Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[C:6]([C:8]1[CH:9]=[C:10]([NH:14][C:15]([C:17]2[CH:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])[CH:20]=[CH:21]C=2O)=[O:16])[CH:11]=[CH:12][CH:13]=1)#[N:7]>O1CCCC1.N1C=CC=CC=1>[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[C:19]1[CH:20]=[CH:21][C:5]2[O:4][C:2](=[O:3])[N:14]([C:10]3[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=3)[C:6]#[N:7])[C:15](=[O:16])[C:17]=2[CH:18]=1
Reactant: N#Cc1cccc(NC(=O)c2cc(-c3ccc(F)cc3F)ccc2O)c1
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1cccc(-n2c(=O)oc3ccc(-c4ccc(F)cc4F)cc3c2=O)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 49 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 9 (1.4 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% 1HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 21.
Reaction SMILES: [Si]([O:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][CH2:26][C:27]([CH2:31][CH3:32])([OH:30])[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@@H:9]1[C@@:37]2([CH3:38])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:39])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C@@H:21]([S:23][CH2:24][CH2:25][CH2:26][C:27]([CH2:31][CH3:32])([OH:30])[CH2:28][CH3:29])[CH3:22])[CH2:12][C@@H:11]([OH:40])[CH2:10]1
Reactant: CCC(O)(CC)CCCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(O)(CC)CCCS[C@@H](C)C1=CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 79.6 %

Procedure:
Under the same conditions as in Example 9, the crude 1α-(tert-butyldimethylsilyloxy)-3β-hydroxy-20(S)-(4-ethyl-4-hydroxyhexylthio)pregna-5,7,16-triene (71.4 mg) obtained in Example 8, tetrahydrofuran (2 ml) and 1M tetra-n-butyl-ammonium fluoride solution in tetrahydrofuran (2 ml) were reacted and worked up, and then the residue was purified by preparative thin layer chromatography (0.5 mm×2, dichloromethane:ethanol=7:1, developed once) to give the title compound as a colorless oil (45.8 mg, 67%, 2 steps).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:16]O.S(Cl)([Cl:20])=O>>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:16][Cl:20]
Reactant: OCc1cnc2cc(C(F)(F)F)ccc2c1O
Reactant: O=S(Cl)Cl
Product: Oc1c(CCl)cnc2cc(C(F)(F)F)ccc12
Yield: 82.6 %

Procedure:
4-Hydroxy-7-trifluoromethyl-3-(hydroxymethyl)-quinoline (3.6 grams) was added to an excess (5.9 grams) of thionyl chloride and the mixture was refluxed for 1 hour. Excess thionyl chloride was then evaporated and the remaining residue was crystallized from hexane to give 4-hydroxy-7-trifluoromethyl-3-(chloromethyl)-quinoline (3.2 grams).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5](=[O:16])[C:6]([CH2:14][OH:15])=[CH:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1.[CH2:17](I)[CH3:18]>CN(C)C=O.ClCCl>[CH2:17]([O:3][C:4]1[C:5](=[O:16])[C:6]([CH2:14][OH:15])=[CH:7][CH:8]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:10]=1)[CH3:18]
Reactant: CC(C)c1ccc(CO)c(=O)c(O)c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1cc(C(C)C)ccc(CO)c1=O
Temperature: 70 °C
Yield: 37.5 %

