Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[O:16])([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14])[O:2][CH:3](Cl)[CH3:4].[C:17]([O-:21])(=[O:20])[CH:18]=[CH2:19].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:1](=[O:16])([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14])[O:2][CH:3]([O:21][C:17](=[O:20])[CH:18]=[CH2:19])[CH3:4]
Reactant: C=CC(=O)OCCCCOC(=O)OC(C)Cl
Reactant: C=CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OCCCCOC(=O)OC(C)OC(=O)C=C
Yield: 89.4 %

Procedure:
1-Chloroethyl 4-acryloyloxybutyl carbonate (1.253 g, 5.00 mmol) is added to a suspension of freeze dried potassium acrylate (0.606 g, 5.50 mmol) and 18-crown-6 (0.066 g, 0.25 mmol) in dimethylformamide (50 ml) under a dry N2 atmosphere. After 5 days at 20° C. the solvent is removed under reduced pressure and the residue dissolved by adding dichloromethane (60 ml) and water (30 ml). After separating the phases the aqueous layer is extracted with dichloromethane (3×30 ml) and the combined organic phase washed with saturated aqueous sodium hydrogen carbonate (50 ml). The organic phase is dried (MgSO4) and the solvent removed under reduced pressure to give 1.28 g (89%) of the title product. 1H NMR (60 MHz, CDCl3): δ 1.58 (3 H, d, J=5 Hz, CH3 --CH), 1.80 (4 H, m, CH2 --CH2), 4.24 (4 H, m, 2 ×CH2 --O), 5.7-6.7 (6 H, m, 2×CH=CH2), 6.87 (1 H, k, J=5 Hz, CH--CH3).
Reaction SMILES: [I-:1].[I-].[I-].[CH2:4]([N:7]([C:11]1[CH:12]=[CH:13][C:14]2[C:23]([CH:24]=1)=[S+:22][C:21]1[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=1)[N:15]=2)[CH2:8][CH2:9][CH3:10])[CH2:5][CH3:6].C(N([C:32]1[CH:33]=[CH:34][C:35]2C([CH:45]=1)=[S+]C1[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=1)[N:36]=2)CCC)CC.C(N(C1C=CC2C(C=1)=[S+]C1C(=CC=CC=1)N=2)CCC)CC.C(NCCCCC)CCCC>>[I-:1].[CH2:37]([N:36]([C:19]1[CH:18]=[CH:17][C:16]2[C:21]([CH:20]=1)=[S+:22][C:23]1[C:14](=[CH:13][CH:12]=[C:11]([N:7]([CH2:8][CH2:9][CH3:10])[CH2:4][CH2:5][CH3:6])[CH:24]=1)[N:15]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH3:45])[CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCN(CCC)c1ccc2nc3ccccc3[s+]c2c1
Agent: CCCCCNCCCCC
Agent: [I-]
Product: CCCCCN(CCCCC)c1ccc2nc3ccc(N(CCC)CCC)cc3[s+]c2c1

Procedure:
This compound was obtained following isolation of 3-(N,N-dipropylamino)-phenothiazin-5-ium triiodide and subsequent treatment with dipentylamine. Precipitation from dichloromethane by addition of diethyl ether yielded purple lustrous crystals. Mass spectrometry: C28H42N3OS requires m/z 452; found m/z=452 (I− not detected by mass spectrometry).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH3:13][O:14][C:15](=[O:55])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[N:27]([CH:35]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:26]=2[CH2:48][CH2:49][OH:50])=[CH:18][C:17]=1[O:51][CH:52]([CH3:54])[CH3:53]>ClCCl>[CH3:13][O:14][C:15](=[O:55])[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=3)[N:27]([CH:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:26]=2[CH2:48][CH2:49][O:50][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:18][C:17]=1[O:51][CH:52]([CH3:53])[CH3:54]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(OCCc2c(CCO)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OCCc2c(CCOS(C)(=O)=O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1OC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Methane sulfonyl chloride (0.03 mL, 0.39 mmol) and Et3N (0.06 mL, 0.43 mmol) were added to a solution of the alcohol from Step 4 (0.10 g, 0.17 mmol) in dichloromethane (8 mL) at 0° C. Reaction was stirred at 0° C. for one hour and then warmed to room temperature and stirred an additional hour. Reaction solution was concentrated by rotary evaporation. Obtained 0.115 g of 4-{2-[1-Benzhydryl-5-chloro-2-(2-methanesulfonyloxy-ethyl)-1H-indol-3-yl]-ethoxy}-2-isopropoxy-benzoic acid methyl ester in quantitative yield.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10]N)=[C:6]([C:12]([F:15])([F:14])[F:13])[CH:5]=1.Cl.O.[NH:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.Cl>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]([F:15])([F:14])[F:13])[C:7]2[NH:10][C:21]3[CH2:22][CH2:23][NH:18][CH2:19][C:20]=3[C:8]=2[CH:9]=1
Reactant: O=C1CCNCC1
Reactant: COc1ccc(NN)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: COc1cc(C(F)(F)F)c2[nH]c3c(c2c1)CNCC3
Yield: 41.8 %

