the procedure for 5-bromoisoquinolin-3-ol and 7-bromoisoquinolin-3-ol, using N-(2-bromobenzyl)-2,2-dimethoxyacetamide. MS (ES+): m/z=224.04/226.03 [MH+]. HPLC: tR=2.39 min (ZQ2, polar—5 min).
Reaction SMILES: CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=[O:8].[CH3:16][O:17][C:18]1[CH:35]=[CH:34][C:33]2[C@H:32]3[N:23]([C:24](=[O:36])[C@@H:25]4[C@H:30]([CH2:31]3)[NH:29][CH2:28][CH2:27][CH2:26]4)[CH2:22][CH2:21][C:20]=2[CH:19]=1>>[CH2:16]1[O:17][C:18]2=[CH:19][C:20]3[CH2:21][CH2:22][N:23]4[C@H:32]([C:33]=3[CH:34]=[C:35]2[O:8]1)[CH2:31][C@H:30]1[C@H:25]([CH2:26][CH2:27][CH2:28][NH:29]1)[C:24]4=[O:36]
Reactant: COc1ccc2c(c1)CCN1C(=O)[C@H]3CCCN[C@H]3C[C@@H]21
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: O=C1[C@H]2CCCN[C@H]2C[C@H]2c3cc4c(cc3CCN12)OCO4

Procedure:
Similarly, replacing the d-10-camphorsulfonic acid salt of (8aS,12aS,13aS)-3-methoxy-5,6,8a,9,10,11,12,12a,13,13a-decahydroisoquino[2,1-g][1,6]naphthyridin-8-one with compounds of formula (IA), obtained, for example, as described in Example 4C, and following the procedures of Example 5A above, the corresponding compounds of formula (I) as a free base are made.
Reaction SMILES: Br[C:2]1[C:7]2[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C(O)C.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.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>[C:20]1([C:2]2[C:7]3[CH2:8][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:11][O:12][C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2cccc(Br)c2C1
Reactant: OB(O)c1ccccc1
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: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2cccc(-c3ccccc3)c2C1
Yield: 60.5 %

Procedure:
A mixture of tert-butyl 6-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (150 mg, 0.457 mmol), a solution of phenylboronic acid (83.4 mg, 0.684 mmol) in ethanol (0.525 ml), 2N aqueous sodium carbonate solution (2 ml), and tetrakis(triphenylphosphine)palladium(0) (63.2 mg, 0.0547 mmol) in toluene (4 ml) was stirred under a nitrogen atmosphere at 95° C. for 12 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (90.0 mg, 58.0%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@H:13]3[CH2:14][NH:15][CH2:16][CH2:17][N:12]3[CH2:11][CH2:10]2)=[N:6][CH:7]=1.F[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@H:13]3[CH2:14][N:15]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]=4)[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Fc1cccc(C(F)(F)F)n1
Reactant: Clc1ccc(O[C@@H]2CCN3CCNC[C@H]23)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: FC(F)(F)c1cccc(N2CCN3CC[C@@H](Oc4ccc(Cl)cn4)[C@H]3C2)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of Example 101B (53 mg, 0.21 mmol) and 2-fluoro-6-(trifluoromethyl)pyridine (41 mg, 0.25 mmol) in dimethyl sulfoxide (0.7 mL) was added N,N-diisopropylethylamine (0.3 mL, 1.73 mmol). The mixture was heated to 90° C. and stirred for 16 hours and then concentrated. The residue was purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=248 nm) to give the title compound. 1H NMR (300 MHz, methanol-d4) δ ppm 1.81-1.96 (m, 1 H), 2.13-2.31 (m, 3 H), 2.40-2.53 (m, 1 H), 2.94-3.05 (m, 2 H), 3.16-3.25 (m, 2 H), 4.34-4.43 (m, 1 H), 4.50 (dd, 1H, J=12, 3 Hz), 5.59 (ddd, 1H, J=7, 4, 2 Hz), 6.81 (d, 1H, J=8 Hz), 6.96 (dd, 2H, J=8, 5 Hz), 7.61-7.71 (m, 2 H), 8.12 (d, 1H, J=2 Hz); MS (DCI) m/z 399 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[C:4]([F:9])[CH:3]=1.C([Li])CCC.[CH2:15]([CH:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)[CH2:16][CH2:17][CH2:18][CH3:19].Cl>O1CCCC1.CCCCCC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:23]2[CH2:24][CH2:25][CH:20]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:21][CH:22]=2)=[C:4]([F:9])[CH:3]=1
Reactant: Fc1cc(Br)ccc1I
Reactant: CCCCCC1CCC(=O)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: CCCCCC1CC=C(c2ccc(Br)cc2F)CC1
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
200 g (0.665 mol) of 1-bromo-3-fluoro-4-iodobenzene were dissolved in 800 ml of tetrahydrofuran, and 440 ml (0.698 mmol) of a 15 percent solution of n-butyllithium in hexane were added dropwise at −70° C. After 30 minutes, a solution of 117 g (0.698 mol) of 4-pentylcyclohexanone in 200 ml of tetrahydrofuran was added, and the batch was left to stirr for 60 minutes, hydrolysed using water and acidified using conc. hydrochloric acid. The organic phase was separated off, washed with water and dried over sodium sulfate, and the solvent was removed under reduced pressure. The crude product was subsequently dissolved in 1.4 l of toluene and, after addition of 6 g of toluenesulfonic acid, heated on a water separator until water of reaction was no longer separated off. The solution was washed with water and evaporated, and the residue was filtered through silica gel with n-heptane, giving 124 g (58%) of 4-bromo-2-fluoro-1-(4-pentylcyclohex-1-enyl)benzene as a yellow oil.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH3:17])[C:9]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:19].O1CCOCC1>>[ClH:19].[NH2:7][C@@H:8]([CH3:17])[C:9]([N:11]1[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1)=[O:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)C(=O)N1CCOCC1

