Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:16]=3)[O:11][C:10]([CH3:24])([CH3:23])[CH:9]=2)=[CH:4][CH:3]=1.[H][H]>C(O)C.[C].[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:16]=3)[O:11][C:10]([CH3:24])([CH3:23])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC1(C)C=C(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2O1
Agent: [Pd]
Solvent: CCO
Product: CC1(C)CC(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2O1

Procedure:
10% Palladium-carbon (water-content ca.50%, 20 mg) was added to a solution of N-[4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen-7-yl]methanesulfonamide (a compound obtained in Example 5, 20 mg) in ethanol (4 mL), and the mixture was stirred under atmospheric pressure of hydrogen at room temperature for 20 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: n-hexane/ethyl acetate=95/5 to 70/30) to give the titled compound (20 mg) as a colorless powder.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:22]=[CH:21][C:11]([O:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:23](#[N:25])[CH3:24]>>[O:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][O:12][C:11]2[CH:21]=[CH:22][C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH2:24][C:23]#[N:25])=[N:7][CH:6]=3)=[CH:9][CH:10]=2)[CH2:16][CH2:17]1
Reactant: CC#N
Reactant: Fc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1
Product: N#CCc1ccc(-c2ccc(OCCN3CCOCC3)cc2)cn1

Procedure:
In another aspect the invention relates to a process for preparing 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide mesylate comprising the steps of: (1) reacting 4-(2-chloroethyl)morpholine with 4-bromophenol to yield 4-(2-(4-bromophenoxy)ethyl)morpholine; (2) coupling 4-(2-(4-bromophenoxy)ethyl)morpholine with 6-fluoropyridin-3-yl-3-boronic acid to yield 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine; (3) reacting 4-(2-(4-(6-fluoropyridin-3-yl)phenoxy)ethyl)morpholine with acetonitrile to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile; (4) converting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetonitrile to methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate; (5) reacting methyl 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)acetate with benzylamine to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide; and (6) contacting 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide with methane sulfonic acid to yield 2-(5-(4-(2-morpholinoethoxy)phenyl)pyridin-2-yl)-N-benzylacetamide mesylate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11].[CH3:12][S:13]([C:15](SC)=[CH:16][N+:17]([O-:19])=[O:18])=O>>[CH3:12][S:13][C:15]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH3:11])=[CH:16][N+:17]([O-:19])=[O:18]
Reactant: CSC(=C[N+](=O)[O-])S(C)=O
Reactant: Cc1[nH]cnc1CCCCN
Product: CSC(=C[N+](=O)[O-])NCCCCc1nc[nH]c1C
Yield: 51 %

Procedure:
Reaction of 4-(4-aminobutyl)-5-methylimidazole (see Example 7 (ii), 0.765 g, 0.005 mol) with 1-methylsulphinyl-1-methylthio-2-nitroethylene(0.91 g, 0.005 mol), gave 1-methylthio-1-[4-(5-methylimidazol-4-yl)butylamino]-2-nitroethylene (0.69 g, 51%) which was treated directly with methylamine to yield 1-methylamino-b 1-[4-(5-methylimidazol-4-yl)butylamino]-2-nitroethylene (0.40 g, 61.9%). This compound was reacted with picric acid to give 1-methylamino-1-[4-(5-methylimidazol-4-yl)butylamino]-2-nitroethylene picrate hemihydrate (0.33 g, 26.3% last stage), m.p. 185°-187°.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N>[Cl:12][C:9]1[CH:10]=[CH:11][C:2]([C:13]#[N:14])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(Cl)ccc1Br
Agent: [C-]#N
Agent: [Zn+2]
Product: COC(=O)c1cc(Cl)ccc1C#N
Temperature: 90 °C
Yield: 88 %