Procedure:
A microwave-compatible seal tube was charged with (4-methoxy-2-trifluoromethyl-phenyl)-hydrazine hydrochloride (406 mg, 1.7 mmol), 4-piperidone monohydrate hydrochloride (268 mg, 1.7 mmol), and 2-PrOH (4 mL). The reaction mixture was saturated with HCl gas and the tube was sealed. The reaction mixture was subjected to microwave irradiation at 120° C. for 12 min. The solids were filtered, washed with ether and treated with sat. NaHCO3 (10 mL). The basic solution was extracted with EtOAc (2×25 mL) and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by column chromatography [silica gel, 5–75% (80:18:2 CHCl3/MeOH/concd NH4OH)/CH2Cl2] provided 8-methoxy-6-trifluoromethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (192 mg, in 42%) as an off-white solid: mp 140–144° C.; 1H NMR (300 MHz, CD3OD) δ 7.10 (d, J=2.0 Hz, 1H), 6.93 (d, J=2.1 Hz, 1H), 3.97 (s, 2H), 3.83 (s, 3H), 3.16 (t, J=5.8 Hz, 2H), 2.87 (t, J=5.7 Hz, 2H); 19F NMR (282 MHz, CD3OD) δ −61.0; ESI MS 271 [C13H13F3N2O+H]+.
Reaction SMILES: N#N.Br[C:4]1[S:8][C:7]([CH2:9][C:10]#[N:11])=[CH:6][CH:5]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:26])O1>COCCOC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:4]1[S:8][C:7]([CH2:9][C:10]#[N:11])=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(Br)s1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Agent: [Pd]
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: N#CCc1ccc(-c2ccccc2N)s1
Temperature: 90 °C
Reaction time: 2 h
Yield: 78.4 %

Procedure:
(The following reaction is done in an oxygenfree N2 atmosphere.) Dissolve tetrakis-(triphenylphosphine)-palladium(0) (29 mg, 2.5 mol %) and nitrile (83) (101 mg, 0.50 mmol) in DME (3.7 mL). The reaction mixture is degassed 5 times and flooded with N2 again. Add 2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenylamine (84) (120 mg, 0.55 mmol), rinse with DME (0.5 mL), add aqu. 1M NaHCO3, degas again (5 times) and stir the reaction solution 2 h at 90° C. (reflux). After cooling to rt partition the reaction mixture between EtOAc and brine (1+1) and extract the separated aqueous layer 3 times with EtOAc. Wash combined organic layer with brine and dry with Na2SO4. Remove solvent under reduced pressure and purify the crude product by preparative radial chromatography (silica gel 60PF, CyH/EtOAc 2+1) to obtain [5-(2-amino-phenyl)-thiophen-2-yl]-acetonitrile (85) as a brownish oil (84 mg, 78%). 1H NMR (400 MHz, CDCl3): 3.89 (br.s, 2H); 5.20-6.50 (br.s, 2H); 6.92 (t, 1H; J=7.6 Hz); 6.95-7.00 (m, 1H); 6.99 (d, 1H; J=3.8 Hz); 7.11 (d, 1H; J=3.8 Hz); 7.21 (dd, 1H; J1=7.6 Hz, J2=1.3 Hz); 7.27 (dd, 1H; J1=7.6 Hz, J2=1.3 Hz).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:19]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrCC=Cc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OCC=Cc1ccccc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 59.1 %

