Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7]1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:11][CH:8]1[CH2:9][CH2:10][N:6]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(S(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methansulfonyl chloride (1.93 ml) added to an ice cooled solution of 3-pyrrolidinol (871.0 mg) and triethylamine (3.47 ml) in dichloromethane (30.0 ml). After 10 mins the coolant was removed and the mixture was stirred at room temperature for 2 h. The mixture was washed with 10% KHSO4 and 10% aq. K2CO3. The organic layer was passed through a hydrophobic frit and the solvent was evaporated.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]1[CH3:15].C[O-].[Na+].[CH:19]([O:22]C(C)C)(C)C.[NH4+].[Cl-]>CO.CN(C=O)C.Cl[Cu].O>[F:1][C:2]1[CH:7]=[C:6]([O:22][CH3:19])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]1[CH3:15]
Reactant: Cc1ccc(C)n1-c1ccc(I)cc1F
Reactant: CC(C)OC(C)C
Agent: Cl[Cu]
Agent: C[O-]
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccc(-n2c(C)ccc2C)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
The crude product from the previous reaction (1-(2-fluoro-4-iodo-phenyl)-2,5-dimethyl-1 H-pyrrole, 70.0 g, 222 mmol) was dissolved in 230 mL of MeOH and 70 mL of DMF. To this solution was added NaOMe (35.9 g, 666 mmol, 3.0 eq) and CuCl (3.3 g, 31 mmol, 15 mol %). The resulting mixture was warmed to reflux for 4 h. After cooling to room temperature, isopropyl ether (IPE) (500 mL), 5% aqueous NH4Cl (220 mL), and water (350 mL) were added, and the mixture was stirred overnight. The mixture was then filtered through celite, the layers were separated, and the aqueous layer extracted with 350 mL of IPE. The combined organic extracts were then washed with 10% aqueous NH4OH (200 mL), and passed through a pad of silica gel (100 g). Concentration provided a brown oil, which crystallized upon standing (45.2 g, 93% yield). Recrystallization from 135 mL of hot hexane provided 30.1 g (62% yield) of product as a brown solid, m.p. 67-69° C. 1H NMR (CDCl3): d 7.12 (t, J=8 Hz, 1H), 6.75 (d, J=8 Hz, 1H), 6.73 (s, 1H), 5.89 (s, 2H), 3.82 (s, 3H), 1.97 (s, 6H); 13C NMR (CDCl3) (9 of 10 lines observed) d 159.1 (d, J=260 Hz), 130.7, 129.5, 109.9 (d, J=3 Hz), 106.0, 105.6, 102.3 (d, J=25 Hz), 55.7, 12.4; MS (El): m/z 219 (100).
Reaction SMILES: C([NH:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH2:7]1)(=O)C>[OH-].[Na+]>[NH2:4][CH2:5][CH:6]1[O:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)[CH2:7]1
Reactant: CC(=O)NCC1CN(CCCOc2ccc(Cl)cc2)CCO1
Agent: [Na+]
Agent: [OH-]
Product: NCC1CN(CCCOc2ccc(Cl)cc2)CCO1
Reaction time: 20 h

Procedure:
A mixture of 2-acetylaminomethyl-4-[3-(4-chlorophenoxy)propyl]morpholine (3.3 g) and 10% aqueous sodium hydroxide solution (60 ml) is refluxed with stirring for 20 hours. The reaction mixture is extracted with chloroform, and the organic layer is washed successively with water and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. Removal of the solvent under reduced pressure gives the title compound as an oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:14])=[O:13])[C:7](=[O:25])[C:6]2([NH:35][C:36](=[O:44])OC1C=CC=CC=1)[C:26]1[C:27]([O:32][CH2:33][CH3:34])=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:2].[CH3:45][N:46]1[CH2:51][CH2:50][CH:49]([N:52]2[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]2)[CH2:48][CH2:47]1.C1COCC1.C(O)(C(F)(F)F)=O>C(#N)C.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])(=[O:13])=[O:14])[C:7](=[O:25])[C:6]2([NH:35][C:36]([N:55]1[CH2:54][CH2:53][N:52]([CH:49]2[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]2)[CH2:57][CH2:56]1)=[O:44])[C:26]1[C:27]([O:32][CH2:33][CH3:34])=[N:28][CH:29]=[CH:30][CH:31]=1)#[N:2]
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: CCOc1ncccc1C1(NC(=O)Oc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOc1ncccc1C1(NC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC)cc2OC)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.2 %

