Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.[OH-].[Na+]>>[O:14]1[CH2:15][CH2:16][N:1]([C:2]2[CH:10]=[CH:9][C:5]3[S:6][CH:7]=[CH:8][C:4]=3[CH:3]=2)[CH2:12][CH2:13]1
Reactant: Nc1ccc2sccc2c1
Reactant: ClCCOCCCl
Agent: [Na+]
Agent: [OH-]
Product: c1cc2cc(N3CCOCC3)ccc2s1
Yield: 69.3 %

Procedure:
5-Aminobenzo[b]thiophene (5.4 g, 0.0362 mole), bis-(2-chloroethyl)ether (5.2 g, 0.0364 mole) and 40% aqueous NaOH (0.073 mole) were stirred vigorously and heated to refluxing for 22 hours. The cooled mixture was extracted with CHCl3. Evaporation of the washed and dried CHCl3 extract under reduced pressure left 7.0 g (88%) of the crude product as a slightly oily, dark yellow solid. This material was combined with 1.75 g of comparable crude product from a previous run. Recrystallization from CH3CN afforded 5.50 g of 5-morpholinobenzo[b]thiophene, m.p. 127°-132° C., that was characterized by nmr.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([N:18]1[CH2:24][CH2:23][CH:22]2[C:20]([CH2:25][OH:26])([CH2:21]2)[CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.CCN(CC)CC>[CH2:11]([N:18]1[CH2:24][CH2:23][CH:22]2[C:20]([CH:25]=[O:26])([CH2:21]2)[CH2:19]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: OCC12CC1CCN(Cc1ccccc1)C2
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CS(C)=O
Product: O=CC12CC1CCN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of oxalyl chloride (0.22 ml, 2.54 mmol) in CH2Cl2 (2 ml) at −55° C. was added a solution of DMSO (0.30 ml, 4.24 mmol) in CH2Cl2 (1 ml). The mixture was stirred for 2 min. Then, a solution of 173 (230 mg, 1.06 mmol) in CH2Cl2 (1 ml) was added dropwise. After stirring for 15 min at −55° C., Et3N (1.4 ml) was added slowly. The mixture was stirred for 5 min and then warmed to room temperature. Aqueous NaHCO3 (5 ml) was added. The two layers were separated; and the aqueous layer was extracted with CH2Cl2 (2×5 ml). The combined organics were dried (Na2SO4), filtered and evaporated to give the crude product. Chromatography (1% MeOH in CH2Cl2) gave 174 as a light red liquid. 1H-NMR (300 MHz, CDCl3) (partial) δ 9.42 (s, 1H), 7.30 (m, 5H); LRMS (calculated for C14H17NO) 215, found 215.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([F:15])=[C:4]([F:16])[N:3]=1.[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[H-].[Na+]>O1CCCC1>[F:16][C:4]1[C:5]([F:15])=[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:7]([F:8])=[C:2]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:3]=1
Reactant: Fc1nc(F)c(F)c(N2CCOCC2)c1F
Reactant: OCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1nc(OCCN2CCOCC2)c(F)c(N2CCOCC2)c1F
Reaction time: 8 h
Yield: 95 %

