Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[C:6]1=O)=[O:4].C(O)(=O)C.Cl(O)(=O)(=O)=O>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][C:7]2[C:12](=[CH:11][CH:10]=[C:9]([O:14][CH3:15])[CH:8]=2)[CH2:13]1)=[O:4]
Reactant: COC(=O)C1Cc2ccc(OC)cc2C1=O
Agent: [Pd]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)C1Cc2ccc(OC)cc2C1
Reaction time: 12 h
Yield: 64.6 %

Procedure:
Combine in a Parr shaker 6-Methoxy-1-oxo-indan-2-carboxylic acid methyl ester (3.14 g, 14.25 mmol), added acetic acid (150 mL), perchloric acid (0.8 mL) and 5% Pd—C (0.14 mmol). After the reaction has been on the parr shaker under 40 atm of H2 pressure at room temperature for 12 hours, filter the reaction mixture through a pad of Celite using ethyl acetate eluent. Then add the filtrate to a separatory funnel and wash with water then brine, and dry the organic layer over Na2SO4. After concentrating under reduced pressure, flash Chromatograph using 8:1 Hexanes:Ethyl acetate to afford 1.9 g, 9.21 mmol (65% yield) of the title compound as a clear oil: 1H NMR (500 MHz, CDCl3); 3.2-3.4 (5H, m), 3.7 (3H, s), 3.8 (3H, s), 6.7-6.8 (2H, m), 7.1-7.2 (1H, m); TLC 1:1 Hexanes:Ethyl acetate Rf:=0.6.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C@@:13]34[C@@H:17]5[CH2:18][C@H:19]6C(CN5CC3)=CCO[C@H]3CC(=O)N([C@H:12]4[C@@H:20]63)C2=[CH:7][C:8]=1[O:9]C.[OH-].[K+]>O>[C:13]1([CH2:5][CH2:4][CH2:3][C@@H:8]([OH:9])[CH3:7])[CH:17]=[CH:18][CH:19]=[CH:20][CH:12]=1
Reactant: COc1cc2c(cc1OC)[C@@]13CCN4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C[C@H](O)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.4 %

Procedure:
S-Brucine salt of the preceding Example (10.0 kg., 14.2 moles) was combined with 121 liters of toluene and 143.8 liters of water. With stirring the pH was adjusted to 1.7 by addition of about 6 liters of 3N HCl. The aqueous layer was separated and extracted with 2×37.85 liters of toluene. Brucine was precipitated from the aqueous layer by adjusting the pH to 11.5 with 50% NaOH. Recrystallization from isopropyl alcohol provides brucine suitable for reuse. The toluene layers were combined, back-washed with 75 liters of water, concentrated to 45 liters. Fresh water (65 liters) and then KOH (85%, 1.90 kg., 28.8 moles) were added and the mixture stirred for one hour at room temperature and then 2 hours at 82°-84° C. The reaction mixture was cooled to 25° C., the toluene layer separated and the aqueous layer washed 3×19 liters of toluene. The toluene layers were combined, washed 1×20 liters saturated NaCl, dried (MgSO4), filtered and concentrated to yield title product as an oil (1.91 kg.), purified by distillation in vacuo (1.64 kg., b.p. 85°-92°/0.1 mm., [alpha]D25 +8.24 to +8.57°). Yield=20.4%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:11]([CH3:13])[CH3:12])=[N:4][CH:5]=[N:6][C:7]=1[N:8]([CH3:10])[CH3:9].ClC1C([N+]([O-])=O)=C(Cl)N=CN=1.CNC.[C:28](Cl)(=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH3:12][N:11]([CH3:13])[C:3]1[C:2]([NH:1][C:28](=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]/[CH:36]=[CH:37]\[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[C:7]([N:8]([CH3:9])[CH3:10])[N:6]=[CH:5][N:4]=1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)Cl
Reactant: CN(C)c1ncnc(N(C)C)c1N
Agent: CNC
Agent: O=[N+]([O-])c1c(Cl)ncnc1Cl
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1c(N(C)C)ncnc1N(C)C