Procedure:
1.00 g (1.63 mmol) of phenyl [5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]carbamate, 596 mg (3.25 mmol) of 1-(1-methylpiperidin-4-yl)piperazine and 8 ml of dried THF were combined and the mixture was stirred at room temperature for 24 hours. The end of the reaction was detected with the aid of analytical HPLC (RP, eluents acetonitrile/water, 0.01% TFA). The solvent was removed, and the residue was purified by preparative HPLC using dichloromethane and 6% methanol as eluents on a Chromolith column (normal phase, from Merck). After repeated column chromatography, it was possible to isolate 230 mg (0.33 mmol, 21%) of the N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide. Alternatively, work-up and purification after the reaction had ended could be carried out as follows: the solvent was removed. The crude material was dissolved in ethyl acetate and extracted with 1 N HCl. The impurities were detected in the organic phase, the product being in the acidic aqueous phase. Accordingly, the aqueous phase was neutralized with 2 N NaOH solution and extracted with ethyl acetate. After drying over magnesium sulphate, filtration and removal of the ethyl acetate under reduced pressure, the product could be crystallized with diethyl ether. The N-[5-cyano-1-[(2,4-dimethoxyphenyl)sulphonyl]-3-(2-ethoxypyridin-3-yl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-(1-methylpiperidin-4-yl)piperazine-1-carboxamide was obtained in yields of >50%.
Reaction SMILES: C1(CCCN)C=CC=CC=1.[CH2:11]1[C:19]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[CH2:13][N:12]1[C:20]([NH:22][C:23]1[N:28]=[N:27][C:26]([C:29]([OH:31])=O)=[CH:25][CH:24]=1)=[O:21].C1C2C(=CC=CC=2)CN1C([NH:43][C:44]1C=C[C:47]([C:48]([OH:50])=O)=[CH:46][CH:45]=1)=O>>[O:50]1[CH2:48][CH2:47][CH2:46][C@H:45]1[CH2:44][NH:43][C:29]([C:26]1[N:27]=[N:28][C:23]([NH:22][C:20]([N:12]2[CH2:11][C:19]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[CH2:13]2)=[O:21])=[CH:24][CH:25]=1)=[O:31]
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccncc3C2)nn1
Agent: NCCCc1ccccc1
Product: O=C(NC[C@@H]1CCCO1)c1ccc(NC(=O)N2Cc3ccncc3C2)nn1

Procedure:
The title compound was prepared as described in Example 1C, substituting (2S)-tetrahydrofuran-2-ylmethamine for 3-phenylpropan-1-amine and 6-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-2-carboxamido)pyridazine-3-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 8.81 (t, J=6.1 Hz, 1H), 8.62 (s, 1H), 8.51 (d, J=5.0 Hz, 1H), 8.31 (d, J=9.3 Hz, 1H), 8.12 (d, J=9.3 Hz, 1H), 7.44 (d, J=5.1 Hz, 1H), 5.05-4.76 (m, 4H), 4.04 (p, J=6.2 Hz, 1H), 3.85-3.74 (m, 1H), 3.70-3.59 (m, 1H), 3.45-3.31 (m, 2H), 1.99-1.72 (m, 3H), 1.69-1.54 (m, 1H); MS (ESI(+)) m/e 369 (M+H)+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([NH:19][CH3:20])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([N:19]([CH3:20])[S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:17][CH:16]=1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CNc1ccc(Cl)cc1
Product: CN(c1ccc(Cl)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1

Procedure:
4-(chlorosulfonyl)benzoic acid (0.5 g, 2.27 mmol) was treated with 4-chloro-N-methylaniline (963 mg, 6.80 mmol) using method A to give 4-(N-(4-chlorophenyl)-N-methylsulfamoyl)benzoic acid as a white solid. Yield: 406 mg (55%). 1H-NMR: 8.11 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.5 Hz, 2H), 3.15 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.Cl.[NH2:19][O:20][CH2:21][CH2:22][NH2:23].N1C=CC=CC=1>C(O)C>[ClH:1].[NH2:23][CH2:22][CH2:21][O:20][N:19]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: N#CCCCCC(=O)c1ccc(Cl)c(Cl)c1
Reactant: NCCON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: N#CCCCCC(=NOCCN)c1ccc(Cl)c(Cl)c1

