Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].COCCO.[Br:8][C:9]1[C:10](/[C:23](/[CH3:36])=[CH:24]/[C:25]2[CH:35]=[CH:34][C:28]([C:29]([O:31]CC)=[O:30])=[CH:27][CH:26]=2)=[CH:11][C:12]2[C:13]([CH3:22])([CH3:21])[CH2:14][CH2:15][C:16]([CH3:20])([CH3:19])[C:17]=2[CH:18]=1>CCOCC>[Br:8][C:9]1[C:10](/[C:23](/[CH3:36])=[CH:24]/[C:25]2[CH:35]=[CH:34][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[CH:11][C:12]2[C:13]([CH3:22])([CH3:21])[CH2:14][CH2:15][C:16]([CH3:19])([CH3:20])[C:17]=2[CH:18]=1
Reactant: CCOC(=O)c1ccc(/C=C(\C)c2cc3c(cc2Br)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: COCCO
Product: C/C(=C\c1ccc(C(=O)O)cc1)c1cc2c(cc1Br)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of sodium hydroxide, 2-methoxyethanol and ether was added to 50 mg (0.11 mmol) of ethyl 4-[(E)-2-(3-bromo-5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalen-2-yl)propen-1-yl]benzoate (Compound 14) and the resulting mixture stirred at room temperature for 17 hours. Solvent was removed in-vacuo and the resulting solid taken-up in water, acidified using 2N HCl, and extracted with ether. The ether extracts were washed with water, brine and dried (MgSO4). The solvent was removed in-vacuo to give the title compound as a white solid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][CH2:6][C@@H:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:4]([CH3:15])[C:3]1=[O:16].[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>C(Cl)Cl>[F:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([NH:28][C@H:29]([C:31]([NH:1][C@H:2]2[CH2:8][CH2:7][CH2:6][C@@H:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:4]([CH3:15])[C:3]2=[O:16])=[O:32])[CH3:30])=[O:27])[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CN1C(=O)[C@@H](N)CCC[C@H]1c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H]1CCC[C@@H](c2ccccc2)N(C)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
To a solution of (3S,7S)-3-amino-1-methyl-7-phenylazepan-2-one (2e) (57 mg) in DCM (3 mL) at 0° C. under N2 was added N-[(3,5-difluorophenyl)acetyl]-L-alanine (95 mg), HOBt-hydrate (88 mg), EDAC.HCl (75 mg) and N-methyl morpholine (42 mg). The reaction mixture was stirred 1 h at 0° C. and 3H at room temperature, then diluted with 30% Hexanes/EtOAc (100 mL). The organic phase was consecutively washed with H2O, 0.2 N HCl, saturated NaHCO3, and brine, dried (Na2SO4), filtered and evaporated. The crude product was purified by flash chromatography (2% MeOH/DCM) to afford the title compound as an off-white solid (80 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 1.40 (d, 3H), 1.51 (m, 1H), 1.90-2.01 (m, 3H), 2.12-2.15 (m, 2H), 2.52 (s, 3H), 3.55 (s, 2H), 4.47-4.56 (m, 1H), 4.92-5.00 (m, 2H), 6.29 (bd, 1H), 6.69-6.76 (m, 1H), 6.84 (bd, 2H), 7.27-7.41 (m, 6H). MS APCI, m/z=444 (M+1)/466 (M+Na). LC/MS 2.54 min., Method A.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O>C(OCC)(=O)C>[CH:11]1[CH:10]=[CH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][C:4]([Br:14])=[CH:5][CH:6]=2)=[CH:13][CH:12]=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Product: Brc1ccc(Nc2ccccc2)cc1
Reaction time: 300 h

Procedure:
In a 1-L conical flask, 51 g (0.3 mol) of diphenylamine was dissolved in 700 mL of ethyl acetate, and then 54 g (0.3 mol) of N-bromosuccinimide (abbreviation: NBS) was added to this solution. About 300 hours later, this mixture solution was washed with water, and then magnesium sulfate was added thereto to remove moisture. This mixture solution was filtered, the filtrate was concentrated, and the resulting substance was collected. Accordingly, a dark brown oily substance, which was the substance to be produced, was obtained, and the amount and yield of the substance were 70 g and 94%, respectively.
Reaction SMILES: C([NH:4][CH:5]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[C:7]2[S:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:6]1=2)(=O)C.[ClH:20]>CO>[ClH:20].[NH2:4][C:5]1[CH2:10][CH2:9][S:8](=[O:12])(=[O:11])[CH:7]2[S:13][C:14]([S:16]([NH2:19])(=[O:18])=[O:17])=[CH:15][C:6]=12
Reactant: CC(=O)NC1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Agent: Cl
Solvent: CO
Product: NC1=C2C=C(S(N)(=O)=O)SC2S(=O)(=O)CC1
Reaction time: 6 h
Yield: 79 %