Procedure:
5-Amino-4,6-bis(dimethylamino)pyrimidine (prepared by reacting commercially available 4,6-dichloro-5-nitro pyrimidine with excess dimethylamine followed by reduction of the nitro group according to the procedure of Jacobs et. al., J. Am. Chem. Soc., 42, 2278 (1920)) was coupled with oleoyl chloride using the procedure described in Example 4 to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[O:22][C:15]3[N:16]=[CH:17][C:18]([F:21])=[C:19](O)[C:14]=3[C:13]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][CH:7]=1.C(Cl)(=O)C([Cl:33])=O>C(Cl)(Cl)Cl>[Cl:33][C:19]1[C:18]([F:21])=[CH:17][N:16]=[C:15]2[O:22][C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:29])[CH3:1])=[CH:7][CH:8]=3)=[C:13]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:14]=12
Reactant: CN(C)CCOc1ccc(-c2oc3ncc(F)c(O)c3c2-c2ccccc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CN(C)CCOc1ccc(-c2oc3ncc(F)c(Cl)c3c2-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The mixture of 2-[4-(2-dimethylaminoethoxy)-phenyl]-5-fluoro-3-phenyl-furo[2,3-b]pyridin-4-ol (6) (121.0 mg, 0.31 mmol) and oxalyl chloride (196.0 mg, 1.54 mmol) in chloroform (3.0 mL) was stirred at 60° C. for 1 hr. The solvent was removed, and the residue was purified by preparative HPLC to give the title compound. MS (m/z), M+H+ 411.1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[NH:15][C:16]([NH2:25])=[C:17]3[C:21]([N:22]=2)=[N:20][C:19]([O:23][CH3:24])=[N:18]3)[CH2:10][CH2:9]1.Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][O:32]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: COc1nc2nc(OCCC3CC3)[nH]c(N)c-2n1
Reactant: BrCCCCC1CCCCO1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CCCCC1CCCCO1

Procedure:
Prepared similarly to Intermediate 213 from 2-[(2-cyclopropylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 2-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])=[CH:10][C:11]=3[CH2:12]2)=[CH:4][CH:3]=1.[CH:24]([C:26]1[S:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25]>>[CH2:16]([N:15]([CH2:20][CH2:21][CH2:22][CH3:23])[C:9]1[CH:10]=[C:11]2[C:6]([C:5]3[CH:4]=[CH:3][C:2]([C:29]4[S:30][C:26]([CH:24]=[O:25])=[CH:27][CH:28]=4)=[CH:14][C:13]=3[CH2:12]2)=[CH:7][CH:8]=1)[CH2:17][CH2:18][CH3:19]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CCCCN(CCCC)c1ccc2c(c1)Cc1cc(Br)ccc1-2
Product: CCCCN(CCCC)c1ccc2c(c1)Cc1cc(-c3ccc(C=O)s3)ccc1-2

Procedure:
As shown in Scheme 1, 7-bromo-9H-fluoren-2-ylamine is reacted with 1-iodobutane to form (7-bromo-9H-fluoren-2-yl)-dibutyl amine (11). Then, (7-bromo-9H-fluoren-2-yl)-dibutyl amine (11) is reacted with 5-formyl-2-thiopheneboronic acid by Suzuki coupling reaction to obtain 5-(7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (12a). Finally, in acetonitrile, 5-(7-dibutylamino-9H-fluoren-2-yl)-thiophene-2-carbaldehyde (12a) is reacted with cyanoacetic acid by using piperidine as a catalyst, to obtain 2-cyano-3-[5-(7-dibutylamino-9H-fluoren-2-yl)-thiophen-2-yl]-acrylic acid (13a).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:31][O:32][CH2:33]/[CH:34]=[CH:35]/[C:36](O)=[O:37]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:36](=[O:37])/[CH:35]=[CH:34]/[CH2:33][O:32][CH3:31])=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: COC/C=C/C(=O)O
Product: COC/C=C/C(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 29.9 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from the compound described in intermediate 2b and (E)-4-methoxybut-2-enoic acid (Intermediate 3), to afford the title compound (11 mg, 29.9%). Data: UPLC (C) Rt: 1.58 min; m/z 498.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:15]([C:16]([O:18]CC)=O)=[CH:14][N:13]=[C:12]([S:21][CH3:22])[N:11]=2)=O)[CH:5]=[CH:4][CH:3]=1.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:26]=1[NH:32][NH2:33]>FC(F)(F)CO>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:10]3[N:11]=[C:12]([S:21][CH3:22])[N:13]=[CH:14][C:15]=3[C:16](=[O:18])[N:32]([C:26]3[C:25]([Cl:24])=[CH:30][CH:29]=[CH:28][C:27]=3[Cl:31])[N:33]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: NNc1c(Cl)cccc1Cl
Reactant: CCOC(=O)c1cnc(SC)nc1C(=O)c1cccc(Cl)n1
Agent: Cl
Solvent: OCC(F)(F)F
Product: CSc1ncc2c(=O)n(-c3c(Cl)cccc3Cl)nc(-c3cccc(Cl)n3)c2n1
Temperature: 108 °C