Procedure:
To a stirred solution of methyl 2-bromo-5-chlorobenzoate from the previous step (11.5 g, 46 mmol) in degassed DMF (50 mL) was added zinc cyanide (2.82 g, 24.0 mmol) and palladium tetrakis-triphenylphosphine (1.0 g, 0.86 mmol) and the mixture was heated to 90° C. for 18 h. The reaction was partitioned between EtOAc (200 mL) and water (100 mL). The organic phase was concentrated in vacuo and the residue was purified by flash chromatography eluting with a gradient of 10%, 15%, 20% ethyl acetate in hexane yielding methyl 5-chloro-2-cyanobenzoate as a white solid (8.0 g, 88% yield). TLC Rf=0.4 (15% EtOAc-hexanes); HPLC RT=3.13 min, method A; 1H NMR (CDCl3, 400 MHz) 8.13 ppm (d, 1H, J=1.83 Hz); 8.09 ppm (d, 1H, J=8.24 Hz); 7.29 ppm (dd, I H, J=8.34, 2.10 Hz); 4.02 ppm (s, 3H).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([Cl:19])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[CH3:20])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][C:22](OC(C)=O)=[O:23].[Al+3].[Cl-].[Cl-].[Cl-]>>[C:22]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[N:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])[C:11]=1[CH3:20])(=[O:23])[CH3:21]
Reactant: Cc1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1c(C)n(S(=O)(=O)c2ccccc2)c2ccc(Cl)cc12
Yield: 86 %

Procedure:
1-Benzenesulfonyl-5-chloro-2-methylindole prepared in accordance with the literature (J. Org. Chem., 47, 757 (1982) was reacted with Ac2O/AlCl3 in a similar manner described in Reference example 2 (3) to give 3-acetyl-1-benzenesulfonyl-5-chloro-2-methylindole. Yield: 86%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]2[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:12][O:13][C:14]=2[CH3:15])=[N:6][CH:7]=1.C([Li])CCC.[O:27]1[CH2:30][C:29](=[O:31])[CH2:28]1.CO>C1COCC1>[CH3:15][C:14]1[O:13][N:12]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]=1[CH2:9][O:8][C:5]1[N:6]=[CH:7][C:2]([C:29]2([OH:31])[CH2:30][O:27][CH2:28]2)=[CH:3][CH:4]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(Br)cn1
Reactant: O=C1COC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CO
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C2(O)COC2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
A solution of 5-bromo-2-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine (100 mg, 0.29 mmol) THF (3 mL) was treated with n-butyl lithium (1.6 M in hexanes, 0.18 mL, 0.29 mmol) at −75° C. Then a solution of 3-oxetanone (22.0 mg, 0.29 mmol) in THF (1 mL) was added and the mixture was stirred for 10 min. Methanol was then added and the mixture was allowed to warm to room temperature. Purification by chromatography (SiO2, ethylacetate/heptane 2:8 to 1:1) afforded the title compound (65 mg, 66%) as a white solid. MS: m/e=339.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@:8]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C@H:12]([CH2:13][OH:14])[C@@H:11]([CH3:15])[O:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCCCCC.CCOC(C)=O.C([O-])(O)=O.[Na+].S(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[NH:7][C@:8]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[C@H:12]([CH:13]=[O:14])[C@@H:11]([CH3:15])[O:10][CH2:9]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1OC[C@@](NC(=O)OC(C)(C)C)(c2ccccc2F)[C@@H]1CO
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@H]1OC[C@@](NC(=O)OC(C)(C)C)(c2ccccc2F)[C@@H]1C=O
Temperature: 25 °C
Yield: 77.3 %

Procedure:
[(3S,4R,5R)-3-(2-Fluoro-phenyl)-4-hydroxymethyl-5-methyl-tetrahydro-furan-3-yl]-carbamic acid tert-butylester (Preparation Example 30-(1)) (1.2 g, 3.60 mmol) dissolved in DCM (26.5 g, 20 mL). 1,1,1-tris(acetyloxy)-,2-benziodoxol-3(1H)-one (3.12 g, 7.3 mmol) was added. The reaction mixture was stirred at RT. The reaction was followed by TLC Hexane/EtOAc 40%. Product Rf was 0.52. The reaction reached completion after 2 h. Work up: 20 ml of sat. aq. NaHCO3 and 20 ml of saturated sodium bisulfite was added. The mixture was then extracted with ether 3×50 ml. The combined organic phases were dried on MgSO4, concentrated and purified by flash chromatography Hexane/EtOAc (5-30%). 900 mg of the title compound was isolated (76% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12](O)=[O:13]>>[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:13]
Reactant: Cc1ccc(C(=O)O)cc1F
Reactant: O=C1CNCCN1
Product: Cc1ccc(C(=O)N2CCNC(=O)C2)cc1F

