Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:3]=1.C([Li])CCC.[CH3:24][Si:25]([CH3:51])([CH3:50])[O:26][C@@H:27]1[C@@H:32]([O:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C@H:31]([O:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C@@H:30]([CH2:43][O:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[O:29][C:28]1=[O:49]>O1CCCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([C@@:28]2([OH:49])[C@H:27]([O:26][Si:25]([CH3:51])([CH3:50])[CH3:24])[C@@H:32]([O:33][Si:34]([CH3:35])([CH3:36])[CH3:37])[C@H:31]([O:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[C@@H:30]([CH2:43][O:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[O:29]2)=[CH:3][C:4]=1[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=1
Reactant: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reactant: C[Si](C)(C)OC[C@H]1OC(=O)[C@H](O[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@@H]1O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]3(O)O[C@H](CO[Si](C)(C)C)[C@@H](O[Si](C)(C)C)[C@H](O[Si](C)(C)C)[C@H]3O[Si](C)(C)C)ccc2Cl)cc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 106.1 %

Procedure:
To a solution of 4-bromo-1-chloro-2-(4-ethoxyphenyl)methyl-benzene (30 g, 92.1 mmol, bought from Shanghai Kinsey pharmaceutical company) in anhydrous tetrahydrofuran (250 mL) was added n-butyllithium (40.3 mL, 96.7 mmol, 2.4 M in n-hexane) dropwise at −78° C. The mixture was stirred at −78° C. for 40 min and a solution of (3R,4S,5R,6R)-3,4,5-tris(trimethylsilyloxy)-6-(trimethylsilyloxymethyl) tetrahydropyran-2-one 1b (47.3 g, 101.3 mmol) in anhydrous tetrahydrofuran (50 mL) was added dropwise. After the addition, the mixture was further stirred at −78° C. for 5 hours and then quenched with 100 mL of saturated aqueous ammonium chloride. The mixture was allowed to warm up to room temperature and concentrated in vacuo. To the residue was added 150 mL of water. The resulting mixture was extracted with ethyl acetate (150 mL×3). The combined organic layers were washed with saturated aqueous sodium chloride (200 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to give the title compound 1c as pale yellow oil (69.7 g, 100%). This crude product was used in next step without further purification.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH:24]([OH:27])[CH2:25][CH3:26])=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:29]=[CH:28][C:6]([O:7][CH2:8][C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[C:24](=[O:27])[CH2:25][CH3:26])=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1
Reactant: CCC(O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
To a solution of 1-{2-[2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazol-5-yl]-phenyl}-propan-1-ol (0.100 g, 0.235 mmol, Example 9, Compound 143) in CH2Cl2 (3 mL) was added Dess-Martin periodinane (0.159 g, 0.375 mmol). After stirring at rt for 2 hours, The reaction mixture was concentrated, and the residue was purified by chromatography (silica, hexanes: EtOAc, 2:1) to afford the title compound as a white solid (0.087 g, 87%).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8]C)=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:4][C:3]=1[O:13][CH3:14].CCCCCC.BrB(Br)Br.O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][CH:5]=[C:6]([N+:10]([O-:12])=[O:11])[C:7]=1[OH:8]
Reactant: COc1ccc([N+](=O)[O-])c(OC)c1F
Agent: BrB(Br)Br
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCCCCC
Product: COc1ccc([N+](=O)[O-])c(O)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 61.6 %