Procedure:
To a suspension of Example 159A (512 mg, 1.516 mmol) in 2,2,2-trifluoroethanol (15 mL) was added 2,6-dichlorophenylhydrazine hydrochloride (324 mg, 1.516 mmol). This mixture was heated in a sealed tube at 108° C. overnight. The mixture was partitioned between ethyl acetate and brine. The organic phase was concentrated, and the residue was purified by flash chromatography (15-50% ethyl acetate in hexane) to provide the title compound. MS (DCI/NH3) m/z 451 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=2)[C:10]=1[C:11]([F:14])([F:13])[F:12])=[O:5])[CH3:2].[F:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.C([O-])([O-])=O.[Na+].[Na+]>C(#N)C>[F:22][C:23]1[C:28]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([N:9]3[C:10]([C:11]([F:14])([F:13])[F:12])=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=[N:8]3)[N:16]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(Cl)n2)c1C(F)(F)F
Reactant: OB(O)c1cccnc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccnc3F)n2)c1C(F)(F)F
Temperature: 100 °C
Reaction time: 0.83 h

Procedure:
A mixture of the title compound from Example 1 Step A (100 mg, 0.3 mmol), (2-fluoropyridin-3-yl)boronic acid (66 mg, 0.47 mmol), trans dichlorobis(triphenylphosphine) palladium (II) (31.0 mg, 0.05 mmol), Na2CO3 (0.47 mL, 2.0 M aqueous, 0.94 mmol) and acetonitrile (1 mL) in a nitrogen-filled capped vial was stirred at 100° C. After 50 min, the mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. Purification by flash chromatography on silica gel using hexane:EtOAc (6:1 to 4:1 v/v) as mobile phase provided the title compound: LCMS m/z 381.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 8.63 (m, 1H), 8.27 (m, 1H), 8.13 (s, 1H), 8.10 (d, J=7.9 Hz, 1H), 8.03 (t, J=7.9 Hz, 1H), 7.70 (d, J=7.8 Hz, 1H), 7.35 (m, 1H), 4.39 (q, J=7.1 Hz, 2H), 1.39 (t, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C([O:55][C:56](=O)[CH:57]([CH2:68][C:69]1[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1)[CH2:58][NH:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=1)C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[CH2:68]([CH:57]1[CH2:58][N:59]([CH2:60][C:61]2[CH:62]=[CH:63][C:64]([F:67])=[CH:65][CH:66]=2)[C:19](=[O:21])[C:18]([C:12]2[NH:11][C:10]3[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=3[S:14](=[O:16])(=[O:17])[N:13]=2)=[C:56]1[OH:55])[C:69]1[CH:70]=[CH:71][CH:72]=[CH:73][CH:74]=1
Reactant: CCOC(=O)C(CNCc1ccc(F)cc1)Cc1ccccc1
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Agent: CC[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(C1=C(O)C(Cc3ccccc3)CN(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.6 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.108 g, 0.306 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.128 g, 0.337 mmol) and 4-methylmorpholine (0.067 mL, 0.609 mmol) were added sequentially to a solution of rac-2-benzyl-3-(4-fluoro-benzylamino)-propionic acid ethyl ester (0.096 g, 0.304 mmol) in N,N-dimethylformamide (4 mL) at 25° C. The reaction mixture was stirred at 25° C. for 18 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (4 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (0.394 mL, 1.22 mmol) was added and the reaction mixture was heated to 60° C. for 20 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 50-100% ethyl acetate in hexanes) to afford (after trituration with diethylether) rac-N-{3-[5-benzyl-1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.058 g, 0.096 mmol, 32%) as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ: 2.46 (1H, d, J=11.1 Hz), 2.69-2.78 (1H, m), 2.92-2.98 (1H, m), 2.95 (3H, s), 3.01 (1H, d, J=3.9 Hz), 3.28-3.32 (1H, m), 4.24 (2H, d, J=5.5 Hz), 4.37 (1H, d, J=13.9 Hz), 4.66 (1H, d, J=14.9 Hz), 6.88-6.90 (2H, m), 7.13-7.20 (5H, m), 7.28-7.31 (2H, m), 7.58 (1H, t, J=6.3 Hz). LC-MS (ESI) calculated for C26H25FN4O6S3 604.09. found 605.4 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:30][C:29]([CH3:32])([CH3:31])[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([OH:35])=O)[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.[CH3:36][S:37]([NH2:40])(=[O:39])=[O:38]>CN(C)C1C=CN=CC=1.ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([CH:21]3[CH2:30][C:29]([CH3:31])([CH3:32])[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:33]([NH:40][S:37]([CH3:36])(=[O:39])=[O:38])=[O:35])[CH:27]=4)[NH:22]3)[CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(c3cccc(C4CC(C)(C)c5cc(C(=O)O)ccc5N4)c3)CC2)c(C)c1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(N2CCN(c3cccc(C4CC(C)(C)c5cc(C(=O)NS(C)(=O)=O)ccc5N4)c3)CC2)c(C)c1
Yield: 20 %