Procedure:
60% oily sodium hydride (256 mg, 6.4 mmol) was added to a solution of 2-hydroxy-7-hydroxymethyl-4-isopropyl-2,4,6-cycloheptatrien-1-one (1.13 g, 5.82 mmol) in dimethylformamide (5 ml) with stirring. Then, ethyl iodide (0.7 ml, 8.75 mmol) was added and the reaction mixture was heated at 70° C. for 3 hours. The reaction solution was diluted with dichloromethane, washed with water, and dried over sodium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [eluent:hexane/ethyl acetate (2:3)] to give 485 mg of 2-ethoxy-7-hydroxymethyl 4-isopropyl-2,4,6-cycloheptatrien-1-one as a pale yellow amorphous powder (yield: 76%).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:16](=[O:19])[NH:17][N:18]=2)[C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.Cl[CH2:21][C:22]1[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[C:3]2[N:4]([C:16](=[O:19])[N:17]([CH2:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=3)[N:18]=2)[C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c2n[nH]c(=O)n12
Reactant: Cc1nc(C(F)(F)F)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(Br)c(-c3ccc(Cl)cc3)cc(C)n2c1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a solution of 8-bromo-7-(4-chlorophenyl)-5-methyl-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (42 mg, 0.124 mmol), and 3-(chloromethyl)-2-methyl-6-(trifluoromethyl)pyridine (39 mg, 0.186 mmol) in anhydrous DMF (0.5 mL) was added anhydrous potassium carbonate (34.6 mg, 0.25 mmol). The resulting suspension was stirred under argon at 80° C. for 1 h. After cooling to room temperature, the reaction mixture was diluted with water (10 mL). The resulting precipitate was filtered, washed with water, and dried in a vacuum oven at 60° C. for 16 h to afford 56 mg (89%) of the title compound as an off-white solid. HPLC/MS: retention time=4.15 min, [M+H]+=512.2.
Reaction SMILES: O[CH2:2][C@H:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:4]1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=O)[O:29]C2C=CC=CC=2)=[CH:23][C:22]=1[C:37]([F:40])([F:39])[F:38])#[N:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>CC(N(C)C)=O.CCOC(C)=O>[C:19]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:2][C@@H:3]3[CH2:4][N:5]([C:9]([O:11][CH2:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:10])[CH2:6][CH2:7][N:8]3[C:28]2=[O:29])=[CH:23][C:22]=1[C:37]([F:38])([F:39])[F:40])#[N:20]
Reactant: N#Cc1ccc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Reactant: O=C(OCc1ccccc1)N1CCN[C@H](CO)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N2C[C@@H]3CN(C(=O)OCc4ccccc4)CCN3C2=O)cc1C(F)(F)F
Temperature: 40 °C
Reaction time: 0.25 h
Yield: 51.3 %

Procedure:
To (S)-benzyl 3-(hydroxymethyl)piperazine-1-carboxylate (256 mg, 1.02 mmol) in DMA (1 mL) was added phenyl 4-cyano-3-(trifluoromethyl)phenylcarbamate (250 mg, 0.82 mmol), and the mixture was heated to 40° C. for 5 h. The reaction was cooled to RT, and PPh3 (321 mg, 1.22 mmol) followed by DIAD (241 μL, 1.22 mmol) were added to the reaction. After stirring for 15 min at RT, the reaction was diluted with EtOAc (20 mL) and washed twice with 0.5 N NaOH (10 mL), then twice with sat'd brine (10 mL). The EtOAc was dried over MgSO4 then concentrated in vacuo. The residue was taken up in CH2Cl2 (5 mL) and cooled to −10° C., and Et2O (5 mL) was added. The resulting precipitate was collected by filtration and rinsed with cold 1:1 Et2O:CH2Cl2 to give Example 1, (R)-benzyl 2-(4-cyano-3-(trifluoromethyl)phenyl)-3-oxo-hexahydroimidazo[1,5-a]pyrazine-7(1H)-carboxylate 187 mg (52%). HPLC RT: 3.253 min (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous MeOH over 4 minutes containing 0.1% TFA, 4 ml/min, monitoring at 220 nm). (M+H)+:445.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[SH:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]>>[C:1]([CH2:2][CH2:3][S:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])#[N:4]
Reactant: O=C(O)CCS
Reactant: C=CC#N
Product: N#CCCSCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 47.2 %