Procedure:
To a solution of 2-fluoro-1,3-dimethoxy-4-nitrobenzene (1.5 g) in toluene (100 mL) was added 1 M tribromoborane hexane solution (16 mL) at 0° C., and the mixture was stirred at room temperature for 15 hr. Water was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 10 min. The reaction solution was extracted with ethyl acetate, and the obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (860 mg).
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[F:32][C:33]([F:43])([F:42])[C:34]1[CH:39]=[CH:38][C:37]([Mg]Br)=[CH:36][CH:35]=1.CCCCCC.C(OCC)(=O)C>C1COCC1.CO>[F:32][C:33]([F:43])([F:42])[C:34]1[CH:39]=[CH:38][C:37]([C:3]2[S:4][C:5]3[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=3[C:7]=2[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:12][CH:11]=2)=[O:9])=[CH:36][CH:35]=1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Reactant: FC(F)(F)c1ccc([Mg]Br)cc1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(-c3ccc(C(F)(F)F)cc3)sc2c1
Yield: 80.5 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone (1.0 g, 2.28 mmol) in THF (20 mL) was treated with a 0.69 M THF solution of 4-trifluoromethylphenylmagnesium bromide (10 mL, 6.9 mmol) (prepared from 4-bromobenzotrifluoride, catalytic iodine, and magnesium turnings in THF) to provide, after radial chromatography (silica gel, 4:1:.05-3:1:.05 hexane:ethyl acetate:MeOH, under an ammonia atmosphere) 991 mg (81%) of the title compound as a yellow oil: 1H NMR d 1.45 (m, 2H), 1.63 (m, 4H), 2.54 (m, 4H), 2.79 (t, J=5.8 Hz, 2H), 3.89 (s, 3H), 4.13 (t, J=5.8 Hz, 2H), 6.78 (d, J=8.8 Hz, 2H), 6.98 (dd, J=8.9, 2.3 Hz, 1H), 7.34 (d, J=2.2 Hz, 1H), 7.48 (d, J=8.4 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.8 Hz, 2H); 13C NMR d 24.0, 25.7, 55.0, 55.6, 57.6, 66.1, 104.4, 114.4, 115.3, 115.8, 124.5, 125.5 (q, J=3.0 Hz), 129.1, 130.2, 132.3, 133.2, 133.6, 137.3, 139.7, 140.6, 158.2, 163.3, 192.6; MS (FD+) m/e 539 (M+); Anal. calc'd. for C30H28F3NO3S: C, 66.77; H, 5.24; N, 2.60. Found: C, 66.78; H, 5.30; N, 2.43.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.O.[C:22]([OH:26])(=[O:25])[CH:23]=O>>[CH2:19]([O:18][C:16]([C:3]1[C:2]([NH:1][CH2:23][C:22]([OH:26])=[O:25])=[CH:7][C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)=[CH:5][N:4]=1)=[O:17])[CH3:20]
Reactant: O=CC(=O)O
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Solvent: O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCC(=O)O

Procedure:
This compound was prepared from ethyl 3-amino-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate and glyoxylic acid monohydrate employing methods similar to those described in Example 11, Step 1 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 13.1 (1H, br), 7.91 (1H, t, J=5 Hz), 7.78 (1H, d, J=1 Hz), 7.29 (2H, dd, J=9, 6 Hz), 7.09 (1H, t, J=9 Hz), 7.02 (1H, s), 4.25 (2H, q, J=7 Hz), 3.92 (2H, d, J=5 Hz), 3.90 (2H, s), 1.27 (3H, t, J=7 Hz); ES+ MS: 333 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:21]=[C:20]([CH3:22])[C:19]3[C:14](=[CH:15][C:16]([N:23]([C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:24][C:25]([O:27]CC)=[O:26])=[CH:17][CH:18]=3)[N:13]=2)=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].[OH-].[Na+]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][C:12]2[CH:21]=[C:20]([CH3:22])[C:19]3[C:14](=[CH:15][C:16]([N:23]([C:30](=[O:37])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH2:24][C:25]([OH:27])=[O:26])=[CH:17][CH:18]=3)[N:13]=2)=[CH:8][CH:9]=1)(=[NH:2])[NH2:3]
Reactant: CCOC(=O)CN(C(=O)c1ccccc1)c1ccc2c(C)cc(COc3ccc(C(=N)N)cc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(COc2ccc(C(=N)N)cc2)nc2cc(N(CC(=O)O)C(=O)c3ccccc3)ccc12