Procedure:
A mixture of 2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (100 mg, 0.21 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (60 mg, 0.31 mmol), 4-dimethylaminopyridine (38 mg, 0.31 mmol), methane sulfonamide (60 mg, 0.63 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent to afford the oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded N-(2-{3-[4-(2,4-dimethyl-phenyl)-piperazin-1-yl]-phenyl}-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl)-methanesulfonamide (23 mg, 20%) as a light yellow solid: MS (ESI) M+1=547.3.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].[NH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.[OH-].[K+].C>ClCCl.C(N(CC)CC)C.C(OCC)(=O)C.C(O)C>[N:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][N:9]2[CH2:2][CH2:3][CH2:4][S:5]2(=[O:7])=[O:6])=[CH:13][CH:14]=1
Reactant: NCCc1ccncc1
Reactant: O=S(=O)(Cl)CCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=S1(=O)CCCN1CCc1ccncc1
Reaction time: 16 h

Procedure:
A solution of 3-chloropropanesulphonyl chloride (20.0 g) in dichloromethane (200 cm3) was added dropwise over 1.5 hours to a stirred solution of 4-(2-aminoethyl)pyridine (13.8 g) in dichloromethane (200 cm3) and triethylamine (15 cm3) at 0° C. The ice bath was removed and the mixture was stirred for 16 hours. Saturated aqueous sodium carbonate (100 cm3) was then added and the organic phase was dried (MgSO4) and evaporated in vacuo to yield an oil which was suspended in abs. ethanol (500 cm3) and heated under reflux with potassium hydroxide (6.3 g) for 0.5 hours. The mixture was cooled and filtered and the filtrate was evaporated in vacuo to yield an oil which was taken into warm ethyl acetate (100 cm3), charcoal was added and the mixture was filtered. The filtrate was passed through a "Florisil" column (Trade Mark, Hopkin and Williams) and eluted further with ethyl acetate to obtain a colourless oil. Crystallisation from ethyl acetate gave 2-[2-(4-pyridyl)ethyl]isothiazolidine-1,1-dioxide as colourless needles, m.p. 70° C. (15.0 g).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].I[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1.[NH2:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1>O.CN(C)C=O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:19]1[C:14]([C:41]2[CH:42]=[C:37]([NH2:36])[CH:38]=[CH:39][CH:40]=2)=[N:15][C:16]([CH3:35])=[CH:17][CH:18]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: Nc1cccc(B(O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(N)c3)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
Toluene (1 ml), N,N-dimethylformamide (0.5 ml), and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (28 mg), and 3-aminophenylboronic acid (162 mg) under an argon atmosphere, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The ethyl acetate layer was then washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (39 mg, yield 85%).
Reaction SMILES: [S:1](Cl)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[OH:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([OH:19])[CH3:18]>N1C=CC=CC=1>[OH:19][CH:17]([CH3:18])[CH2:16][N:15]([S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2])[CH2:14][CH2:13][O:12][S:1]([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(O)CNCCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN(CC(C)O)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Tosyl chloride (11.60 g, 60.80 mmol) was added in small portions to a stirred solution of 1-(2-Hydroxy-ethylamino)-propan-2-ol (3.60 g, 30.25 mmol) in anhydrous pyridine at 0° C. The reaction was stirred at room temperature for 24 h and then poured onto ice-water (200 ml). The mixture was extracted into DCM (100 ml). The organic extract washed with 2N HCl, water, and was evaporated in vaccuo to give a brown residue which was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]([F:21])([F:20])[F:19])[C:12]([OH:14])=[O:13])C1C=CC=CC=1.[H][H]>[Pd].CO.C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[C:18]([F:19])([F:20])[F:21])[C:12]([OH:14])=[O:13]
Reactant: [H][H]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(O)c1ccc(C(F)(F)F)c(O)c1
Yield: 86 %