Procedure:
The title compound was prepared according to the procedure described in Step-1 of Intermediate F using piperazin-2-one and 3-fluoro-4-methylbenzoic acid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]([CH3:27])=[CH:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>O1CCCC1>[CH3:14][C:15]([CH3:27])=[CH:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH:23][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2)=[O:13]
Reactant: O=C(O)c1ccc2ncccc2c1
Reactant: CC(C)=CCOc1cccc(CN)c1
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)=CCOc1cccc(CNC(=O)c2ccc3ncccc3c2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
6-Quinolinecarboxylic acid (100 mg, 0.577 mmol), 3-(3-methyl-2-butenyloxy)-benzylamine described in Preparation Example 134 (112 mg, 0.635 mmol), benzotriazol-1-yl-tris(dimethylamino)phosphonium hexafluorophosphate (306 mg, 0.693 mmol) and triethylamine (0.12 mL, 0.87 mmol) were dissolved in tetrahydrofuran (5 mL), and the solution was stirred at room temperature for 3 hours. The solvent was evaporated in vacuo, the obtained residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=4:1), and the title compound (153 mg, 80.1%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([C:9]([NH:14][CH2:15][CH2:16][CH3:17])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH:18](=O)[CH2:19][CH3:20].S(=O)(=O)(O)O.[BH4-].[Na+].[OH-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[C:3]2[N:4]([C:9]([N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[C:10]([S:12][CH3:13])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CCCNc1c(SC)nc2c(Br)cc(C)cn12
Reactant: CCC=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)c1c(SC)nc2c(Br)cc(C)cn12
Reaction time: 3 h
Yield: 67.6 %

Procedure:
N-[8-Bromo-6-methyl-2-(methylsulfanyl)imidazo[1,2-a]pyridin-3-yl]-N-propylamine (103 mg) and propionaldehyde (57 mg) were dissolved in tetrahydrofuran (1:2 mL), then 3M sulfuric acid (0.24 mL) was added thereto, followed by adding sodium borohydride (24 mg) under ice-cooling, and then the mixture was stirred for 3 hours. Water was added to the reaction mixture, which was neutralized with a 2N aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:9) to give the title compound (79 mg) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: O=[N+]([O-])c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: Cc1nccn1-c1nc(NCCc2ccc3c(c2)OCO3)c2cc([N+](=O)[O-])sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:14]2[CH:26]=[CH:25][C:17]([C:18]([O:20]C(C)(C)C)=[O:19])=[C:16]([NH:27][C:28]([C:30]3[CH:31]=[N:32][C:33]([C:36]4[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=4)=[CH:34][CH:35]=3)=[O:29])[CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[C:8]1([C:14]2[CH:26]=[CH:25][C:17]([C:18]([OH:20])=[O:19])=[C:16]([NH:27][C:28]([C:30]3[CH:31]=[N:32][C:33]([C:36]4[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=4)=[CH:34][CH:35]=3)=[O:29])[CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(-c2ccncc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1ccc(-c2ccncc2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.4 %

Procedure:
Trifluoroacetic acid (5 mL) was added to the obtained tert-butyl 4-phenyl-2-(6-(pyridin-4-yl)pyridine-3-carboxamido)benzoate (25 mg), followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and water was added to the obtained residue. After adjusting the pH to 5.5 with a saturated aqueous solution of sodium bicarbonate, the solid substance was collected by filtration to obtain 20 mg of 4-phenyl-2-(6-(pyridin-4-yl)pyridine-3-carboxamido)benzoic acid as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:9](OC(OCC)OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[O:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[N:1]=[CH:9]1
Reactant: Nc1ncccc1O
Reactant: CCOC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: c1cnc2ncoc2c1
Temperature: 140 °C