Procedure:
A mixture of 5,6-dihydro-4-acetamido-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide, from Example 23, (2.0 g, 0.0062 mol) in CH3OH (20 ml) and 12N HCl (20 ml) was heated at reflux. After 6 hours, the solution was concentrated to dryness and the residue was treated with absolute ethanol. The mixture was concentrated to dryness and this procedure was repeated 4X. The final ethanol treatment was stirred, allowed to stand in the freezer overnight and filtered to yield 1.55 g (79%) of product; m.p. 251°-253° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15](O)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH:20]=1>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[N:17]3[C:12]([CH:13]=[N:14][C:15]([NH:31][C:28]4[CH:27]=[CH:26][C:25]([C:21]5[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=5)=[CH:30][CH:29]=4)=[N:16]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc(-c2cccnc2)cc1
Reactant: COc1ccc(-c2ccc3cnc(O)nn23)cn1
Product: COc1ccc(-c2ccc3cnc(Nc4ccc(-c5cccnc5)cc4)nn23)cn1

Procedure:
[7-(6-Methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-pyridin-3-yl-phenyl)-amine was prepared from 7-(6-methoxy-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 4-pyridin-3-yl-phenylamine in an analogous manner to Example 1052a. Product isolated as a yellow foam (31 mg, 26%). LCMS (m/e) 395 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.87 (s, 1H), 8.80 (s, 1H), 8.74 (s, 1H), 8.61-8.54 (m, 1H), 8.42 (d, 1H, J=8.7 Hz), 7.88 (d, 1H, J=7.8 Hz), 7.73 (d, 2H, J=8.1 Hz), 7.57 (d, 2H, J=8.1 Hz), 7.40-7.31 (m, 1H), 7.02-6.84 (m, 4H), 4.03 (s, 3H).
Reaction SMILES: C=O.[C:3](=O)([O-])[O-:4].[K+].[K+].[CH3:9][O:10][C:11]([C:13]1([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:17][CH2:16][CH:15]([CH3:18])[C:14]1=[O:19])=[O:12]>O>[CH3:9][O:10][C:11]([C:13]1([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[CH2:17][CH2:16][C:15]([CH2:3][OH:4])([CH3:18])[C:14]1=[O:19])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)C1=O
Agent: C=O
Agent: [K+]
Solvent: O
Product: COC(=O)C1(Cc2ccc(Cl)cc2)CCC(C)(CO)C1=O

Procedure:
A 37% formaldehyde aqueous solution (0.90 ml) and potassium carbonate (2.00 mmol) were added to 1-(4-chlorobenzyl)-3-methyl-2-oxocyclopentanecarboxylic acid methyl ester (Compound VIII-1) (4.00 mmol), and the resultant mixture was stirred at room temperature for 4 hours. After the reaction, water was added to the resultant reaction solution, and the solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, and thereafter dried over anhydrous sodium sulfate. The solvent was distilled off, and a residue was purified with the use of a silica gel column. In this way, Compound VII-1 in the form of two isomers (isomer VII-1a and isomer VII-1b) was obtained. Note that Compound VIII-1 was synthesized in accordance with a method described in Patent Literature 1.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6].[N:9]1([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:26][C:25](=[O:27])[C:24]4([CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[N:23]=3)=[CH:18][CH:17]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.O>CN(C)C=O>[N:9]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([NH:23][C:24]3([C:25]([NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:27])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:26])=[CH:20][CH:21]=2)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1
Reactant: CSCC[C@H](N)CO
Reactant: O=C1OC(c2ccc(CN3CCOCC3)cc2)=NC12CCCCC2
Solvent: CN(C)C=O
Solvent: O
Product: CSCC[C@@H](CO)NC(=O)C1(NC(=O)c2ccc(CN3CCOCC3)cc2)CCCCC1
Reaction time: 8 h
Yield: 48.3 %

