Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1([O:27][CH2:28][CH3:29])[CH2:9][N:8]([C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:11])[CH:7](CO)[CH2:6][CH2:5]1)[CH3:2].[CH3:30][CH2:31][OH:32]>>[CH2:1]([O:3][C:4]1([O:27][CH2:28][CH3:29])[CH2:9][N:8]([C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])[CH:7]([CH2:7][N:8]2[C:31](=[O:32])[C:30]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:10]2=[O:11])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC1(OCC)CCC(CO)N(C(=O)c2nc(C)sc2-c2ccc(F)cc2)C1
Reactant: CCO
Product: CCOC1(OCC)CCC(CN2C(=O)c3ccccc3C2=O)N(C(=O)c2nc(C)sc2-c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to general procedure I using rac-(5,5-diethoxy-2-(hydroxymethyl)piperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone. 1H NMR (CDCl3, 400 MHz) δ 7.73-7.71 (m, 2H), 7.63-7.62 (m, 2H), 7.38-7.35 (m, 2H), 7.21-6.91 (m, 2H), 4.86-4.81 (m, 1H), 4.10-4.03 (m, 2H), 3.10 (d, 1H), 2.27 (s, 3H), 1.89-1.83 (m, 1H), 1.70-1.61 (m, 1H), 1.32-1.28 (m, 2H), 1.19-1.03 (m, 6H). MS (ESI) 506 (M+H): desired product lost EtOH in LC/MS.
Reaction SMILES: Cl[CH2:2][C@@H:3]([CH3:13])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[F:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][C@H:3]([CH3:13])[CH2:2][N:28]1[CH2:29][CH2:30][CH:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=2)[CH2:26][CH2:27]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: C[C@H](CCl)COc1cccc(F)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@@H](C)COc3cccc(F)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{[(2S)-3-chloro-2-methylpropyl]oxy}-3-fluorobenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 413.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:6][N:5]([C:7]2[N:12]=[CH:11][C:10]([C:13]3[CH2:14][CH2:15][N:16](C(OC(C)(C)C)=O)[CH2:17][CH:18]=3)=[CH:9][N:8]=2)[CH2:4]1.Cl.O1CCOCC1>[C].[Pd].CCO>[CH3:1][O:2][CH:3]1[CH2:4][N:5]([C:7]2[N:8]=[CH:9][C:10]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[CH:11][N:12]=2)[CH2:6]1
Reactant: COC1CN(c2ncc(C3=CCN(C(=O)OC(C)(C)C)CC3)cn2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: COC1CN(c2ncc(C3CCNCC3)cn2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 41.3 %

Procedure:
tert-Butyl 4-[2-(3-methoxyazetidin-1-yl)pyrimidin-5-yl]-3,6-dihydropyridine-1(2H)-carboxylate (483 mg) was mixed with EtOH (5 ml), and 10% palladium carbon (100 mg) was added thereto, followed by stirring at room temperature for 5 hours under hydrogen atmosphere. The reaction mixture was filtered using Celite as a filtration adjuvant, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc). The purified product thus obtained was mixed with EtOH (5 ml), and 4 M hydrogen chloride/dioxane (3.5 ml) was added thereto, followed by stirring at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and then mixed with EtOH (5 ml), and potassium carbonate (2.0 g) was added thereto, followed by stirring at 80° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain 2-(3-methoxyazetidin-1-yl)-5-(piperidin-4-yl)pyrimidine (143 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:23])[F:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:27])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([F:24])([F:22])[F:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccccc1C(F)(F)F)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.5 h
Yield: 263.2 %