Procedure:
A mixture of 2-amino-3-hydroxy pyridine (25 g, 227 mmol), triethylorthoformate (75 ml) and p-toluenesulfonic acid (61 mg) was heated at 140° C. for 8 hours. Excess triethylorthoformate was removed under vacuum. The product was crystallized from ethyl acetate to yield 22.5 g of oxazolo[4,5-b]pyridine; H1NMR (DMSO-δ): 9.26 (1H, s), 8.78 (1H, d), 8.45 (1H, d), 7.7(1H, dd); MS: 120.8 (M+1).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C@@H:6]([N:11]([CH3:19])[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:7]([CH3:10])[CH2:8][OH:9].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:9][CH2:8][C@@H:7]([CH3:10])[C@H:6]([N:11]([C:12]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:18])[CH3:19])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](CO)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](COS(C)(=O)=O)[C@@H](c1ccco1)N(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a solution of tert-butyl ((1S,2S)-1-(furan-2-yl)-3-hydroxy-2-methylpropyl)(methyl)-carbamate (108 mg, 0.40 mmol) in DCM (2 mL) at 0° C. was added triethylamine (81 mg, 0.112 ml, 0.80 mmol, 2 equiv) followed by methanesulfonylchloride (55 mg, 0.037 ml, 0.48 mmol, 1.2 equiv) and the solution was stirred at 0° C. for 1 hour. The solution was diluted with 10 mL DCM and washed with sat. NH4Cl solution, water and brine. After drying over MgSO4 the solution was concentrated in vacuo to give crude product 2.16a (140 mg, 99% yield). 1H NMR (CDCl3, 400 MHz) 7.38 (dd, J=1.76, 0.98 Hz, 1H) 6.35 (dd, J=3.13, 1.96 Hz, 1H) 6.31 (br. s., 1H) 5.29-5.32 (m, 1H) 4.16 (dd, J=9.98, 3.33 Hz, 1H) 3.90 (br. s., 1H) 2.89-2.96 (m, 3H) 2.68-2.75 (m, 3H) 2.55-2.67 (m, 1H) 1.48 (br. s., 9H) 1.11 (d, J=6.65 Hz, 3H)
Reaction SMILES: [C:1]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH2:8][C:9]1[C:17]2[C:16]([C:18](O)=[O:19])=[CH:15][CH:14]=[C:13]([CH3:21])[C:12]=2[NH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[CH2:25][N:26]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CN>CN(C=O)C.O>[CH3:25][NH:26][C:18]([C:16]1[C:17]2[C:9]([CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:23])[CH3:22])=[CH:10][NH:11][C:12]=2[C:13]([CH3:21])=[CH:14][CH:15]=1)=[O:19]
Reactant: Cc1ccc(C(=O)O)c2c(CCO[Si](C)(C)C(C)(C)C)c[nH]c12
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C)c2[nH]cc(CCO[Si](C)(C)C(C)(C)C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
To a solution of 3-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-7-methyl-1H-indole-4-carboxylic acid (150 mg, 0.45 mmol), EDCI (104 mg, 0.54 mmol) and HOBt (91.2 mg, 0.68 mmol) in DMF (3 mL) was added diisopropylethylamine (0.39 mL, 2.25 mmol) at room temperature. A solution of methylamine (0.45 mL of 2.0 M in THF, 0.90 mmol) was added to the mixture and the mixture was stirred overnight at room temperature. The solution was diluted with H2O (5 mL) and extracted with EtOAc (3×10 mL). The organic solution was washed brine (20 mL), dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 40% EtOAc in hexanes) to give 140 mg (90%) of title compound as a pale yellow solid. 1H NMR (CDCl3): 300 MHz δ 8.28 (bs, 1H), 7.20 (m, 2H), 7.00 (d, J=7.35 Hz, 1H), 6.40 (bs, 1H), 3.91 (t, J=6.41 Hz, 2H), 3.08 (m, 5H), 2.54 (s, 3H), 0.88 (s, 9H), −0.08 (s, 6H).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[O:7][C:8]([C:12](=O)[CH2:13]Cl)=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].[NH2:16][C:17]([NH2:19])=[S:18]>C(O)C>[C:1]([NH:4][CH2:5][C:6]1[O:7][C:8]([C:12]2[N:16]=[C:17]([NH2:19])[S:18][CH:13]=2)=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2]
Reactant: NC(N)=S
Reactant: CC(=O)NCc1oc(C(=O)CCl)cc1C
Solvent: CCO
Product: CC(=O)NCc1oc(-c2csc(N)n2)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A suspension of 2-acetamidomethyl-5-chloroacetyl-3-methylfuran (24.8 g) and thiourea (8.2 g) in ethanol (250 ml) was stirred at room temperature for 2 hours. The resulting precipitate was collected by filtration and then dissolved in water (200 ml). The mixture was alkalized with an aqueous potassium carbonate solution. The resulting precipitate was collected by filtration to afford 4-(5-acetylaminomethyl-4-methylfuran-2-yl)-2-aminothiazole (16.7 g).
Reaction SMILES: [FH:1].[FH:2].F.C(N(CC)CC)C.O=[C:12]1[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1.C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[F:1][C:12]1([F:2])[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCC(F)(F)CC1
Temperature: 25 °C
Yield: 69 %