Procedure:
Prepared analogously to Example 3 from 2-[(4-amidinophenyl)-oxymethyl]-4-methyl-7-[N-(ethoxycarbonylmethyl)-benzoylamino]-quinoline and sodium hydroxide solution.
Reaction SMILES: [CH2:1]([C@H:8]([NH:33]C(=O)OC(C)(C)C)[C@@H:9]([OH:32])[CH2:10][N:11]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:12][C:13](=[O:24])[C@@H:14]([NH:19][C:20]([O:22][CH3:23])=[O:21])[C@@H:15]([CH3:18])[CH2:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C1COCC1>[NH2:33][C@@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@@H:9]([OH:32])[CH2:10][N:11]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:12][C:13]([C@@H:14]([NH:19][C:20](=[O:21])[O:22][CH3:23])[C@@H:15]([CH3:18])[CH2:16][CH3:17])=[O:24]
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccccc1)C[C@H](O)[C@@H](N)Cc1ccccc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 91.1 %

Procedure:
A solution of Example 26B (4.57 g, 8.2 mmol) in THF (60 mL) was treated with 4N HCl (14.4 mL). stirred at 60° C. for 3 hrs, and cooled to room temperature. The solvents were evaporated, and the crude residue was partitioned between ethyl acetate and 10% sodium bicarbonate. The organic layer was separated, washed with 10% sodium bicarbonate, brine, dried over sodium sulfate, filtered and the solvents were evaporated to give 3.41 g (89%) of the title compound.
Reaction SMILES: [ClH:1].Cl.Cl.[NH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][CH2:12][NH:13]CC1C=CC(C#N)=CC=1)[CH3:9].C(C1C=CC(C=O)=CC=1)#N.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH:41]=O)=[CH:36][CH:35]=1>>[ClH:33].[ClH:1].[ClH:33].[NH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH2:10][CH2:11][CH2:12][NH:13][CH2:41][CH2:40][C:37]1[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=1)[CH3:9]
Reactant: O=CCc1ccc(Cl)cc1
Reactant: CN(CCCN)CCCNCc1ccc(C#N)cc1
Agent: Cl
Agent: N#Cc1ccc(C=O)cc1
Product: CN(CCCN)CCCNCCc1ccc(Cl)cc1
Yield: 51 %

Procedure:
In a similar manner to that described above, N-{3-[N-(3-aminopropyl)-N-methylamino]propyl}-p-cyanobenzylamine trihydrochloride (81% yeild) and N-{3-[N-(3-aminopropyl)-N-metylamino]propyl}-2-(p-chlorophenyl)ethylamine trihydrochloride (51% yield) were obtained from p-cyanobenzaldehyde and p-chlorophenylacetaldehyde, respectively. The physicochemical properties of these compounds were as shown in Table 8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11](C(=O)[C@H](OC)C3C=CC=CC=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Li+].[B-](CC)(CC)CC.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CO[C@@H](C(=O)N1CCC[C@@H](c2cc(Cl)cc(Cl)c2)C1)c1ccccc1
Agent: CC[B-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1cc(Cl)cc(C2CCCNC2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.6 %

