Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15](=[N:24][NH2:25])[NH:16][C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[Cl:23])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1.[C:27](C1NC=CN=1)(C1NC=CN=1)=[O:28].C(=O)(O)[O-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]4[N:16]([C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=5[Cl:23])[C:27](=[O:28])[NH:25][N:24]=4)=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:26]=1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Reactant: NN=C(Nc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2cc3c(s2)-c2ccc(Br)cc2OCC3)n1-c1ccccc1Cl
Temperature: 25 °C
Yield: 56.4 %

Procedure:
To a solution of crude 8-bromo-N-(2-chlorophenyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carbohydrazonamide (about 1.15 mmol) in dry THF (10 mL) was added carbonyl diimidazole (373 mg, 2.3 mmol). The reaction mixture was stirred at room temperature until completion judged by LCMS. Aqueous sodium bicarbonate was added and the mixture extracted with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate, concentrated and the residue purified by flash column chromatography (10-100% ethyl acetate in hexanes) to give 279 as a colorless solid (308 mg). 1H NMR (dmso-d6, 400 MHz) δ 12.32 (s, 1H), 7.75-7.59 (m, 4H), 7.42 (m, 1H), 7.27-7.21 (m, 2H), 6.53 (s, 1H), 4.21 (t, 2H), 2.97 (t, 2H). MS (ESI) 476.0.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:33])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH2:24][CH2:25][CH2:26][C:27]([O:29]CC)=[O:28])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][C:13](=[O:32])[CH:12]=1.CO>C1COCC1>[Cl:3][C:4]1[CH:5]=[N:6][CH:7]=[C:8]([Cl:33])[C:9]=1[NH:10][C:11]1[C:20]2[C:15](=[C:16]([O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[O:14][C:13](=[O:32])[CH:12]=1
Reactant: CCOC(=O)CCCOc1c(OC)ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCC(=O)O
Reaction time: 4 h

Procedure:
Lithium hydroxide (0.5 mL, IM, 0.5 mmol) was added to a solution of ethyl 4-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)butanoate (12 mg, 0.026 mmol, Example 36), MeOH (0.5 mL), and THF (1.5 mL). The mixture was stirred 4 h, quenched with 1N HCl (20 mL), and extracted with EtOAc (30 mL×2). The organic extract was dried, filtered, and concentrated to give 4-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)butanoic acid: 1H NMR (400 MHz, DMSO-d6): δ 9.52 (s, 1H), 8.81 (s, 2H), 7.94 (d, 1H), 7.20 (d, 1H), 4.64 (s, 1H), 4.00 (t, 2H), 3.91 (s, 3H), 2.46 (t, 2H), 1.88 (m, 2H); MS (ESI): 438.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1.[Cl:16][C:17]1[CH:30]=[CH:29][C:20]2[S:21][C:22]([S:25](Cl)(=[O:27])=[O:26])=[C:23]([CH3:24])[C:19]=2[CH:18]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:25]([C:22]2[S:21][C:20]3[CH:29]=[CH:30][C:17]([Cl:16])=[CH:18][C:19]=3[C:23]=2[CH3:24])(=[O:27])=[O:26])=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]1
Reactant: CN1CCN(c2cc(N)ccc2Cl)CC1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Product: Cc1c(S(=O)(=O)Nc2ccc(Cl)c(N3CCN(C)CC3)c2)sc2ccc(Cl)cc12

Procedure:
The title compound (E119) was prepared from 4-chloro-3-(4-methylpiperazin-1-yl)benzenamine (EP 0533267A, intermediate 42) (50 mg, 0.22 mmol) and 5-chloro-3-methylbenzo[b]thiophene-2-sulfonyl chloride (62 mg, 0.22 mmol) using the method of Example 1 (49 mg, 44%) MH+=470/472.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[C:35](Cl)=[O:36]>>[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][CH2:2][NH:1][C:35]([C:25]3[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:27][O:28][C:24]=3[CH3:23])=[O:36])[CH2:6][CH2:7]2)[CH:16]=[CH:15][CH:14]=1)(=[O:22])[CH:19]([CH3:20])[CH3:21]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)Cl
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: Cc1onc(-c2ccccc2)c1C(=O)NCCCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 5-methyl-3-phenyl-4-isoxazolecarbonyl chloride: ESMS m/e: 489.1 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[O:8][CH2:9][CH2:10][CH2:11][CH2:12][N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CNCCN1
Reactant: ClCCCCOC(c1ccccc1)c1ccccc1
Product: c1ccc(C(OCCCCN2CCNCC2)c2ccccc2)cc1