Procedure:
In 200 ml of DMF, 41.4 g of N-hydroxyphthalimide and 18 g of potassium carbonate were suspended. Fifty grams of cinnamyl bromide were added, followed by stirring at 120° C. for 5 hours. After completion of the reaction, the reaction mixture was cooled and then poured into about 500 ml of water. Crystals thus precipitated were collected by filtration, dried and then recrystallized from a mixed solvent of acetone and isopropyl ether, thereby obtaining 41.9 g of N-cinnamyloxyphthalimide.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:3]=1.[CH:12]1(/[CH:18]=[C:19](\B2OC(C)(C)C(C)(C)O2)/[CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[F-].[Cs+]>O1CCOCC1.C1(P([Pd-4](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)C=CC=CC=1>[CH:12]1(/[CH:18]=[C:19](\[C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:3]=2)/[CH2:20][OH:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Reactant: CS(=O)(=O)c1cccc(Br)c1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1cccc(/C(=C\C2CCCCC2)CO)c1
Yield: 51.7 %

Procedure:
According to the procedure described for example 26b the use of 1-bromo-3-methanesulfonyl-benzene (1.07 g, 4.55 mmol), (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (1.57 g, 5.92 mmol), caesium fluoride (2.07 g, 13.7 mmol) and tetrakis(triphenylphosphino)palladium(0) (525 mg, 455 μmol) in 40 mL dioxane with heating to reflux for 16 h gives a brown oil. Purify the crude product by column chromatography, eluting with a gradient from 100:0 to 0:100 hexanes:ethyl acetate to obtain (E)-3-cyclohexyl-2-(3-methanesulfonyl-phenyl)-prop-2-en-1-ol (693 mg) as a brown oil. MS (m/e): 277 [(M−H2O)+H].
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:14][CH3:15])(=[O:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].I[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1.Cl>>[F:24][C:23]([F:26])([F:25])[C:19]1[CH:18]=[C:17]([CH:8]([C:7]([O:14][CH3:15])=[O:13])[C:9]([O:11][CH3:12])=[O:10])[CH:22]=[CH:21][CH:20]=1
Reactant: FC(F)(F)c1cccc(I)c1
Reactant: COC(=O)CC(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(C(=O)OC)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.9 %

Procedure:
Dioxane (100 mL) was purged with nitrogen gas for 10 minutes. Phenanthrolene (1.0 g) and copper (I) iodide (1.0 g) were added to the dioxane, the suspension was allowed to stir under a nitrogen atmosphere for 5 minutes, and then cesium carbonate (18.72 g, 57.45 mmol), dimethyl malonate (5.46 g, 50.6 mmol), and 1-iodo-3-(trifluoromethyl)benzene (12.5 g, 46.0 mmol) were added. The reaction mixture was heated to reflux for 18 hours and then cooled to room temperature. Aqueous 1N HCl was added to the reaction mixture, the layers were separated, and the aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over magnesium sulfate and filtered. Celite® diatomaceous filter aid (5 g) was added to the filtrate, and the resulting suspension was concentrated under reduced pressure at 50° C. to yield a solid consisting of the crude product adsorbed onto Celite®. This solid was purified by silica gel chromatography eluting with a gradient of 100% hexanes to 25% ethyl acetate in hexanes to yield 7.36 g (58.0%) of the title product. 1H NMR (CDCl3) δ 7.59-7.65 (m, 3H), 7.49 (t, 1H), 4.70 (s, 1H), 3.76 (s, 6H).
Reaction SMILES: [CH3:1][S:2][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH:10]=[CH:9]2.[CH:13]1([CH:16]([C:18]2[CH:28]=[CH:27][C:21]3[O:22][C:23]([F:26])([F:25])[O:24][C:20]=3[CH:19]=2)O)[CH2:15][CH2:14]1.ClC1C=CC(C(C2CC2)C2C3C(=C(CSC)C=CC=3)NC=2)=CC=1>>[CH:13]1([CH:16]([C:18]2[CH:28]=[CH:27][C:21]3[O:22][C:23]([F:25])([F:26])[O:24][C:20]=3[CH:19]=2)[C:9]2[C:8]3[C:12](=[C:4]([CH2:3][S:2][CH3:1])[CH:5]=[CH:6][CH:7]=3)[NH:11][CH:10]=2)[CH2:14][CH2:15]1
Reactant: OC(c1ccc2c(c1)OC(F)(F)O2)C1CC1
Reactant: CSCc1cccc2cc[nH]c12
Agent: CSCc1cccc2c(C(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Product: CSCc1cccc2c(C(c3ccc4c(c3)OC(F)(F)O4)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The title compound was prepared starting from 500 mg (2.82 mmol) of the compound from Example 8A and 644 mg (2.82 mmol) of the compound from Example 157A in analogy to the synthesis of the compound from Example 227. A difference was that stirring at RT was for 45 min. 661 mg (60% of theory) of the target compound were obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 4 h