Procedure:
A solution of triethylamine trihydrofluoride (0.479 mL, 2.94 mmol) in DCE (6 mL) at RT was treated with XtalFluor-M (1.071 g, 4.41 mmol) followed by ethyl 4-oxocyclohexanecarboxylate (0.500 g, 2.94 mmol) and the mixture heated to reflux for 2.5 h. The mixture was cooled to RT, treated with satd. NaHCO3 and stirred overnight. The mixture was diluted with DCM, the layers separated, the aqueous layer extracted with additional DCM (1×) and the combined organics were dried over MgSO4 and filtered through a small pad of silica gel, rinsing well with DCM. The filtrate was concentrated to dryness and purified via silica gel chromatography (DCM/Hex) to afford ethyl 4,4-difluorocyclohexanecarboxylate (390 mg, 69%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6): δ 4.05 (q, J=7.1 Hz, 2H), 2.49 (m, 1H), 2.02-1.77 (m, 6H), 1.65-1.50 (m, 2H), 1.16 (t, J=7.1 Hz, 3H).
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:29])=[C:19]([C@@:21]2([CH3:28])[NH:26][C:25](=[S:27])[CH2:24][O:23][CH2:22]2)[CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:30]>O1CCOCC1>[ClH:30].[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:29])=[C:19]([C@@:21]2([CH3:28])[NH:26][C:25](=[S:27])[CH2:24][O:23][CH2:22]2)[CH:20]=1
Reactant: C[C@@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)COCC(=S)N1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@]1(c2cc(N)ccc2F)COCC(=S)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A solution of (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5-methyl-morpholin-3-thione (0.795 g, 1.97 mmol) in dioxane (10 ml) was treated dropwise at room temperature with hydrochloric acid (1M). The yellow reaction mixture was stirred at room temperature overnight. For the workup, the solution was evaporated at reduced pressureand. The yellow oil was dissolved in ether (15 ml), and the solution was extracted with hydrochloric acid (1M, 15 ml). The aqueous layer was extracted with ether (15 ml), then the combined organic layers were extracted with hydrochloric acid (1M, 5 ml). The combined aqueous layers were evaporated at reduced pressure and yielded the (R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-morpholine-3-thione hydrochloride as a yellow solid (0.47 g, 87%) which was pure enough to be engaged in the next step without further purification; (calculated) C11H13FN2OS [240.30]; (found) [M+H]+=241.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18])[CH:5]=[O:6].[CH2:25]([C@H:32]1[CH2:36][O:35][C:34](=[O:37])[N:33]1[C:38](=[O:43])[CH2:39][O:40][CH2:41][CH3:42])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC>>[CH2:25]([C@H:32]1[CH2:36][O:35][C:34](=[O:37])[N:33]1[C:38](=[O:43])[C@@H:39]([O:40][CH2:41][CH3:42])[C@H:5]([OH:6])[C:4]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])=[C:2]([CH3:1])[CH:3]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cc(C=O)ccc1OCCc1nc(-c2ccccc2)oc1C
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)c(C)c1

Procedure:
In analogy to the procedures described in examples 11 a] to 11 c], 3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde (example 114 b]) was reacted with (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one and nBu2BOTf to yield (S)-4-benzyl-3-((2S,3R) -2-ethoxy-3-hydroxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one (according to NMR, one of the four isomers is strongly predominating; the configuration was tentatively assigned as 2S, 3R according to Tetrahedron Asymmetry 1999, 1353). Reduction of (S)-4-benzyl-3-((2S,3R)-2-ethoxy-3-hydroxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one with triethylsilane in trifluoroacetic acid then gave (S)-4-benzyl-3-((2S)-2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one. The (S)-4-benzyl-3-((2S)-2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionyl)-oxazolidin-2-one was subsequently saponified with 1N NaOH in THF to yield (S)-2-ethoxy-3-{3-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-propionic acid as colorless solid. The enantiomeric excess was judged according to chiral HPLC (Chiralpak-AD) to be 99.3%.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[NH2:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31]>>[CH3:32][C:29]([NH:28][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[CH:10][CH:9]=[CH:8][N:7]=3)[CH2:16][CH2:15]2)=[O:18])=[N:20][CH:21]=1)=[O:24])([CH3:33])[CH2:30][OH:31]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: CC(C)(N)CO
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NC(C)(C)CO)cn2)CC1
Yield: 74 %

Procedure:
By the same procedure as described in the example 1, synthesis was carried out starting with 6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid and using 2-amino-2-methyl-1-propanol. Then, the product was recrystallized with ethyl acetate and ether to give a desired compound.