Procedure:
4-(2,3,5,6-Tetrafluoro-pyridin-4-yl)-morpholine (2.36 g; 10 mmol) was dissolved in tetrahydrofuran (50 mL). To the solution was added 4-(2-hydroxyethyl)-morpholine (1.57 g; 12 mmol) followed by sodium hydride (288 mg; 12 mmol), and it was stirred overnight. The solvent was then evaporated, and the solid was purified by column chromatography to give 4-[2,3,5-trifluoro-6-(2-morpholin-4-yl-ethoxy)-pyridin-4-yl]-morpholine (3.3 g).
Reaction SMILES: CS([C:4]1[S:5][C:6]2[CH:12]=[C:11]([CH2:13][N:14]3[C:18]4=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=[C:17]4[N:16]=[CH:15]3)[CH:10]=[CH:9][C:7]=2[N:8]=1)=O.[NH2:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[OH:34].CCN(C(C)C)C(C)C>CC(N(C)C)=O.CCOC(C)=O>[F:25][C:23]([F:24])([F:26])[C:21]1[CH:22]=[C:17]2[N:16]=[CH:15][N:14]([CH2:13][C:11]3[CH:10]=[CH:9][C:7]4[N:8]=[C:4]([NH:27][C@@H:28]5[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]5[OH:34])[S:5][C:6]=4[CH:12]=3)[C:18]2=[N:19][CH:20]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(C(F)(F)F)cnc43)cc2s1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(C(F)(F)F)cnc43)cc2s1
Temperature: 130 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
A mixture of 2-(methylsulfinyl)-6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazole (180 mg, 0.45 mmol), (1R,2R)-2-aminocyclohexanol (112 mg, 0.97 mmol) and DIEA (261 mg, 2 mmol) in DMA (2 mL) was stirred at 130° C. overnight. The reaction mixture was diluted with EtOAc and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford (1R,2R)-2-((6-((6-(trifluoromethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol as a yellow solid (64 mg, 31.8%). 1H NMR (300 MHz, DMSO-d6) δ 8.84 (s, 1H), 8.78 (d, J=1.2 Hz, 1H), 8.55 (d, J=1.5 Hz, 1H), 7.95 (d, J=7.8 Hz, 1H), 7.68 (d, J=1.5 Hz, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.25-7.22 (m, 1H), 5.55 (s, 2H), 4.71 (d, J=5.1 Hz, 1H), 3.52-3.50 (m, 1H), 3.37-3.33 (m, 1H), 2.08-2.01 (m, 1H), 1.87-1.85 (m, 1H), 1.64-1.60 (m, 2H), 1.29-1.19 (m, 4H). LCMS (ESI) m/z 448 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([C:9]#[N:10])[S:8][C:4]=2[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][CH2:21]Cl)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[C:9]([C:7]1[S:8][C:4]2[CH:3]=[C:2]([O:1][CH2:21][S:20][C:17]3[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=3)[CH:12]=[CH:11][C:5]=2[N:6]=1)#[N:10]
Reactant: N#Cc1nc2ccc(O)cc2s1
Reactant: ClCSc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1nc2ccc(OCSc3ccc(Cl)cc3)cc2s1
Temperature: 25 °C
Yield: 37 %

Procedure:
The mixture of 6-hydroxy-2-cyanobenzothiazole (0.45 g, 2.59 mmol), 1-chloro-4-chloromethylthiobenzene (0.50 g, 2.59 mmol), potassium carbonate (0.36 g, 2.61 mmol) and sodium iodide (0.01 g) in acetone (30 ml) was heated to reflux 30 minutes. Upon cooling to room temperature, the insoluble solid was removed by filtration. The solvent of filtrate was removed under reduced pressure, the residue was dissolved minimum amount of acetone with heating. The solution was cooled at 0° C. and yellow crystals were formed immediately. The solid was collected by filtration to give a yield of 37%.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:13][CH:12]=1)(=O)=O.[C-:35]#[N:36].[K+]>>[CH3:24][C:23]1[O:22][C:21]([C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)=[N:20][C:19]=1[CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:35]#[N:36])=[CH:12][CH:13]=1
Reactant: [C-]#N
Reactant: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCCCOS(C)(=O)=O)cc1
Agent: [K+]
Product: Cc1oc(-c2ccc3ccccc3c2)nc1COc1ccc(CCCCCC#N)cc1