Procedure:
In this example, 6.05 g of 4-benzyloxyphenylacetic acid obtained as in Example 1, is dissolved in 125 ml of thionyl chloride, and boiled for 4 hours. Excess thionyl chloride is distilled off under reduced pressure, and the residue is dried, whereby 4-benzyloxyphenylacetic acid chloride is obtained. The thus obtained product is then dissolved in 25 ml of anhydrous benzene, and the resulting solution is added dropwise to 8.3 g of triethyl phosphite in a nitrogen gas stream with stirring under ice cooling.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[C:7]([CH2:9][C:10]([OH:12])=O)#[N:8].[F:13][C:14]([F:23])([F:22])[C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.O>[F:13][C:14]([F:22])([F:23])[C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:10](=[O:12])[CH2:9][C:7]#[N:8])=[CH:20][CH:21]=1
Reactant: N#CCC(=O)O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#CCC(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Phosphorus pentachloride (83.3 g; 0.40 mol) is introduced into a solution of cyanoacetic acid (34.0 g; 0.40 mol) in 1,2 l of dichloromethane and the mixture is heated under reflux for 30 minutes. 4-Trifluoromethylaniline (41.0 g, 0.26 mol) is then introduced into said mixture within about 10 minutes and the reaction mixture is heated under reflux for 2 hours. After cooling to 20° C., the reaction mixture is treated with 500 ml of water and then stirred for 30 minutes. The aqueous phase is neutralized with sodium carbonate and the precipitate is filtered off with suction. The filter cake is washed with water and dried. 55.2 g of N-(4-trifluoromethylphenyl)cyanoacetamide are thus obtained in crystalline form. Melting point: 194°-195.5° C.
Reaction SMILES: [CH:1]([Si:4]([C:11]#[CH:12])([CH:8]([CH3:10])[CH3:9])[CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C(N(CC)CC)C.O=O.[Br:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1>O1CCCC1.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:12]#[C:11][Si:4]([CH:5]([CH3:6])[CH3:7])([CH:1]([CH3:3])[CH3:2])[CH:8]([CH3:10])[CH3:9])=[CH:25][CH:24]=1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Reactant: Brc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: O=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)[Si](C#Cc1ccc(Br)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
11.6 mL triisopropylsilylacetylen and 14.4 mL triethylamine followed by 0.2 g copper iodide and 0.73 g bis-(triphenylphosphine)-palladium dichloride are added under argon to an oxygen-free solution of 15.0 g 4-bromo-1-iodo-benzene in 150 mL dry tetrahydrofuran. The solution is stirred for 16 h at ambient temperature and then filtered through Celite and evaporated down. The residue is purified by chromatography on silica gel (cyclohexane).
Reaction SMILES: O=O.[CH3:3][O:4]/[C:5](=[CH:9]\[C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)/[C:6]([OH:8])=[O:7].C1([C@@H](N)C)C=CC=CC=1.[H][H]>C1COCC1.ClCCl>[CH3:3][O:4][C@@H:5]([CH2:9][C:10]1[C:15]2[S:16][CH:17]=[CH:18][C:14]=2[C:13]([O:19][CH2:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: [H][H]
Reactant: CO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Agent: C[C@H](N)c1ccccc1
Agent: O=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[C@@H](Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)c2ccsc12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a glove box (O2 content≦2 ppm), a 50-ml stainless steel autoclave was charged with 2.26 mg of [Ru(η5-2,4-DMP)((S)—(R)-(3,5-Me2-4-MeOPh)2PF—PtBu2)(NCMe)]BF4 (0.0023 mmol, S/C 1,000) and 6 ml of dichloromethane. The resulting violet solution was stirred for 2 h at r.t. Then, 1.00 g of (Z)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-acrylic acid (2.30 mmol), 4 ml of dichloromethane, 10 ml of THF and 0.06 ml of (S)-1-phenylethylamine (0.47 mmol) were added. The autoclave was sealed and the hydrogenation was run under stirring at 40° C. under 30 bar of hydrogen. After 16 h the autoclave was opened and the yellowish solution was rotary evaporated to dryness (50° C./5 mbar) to afford the crude (S)-2-methoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzo[b]thiophen-7-yl}-propionic acid (Acid I) as a white solid with a chemical purity of 99.5% (>99.9% conversion) and an enantiomeric purity of 87%.
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([CH2:11][N:12]([CH3:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[S:3].Cl.[CH2:16](I)[CH3:17]>C(#N)C.O1CCOCC1>[CH2:16]([S:3][C:2](=[NH:4])[NH:1][C:5]1[CH:6]=[C:7]([CH2:11][N:12]([CH3:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[CH3:17]
Reactant: CN(C)Cc1cccc(NC(N)=S)c1
Reactant: CCI
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CCSC(=N)Nc1cccc(CN(C)C)c1
Yield: 18.6 %