Procedure:
Synthesized according to General procedure 35. To a solution of (R)-1-((S)-3-(3,5-dichlorophenyl)piperidin-1-yl)-2-methoxy-2-phenylethanone (98 mg, 0.26 mmol) in anhydrous THF (9 mL) under nitrogen at 0° C. was added Super-hydride (1.0 M in THF, 1.63 mL, 1.63 mmol) dropwise. The solution was stirred at 0° C. for 2 h, and then poured into 2M aqueous HCl (3 mL). The aqueous phase was washed twice with Et2O (2×3 ml), then basified by addition of NH4OH at 0° C. The product was extracted with DCM (3×3 ml), the organic phases were combined, dried over sodium sulfate, filtered, then concentrated under reduced pressure, providing 3-(3,5-dichlorophenyl)piperidine (59 mg, 67%) which was arbitrarily assigned the (S)-configuration, as a pale yellow oil. This material was used without further purification. 1H-NMR (400 MHz, CDCl3) δ 7.22 (s, 1H), 7.20 (t, J=1.8 Hz, 1H), 7.09 (d, J=1.8 Hz, 2H), 3.17-3.05 (m, 2H), 2.65-2.57 (m, 3H), 2.01-1.96 (m, 1H), 1.81-1.77 (m, 1H), 1.60-1.53 (m, 2H), 1.60-1.53 (m, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=230.3; tR=1.10 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:18][OH:19])[CH:5]=[C:6]([O:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:7]=1>O1CCOCC1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][CH2:9][CH2:10][NH:11][C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)[CH:7]=1)[CH:18]=[O:19]
Reactant: OCc1cc(Br)cc(OCCNc2ccncc2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: O=Cc1cc(Br)cc(OCCNc2ccncc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
A suspension of {3-bromo-5-[2-(pyridin-4-ylamino)-ethoxy]-phenyl}-methanol (1.4 g) and manganese dioxide (3.2 g) in 1,4-dioxan (50 ml) was heated to reflux with stirring under an atmosphere of dry nitrogen for 8 h. After cooling to room temperature the mixture was stirred at room temperature for 16 h, and then filtered through Harborlite® and the pad washed with hot methanol. The combined filtrates were evaporated to dryness under reduced pressure to give the title compound as an off-white solid (1.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH2:5]2.[C:15](Cl)(=[O:17])[CH3:16].Cl>CN(C1C=CN=CC=1)C>[C:15]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([NH2:13])=[O:12])[C:6](=[O:14])[CH2:5]2)(=[O:17])[CH3:16]
Reactant: CC(=O)Cl
Reactant: NC(=O)N1C(=O)Cc2cc(N)ccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CC(=O)Nc1ccc2c(c1)CC(=O)N2C(N)=O
Reaction time: 0.25 h

Procedure:
A slurry of 0.5 g. (2.6 mmole) of 5-amino-2-oxindole-1-carboxamide and 0.35 g. of 4-(N,N-dimethylamino)pyridine was stirred at 10° C., and then 0.20 ml. (2.8 mmole) of acetyl chloride was added. Stirring was continued at ca -10° C. for 20 minutes and at room temperature for 15 minutes, and then 20 ml. of 1N hydrochloric acid was added. The solid was recovered by filtration, and dried, to give 0.20 g. of the title compound as a cream-colored solid.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:25]([CH2:26][CH2:27][C@:6]12[CH3:7])[C@:19]1([CH2:20][O:21]C(=O)C)[C:14]([CH2:15][C@@H:16]([O:28][CH2:29][CH3:30])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:25]([CH2:26][CH2:27][C@:6]12[CH3:7])[C@:19]1([CH2:20][OH:21])[C:14]([CH2:15][C@@H:16]([O:28][CH2:29][CH3:30])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CCO[C@H]1CC[C@@]2(COC(C)=O)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCO[C@H]1CC[C@@]2(CO)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3β-Ethoxy-5-androstene-17β,19-diol diacetate is added to an aqueous methanol solution of potassium carbonate and the reaction solution stirred at room temperature for about 2 hours. The reaction mixture is poured onto water, and the oil which results is extracted into ether. The ether extract is washed with water, dried over magnesium sulfate and concentrated to dryness. Crystallization of the residue from an ether-pentane mixture yields 3β-ethoxy-5-androstene-17β,19-diol 17-acetate.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)=[O:6].[CH2:14](O)[CH2:15][OH:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:15]1[O:16][C:5]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)([CH2:4][CH2:3][CH2:2][Cl:1])[O:6][CH2:14]1
Reactant: OCCO
Reactant: O=C(CCCCl)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Fc1ccc(C2(CCCCl)OCCO2)cc1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of γ-chloro-p-fluorobutyrophenone (50 g, 0.25 mole, commercially available); ethylene glycol (50 mL); p-toluene sulfonic acid (0.1 g) in 300 mL benzene is refluxed for 18 hrs with water of reaction being removed by means of a Dean Stark water trap. Upon cooling to room temperature, the reaction mixture is washed with dilute sodium bicarbonate, dried (MgSO4), filtered and the benzene removed by concentration in vacuo. The residual oil was distilled to give 57.7 g (93%) of product, b.p. 106-112/0.01 Torr.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:25]=[CH:24][C:12]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[C:11]([C:26]([F:29])([F:28])[F:27])[CH:10]=2)O1.[NH2:31][C:32]1[C:33]([C:41]#[N:42])=[N:34][C:35](Cl)=[CH:36][C:37]=1[NH:38][CH3:39].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C(OCC)(=O)C.O>[NH2:31][C:32]1[C:37]([NH:38][CH3:39])=[CH:36][C:35]([C:9]2[CH:25]=[CH:24][C:12]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[C:11]([C:26]([F:27])([F:28])[F:29])[CH:10]=2)=[N:34][C:33]=1[C:41]#[N:42]
Reactant: CNc1cc(Cl)nc(C#N)c1N
Reactant: CC(C)(C)OC(=O)NCCOc1ccc(B2OC(C)(C)C(C)(C)O2)cc1C(F)(F)F
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNc1cc(-c2ccc(OCCNC(=O)OC(C)(C)C)c(C(F)(F)F)c2)nc(C#N)c1N