Procedure:
A mixture of 7.2 mmol (1.85 g) of 3', 4'-dichloro-5-cyanovalerophenone (melting point 49°-51° C), 7.2 mmol (1.08 g) of 2-aminooxyethylamine dihydrochloride, 1.0 ml of pyridine and 7 ml of absolute ethanol was refluxed for 3 hours. The reaction mixture was then further processed in a manner identical to that described in Example 1. After crystallization from an ethanol-ether mixture the above entitled compound was obtained with a melting point of 134°-135° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([S:11][CH3:12])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26](=[O:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C[Si](Cl)(C)C.O>C(O)CCC.CCOC(C)=O>[CH3:12][S:11][C:4]1[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:21][CH2:22][N:23]([C:26](=[O:28])[CH3:27])[CH2:24][CH2:25]3)=[CH:18][CH:19]=2)[N:3]=1
Reactant: CSc1nc(Cl)nc2[nH]ccc12
Reactant: CC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: O
Product: CSc1nc(Nc2ccc(N3CCN(C(C)=O)CC3)cc2)nc2[nH]ccc12
Temperature: 116 °C
Yield: 48.7 %

Procedure:
A mixture of 2-chloro-4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidine (484 mg, 2.43 mmol), 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone (645 mg, 2.95 mmol) and trimethylsilyl chloride (0.500 mL, 3.95 mmol) in nBuOH (10 mL) was heated at 116° C. for 48 h. After cooling down, H2O and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give 1-(4-(4-(4-(methylthio)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)phenyl)piperazin-1-yl)ethanone as a solid (453 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][CH2:9][CH2:8][C:7]2=[O:12]>C(O)(=O)C>[C:6]1([CH2:7][CH2:8][C:9]2[N:10]3[C:11]4[C:6]([C:7](=[O:12])[CH2:8][CH2:9]3)=[CH:5][CH:4]=[CH:3][C:2]=4[N:1]=2)[CH:11]=[CH:2][CH:3]=[CH:4][CH:5]=1
Reactant: Nc1cccc2c1NCCC2=O
Solvent: CC(=O)O
Product: O=C1CCn2c(CCc3ccccc3)nc3cccc1c32
Yield: 82.2 %

Procedure:
A hundred grams of 3-phenylpropionitrile was dissolved in anhydrous ether (200 mL), followed by addition of dry methanol (38 mL) and bubbling with hydrogen chloride gas. The reaction solution was stored overnight in a refrigerator and the precipitating crystals were collected by filtration with ether, yielding colorless crystals (152 g). The resulting crystals (15 g) and 8-amino-2,3-dihydro-4(1H)-quinolinone (10 g) were dissolved in acetic acid (50 mL) and heated under reflux for 8 hrs. The solvent was removed under reduced pressure and a saturated aqueous solution of sodium hydrogencarbonate was added to the residue, thereby making it alkaline. Following extraction with ethyl acetate, the organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography to yield the titled compound as pale yellow crystals (7.0 g). The crystals thus obtained had spectrum data and a melting point that agreed with those obtained in Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7](I)[N:6]=1)=[O:4].[C:25]([Cu])#[N:26].C(Cl)Cl.Cl>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:25]#[N:26])[N:6]=1)=[O:4]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(I)c2ccc(=O)n(Cc3ccccc3)c2c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1nc(C#N)c2ccc(=O)n(Cc3ccccc3)c2c1O
Temperature: 120 °C
Yield: 61.9 %

Procedure:
A mixture of 1-benzyl-8-hydroxy-5-iodo-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (113 mg, 0.26 mmol) and CuCN (46 mg, 0.52 mmol) in DMF (3 mL) was heated at 120° C. for 8 min. After cooling to r.t., CH2Cl2 (50 mL) and 4 M HCl (50 mL) were added. The mixture was stirred vigorously until no more solid was present. The aqueous layer was extracted with additional CH2Cl2, and organic layers were combined, washed with water, and dried over MgSO4. After evaporating the solvent, the crude product was purified by silica gel chromatography (100% CH2Cl2) to give 54 mg of the title compound. MS: (−) m/z 334.30 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][N:19]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Cl:24][C:23]1[C:18]([N:14]2[CH2:15][CH2:16][CH:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:9])=[O:10])[CH2:12][CH2:13]2)=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C1CCNCC1
Reactant: Clc1cccnc1Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Cl)cc1)C1CCN(c2ncccc2Cl)CC1
Yield: 39.7 %