Procedure:
To a solution of the compound (43.5 mg) obtained in Example 40 in acetonitrile (5 ml), a solution of hydrogen chloride in 1,4-dioxane (4N, 0.1 ml) and ethyl iodide (50 mg) were added and heated under reflux for 5 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by basic silica gel column chromatography (eluent, methylene chloride methanol=5:1) to give 9.2 mg of the titled compound (yield, 19%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[NH:13]1[CH2:18][CH2:17][O:16][CH:15]([CH2:19][OH:20])[CH2:14]1.C(N(CC)CC)C>C(#N)C>[N:4]1([CH2:3][CH2:2][N:13]2[CH2:18][CH2:17][O:16][C@H:15]([CH2:19][OH:20])[CH2:14]2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: OCC1CNCCO1
Reactant: ClCCN1CCc2ccccc21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: OC[C@@H]1CN(CCN2CCc3ccccc32)CCO1

Procedure:
A microwave vial was charged with 1-(chloroethyl)-indoline (compound 50; 724 mg, 4.00 mmol), hydroxymethylmorpholine (compound 54; 562 mg, 4.80 mmol), triethylamine (2.2 ml, 16.00 mmol) and acetonitrile (4 ml). The vial was irradiated with microwaves for 2 hrs at 100° C., 40 min at 120° C. and 1 hr at 110° C. The residue was purified by flash column chromatography (silica, DCM/MeOH 1:0 to 8:2); and the product was isolated as an off-white solid (347 mg; 33%).
Reaction SMILES: [OH:1][CH:2]1[CH:6]([CH2:7][OH:8])[O:5][CH:4]([N:9]2[CH:17]=[N:16][C:15]3[C:14](=[O:18])[NH:13][C:12]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[N:11][C:10]2=3)[CH:3]1[O:25][CH3:26].[C:27](Cl)(C1C=CC=CC=1)([C:36]1[CH:43]=[CH:42][C:39]([O:40][CH3:41])=[CH:38][CH:37]=1)[C:28]1[CH:35]=[CH:34][C:31]([O:32][CH3:33])=[CH:30][CH:29]=1>N1C=CC=CC=1>[CH3:41][O:40][C:39]1[CH:38]=[CH:37][C:36]([CH:27]([C:28]2[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[CH:34][CH:35]=2)[O:8][CH:7]([C:28]2[CH:35]=[CH:34][CH:31]=[CH:30][CH:29]=2)[CH:6]2[O:5][CH:4]([N:9]3[CH:17]=[N:16][C:15]4[C:14](=[O:18])[NH:13][C:12]([NH:19][C:20](=[O:24])[CH:21]([CH3:22])[CH3:23])=[N:11][C:10]3=4)[CH:3]([O:25][CH3:26])[CH:2]2[OH:1])=[CH:43][CH:42]=1
Reactant: COC1C(O)C(CO)OC1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: c1ccncc1
Product: COc1ccc(C(OC(c2ccccc2)C2OC(n3cnc4c(=O)[nH]c(NC(=O)C(C)C)nc43)C(OC)C2O)c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 41.1 %