Procedure:
Using 4-(diphenylmethoxy)butyl chloride and piperazine, the procedure of Reference Example 16 was otherwise repeated to provide the title compoud.
Reaction SMILES: ClCCl.Cl.[F:5][C:6]([F:17])([F:16])[C:7]([N:9]1[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]1)=[O:8].[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH:28]=O)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[O:18]1[C:23]2[CH:24]=[CH:25][C:26]([CH2:28][NH:15][CH:12]3[CH2:13][CH2:14][N:9]([C:7](=[O:8])[C:6]([F:5])([F:16])[F:17])[CH2:10][CH2:11]3)=[CH:27][C:22]=2[O:21][CH2:20][CH2:19]1
Reactant: NC1CCN(C(=O)C(F)(F)F)CC1
Reactant: O=Cc1ccc2c(c1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(N1CCC(NCc2ccc3c(c2)OCCO3)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 20 mL of a dichloromethane suspension containing 1.0 g of 1-(trifluoroacetyl)piperidine-4-amine hydrochloride, 0.71 g of 2,3-dihydro-1,4-benzodioxin-6-carbaldehyde and 0.25 mL of acetic acid were added, the mixture was stirred at room temperature for 2 hours. The reaction mixture was added with 1.37 g of sodium triacetoxyborohydride was added and stirred at the same temperature for 30 minutes. The solvent was removed under reduced pressure, then water and ethyl acetate were added thereto, and the reaction mixture was adjusted to pH 1.5 with 1 mol/L hydrochloric acid. The aqueous layer was separated and washed with ethyl acetate, then ethyl acetate was added thereto, and the resultant solution was adjusted to pH 7.8 with an aqueous saturated sodium hydrogen carbonate solution. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, and the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 1.4 g of a colorless oily substance, N-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-1-(trifluoroacetyl)piperidine-4-amine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21](SC)[N:20]=3)=[C:17]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:16](=[O:34])[N:15]2[CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:37]1C=CC=C(C(OO)=O)C=1.[S:47](=[O:50])(O)[O-:48].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([S:47]([CH3:37])(=[O:50])=[O:48])[N:20]=3)=[C:17]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[C:16](=[O:34])[N:15]2[CH3:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S([O-])O
Reactant: CSc1nccc(-c2c(-c3ccc(F)cc3)c(=O)n(C)n2C2CCN(C(=O)OC(C)(C)C)CC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c(-c2ccc(F)cc2)c(-c2ccnc(S(C)(=O)=O)n2)n1C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.08 h

Procedure:
To a solution of 4-[4-(4-fluorophenyl)-2-methyl-5-(2-methylsulfanyl-pyrimidin-4-yl)-3-oxo-2,3-dihydro-pyrazol-1-yl]-piperidine-1 carboxylic acid tert-butyl ester, 11, (5.9 g, 12 mmol) in CHCl3 (200 mL) at 0° C. is added meta-chloroperbenzoic acid (4 g, 23.37 mmol). After stirring for 5 minutes, saturated sodium bisulfite (20 mL) is added and the reaction mixture stirred for an additional 5 minutes. The aqueous phase is extracted three times with CH2Cl2, the combined organic phases washed with saturated sodium bicarbonate, dried (MgSO4), filtered and concentrated in vacuo. The crude material is used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8](=[O:12])[CH:9](Br)[CH3:10])[CH:5]=[CH:6][CH:7]=1.[NH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:16]>C(#N)C.C(OCC)(=O)C>[OH:12][C:8]1([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[O:16][CH2:15][C:14]([CH3:18])([CH3:17])[NH:13][CH:9]1[CH3:10]
Reactant: CC(Br)C(=O)c1cccc(Cl)c1
Reactant: CC(C)(N)CO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1NC(C)(C)COC1(O)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of 3′-chloro-2-bromo-propiophenone (61.2 g, 247 mmol) in acetonitrile (752 mL) was added 2-amino-2-methyl-1-propanol (56.5 g, 630 mmol). The reaction mixture was allowed to reflux for 8 hours, then slowly cooled to room temperature. The solution was concentrated in vacuo to provide a yellow solid. The crude material was dissolved in 600 mL of ethyl acetate and washed with water (300 mL×2). The ethyl acetate layer was dried (MgSO4), filtered, and concentrated in vacuo to give the product in 90% yield. 1H NMR (CDCl3) δ0.82 (d, J=6.6 Hz, 3H), 1.07 (s, 3H), 1.39 (s, 3H), 3.19 (q, J=6.5 Hz, 1H), 3.42 (d, J=11.2 Hz, 1H), 3.83 (d, J=11.2 Hz, 2H), 7.2-7.65 (m, 4H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]([NH:11][CH:12]([CH3:15])[CH2:13][CH3:14])=[N:7][C:8]=1[CH:9]=O)#[N:2].O.[NH2:22][NH2:23]>CO>[C:1]([C:3]1[C:8](=[CH2:9])[NH:7][C:6]([NH:11][CH:12]([CH3:15])[CH2:13][CH3:14])=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:4]=1[NH:22][NH2:23])#[N:2]
Reactant: CCOC(=O)c1cc(C#N)c(C=O)nc1NC(C)CC
Reactant: NN
Solvent: O
Solvent: CO
Product: C=C1NC(NC(C)CC)=C(C(=O)OCC)C(NN)=C1C#N