Procedure:
((1S)-Methyl-2-morpholin-4-yl-2-oxo-ethyl)-carbamic acid tert-butyl ester (3.88 g, 15 mmol) was dissolved in 4M HCl-dioxane (20 ml) at 25° C. for 1.25 hours. The mixture was concentrated and the residue triturated with ether and dried: Yield 2.51 g, 86%.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=[O:16])[CH:13]([CH3:15])[CH3:14].O>CN(C=O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]([NH:1][C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CC(C)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)C(=O)Nc1ccc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
To a solution of 2-amino-5-chloro-benzoic acid (3.43 g, 20 mmol) in DMF (10 mL) cooled in an ice-water bath was added isobutyryl chloride (2.11 mL, 20 mmol). The reaction was stirred for 2 hours while warming to room temperature. Water (20 mL) was added and the mixture was stirred vigorously for 1 hour. The precipitate was then collected by vacuum filtration to give the product as a pale yellow solid (3.20 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 8.52 (d, J=9.0 Hz, 1H), 7.92 (d, J=2.6 Hz, 1H), 7.66 (dd, J=9.0, 2.7 Hz, 1H), 2.58 (septet, J=6.9 Hz, 1H), 1.16 (d, J=6.9 Hz, 6H).
Reaction SMILES: C([NH:4]O)(=O)C.CC(C)([O-])C.[K+].F[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16].[OH2:21]>CN(C)C=O>[O:21]1[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=2[C:15]([NH2:4])=[N:16]1
Reactant: N#Cc1ccccc1F
Reactant: O
Reactant: CC(=O)NO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1noc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of acetohydroxamic acid (10.0 g, 133 mmol) in N,N-dimethylformamide (150 ml) was added potassium tert-butoxide (14.9 g, 133 mmol), and the mixture was stirred at room temperature for 30 minutes. 2-Fluorobenzonitrile (18.0 g, 133 mmol) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from hexane to give 4.80 g (27.0%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH2:20][CH2:21][CH2:22]C1CCCNC1)[CH:10]=2)=[O:5])[CH3:2].Cl.[CH3:30][CH:31]([O:33][C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:41]([N:43]2[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]2)=[O:42])=[CH:36][CH:35]=1)[CH3:32]>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[N:46]1[CH2:45][CH2:44][N:43]([C:41](=[O:42])[NH:40][C:37]3[CH:38]=[CH:39][C:34]([O:33][CH:31]([CH3:30])[CH3:32])=[CH:35][CH:36]=3)[CH2:48][CH2:47]1)=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH2:20][CH2:21][CH2:22][N:8]1[CH2:9][CH2:14][CH2:15][CH2:6][CH2:7]1)[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(OCCCC3CCCNC3)c(OC)cc2c1Cl
Reactant: CC(C)Oc1ccc(NC(=O)N2CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc(OCCCN3CCCCC3)c(OC)cc2c1N1CCN(C(=O)Nc2ccc(OC(C)C)cc2)CC1
Temperature: 40 °C