Procedure:
Compound 16.2 (6.18 g, 17.19 mmol) was dissolved in 15 mL anhydrous pyridine, and treated with DMTCl (6.4 g, 18.91 mmol). The mixture was stirred for 12 h and poured on to 200 mL ice-water, filtered, and the solid was washed with 2×100 mL water. The solid was redissolved in 200 mL ethyl acetate. The organic layer was washed with 3×100 mL water, dried over MgSO4, filtered, and concentrated down under reduced pressure. The residue was subjected to a silica gel column chromatography to yield product 16.3 (2.6 g, 23% yield).
Reaction SMILES: [OH:1][CH:2]([C:5]1[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=1)[CH2:3][NH2:4].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22](=O)[CH3:23])=[CH:17][CH:16]=1>>[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[S:8][CH:9]=2)[CH3:23])=[CH:17][CH:16]=1
Reactant: CC(=O)Cc1ccc(O)cc1
Reactant: NCC(O)c1csc(C(F)(F)F)n1
Product: CC(Cc1ccc(O)cc1)NCC(O)c1csc(C(F)(F)F)n1

Procedure:
Prepared by analogy to Example 13 by reaction of 2-hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)ethanamine with 4-hydroxyphenyl-propan-2-one followed by purification of the base on a silica gel column using chloroform/methanol =9:1 as eluant.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([NH2:14])=[O:13])[CH:3]=1.Cl[C:16]([S:18]Cl)=[O:17].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]2[O:13][C:16](=[O:17])[S:18][N:14]=2)[CH:3]=1
Reactant: NC(=O)c1cc(Br)c2ccccc2c1
Reactant: O=C(Cl)SCl
Solvent: O
Solvent: Cc1ccccc1
Product: O=c1oc(-c2cc(Br)c3ccccc3c2)ns1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 4-bromonaphthalene-2-carboxylic amide (1.10 g) in toluene (11.0 mL) was added chlorocarbonylsulfenyl chloride (0.73 mL), and the mixture was stirred at 100° C. for 18 hours. To the reaction solution was added water (50 mL). The precipitated solid was collected by filtration, and washed with water and hexane to give 5-(4-bromonaphthalene-2-yl)-[1,3,4]oxathiazole-2-one (1.13 g). This compound (1.12 g) was dissolved in dichlorobenzene (18 mL). To the solution was added ethyl cyanoformate (1.42 mL), and the mixture was stirred at 160° C. for 22 hours. To the mixture was added water (30 mL) at room temperature, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate) to give the title compound (1.21 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:18]=[O:19])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:4][CH:3]=1.[CH3:20][Mg]Br.CCOCC>O1CCCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH:18]([OH:19])[CH3:20])[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: O=Cc1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cc2ccc(Cl)cc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 6-chloro-1-(3-fluorophenyl)-1H-indole-2-carbaldehyde (50 mg, 0.18 mmol) in tetrahydrofuran (5 mL) was added 3.0 M methylmagnesium bromide in ether (0.091 mL, 0.27 mmol). The reaction was stirred at room temperature for 1 hour, quenched with water, and then extracted with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over MgSO4 and concentrated to give the desired product (51 mg). The crude product was used directly in next step. LCMS calculated for C16H14ClFNO(M+H)+: m/z=290.1. Found: 289.7.