Procedure:
2.8 g of 5-cyano-6-formyl-2-[(1-methylpropyl)amino]-3-pyridine-carboxylic acid, ethyl ester (0.01 mol) are dissolved in 10 ml of methanol and 1 g of hydrazine hydrate is added with stirring. After standing over night the title compound precipitates. Yield 2.1 g (73%); m.p. 120°-121° C. (methanol).
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=4)[NH:19][C:18]3=[O:27])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:28])[CH3:2].C(O)(=O)C.[Br:35]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>ClC(Cl)(Cl)Cl>[Br:35][CH:10]1[CH2:11][N:6]([CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:29][CH3:30])[C:7](=[O:28])[C:8]2[C:14]([CH3:15])=[C:13]([CH:16]=[C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=4)[NH:19][C:18]3=[O:27])[NH:12][C:9]1=2
Reactant: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)O
Product: CCN(CC)CCN1CC(Br)c2[nH]c(C=C3C(=O)Nc4ccc(F)cc43)c(C)c2C1=O
Temperature: 25 °C
Yield: 21.5 %

Procedure:
A stirred solution of 5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (82 mg, 0.2 mmol) prepared from Example 1 in 2 ml of tetrachloromethane was added with acetic acid (20 ml), N-bromosuccinimide (43 mg, 0.24 mmol) and azobisisobutyronitrile (2 mg, 0.012 mmol). The mixture was heated to reflux for 45 minutes, cooled down to room temperature filtered and concentrated under reduced pressure. The resulting mixture was purified by silica gel column chromatography to give the mixture (21 mg) of 7-bromo-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one and 3-bromomethyl-5-(2-diethylamino-ethyl)-2-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one which was used as such.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:22])[NH:17][CH2:18][C:19](F)=[O:20])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16](=[O:22])[NH:17][CH2:18][C:19](=[O:20])[NH:7][CH2:8][CH2:9][SH:10])([CH3:14])([CH3:12])[CH3:13]
Reactant: NCCS
Reactant: CC(C)(C)OC(=O)NCC(=O)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCCS
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 50 mL round-bottom flask charged with a solution of sodium bicarbonate (141 mg, 1.68 mmol) in 8.2 mL water was added 2-aminoethanethiol hydrochloride (102.5 mg, 0.90 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25a (145.6 mg, 0.82 mmol) in 8.2 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 132.8 mg (69% from 24a) of clean 26a as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1.[CH3:30][S:31](Cl)(=[O:33])=[O:32].CCN(C(C)C)C(C)C>>[CH3:30][S:31]([N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[C:12]([C:13]3[N:14]=[C:15]4[CH:21]=[CH:20][N:19]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:16]4=[N:17][CH:18]=3)=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:2]1)(=[O:33])=[O:32]
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@H]3CCNC3)cnc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)CCOCn1ccc2nc(-c3cccnc3N[C@H]3CCN(S(C)(=O)=O)C3)cnc21

Procedure:
((S)-1-Methanesulfonyl-pyrrolidin-3-yl)-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine was prepared from (S)-pyrrolidin-3-yl-{3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-amine and methanesulfonyl chloride, using DIPEA as base and following the general synthetic procedures described in the above Examples.
Reaction SMILES: [Cl:1][C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[F:7][B-:8]([F:11])([F:10])[F:9].[CH3:12][O+](C)C>C(Cl)Cl>[F:7][B-:8]([F:11])([F:10])[F:9].[Cl:1][C:2]1[S:6][CH:5]=[N+:4]([CH3:12])[CH:3]=1
Reactant: Clc1cncs1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[n+]1csc(Cl)c1