Procedure:
The mixture of acrylonitrile (5.31 g.) and 3-mercaptopropionic acid (10.6 g.) was stirred for 1 day at ambient temperature and distilled under reduced pressure to give colorless liquid of 3-(2-cyanoethylthio)propionic acid (7.5 g.). B. p. 124°-126° C./10-13 mm Hg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH:18]1([C:21]#[C:22][C:23]2[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=2)[CH2:20][CH2:19]1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([C:22]#[C:21][CH:18]4[CH2:20][CH2:19]4)=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ccc(C#CC2CC2)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ccc(C#CC4CC4)cn3)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 5-cyclopropylethynyl-pyridine-2-carboxylic acid (CAS 1174322-62-3; WO2009091016) following procedure I yielded the title compound as a white foam. MS (ISP): m/z=411.3 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:15]=2)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1.[NH2:34][C:35]1[C:40]([CH:41]([OH:47])[C:42]([N:44]([CH3:46])[CH3:45])=[O:43])=[CH:39][C:38](Br)=[CH:37][N:36]=1.C(=O)(O)[O-].[Na+]>C(#N)C.O1CCCC1>[NH2:34][C:35]1[C:40]([CH:41]([OH:47])[C:42]([N:44]([CH3:45])[CH3:46])=[O:43])=[CH:39][C:38]([C:14]2[CH:15]=[C:16]3[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])=[CH:9][N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:11]3=[N:12][CH:13]=2)=[CH:37][N:36]=1
Reactant: CC1(C)OB(c2cnc3c(c2)c(-c2ccccc2F)cn3COCC[Si](C)(C)C)OC1(C)C
Reactant: CN(C)C(=O)C(O)c1cc(Br)cnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CN(C)C(=O)C(O)c1cc(-c2cnc3c(c2)c(-c2ccccc2F)cn3COCC[Si](C)(C)C)cnc1N
Temperature: 80 °C
Yield: 39.3 %

Procedure:
3-(2-Fluoro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (289 mg, 0.617 mmol), 2-(2-amino-5-bromo-pyridin-3-yl)-2-hydroxy-N,N-dimethyl-acetamide (168.5 mg, 0.617 mmol) and dichloro[1,1′-bis(diphenyl-phosphino)ferrocene]palladium(II) dichloromethane adduct (25 mg, 0.031 mmol) were combined in 1:1 acetonitrile/tetrahydrofuran (4 mL) under nitrogen. Saturated sodium bicarbonate was added (4 mL), also under nitrogen, and the mixture was capped and heated for 18 h at 80° C. After cooling, the aqueous layer was removed and the organic layer was purified by silica gel chromatography using DCM and MeoH as eluent to afford 2-{2-Amino-5-[3-(2-fluoro-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-2-hydroxy-N,N-dimethyl-acetamide (130 mg, 39.3%). MS: m/z 536 (M+H+).
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].[CH3:30][S:31]([C:34]1(F)[CH:39]=[CH:38][CH:37]=[CH:36][CH2:35]1)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[S:31]([CH3:30])(=[O:33])=[O:32])[CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: CS(=O)(=O)C1(F)C=CC=CC1
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1cc2ccccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 38.3 %

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride (10 g, 23.7 mmol) obtained in Step 2 and 1-flourophenyl methyl sulfone (4.9 g, 28.4 mmol) in 50 ml of dimethylformamide, was added potassium carbonate (8.2 g, 59.3 mmol). The reaction mixture was stirred overnight at about 100° C., cooled to room temperature, diluted with 200 ml of ethyl acetate, and washed with brine. The resulting organic layer was dried and concentrated on sodium sulfate. The resulting residue was purified with column chromatography to give 4.9 g of the titled compound as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])=[C:4]([Cl:19])[CH:3]=1.C([Li])CCC.CCCCCC.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O1CCCC1>[Cl:19][C:4]1[C:5]([O:8][Si:9]([CH:13]([CH3:15])[CH3:14])([CH:16]([CH3:18])[CH3:17])[CH:10]([CH3:11])[CH3:12])=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CC(C)[Si](Oc1ccc(Cl)cc1Cl)(C(C)C)C(C)C
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1c(Cl)ccc(O[Si](C(C)C)(C(C)C)C(C)C)c1Cl
Reaction time: 1 h