Procedure:
According to the method described for Reference Example 38, 5-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]pentyl methanesulfonate was allowed to react with potassium cyanide to give 6-[4-[5-methyl-2-(2-naphthyl)-4-oxazolylmethoxy]phenyl]hexanenitrile. Recrystallization from ethyl acetate--isopropyl ether gave colorless prisms, m.p.116°-117° C.
Reaction SMILES: C(C1[CH:4]=[C:5]2[C:10](=[C:11]3[S:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:12]=13)[CH:9]=[N:8][CH:7]=[CH:6]2)#N.[OH-].[K+].[C:22]([OH:25])(=[O:24])[CH3:23]>OCC(CO)O.O>[C:22]([C:23]1[CH:4]=[C:5]2[C:10](=[C:11]3[S:15][C:14]4[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=4[C:12]=13)[CH:9]=[N:8][CH:7]=[CH:6]2)([OH:25])=[O:24]
Reactant: CC(=O)O
Reactant: N#Cc1cc2ccncc2c2sc3ccccc3c12
Agent: [K+]
Agent: [OH-]
Solvent: OCC(O)CO
Solvent: O
Product: O=C(O)c1cc2ccncc2c2sc3ccccc3c12

Procedure:
One hundred thirty mg (0.5 mM) of 6-cyanobenzothieno[3,2-h]isoquinoline (4), prepared in Example 1, was suspended in a hot solution of 168 mg (3 mM) KOH in 1 ml glycerine. The reaction mixture was stirred and heated at 160° C.-170° C. overnight. The resulting yellow solution was cooled, diluted with water and made slightly acidic with glacial acetic acid. A yellow precipitate was collected, washed with water, and air dried to yield 120 mg of product. This initial product was recrystallized from a mixture of DMSO and water to give 78 mg product, mp greater than about 305° C. This then was dried at 80° C./0.2 mm overnight, and characterized as compound 6 using I.R. and mass spectrometry.
Reaction SMILES: [CH3:1][C:2](=[O:10])/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H]>CC(O)C>[CH3:1][CH:2]([OH:10])/[CH:3]=[CH:4]/[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCC/C=C/C(C)=O
Reactant: [H][H]
Solvent: CC(C)O
Product: CCCCC/C=C/C(C)O
Reaction time: 16 h
Yield: 95 %

Procedure:
Chiral hydrogenation of (E)-3-nonene-2-one was carried out(see formula (14) below). That is, a reaction was carried out in accordance with the procedures of Example 4 using the (S,SS)-ruthenium hydride complex (1.5 mg; 0.00125 mmol) synthesized in Example 2 and using (E)-3-nonene-2-one (701 mg; 5.0 mmol) (made by Tokyo Kasei Kogyo Co., Ltd.)as the substrate and 2-propanol (2.5 mL) as the solvent. However, the hydrogen pressure was set to 8 atmosphere, the reaction temperature was set to 25° C., and the reaction time was set to 16 hours. As a result, (E)-3-nonene-2-ol was obtained at a GC yield of 95%, isolation yield of 93% (668 mg; 4.65 mmol), and enantiomeric excess of 99%. GC (column: Chirasil-DEX CB; column temperature: 65° C.; injection and detection temperature: 200° C.; helium pressure: 41 kPa; tR of (R)-(E)-3-nonene-2-ol: 70.5 minutes(99.6%); tR of (S)-(E)-3-nonene-2-ol:80.7 minutes (0.4%)); [α]26D+21.16° (c:1.042; CHCl3); absolute structure: R; literature value: [α]25D+10.68° (c:1.03; CHCl3), 97% ee (R).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[CH:4]([C:19]([NH:21][C:22]2([C:25]3[CH:34]=[CH:33][C:28]([C:29]([O:31]C)=[O:30])=[CH:27][CH:26]=3)[CH2:24][CH2:23]2)=[O:20])[CH2:3]1.O[Li].O>>[CH3:1][C:2]1([CH3:35])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)[CH:4]([C:19]([NH:21][C:22]2([C:25]3[CH:26]=[CH:27][C:28]([C:29]([OH:31])=[O:30])=[CH:33][CH:34]=3)[CH2:24][CH2:23]2)=[O:20])[CH2:3]1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC(C)(C)CCN3Cc3ccc(C(F)(F)F)cc3)CC2)cc1
Agent: [Li]O
Solvent: O
Product: CC1(C)CCN(Cc2ccc(C(F)(F)F)cc2)C(C(=O)NC2(c3ccc(C(=O)O)cc3)CC2)C1
Yield: 64.5 %