Procedure:
To the DMF solution (3 mL) of the 4-chloroquinoline (0.175 g, 0.487 mmol) from step A added K2CO3 (0.155 g, 1.10 mmol) followed by N-[4-(methylethoxy)phenyl]piperazinylcarboxamide hydrochloride (0.169 g, 0.535 mmol). The reaction mixture was heated to 40° C. overnight, during that period starting materials were consumed. After cooling diluted with EtOAc/water and the layers were separated. The organic layer was dried, filtered and evaporated to afford desired product as a crude residue. The crude residue was purified by RP-HPLC to afford 4-{4-(4-Isopropoxy-phenylcarbamoyl)piperazin-1-yl]-6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-3-carboxylic acid ethyl ester (0.170 g, 50%). MS(ES) 634 (M+H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([OH:27])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[C:23]([O:27][S:36]([CH3:35])(=[O:38])=[O:37])[C:24]=1[O:25][CH3:26])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:36]([CH3:35])(=[O:38])=[O:37])[CH2:9]1)=[O:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(=O)N2CCC(CCO)(c3ccccc3)C2)cc(O)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OS(C)(=O)=O)c1OC
Temperature: -5 °C
Reaction time: 18 h

Procedure:
Combine 1-(3,4-dimethoxy-5-hydroxybenzoyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (0.95 g, 2.6 mmol) and triethylamine (1.0 mL, 7.7 mmol) in dichloromethane (15 mL). Cool the reaction mixture to −5° C. with an salt-ice bath. Slowly, add methanesulfonyl chloride (0.45 mL, 5.8 mmol). Warm to ambient temperature. After 18 hours, quench the reaction by the addition of ice. Separate the organic layer and extract with aqueous 1M hydrochloric acid solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[N:6][C:7]=1Cl.[I-].[Na+].[I:16][Si](C)(C)C.ClC1C=C(C(OCC)=O)C=NC=1>C(#N)CC>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[N:6][C:7]=1[I:16]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)I
Agent: CCOC(=O)c1cncc(Cl)c1
Agent: [I-]
Agent: [Na+]
Solvent: CCC#N
Product: CCOC(=O)c1cnc(I)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 5,6-dichloro-3-pyridinecarboxylate (1.00 g, 4.54 mmol) in propionitrile (30 ml) stirred under nitrogen at room temperature was added sodium iodide (2.044 g, 13.63 mmol) and iodotrimethylsilane (0.784 ml, 4.54 mmol). After stirring for 30 min, solvent was evaporated to dryness. The obtained brown oil was dissolved in water and pH was adjusted to basic with 2N NaOH. The aqueous phase was extracted with DCM, dried over anhydrous MgSO4 and concentrated under reduced pressure. Purification by flash chromatography using Flashmaster II, a 10 g silica gel cartridge, and mixtures of DCM/MeOH as eluent afforded a mixture of final product and ethyl 5-chloro-3-pyridinecarboxylate. The mixture was repurification by flash chromatography using Flashmaster II, a 50 g Merck silica gel cartridge, and mixtures of DCM/MeOH as eluent afforded the expected product ethyl 5-chloro-6-iodo-3-pyridinecarboxylate as a white solid.