Procedure:
10% Pd/C (590 mg) was added to 3-benzyloxy-4-trifluoromethyl-benzoic acid in a methanol-ethyl acetate mixed solvent (1:1), and the mixture was stirred at room temperature for two days in a hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to give 3-hydroxy-4-trifluoromethyl-benzoic acid (582 mg, 86%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:25]4[CH2:26][CH2:27][N:22]([CH2:20][CH3:21])[CH2:23][CH2:24]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: CCN1CCNCC1
Solvent: O
Product: CCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Yield: 94.7 %

Procedure:
26.5 parts by weight of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylic acid and 35.3 parts by weight of 1-ethyl-piperazine in 200 parts by volume of water are heated under reflux for 90 minutes, and the mixture is cooled, brought to pH 7.5 using acid and worked up. 34.0 g (94.7%) of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(4-ethyl-1-piperazinyl)-3-quinolinecarboxylic acid are obtained.
Reaction SMILES: [OH-].[Na+].Cl[C:4]1[C:9]([N:10]([CH3:35])[C:11]([C:13]2[C:14]([NH:32][CH2:33][CH3:34])=[N:15][CH:16]=[C:17]([CH2:19][CH2:20][O:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][CH:23]=3)[CH:18]=2)=[O:12])=[CH:8][CH:7]=[CH:6][N:5]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:33]([N:32]1[C:14]2[N:15]=[CH:16][C:17]([CH2:19][CH2:20][O:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[CH:24][CH:23]=3)=[CH:18][C:13]=2[C:11](=[O:12])[N:10]([CH3:35])[C:9]2[CH:8]=[CH:7][CH:6]=[N:5][C:4]1=2)[CH3:34]
Reactant: CCNc1ncc(CCOc2ccnc3ccccc23)cc1C(=O)N(C)c1cccnc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN1c2ncc(CCOc3ccnc4ccccc34)cc2C(=O)N(C)c2cccnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.47 g NaOH and 40 ml toluene were charged into a three-neck flask equipped with temperature couple and addition funnel. The mixture was brought to 20° C. Next, 10.02 g of N-(2-chloro(3-pyridyl))[2-(ethylamino)-5-(2-(4-quinolyloxy)ethyl)(3-pyridyl)]-N-methylcarboxamide and 0.7 g tetrabutylammonium bromide were dissolved in 50 ml of toluene at 60-70° C. and allowed to cool to room temperature. The solution of N-(2-chloro(3-pyridyl))[2-(ethylamino)-5-(2-(4-quinolyloxy)ethyl)(3-pyridyl)]-N-methylcarboxamide and TBAB was charged to the addition funnel and slowly added to the slurry from NaOH in Toluene. The reaction mixture was kept at 20-30° C. and stirred overnight. Reaction monitoring was performed with HPLC. During the reaction the product crystallized from the reaction mixture. In the event that the reaction had not completed after 16 h the reaction mixture was heated up to 30° C. and kept there until the reaction was complete. The reaction mixture was quenched with 25 ml saturated NH4Cl solution. A temperature increase from 20.8° C. to 25.5° C. was observed. The reaction mixture was heated to 85-90° C. The precipitate dissolved upon heating and a slow release of a gas (Ammonia) was observed. Phase separation at 85-90° C. was performed. The lower aqueous layer was analyzed for product and pH (target: pH=6) and then discarded. 41 ml of toluene/water (about 40 ml toluene, 1 ml water) was azeotropically distilled off the solution under reduced pressure. The solution was slowly cooled to room temp., then to 0° C. and stirred for at least 30 min at 0° C. to complete crystallization. The crystals were collected by filtration and washed twice with 10 ml of cooled toluene at 0° C. Crude Yield: 8.436 g; yellowish to off-white crystals. The off-white to yellow product was dried at 50° C. under vacuum over night.