Procedure:
The title compound (E12) (88.4 mg) was prepared according to the general procedure for esters hydrolysis (Method C) starting from methyl 4-(1-(4,4-dimethyl-1-(4-(trifluoromethyl)benzyl)piperidine-2-carboxamido)cyclopropyl)benzoate (enantiomer 2) (D131 b) (141 mg). (LiOH H2O: 4 eq; reaction time: 18 hrs)
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a suspension of sodium hydride in DMF (50 ml) at 0° C. was added dropwise a solution of methyl 3-(4-hydroxyphenyl)propionate (10.0 g, 55.5 mmol) and benzyl bromide (7.93 ml, 66.7 mmol) dissolved in DMF (100 ml). The mixture was stirred at room temperature for 16 hours, cooled to 0° C., quenched with aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (2×150 ml). The combined organic layers were washed with aqueous ammonium chloride (50 ml), brine (3×60 ml), dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from hexane-ethyl acetate to give the title compound (13.7 g, 91%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]([CH3:12])[C:10](=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[C:14]([O:13][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([CH3:1])[C:11]=1[CH3:12])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: CC1=Nc2ccccc2C(=O)C1C
Product: CC(=O)Oc1c(C)c(C)nc2ccccc12

Procedure:
A solution of 1.73 g of 2,3-dimethyl-4-quinolone in 25 ml of acetic anhydride was stirred at 130° C. for 8 hours. The solution was evaporated to remove the solvent under reduced pressure, and 30 ml of chloroform was added to the solution. The mixture was washed with an aqueous saturated sodium hydrogen carbonate solution and water and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the crude product thus obtained was purified by silica gel column chromatography (Wako Gel C-200) to give 1.87 g of 4-acetoxy-2,3-dimethylquinoline.
Reaction SMILES: [CH3:1][NH:2][N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[O:9].[Cl:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21]([CH:25]=O)=[CH:22][CH:23]=3)[CH:18]=[N:17]2)=[C:13]([C:29]([F:32])([F:31])[F:30])[CH:12]=1>>[Cl:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2[C:24]3[C:19](=[CH:20][C:21](/[CH:25]=[C:6]4/[C:7](=[O:8])[N:3]([NH:2][CH3:1])[C:4](=[O:9])[S:5]/4)=[CH:22][CH:23]=3)[CH:18]=[N:17]2)=[C:13]([C:29]([F:30])([F:32])[F:31])[CH:12]=1
Reactant: CNN1C(=O)CSC1=O
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Product: CNN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C1=O

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(methylamino)-1,3-thiazolidine-2,4-dione was prepared from 3-methylaminothiazolidine-2,4-dione (from Example 357) and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure E.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:23][C:24]1[CH:33]=[CH:32][C:27]2[O:28]C(=O)[O:30][C:26]=2[CH:25]=1)[C:10]([O:12][C@H:13]([CH3:22])[C@H:14]([O:16][C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])[CH3:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(=O)(O)[O-].[Na+].C(#N)C>[OH:30][C:26]1[CH:25]=[C:24]([CH2:23][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][C@H:13]([CH3:22])[C@H:14]([O:16][C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])[CH3:15])=[O:11])[CH:33]=[CH:32][C:27]=1[OH:28]
Reactant: CC(C)C(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc2oc(=O)oc2c1)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(C)C(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc(O)c(O)c1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 110.2 %