Procedure:
43 mg (0.32 mmol) of L-methioninol was added to a solution of 100 mg (0.29 mmol) of 2-[4-(4-morpholinylmethyl)phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 3 ml of N,N-dimethylformamide, and the mixture was stirred overnight. Water was slowly added thereto and the precipitated crystal was collected by filtration. The obtained crystal was dried under reduced pressure to obtain 65 mg (49%) of the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)=[CH:30][CH:29]=1.C(N(C(C)C)CC)(C)C>CS(C)=O>[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][C:35]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:36])=[CH:30][CH:29]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: COc1ccc(NC(=O)Oc2ccccc2)cn1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
A solution of 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (0.371 g, 1.00 mmol) (from Example 1, Step 5) and phenyl 6-methoxypyridin-3-ylcarbamate (0.244 g, 1.00 mmol, from Step 1) in DMSO (2.5 mL) was treated with diisopropylethylamine (0.155 g, 1.2 mmol) and heated to 50° C. After 3 h, the reaction mixture was partitioned between water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10% of the 1N NH3 in MeOH, in dichloromethane) to afford the title compound (280 mg, 58%) as white crystals after trituration in diethyl ether. MS (APCI 10V) AP+ 485.30; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 (t, J=5.46 Hz, 2H) 2.46 (t, J=5.46 Hz, 2H) 3.46 (t, J=5.46 Hz, 2H) 3.54 (t, J=5.46 Hz, 2H) 3.76 (s, 3H) 6.38 (s, 1H) 6.69 (d, J=8.77 Hz, 1H) 7.03 (m, 2H) 7.12 (d, J=7.80 Hz, 1H) 7.21 (d, J=8.60 Hz, 1H) 7.4 (dd, J=8.5 Hz, 1 Hz, 1H) 7.73 (dd, J=8.9 Hz, 2.7 Hz, 1H) 8.14 (d, J=2.5 Hz, 1H) 8.20 (dd, J=8.77 Hz, 2.5 Hz, 1H) 8.49 (s, 1H) 8.55 (d, J=2.5 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][NH:16][C:15](=[O:19])[CH2:14]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][CH:30]([CH2:33]Br)[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[CH2:3]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH2:33][CH:30]2[CH2:31][CH2:32][N:27]([C:25]([O:24][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:26])[CH2:28][CH2:29]2)[C:15](=[O:19])[CH2:14]1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: O=C1CN(C(=O)OCc2ccccc2)CCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1
Reaction time: 16 h

Procedure:
Sodium hydride (60%, 0.27 g, 6.7 mmol) is added to a solution of 4-benzyloxycarbonyl-2-oxo-piperazine (1.58 g, 6.7 mmol) in dry DMF (40 mL). After 30 minutes 4-bromomethyl-piperidine-1-carboxylic acid tert-butyl ester (1.87 g, 6.7 mmol) is added and the reaction is allowed to stir for 16 h. The solvent is removed in vacuo and the residue is dissolved in ether and washed with NH4Cl. The aqueous phase is back-extracted with ether and the combined ether fractions are washed with water and brine to provide 4-(1-tert-butoxycarbonyl-piperidin-4-ylmethyl)-3-oxo-piperazine-1-carboxylic acid benzyl ester which is used without further purification. 1H NMR (300 MHz, CDCl3) δ 7.36 (s, 5H), 5.16 (d, 2H), 4.16 (s, 2H), 4.13 (br, 2H), 3.73-3.69 (m, 2H), 3.44-3.30 (m, 6H), 2.68 (bt, 2H), 1.85-1.73 (m, 1H), 1.58 (bd, 2H), 1.46 (s, 9H), 1.25-1.10 (m, 2H); MS (ion spray) 432 (M+H)+.
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[NH:17]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:18]1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:17]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH2:18]1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: c1cncc(C2CCNC2)c1
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Product: CCCC[C@@H](C(=O)N1CCC(c2cccnc2)C1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5 and commercially available 3-pyrrolidin-3-yl-pyridine A-5 according to General Procedure B.
Reaction SMILES: [F:1][C:2]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:29]=[C:28]([Cl:30])[C:27]([Cl:31])=[C:26]([Cl:32])[CH:25]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[CH3:39][NH:40][CH3:41]>C(Cl)Cl.C1COCC1>[CH3:39][N:40]([CH3:41])[C:6]([CH:4]1[CH2:5][C:2]([F:1])([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH2:19][C:18]([C:24]4[CH:25]=[C:26]([Cl:32])[C:27]([Cl:31])=[C:28]([Cl:30])[CH:29]=4)([C:20]([F:23])([F:22])[F:21])[O:17][N:16]=3)=[CH:13][CH:14]=2)[CH2:3]1)=[O:8]
Reactant: CNC
Reactant: O=C(O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)C1CC(F)(c2ccc(C3=NOC(c4cc(Cl)c(Cl)c(Cl)c4)(C(F)(F)F)C3)cc2)C1
Reaction time: 1 h
Yield: 29 %