Procedure:
Starting material prepared by reaction of 5-chlorothiazole with trimethyloxonium tetrafluoroborate in CH2Cl2 at ambient temperature for 3 hours to give 5-chloro-3-methylthiazolium tetrafluoroborate.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:10]=[O:11])=[C:7]([OH:9])[CH:8]=1)[CH3:2].Br[CH:13]([CH3:17])[C:14]([O-:16])=[O:15].[C:18](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:10]=[O:11])=[C:7]([CH:8]=1)[O:9][CH:13]([CH3:17])[C:14]([O:16][CH3:18])=[O:15])[CH3:2]
Reactant: CCc1ccc(C=O)c(O)c1
Reactant: CC(Br)C(=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1ccc(C=O)c(OC(C)C(=O)OC)c1

Procedure:
A stirred solution of 21.8 grams (0.15 mole) of 5-ethyl-2-formylphenol, 24.2 grams (0.15 mole) of methyl DL-2-bromopropanoate, and 30 grams (0.22 mole) of potassium carbonate in 300 mL of acetone was heated at reflux for about 18 hours. After this time, the reaction mixture was cooled and concentrated under reduced pressure to a residue. The residue was taken up in methylene chloride, washed first with water, and then with an aqueous 10% sodium hydroxide solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel, using a gradient elution starting with 50% methylene chloride in hexane and progressing to 100% methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 9.8 grams of methyl 2-(5-ethyl-2-formylphenoxy)propanoate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([F:8])[CH:7]=1.CN(C)[CH2:13][CH2:14]N(C)CCN(C)C.C([Li])CCC.C([C:30](=[O:34])[C:31]([O-:33])=[O:32])C.Cl>C1COCC1.O>[CH2:13]([O:33][C:31](=[O:32])[CH:30]([C:7]1[C:2]([F:1])=[CH:3][C:4]([O:9][CH3:10])=[CH:5][C:6]=1[F:8])[OH:34])[CH3:14]
Reactant: CCC(=O)C(=O)[O-]
Reactant: COc1cc(F)cc(F)c1
Reactant: CN(C)CCN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1c(F)cc(OC)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.3 %

Procedure:
To a solution of 3,5-difluoroanisole (20 g) in THF (200 ml) was added pentamethyldiethylenetriamine (24.05 g). The mixture was cooled to −75° C. n-butyllithium (85 ml, 1.6 M in hexane) was added in such a way that the temperature did not exceed −67° C. The mixture was stirred for 2 h. Ethylglyoxalate (55.5 g, 50% in toluene) was added and the mixture was stirred for a further 2 h. Afterwards, the mixture was allowed to warm up to rt. Water was added and the mixture was made acidic (pH 3) with 25% HCl. The mixture was extracted with EtOAc. The organic phase was washed with 0.5 N HCl, dried, filtered and concentrated. The product was purified by flash chromatography (SiO2, cyclohexane/EtOAc 7:1) to give (RS)-(2,6-difluoro-4-methoxy-phenyl)-hydroxy-acetic acid ethyl ester (13.09 g). Colorless oil. MS 246.1 ([M]+)
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[OH2:6].[OH-].[Na+].[SH2:9]>CO>[Cl:2][CH2:1][CH:3]([OH:6])[CH2:4][S:9][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2]
Reactant: O
Reactant: ClCC1CO1
Reactant: S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OC(CCl)CSCC(O)CCl
Temperature: 10 °C
Yield: 96 %

Procedure:
185 g (2.0 mol) of epichlorohydrin, 30 g of water, 5 g of methanol and 1.5 g of 32% aqueous solution of sodium hydroxide were mixed together, and 35 g (1.0 mol) of hydrogen sulfide was blown into the mixture with stirring with the temperature of the solution being maintained at 5 to 15° C., thereby obtaining 210 g (0.96 mol, yield: 96%) of bis(3-chloro-2-hydroxypropyl)sulfide.
Reaction SMILES: [CH2:1]([N:13]([CH2:16][CH2:17][OH:18])[CH2:14][CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:19][O:20][C:21]([O:35][CH3:36])([C:31]([F:34])([F:33])[F:32])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1.C(N(CCOC1C=CC(CCC(OC)=O)=CC=1)C)CCCCCCCCCCC>>[CH2:14]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:16][CH2:17][O:18][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][CH2:22][C:21]([O:20][CH3:19])([O:35][CH3:36])[C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=1)[CH3:15]
Reactant: COC(CCc1ccc(O)cc1)(OC)C(F)(F)F
Reactant: CCCCCCCCCCCCN(CC)CCO
Agent: CCCCCCCCCCCCN(C)CCOc1ccc(CCC(=O)OC)cc1
Product: CCCCCCCCCCCCN(CC)CCOc1ccc(CCC(OC)(OC)C(F)(F)F)cc1
Yield: 45.6 %