Procedure:
tert-Butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-phenoxy)ethylcarbamate (4.34 mmol, 1.87 g), 3-amino-6-chloro-4-(methylamino)-picolinonitrile (4.34 mmol, 0.792 g), potassium phosphate (13.01 mmol, 2.76 g), tricyclohexylphosphine (0.520 mmol, 0.146 g), and tris(dibenzylacetone)dipalladium (0) (0.217 mmol, 0.199 g) were dissolved in Dioxane (20 ml) and Water (10.00 ml) and stirred under nitrogen at 100° C. for 2 hrs. The mixture was diluted with ethyl acetate and filtered through celite. Organic layer was washed with water and separated from the aqueous layer, the organic layer was concentrated in vacuo. This was purified by silica chromatography, eluting with heptane—50/50 heptane/EtOAc to afford tert-butyl 2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoro-methyl)phenoxy)ethylcarbamate. (0.51 g)
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][CH2:6][C:5]([CH:8]([CH3:11])[CH:9]=[O:10])=[C:4]2[C:12]([CH3:18])([CH3:17])[CH:13]3[CH2:16][C:3]12[CH2:15][CH2:14]3.[CH3:20][Mg]Br>C(OCC)C>[CH3:19][C:2]1([CH3:1])[CH2:7][CH2:6][C:5]([CH:8]([CH3:11])[CH:9]([OH:10])[CH3:20])=[C:4]2[C:12]([CH3:18])([CH3:17])[CH:13]3[CH2:16][C:3]12[CH2:15][CH2:14]3
Reactant: CC(C=O)C1=C2C(C)(C)C3CCC2(C3)C(C)(C)CC1
Reactant: C[Mg]Br
Solvent: CCOCC
Product: CC(O)C(C)C1=C2C(C)(C)C3CCC2(C3)C(C)(C)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.2 %

Procedure:
9b (1.7 g, 6.5×10−3 mol) in diethyl ether (50 ml) was added dropwise at 10° C. to a solution of methylmagnesium bromide (3 ml of 3M diethyl ether solution, 9.0×10−3 mol) in the same solvent (50 ml). The reaction mixture was stirred at r. t. for additional 2 h, poured into ice-cold 0.1M HCl (100 ml) and extracted with MTBE (100 ml). The organic phase was washed with brine (2×50 ml), dried (MgSO4), concentrated in vacuo and purified by recrystallisation from hexane to afford 3-(2,2,7,7-tetramethyltricyclo[6.2.1.01,6]undec-5-en-5y-1)butan-2-ol (10b, 1.1 g, 61% yield, white prisms, m.p. 119-121° C.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]1[CH2:17][CH2:16]1)=[O:14])=[C:5]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]([CH3:28])[CH3:27])=[CH:21][CH:20]=1.[Cl:29][C:30]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]>>[Cl:29][C:30]1[CH:35]=[C:34]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[F:12])[N:8]=[CH:7][C:6]([C:13]([CH:15]2[CH2:16][CH2:17]2)=[O:14])=[C:5]3[NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][N:26]([CH3:27])[CH3:28])=[CH:23][CH:24]=2)[CH:33]=[C:32]([F:45])[C:31]=1[OH:46]
Reactant: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3cc(F)c(Br)cc23)cc1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Product: CN(C)Cc1ccc(Nc2c(C(=O)C3CC3)cnc3cc(F)c(-c4cc(F)c(O)c(Cl)c4)cc23)cc1
Yield: 24.1 %