Procedure:
(1R,2R)-1-Methyl-2-(2-methylpropanoyloxy)propyl (2S)-2-[(tert-butoxy)carbonylamino]-3-(2-oxobenzo[3,4-d]1,3-dioxolen-5-yl)propanoate (17) (6.4 g, 13.83 mmol) was dissolved in 50 mL of mixture of sat. sodium bicarbonate and acetonitrile (1:1). The resulting mixture was stirred at 60° C. under nitrogen for 60 min. TLC indicated a completed reaction. Acetonitrile was removed under reduced pressure. The product was extracted with methyl tert-butyl ether. The organic layer was collected, washed with 10% citric acid, dried over MgSO4, and concentrated to provide the title compound (18) (6.7 g, 100% yield). 1H NMR (400 MHz, CDCl3): δ 1.13-1.16 (m, 12H), 1.42 (s, 9H), 2.54 (m, 1H, J=7.2 Hz), 2.94 (d, 2H, J=6.0 Hz), 4.47 (dd, 1H, J=6.8, 14 Hz), 4.91 (m, 1H), 4.97 (m, 1H), 5.02 (d, 1H, NH, J=8.4 Hz), 6.53 (dd, 1H, J=2, 8 Hz), 6.66 (d, 1H, J=2 Hz), 6.74 (d, 1H, J=8 Hz). MS (ESI) m/z 439.9 (M+H)+.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].[CH3:6][C:7]([CH3:39])([CH3:38])[C:8](=[O:37])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH2:32][CH2:33]Cl)(=[O:31])=[O:30])=[C:24]([CH3:35])[CH:23]=2)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][C:12]=1[CH3:36]>C1COCC1>[CH3:6][C:7]([CH3:39])([CH3:38])[C:8](=[O:37])[CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][S:29]([CH2:32][CH2:33][S:3][CH2:1][CH3:2])(=[O:31])=[O:30])=[C:24]([CH3:35])[CH:23]=2)([CH2:20][CH3:21])[CH2:18][CH3:19])=[CH:13][C:12]=1[CH3:36]
Reactant: CCS
Reactant: CCC(CC)(c1ccc(NS(=O)(=O)CCCl)c(C)c1)c1ccc(OCC(=O)C(C)(C)C)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCSCCS(=O)(=O)Nc1ccc(C(CC)(CC)c2ccc(OCC(=O)C(C)(C)C)c(C)c2)cc1C
Temperature: 25 °C
Yield: 50.6 %

Procedure:
A 0° C. solution of ethanethiol (0.1 mL, 1.35 mmol) in THF (5 mL) is treated with NaH (81 mg, 2 mmol, 60% in mineral oil) and stirred for 10 m. The mixture is added a solution of N-(4-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-2-methyl-phenyl)-2-chloro-ethanesulfonamide (500 mg, 1 mmol) in THF (10 mL), warmed to RT, and stirred overnight. The reaction is concentrated, dissolved in CH2Cl2, and washed with 0.2 N HCl. The organic layer is concentrated and chromatographed (0%-20% EtOA/Hex) to give the title compound (270 mg, 51%).
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][C:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH2:1]([C:5]1[C:9]([CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([NH:26][C:23]3([CH3:22])[CH2:25][CH2:24]3)=[O:18])=[CH:14][N:13]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)O)cn1
Reactant: CC1(N)CC1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC2(C)CC2)cn1
Yield: 70 %

Procedure:
As described for example 19b, 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.34 mmol) was converted, using 1-methylcyclopropylamine instead of L-2,2,2-trifluoro-1-(methyl)ethylamine, to the title compound (83 mg, 70%) which was obtained as a white solid after purification by chromatography (silica, heptane:ethyl acetate=1:0 to 2:1). MS: m/e=342.3 [M−H]−.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14])=[CH:5][CH:4]=1.Br[C:18]1[CH:19]=[CH:20][C:21]2[N:27]([CH3:28])[CH2:26][CH2:25][C:24]([C:29]([NH:31][C:32]3[CH:37]=[CH:36][C:35]([CH2:38][N:39]([CH3:46])[CH:40]4[CH2:45][CH2:44][O:43][CH2:42][CH2:41]4)=[CH:34][CH:33]=3)=[O:30])=[CH:23][C:22]=2[CH:47]=1.C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[CH2:13]([O:12][CH2:11][CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:18]2[CH:19]=[CH:20][C:21]3[N:27]([CH3:28])[CH2:26][CH2:25][C:24]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([CH2:38][N:39]([CH3:46])[CH:40]5[CH2:45][CH2:44][O:43][CH2:42][CH2:41]5)=[CH:36][CH:37]=4)=[O:30])=[CH:23][C:22]=3[CH:47]=2)=[CH:4][CH:5]=1)[CH3:14]
Reactant: CN1CCC(C(=O)Nc2ccc(CN(C)C3CCOCC3)cc2)=Cc2cc(Br)ccc21
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
In a mixture of water:ethanol:toluene (1:1:10, v/v, 18.0 ml) were dissolved 4-(2-ethoxyethoxy)phenyl borate (315 mg) and 7-bromo-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (485 mg). To the solution was added potassium carbonate (332 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (46 mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (30 g, ethyl acetate:ethanol=9:1) and recrystallized from ethanol to give 7-[4-(2-ethoxyethoxy)phenyl]-1-methyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 9) (230 mg, 40%) as yellow crystals.
Reaction SMILES: [C:1]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:4])[CH2:2][CH3:3].C(OCC)(=O)CC(C)=O>>[OH:4][CH:1]([CH2:2][CH3:3])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(=O)CC
Solvent: CCOC(=O)CC(C)=O
Product: CCOC(=O)CC(O)CC
Yield: 50 %