Procedure:
Using the procedure from Example 7A, 4-[(4-chlorophenyl)sulfonyl]piperidine (100 mg, 0.38 mmol) was reacted with 2,3-dichloropyridine (114 mg, 0.76 mmol), DIEA (0.27 ml, 1.52) and 1,4-dioxane (0.3 ml) at 190° C. to afford the title compound (56 mg), a white solid, in 40% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([C:33]([NH:35][CH2:36][CH2:37][C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)=[O:34])=[CH:31][CH:30]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.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]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:13])[F:15])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([C:33](=[O:34])[NH:35][CH2:36][CH2:37][C:38]2[S:39][CH:40]=[CH:41][CH:42]=2)=[CH:31][CH:30]=1
Reactant: NCc1ccc(C(=O)NCCc2cccs2)cc1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: O=C(NCCc1cccs1)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 73.9 %

Procedure:
Use a method similar to the General Procedure 5-3, react 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250 mg, 0.588 mmol) with 4-aminomethyl-N-(2-thiophen-2-yl-ethyl)-benzamide (306 mg, 1.176 mmol) using palladium(II) acetate (26 mg, 0.118 mmol), tris(dibenzylideneacetone)dipalladium(0) (53 mg, 0.059 mmol), BINAP (220 mg, 0.353 mmol) and cesium carbonate (383 mg, 1.176 mmol) in dioxane (6 mL). Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 7:3 and 1:1) to give 7-chloro-6-{4-[(2-thiophen-2-yl-ethyl)-carbamoyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (233 mg, 91%). MS (ES+) m/z: 535 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[C:24]([CH3:27])[CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:29])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1COCC1.[NH:37]1[CH2:40][CH2:39][CH2:38]1>>[N:37]1([C:22]2[N:21]=[C:20]([CH2:19][N:15]3[C@@H:14]([CH3:29])[C@@H:13]([C:5]4[CH:4]=[C:3]([C:2]([F:31])([F:30])[F:1])[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=4)[O:17][C:16]3=[O:18])[C:25]([Br:26])=[C:24]([CH3:27])[CH:23]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: C1CNC1
Reactant: Cc1cc(Cl)nc(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1Br
Solvent: C1CCOC1
Product: Cc1cc(N2CCC2)nc(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1Br
Temperature: 150 °C

Procedure:
In a microwave tube, (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloro-4-methylpyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (500 mg, 0.940 mmol) was dissolved in a 2M solution of azetidine in THF (8 mL, 16.0 mmol). The tube was sealed and the reaction was heated to 150° C. for 2 hr in the microwave. The reaction was then cooled and concentrated. The residue was purified via flash chromatography on silica gel (0 to 75% ethyl acetate/hexanes) to afford (4S,5R)-3-[(6-azetidin-1-yl-3-bromo-4-methylpyridin-2-yl)methyl]-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one. LCMS=551.9 and 553.9 (M+H)+. 1H NMR (CDCl3, 500 MHz) δ 7.87 (s, 1H), 7.77 (s, 2H), 6.09 (s, 1H), 5.77 (d, J=8.7 Hz, 1H), 4.87 (d, J=17.2 Hz, 1H), 4.37 (m, 1H), 4.21 (d, J=16.9 Hz, 1H), 3.99 (m, 4H), 2.38 (m, 2H), 2.30 (s, 3H), 0.77 (d, J=6.7 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4](S(C)(=O)=O)[N:3]=1.[F:22][C:23]([F:32])([F:31])[C:24]1[CH:25]=[C:26]([OH:30])[CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([O:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:31])[F:32])[CH:25]=2)[N:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(S(C)(=O)=O)n1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(Oc2cccc(C(F)(F)F)c2)n1
Yield: 96.8 %

Procedure:
0.32 g of the compound from example 2 are stirred with 0.18 g 3-trifluoromethylphenol and 0.25 g potassium carbonate in 25 ml dry acetonitrile at reflux for 4 hrs. The mixture is diluted with water and extracted with ethyl acetate. 0.39 g of the title compound were isolated (m.p. 124-127° C.).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([S:42](Cl)(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:42]([C:38]4[CH:39]=[CH:40][CH:41]=[C:36]([O:35][CH3:34])[CH:37]=4)(=[O:44])=[O:43])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Br)ccc4ncc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.24 mmol) in dichloromethane (6 ml) was added 3-methoxybenzene-1-sulfonyl chloride (37.08 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 30 mg (42%); 1H NMR (CDCl3, 300 MHz): δ 9.566 (s, 1H), 7.951-7.981 (d, 1H, J=9 Hz), 7.757-7.784 (d, 1H, J=8.1 Hz), 7.636-7.729 (m, 3H), 7.606-7.643 (dd, 1H, J=9 Hz, 2.1 Hz), 7.419-7.479 (m, 3H,), 7.208-7.230 (m, 1H), 6.957-6.963 (d, 1H, 1.8 Hz), 3.833 (s, 3H), 1.795 (s, 6H); MS: m/z 546 [M+-(OCH3)].
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[CH3:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:22][CH:21]=1>>[CH2:12]([O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:28]2[CH2:29][CH2:30][C:25]([CH2:24][C:23]3[CH:22]=[CH:21][C:20]([CH3:19])=[CH:33][CH:32]=3)([OH:31])[CH2:26][CH2:27]2)=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(CC2(O)CCNCC2)cc1
Reactant: BrCCOc1ccc(OCc2ccccc2)cc1
Product: Cc1ccc(CC2(O)CCN(CCOc3ccc(OCc4ccccc4)cc3)CC2)cc1