Procedure:
2-[N-Dodecyl-N-ethylamino]ethanol (250 mg, 0.96 mmol) and 4-(3,3-dimethoxy-4,4,4-trifluorobut-1-yl)phenol (230 mg, 0.87 mmol) were reacted under Mitsunobu conditions as described in the preparation of 3-[4-[2-(N-dodecyl-N-methylamino)ethoxy]phenyl]propanoic acid, methyl ester. The usual work-up followed by chromatography on silica gel (Hexane/ethyl acetate 95:5 to 80:20) afforded the title compound (200 mg, 46%) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([F:22])[CH:18]=2)[N:13]=1.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>O1CCCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([F:22])[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: Fc1ccc2nc(Cl)ccc2c1
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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(-c2ccc3cc(F)ccc3n2)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 80.1 %

Procedure:
3-methylphenyl boronic acid (13 mmol), 2-chloro-6-fluoroquinoline (10 mmol), tetrakis(triphenylphosphine)palladium(0) (0.5 mmol) and potassium carbonate (15 g) are put in a two-neck round-bottom flask and dissolved in tetrahydrofuran (THF) (30 mL) and H2O (10 mL). Subsequently, the resulting solution is stirred in a bath under a temperature of about 100° C. for 24 hours. After completion of the reaction, THF and toluene are removed. The reaction mixture is extracted with dichloromethane and water, and then being distilled under reduced pressure. The resulting residence is filtered by silica gel column and distilled under reduced pressure again. Next, by re-crystallizing and filtering, 2-(3-methylphenyl)-6-fluoroquinoline (1.9 g) is yielded.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([Cl:6])=[O:5].[CH3:12][N:13]1[CH2:18][CH2:17][CH:16]([O:19][C:20]2[CH:21]=[C:22]([NH2:26])[CH:23]=[CH:24][CH:25]=2)[CH2:15][CH2:14]1>O1CCOCC1>[ClH:6].[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:20]([O:19][CH:16]2[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][CH2:15]2)[CH:21]=1)=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CN1CCC(Oc2cccc(N)c2)CC1
Solvent: C1COCCO1
Product: CN1CCC(Oc2cccc(NC(=O)c3c(F)cccc3F)c2)CC1
Product: Cl
Temperature: 110 °C

Procedure:
Using a method similar to Example 1, add 2,6-difluoro-benzoyl chloride (0.68 ml, 0.544 mmol) to a solution of 3-(1-methyl-piperidin-4-yloxy)-phenylamine (preparation 24, 102 mg, 0.494 mmol) in dioxane (3.5 mL) in a sealed tube and heat at 110° C. for 2 hr. Purification by SCX column, eluting with ammonia (2.0 N in methanol) gives the title compound as the free base (154 mg, 90%). Following a method similar to Example 1 gives the title compound as the hydrochloride salt (147 mg, white solid). Mp: 136-8° C.; mass spectrum (free base, ion spray): m/z=347.1 (M+1); 1H NMR (free base, CDCl3): 7.62 (bs, N—H), 7.47 (s, 1H), 7.42 (t, J=2.0 Hz, 7.4 Hz, 1H), 7.24 (t, J=8.1 Hz, 1H), 7.04-6.97 (m, 3H), 6.73 (dd, J=2.0 Hz, 8.1 Hz, 1H), 4.43-4.35 (bm, 1H), 2.75-2.67 (bm, 2H), 2.39-2.33 (bm, 2H), 2.32 (s, 3H), 2.09-2.00 (bm, 2H), 1.92-1.82 (bm, 2H). Analysis calculated for C19H21ClF2N2O2.0.5H2O: C, 58.24; H, 5.66; N, 7.15. Found C, 58.56; H, 5.50; N, 7.12.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[CH2:8]([O:10][C:11]1[N:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1)[CH3:9]>C1COCC1>[CH2:8]([O:10][C:11]1[N:16]=[CH:15][C:14]([O:1][C@@H:2]2[CH2:6][CH2:5][NH:4][C:3]2=[O:7])=[CH:13][CH:12]=1)[CH3:9]
Reactant: O=C1NCC[C@@H]1O
Reactant: CCOc1ccc(O)cn1
Solvent: C1CCOC1
Product: CCOc1ccc(O[C@@H]2CCNC2=O)cn1

Procedure:
A mixture of (S)-3-hydroxy-pyrrolidin-2-one (8.07 g), 6-ethoxypyridin-3-ol (11.0 g) and THF (100 mL) was purged with argon. Triphenylphosphine (20.7 g) was added followed by slow addition of DIAD (16.0 g). After 2 hours the mixture was concentrated and the residue purified by SGC (eluent: EA) to provide the subtitle compound. MS ESI+: m/z=223 [M+H]+.