Procedure:
Ethyl 3-hydroxyvalerate was prepared following the procedure as described in step 1) of Preparation Example 2, except for that ethyl propionylacetate was used to replace for ethyl acetoacetate. Yield 50%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][CH2:13][C@H:12]([CH:15]=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[CH2:18]([CH:22]([CH2:25]O)[CH2:23][OH:24])[CH2:19][CH2:20][CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:10][CH2:11][C@H:12]([CH:15]3[O:24][CH2:23][CH:22]([CH2:18][CH2:19][CH2:20][CH3:21])[CH2:25][O:16]3)[CH2:13][CH2:14]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C[C@H]1CC[C@H](c2ccc(F)c(F)c2)CC1
Reactant: CCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCC1COC([C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)OC1

Procedure:
A mixture of 2.2 g of trans-4-(3,4-difluorophenyl)-cyclohexanecarbaldehyde (obtainable by converting the corresponding acid into the chloride and Rosenmund reduction), 1.32 g of 2-butylpropane-1,3-diol, 0.01 g of p-toluenesulfonic acid and 15 ml of toluene is boiled on a water separator for 3 hours, cooled, washed with water and evaporated, to give 2-[trans-4-(3,4-difluorophenyl)cyclohexyl]-5-butyl-1,3-dioxane.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:38]2[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[CH:41]=[N:40][CH:39]=2)O1>>[CH:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:38]([C:2]2[N:3]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18]([CH3:23])([CH3:22])[C:19]([NH2:21])=[O:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:39][N:40]=1
Reactant: CC1(C)OB(c2cncc3ccccc23)OC1(C)C
Reactant: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: CC(C)(C(N)=O)N1CCN(Cc2cc3nc(-c4cncc5ccccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
Following General Procedure A for Suzuki coupling, 2-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoquinoline were reacted to give 160. LCMS: M+H+=532.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[N:46]1([CH2:51][CH2:52][CH2:53][N:54]2[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]2)[CH2:50][CH2:49][CH2:48][CH2:47]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:24])[C:6]([S:10]([N:13]([CH3:14])[CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21]([N:57]3[CH2:56][CH2:55][N:54]([CH2:53][CH2:52][CH2:51][N:46]4[CH2:47][CH2:48][CH2:49][CH2:50]4)[CH2:59][CH2:58]3)=[O:22])[N:20]=2)(=[O:12])=[O:11])=[C:7]([CH3:9])[CH:8]=1
Reactant: C1CCN(CCCN2CCNCC2)C1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N3CCN(CCCN4CCCC4)CC3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-oxazole-4-carboxylic acid (100 mg, 0.28 mmol), EDCI (75 mg, 0.39 mmol), HOBt (57 mg, 0.42 mmol) DIPEA (0.06 mL, 0.33 mmol), 1-(3-pyrrolidin-1-yl-propyl)-piperazine (66 mg, 0.33 mmol) and DCM (10 mL).