Procedure:
To a solution of 1,3-dichloro-4-triisopropylsilyloxybenzene (6.00 g) in tetrahydrofuran (50 ml) at -60° C. was added dropwise n-butyllithium, 1.6M solution of hexane (12.9 ml) over 30 minutes under nitrogen and the mixture was stirred for 1 hour at the same temperature. A solution of ethyl chloroformate in tetrahydrofuran (20 ml) was added dropwise to the mixture over 20 minutes at -60° C. The resulting mixture is stirred for 1 hour at -60° C., the cooling bath was removed, and temperature was allowed to rise to 20° C. A solution of ammonium chloride (2 g) in water (37 ml) was then added over 5 minutes followed by ethyl acetate (40 ml) and brine (40 ml). The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:10 to 1:6) to give ethyl 2,6-dichloro-3-triisopropylsilyloxybenzoate (1.59 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9](C(OCC2C3C=CC=CC=3C3C2=CC=CC=3)=O)[CH2:8][CH2:7][N:6]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:4].C(NCC)C>CN(C=O)C>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][N:6]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:4]
Reactant: COC(=O)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCN1C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COC(=O)C1CNCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperazine-1,2,4-tricarboxylic acid 1-tert-butyl ester 4-(9H-fluoren-9-ylmethyl) ester 2-methyl ester (2.03 mmol) in DMF (4.0 mL) was added diethylamine (5%) and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and purified using ethyl acetate/methanol (10%). ESI-MS m/z: 245(M+1), UV retention time: 0.78 min.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:15][CH2:16][OH:17])[CH2:10][CH2:9]1)C1C=CC=CC=1.[BrH:18].[H][H]>C(O)C.[Pd]>[BrH:18].[OH:17][CH2:16][CH2:15][O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: OCCOC1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: OCCOC1CCNCC1

Procedure:
A solution of (B) (12 g) in ethanol (200 ml) was neutralized with an ethanolic solution of hydrogen bromide and hydrogenated in the presence of 10% palladium on carbon (2.4 g). After 5 hours the uptake of hydrogen ceased and the catalyst was removed by filtration. The filtrate was taken to dryness in vacuo to give (C) as a semicrystalline solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:10][CH:9]1[C:11]1[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=1.[IH:26]>O1CCOCC1>[IH:26].[I:26][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([CH3:21])=[C:15]([S:17]([NH2:20])(=[O:19])=[O:18])[CH:16]=1)[CH2:10][NH:8][CH2:7][CH2:6][O:5][C:4]1[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=1[O:2][CH3:1]
Reactant: COc1ccccc1OCCN1CC1c1ccc(C)c(S(N)(=O)=O)c1
Agent: I
Solvent: C1COCCO1
Product: COc1ccccc1OCCNCC(I)c1ccc(C)c(S(N)(=O)=O)c1
Yield: 70.3 %

Procedure:
In 50 ml of dioxane was dissolved 2.5 g of 5-{1-[2-(2-methoxyphenoxy)ethyl]aziridin-2-yl}-2-methylbenzenesulfonamide and after adding thereto 1 g of concentrated hydroiodic acid, the mixture was stirred overnight. After the reaction was over, the solvent was distilled off under reduced pressure and the residue was washed thrice with 30 ml of water and then thrice with 200 ml of ether and crystallized by the addition of ethyl acetate. The crystals were recovered by filtration, washed with water, and dried to provide 1.7 g of 5-{1-iodo-2-[2-(2-methoxyphenoxy)ethylamino]ethyl}-2-methylbenzenesulfonamide hydroiodide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:37])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=3[O:34][CH2:35][CH3:36])=[N:9]2)=[CH:4][CH:3]=1.[OH:38][CH2:39][CH2:40][NH:41][CH2:42][CH2:43][OH:44]>>[OH:38][CH2:39][CH2:40][N:41]([CH2:42][CH2:43][OH:44])[C:21]([N:11]1[C:12]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([CH3:37])[N:9]=[C:10]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:32])([F:33])[F:31])=[CH:26][C:25]=1[O:34][CH2:35][CH3:36])=[O:22]
Reactant: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: OCCNCCO
Product: CCOc1cc(C(F)(F)F)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)N(CCO)CCO