Procedure:
Following general procedure D, ((6-bromo-4-(4-((dimethylamino)methyl)phenylamino)-7-fluoroquinolin-3-yl)(cyclopropyl)methanone (40 mg, 0.090 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (31 mg, 0.113 mmol) to afford the desired product (11 mg, 24%) as a yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 10.70 (s, 1H), 9.06 (s, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.75 (d, J=12 Hz, 1H), 7.26 (d, J=8.5 Hz, 2H), 7.21 (d, J=6.5 Hz, 2H), 7.09 (d, J=8.5, 2H), 3.40 (s, 2H), 2.77 (quint, J=15 Hz, 1H), 2.13 (s, 6H), 0.86 (m, 4H); ESI MS m/z 508, [C28H24ClF2N3O2+H]+; HPLC 98.7% (AUC), tR=10.83 min.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=1>CC1C=NC=CC=1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: Clc1cccnc1Cl
Solvent: Cc1cccnc1
Product: Clc1cccnc1NCCCOc1cccc(CN2CCCCC2)c1
Yield: 37.2 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (2.17 g) and 2,3-dichloropyridine (1.27 g) were dissolved in 3-methylpyridine (6 ml) and stirred under reflux for 16 hours. The majority of the reaction solvent was removed by vacuum distillation (120 torr, 70°-80° C.) and the residue was neutralised with aqueous potassium carbonate (5%; 40 ml), washed with water (2×100 ml) and extracted into chloroform (40 ml). The chloroform extract was evaporated under reduced pressure and subjected to column chromatography (chloroform:methanol 25:1) to give the title compound as an oil (1.15 g). This was treated with oxalic acid as in Example 1 to give 2-[3-[3-(piperidinomethyl)phenoxy]propylamino]-3-chloropyridine dioxalate (1.1 g), m.p. 154°-155° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:7][S:6](=O)[CH2:5][CH2:4]1)#[N:2].C(O)(=O)C.O.[NH2:14][NH2:15]>C(O)C>[NH:14]1[C:4]2[CH2:5][S:6][CH2:7][C:3]=2[C:1]([NH2:2])=[N:15]1
Reactant: NN
Reactant: N#CC1CCS(=O)C1
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1n[nH]c2c1CSC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a suspension of 1.00 g (7.86 mmol) of 4-cyanotetrahydrothiophenone in 6 mL of ethanol was added 0.275 mL (286 mg, 4.76 mmol) of glacial acetic acid, followed by 0.475 mL (489 mg, 9.77 mmol) of hydrazine hydrate. The resulting clear solution was stirred overnight under nitrogen with heating in an oil bath at 80° C. The cooled reaction mixture was then partitioned between ethyl acetate and saturated sodium bicarbonate aqueous solution. The aqueous phase was re-extracted with an additional portion of ethyl acetate. The combined organic fractions were washed with saturated sodium chloride aqueous solution, then dried over anhydrous sodium sulfate, filtered, and concentrated to a syrup. Trituration of this oil with dichloromethane containing a small amount (less than 3%) of methanol resulted in crystallization. The suspension was heated to gentle reflux for a few minutes and then cooled. The solid was collected on a filter and washed with a small volume of dichloromethane to yield the title compound as almost colorless crystals. LC-MS 142 (M+1).