Procedure:
To a stirred solution of 3-fluoro-3-{4-[5-(3,4,5-trichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-phenyl}-cyclobutanecarboxylic acid (Preparation 7, 0.085 g, 0.166 mmol) in DCM (4 mL) was added oxalyl chloride (0.025 g, 0.199 mmol) at 0° C. and stirred for 1 hour. After 1 hour, saturated solution of dimethyl amine in THF (4 mL) was added. Resulting reaction mixture was stirred at room temperature for 16 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afford crude. Crude was purified by column chromatography on silica gel (100-200 mesh size). Compound was eluted using 0.7% methanol in DCM to afford off white solid (0.026 g, 29%). 1H-NMR (400 MHz, CDCl3) δ: 2.72-2.78 (m, 2H), 2.87-2.92 (m, 1H), 2.94 (s, 3H), 2.98 (s, 3H), 2.99-3.09 (m, 2H), 3.68 (d, 1H, J=17.2 Hz), 4.08 (d, 1H, J=17.16 Hz), 7.54 (d, 2H, J=8.16 Hz), 7.64 (s, 2H), 7.70 (d, 2H, J=8.24 Hz); LC-MS (m/z): [M−H] 534.60.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[C:24]([F:31])[C:23]=1[F:32].[CH3:33][C:34]([Si:37](Cl)([CH3:39])[CH3:38])([CH3:36])[CH3:35]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[Si:37]([O:18][CH2:17][C@H:10]1[O:9][C@:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[C:24]([F:31])[C:23]=3[F:32])[CH:4]=2)([O:19][CH3:20])[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@@H:11]1[OH:16])([C:34]([CH3:36])([CH3:35])[CH3:33])([CH3:39])[CH3:38]
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)c(F)c1F
Reaction time: 16 h
Yield: 93.6 %

Procedure:
(2S,3R,4S,5S,6R)-2-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-6-(hydroxymethyl)-2-methoxy-tetrahydropyran-3,4,5-triol 3f (3.0 g, 6.8 mmol) was dissolved in 30 mL pyridine, followed by addition of 4-dimethylamino pyridine (166 mg, 1.36 mmol) and TBSCl (1.23 g, 8.2 mmol) in turn. The reaction mixture was stirred for 16 hours. Thereafter, the reaction mixture was concentrated under reduced pressure before 150 mL ethyl acetate were added. The reaction mixture was washed with saturated copper sulfate solution (100 mL) and saturated sodium chloride solution (100 mL) in turn. The organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the title compound (2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[(4-ethoxy-2,3-difluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydro-pyran-3,4,5-triol 3g (3.75 g, white solid), yield: 99.7%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:15][CH2:16][C:17]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:6]([NH:8][C:9](=O)[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:15]([CH2:16][C:17]3([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18]3)[C:9]([C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:6]=2[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1cc(Br)ccc1NCC1(O)CCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)c1nc2cc(Br)ccc2n1CC1(O)CCCC1
Temperature: 140 °C
Reaction time: 23 h
Yield: 37.8 %

Procedure:
To a solution of N-(5-bromo-2-{[(1-hydroxycyclopentyl)methyl]amino}phenyl)-2,2-dimethylpropanamide (Step C, 1.3 g, 3.41 mmol) in toluene (100 mL) was added p-toluenesulfonic acid monohydrate (130 mg, 0.68 mmol) at room temperature and the mixture was stirred at 140° C. for 23 h. After cooling to room temperature, p-toluenesulfonic acid monohydrate (130 mg, 0.68 mmol) was added, and the mixture was heated at 140° C. After stirring for 26 h at 140° C., the mixture was quenched with saturated sodium hydrogen carbonate aqueous solution. The mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate:dichloromethane=5.5:1:0.5 as eluent) to afford the title compound (453 mg, 38%) as a beige amorphous.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([OH:27])[CH2:24][C@H:23]1[C:28]([O:30][CH3:31])=[O:29])=[O:21])([CH3:18])([CH3:17])[CH3:16].[C:32]1(O)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:26][C@@H:25]([O:27][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:24][C@H:23]1[C:28]([O:30][CH3:31])=[O:29])=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: Oc1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 0.1 %