Procedure:
The title compound, MS: m/e=432.6 (M+H+), was prepared from 1-(2-bromoethoxy)-4-(benzyloxy)-benzene and 4-(4-methyl-benzyl)-piperidin-4-ol.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH2:16]([O:18][C:19](=[O:23])[CH:20](O)[CH3:21])[CH3:17].N1C=CC=CC=1>ClCCl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH:20]([CH3:21])[C:19]([O:18][CH2:16][CH3:17])=[O:23])(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)C(C)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(C)OS(=O)(=O)C(F)(F)F
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a stirred solution of trifluoromethanesulfonic anhydride (30 mL, 170 mmol) in anhydrous dichloromethane (50 mL) was added drop-wise a solution of 2-hydroxypropanoic acid ethyl ester (20 g, 170 mmol) and pyridine (14 mL) in dichloromethane (50 mL) at 0° C. (Ice bath) over a period of 1 h under nitrogen. The ice bath was then removed and the reaction mixture was stirred for additional 2 h. The inorganic salt was then filtered off and the organic solution was washed with water, dried over sodium sulfate, and evaporated to give desired product as pink colored oil (37.4 g, 88%) which was used as such for the next step. 1HNMR (300 MHz, CDCl3): δ 1.38 (t, J=4.8 Hz, 3H), 1.77 (d, J=4.8 Hz, 3H), 4.32-4.37 (m, 2H) and 5.28 (q, J=6.9 Hz, 1H).
Reaction SMILES: C([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[O:14]CCO2)=[C:6]([SiH](C)C)[CH:5]=1)C=C.B1C2CCCC1CCC2.C1C=CC([Br:33])=CC=1.C([O-])([O-])=O.[Na+].[Na+].[Al]>C1COCC1.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.CN(C=O)C>[Br:33][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:14])=[CH:6][CH:5]=1
Reactant: Brc1ccccc1
Reactant: C=CCc1ccc(C2OCCO2)c([SiH](C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 3 %

Procedure:
To a solution 2-(4-allyldimethylsilylphenyl)-1,3-dioxolane (3 Scheme 18, 456 mg, 2 mmol) in dry THF (10 mL) under a N2 atmosphere was added 9-BBN (4 mL, 0.5 M solution in THF, 2 mmol) dropwise at 0° C. The mixture was gradually warmed to room temperature and stirred for 5 h. Pd(PPh3)4 (70 mg), 4-bromopolystyrene (500 mg, 1.94 mmol/g), 2 N aqueous Na2CO3 (2 mL, 4 mmol), DMF (5 mL), were added. The reaction flask and reflux condenser were wrapped with aluminum foil, and the mixture was refluxed for 24 h. Pd(PPh3)4 (70 mg) was added to the reaction mixture which was refluxed again for 24 h. The resin was filtered and washed with THF (once), 1:1 THF/water (twice), water (twice), methanol (twice), CH2Cl2 (twice), then dried under reduced pressure. The resin (4 Scheme 18) was agitated in THF/1 N HCl (8:1) for 16 h at 30° C. After washing and drying, an aliquot of the resin (200 mg) was treated with a solution of CH2Cl2 (7 mL) and Br2 (150 μL) for 5 min. The cleavage solution was removed, and the resin was rinsed with CH2Cl2 (3 mL). Concentration of the combined filtrates gave the known 4-bromobenzaldehyde (1 Scheme 18, 11 mg, loading level was determined to be 0.30 mequiv/g); 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J=8.30 Hz, 2 H), 7.77 (d, J=8.30 Hz, 2 H), 10.00 (s, 1 H).