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-4-trifluoromethyl-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with bis-(2-hydroxyethyl)-amine (Sigma) to give the title compound. HR-MS (ES, m/z) calculated for C31H33N3O4F3Cl2 [(M+H)+] 638.1795, observed 638.1797.
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:34]=[CH:33][C:20]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=1)=[O:13]>O.C1COCC1>[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:34]=[CH:33][C:20]([O:21][CH2:22][C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=1)=[O:13]
Reactant: COC(=O)c1ccccc1COc1ccc(CCNC(=O)Nc2ccc(F)cc2F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCc1ccc(OCc2ccccc2C(=O)O)cc1)Nc1ccc(F)cc1F
Yield: 54.8 %

Procedure:
Lithium hydroxide (3.7 mg, 0.154 mmol) in water (1 ml) was added into methyl 2-({4-[2-({[(2,4-difluorophenyl)amino]carbonyl}amino)ethyl]phenoxy}methyl)benzoate (34 mg, 0.077 mmol) dissolved in THF (2 ml). The mixture was then irradiated in a microwave oven (Smith Synthesizer) at 150° C. for 7 minutes and then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜4, and extracted with ethyl acetate (×2). The organic extracts were combined and dried with magnesium sulphate and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 1 g/6 ml) using MeOH/DCM (1:99, 2:98, 4:96 and then 10:90) as eluant gave 18 mg the desired product, yield 55%.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)(=O)=O.[I-:21].[Na+].O>CC(C)=O>[C:11]1([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][I:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OCCCCCc1cccc2ccccc12
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: ICCCCCc1cccc2ccccc12
Yield: 85.9 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 4.1 grams (0.014 mole) of 1-methylsulfonyloxy-5-(naphth-1-yl)pentane, and 4.2 grams (0.028 mole) of sodium iodide in 150 mL of acetone was heated at reflux for 2.5 hours. The reaction mixture was poured into 400 mL of water, and the mixture was extracted with two 100 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 3.9 grams of 5-(naphth-1-yl)pentyl iodide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]=4[Cl:29])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1.O1CCCC1.O.O.[OH-].[Li+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:19]4[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=4[Cl:29])[CH3:18])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:30]=1
Reactant: COC(=O)c1ccc(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2)c1ccc(C(=O)O)cc1Cl
Reaction time: 8 h

Procedure:
To a solution of methyl 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoate (0.180 g, 0.355 mmol) in tetrahydrofuran (6.00 mL, 74.0 mmol) and water (6.00 mL, 333 mmol) was added lithium hydroxide, monohydrate (0.0596 g, 1.42 mmol). The reaction mixture was stirred at room temp. overnight. The reaction mixture was concentrated. The reaction mixture was acidified with 1M HCl then extracted with DCM (3×). The combined organics were dried (Na2SO4), filtered and concentrated to give 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid. To a solution of 4-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-3-chlorobenzoic acid (175 mg, 0.355 mmol;) in methylene chloride (5.1 mL, 79 mmol) was added 1-methyl-piperazine, (0.047 mL, 0.43 mmol), N,N-diisopropylethylamine (0.618 mL, 3.55 mmol) then O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.269 g, 0.710 mmol). The mixture was stirred at room temp. for 2 hr. LCMS indicated the reaction was complete. The reaction was quenched with sat. NH4Cl, extracted with DCM (2×). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (5% MeOH/DCM) to give 8-bromo-N-(2-chloro-4-(4-methylpiperazine-1-carbonyl)phenyl)-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamide (yield 82%). MS: (ESI+) 576.4