Procedure:
DIAD (4.13 ml, 21.0 mmol) was added to a solution of methyl (2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarboxylate (4.69 g, 19.1 mmol), phenol (1.98 g, 21.0 mmol) and triphenylphosphine (5.51 g, 21.0 mmol) in THF (80 ml) under stirring at room temperature in a nitrogen gas stream. The reaction mixture was stirred overnight at room temperature. The residue obtained by concentrating the reaction mixture under reduced pressure was purified by chromatography on a silica gel column (silica gel: 700 g), whereby from chloroform/ethyl acetate (10/1) eluate fractions, the title compound (5.31 mg, 86%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].[CH:10]1([NH2:13])[CH2:12][CH2:11]1>CCOCC>[CH:10]1([NH:13][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[O:3][CH2:1][CH3:2])[CH2:12][CH2:11]1
Reactant: CCOC(CBr)OCC
Reactant: NC1CC1
Solvent: CCOCC
Product: CCOC(CNC1CC1)OCC
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A solution of 2.36 g (12 mmol) of 2-bromoacetaldehyde diethyl acetal and 4.94 g (86.6 mmol) of cyclopropylamine was heated in a closed vessel at 120° C. for 2 h. The reaction mixture was cooled to room temperature and diluted with 75 ml of ether and washed with 5% aq NaOH, followed by water and saturated sodium chloride solution. The organic phase was dried (MgSO4) and concentrated in vacuo. The residue was distilled in vacuo (130° C.-140° C.). 2.01 g of the desired compound were obtained. LC/MS M+H=173
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[N:3]([C:17]2[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: OB(O)c1ccc(F)cc1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: O=Cc1c(Cl)n(-c2ccc(F)cc2)c2ccccc12
Yield: 84 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 4-fluorophenylboronic acid as described in Step 1 of Example 29 to afford 2-chloro-1-(4-fluorophenyl)-1H-indole-3-carboxaldehyde (84% yield) as a cream solid. ESI/MS 274 (M+H); RT 3.64 min; NMR 10.12 (1H, s); 8.20 (1H, d, J=6 Hz); 7.72 (2H, m); 7.58 (2H, m); 7.39 (2H, m); 7.12 (1H, d, J=9 Hz).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([F:8])[C:5]([F:9])=[C:4](F)[C:3]=1[F:11].[CH2:12]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:8][C:6]1[C:5]([F:9])=[C:4]([N:22]2[CH2:23][CH2:24][N:19]([CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:20][CH2:21]2)[C:3]([F:11])=[C:2]([F:1])[N:7]=1
Reactant: Fc1nc(F)c(F)c(F)c1F
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1nc(F)c(F)c(N2CCN(Cc3ccccc3)CC2)c1F
Temperature: 100 °C
Reaction time: 5 h
Yield: 94.1 %

Procedure:
To a solution of pentafluoropyridine (1.76 ml, 16.0 mmol) and 1-benzylpiperazine (2.64 g, 15.0 mmol) in DMSO (20 ml) was added potassium carbonate (4.20 g, 30.4 ml). The suspension was heated to 100° C. and stirred for five hours and allowed to cool to ambient temperature, poured onto water and then extracted with DCM. The extract was washed with brine, water, and dried. Volatile material was removed by evaporation to give the title compound (4.59 g) as an oil. NMR (CDCl3) 2.58 (m, 4H), 3.52 (m, 4H), 3.57 (s, 2H), 7.24-7.38 (m, 5H and CDCL3); m/z 326.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH:25]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([C:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH:25]=5)[CH:21]=[CH:20][C:18]=4[N:19]=3)[CH2:10][CH2:9]2)=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(OC4CCN(c5ncc(F)cn5)CC4)sc3c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
To a solution of tert-butyl 4-(2-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.27 g, 2.482 mmol) in CH2Cl2 (20 mL) was added TFA (1.9 mL, 24.8 mmol). The reaction mixture was stirred at rt overnight. The reaction mixture was diluted with CH2Cl2 (20 mL) and washed sequentially with aq. NaOH (1 N, 30 mL) and brine. The organic layer was dried (Na2SO4), filtered, and concentrated to afford 2-(1-(5-fluoropyrimidin-2-yl)piperidin-4-yloxy)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (1.01 g, 2.459 mmol, 99% yield) as a pale yellow solid. LCMS (m/z)=412 (M+H)+.