Procedure:
To a solution of 4-(2-trifluoromethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.5 g, 0.00053 mole), in DMF (5 mL) was added, NaH (60% w/w dispersion in oil) (0.0696 g, 0.0029 mole) and the resulting mixture was stirred at ambient temperature for 10 minutes under an atmosphere of nitrogen. Methyl iodide (0.617 g, 0.00435 mole) was then added, and stirring was continued for 30 minutes at ambient temperature. The reaction mixture was quenched with aqueous 10% NH4Cl solution and the product was extracted with ether. The organic layer was washed with aqueous NaHCO3 solution followed by brine solution. The ether layer was then collected, dried over sodium sulfate and concentrated under reduced pressure to afford 0.5 g of 4-[methyl-(2-trifluoromethyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester that which was used in the next step without further purification. 4-[Methyl-(2-trifluoromethyl-phenyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester obtained (0.5 g) was stirred in dioxane.HCl (5 mL) for 30 minutes. The reaction mixture was concentrated under reduced pressure to afford 0.36 g (88%) of methyl-piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine hydrochloride which was used in the next step without further purification.
Reaction SMILES: ClC1C=CC2SC=C([CH2:9][N:10]3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44](O)=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.CN>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:10][CH3:9])=[O:45])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: CN
Product: CNC(=O)c1sc(N2CCN(Cc3ccc(F)cc3)C2=O)nc1C
Yield: 41 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with methylamine, the title compound was obtained as a colorless solid in 41% yield: mp 225-227° C.; 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 2H), 7.07-7.01 (m, 2H), 5.66 (br s, 1H), 4.46 (s, 2H), 4.08 (t, J=9.0 Hz, 2H), 3.45 (t, J=9.0 Hz, 2H), 2.94 (d, J=3.0 Hz, 3H), 2.60 (s, 3H); MS (ES+) m/z 349.2 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([NH2:11])[C:7]([NH2:10])=[CH:8][CH:9]=1)[CH2:2][CH3:3].S(=O)(O)[O-].[Na+].[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]=O)=[N:18]1>CN(C)C=O>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]2[NH:10][C:26]([C:19]3[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[NH:17][N:18]=3)=[N:11][C:6]=2[CH:5]=1)[CH2:2][CH3:3]
Reactant: O=Cc1n[nH]c2ccccc12
Reactant: CCCc1ccc(N)c(N)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Temperature: 200 °C

Procedure:
A stirred solution of 4-propyl-benzene-1,2-diamine [57 mg, Reference Example 30(d)] and sodium bisulfite (40 mg) in dimethylformamide (2 ml) was treated with indazole-3-carboxaldehyde [Reference Example 6(l)]. The reaction mixture was heated in a Smith Creator microwave at 200° C. for 13 minutes then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (3:1) to give 3-(5-n-propyl-1H-benzoimidazol-2-yl)-1H-indazole (74 mg) as a pale brown solid. MS: 277.3 (M+H)+. HPLC (METHOD B1): RT=12.81 minutes.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11](=[O:23])[N:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([CH3:16])=[CH:14][N:15]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C1C=CC=CC=1>[Br:1][CH2:16][C:13]1[N:12]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11](=[O:23])[C:10]([Cl:9])=[N:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cn1c(C)cnc(Cl)c1=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)Cn1c(CBr)cnc(Cl)c1=O
Temperature: 75 °C

Procedure:
N-BROMOSUCCINIMIDE (2.61 G, 14.7 MMOL) WAS ADDED TO A STIRRED SOLUTION OF 3-CHLORO-1-ETHOXYCARBONYLMETHYL-6-METHYLPYRAZINONE (3.38 G, 14.7 MMOL) IN DRY BENZENE (50 ML). BENZOYL PEROXIDE (70%, 30 MG, 0.087 MMOL) WAS ADDED AND THE SOLUTION WAS HEATED TO 75° C. AFTER 16 H THE MIXTURE WAS PARTITIONED BETWEEN METHYLENE CHLORIDE AND 5% SODIUM METABISULFITE. THE ORGANIC LAYER WAS DRIED (NA2SO4) AND EVAPORATED IN VACUO. THE RESIDUE WAS PURIFIED BY FLASH COLUMN CHROMATOGRAPHY ON SILICA GEL (30% ETOAC/HEXANES) TO GIVE THE TITLE COMPOUND AS A CRYSTALLINE SOLID:
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[N:18]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[N:18]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCn1nc(-c2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)c2ccc(F)cc21
Temperature: 80 °C
Yield: 58.6 %

Procedure:
N-tert-Butyl-2-(1-(2-(dimethylamino)ethyl)-6-fluoro-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.085 g, 153 μmol) was placed in a sealed tube and dissolved in dichloromethane (2 mL). Trifluoroacetic acid (1.75 g, 1.18 mL, 15.3 mmol) was added and the tube sealed and the mixture heated at to 80° C. After 15 h the mixture was cooled and then concentrated in vacuo. The residue was crystallized from dichloromethane/methanol and cyclohexane to give N-tert-butyl-2-(1-(2-(dimethylamino)ethyl)-6-fluoro-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (38 mg, 89.7 μmol, 58.5%) as a white powder. MS (M+H)+=424; 1H NMR (CDCl3) δ: 9.07 (s, 1H), 8.42-8.50 (m, 1H), 8.24 (s, 1H), 7.33-7.41 (m, 1H), 7.02 (s, 1H), 4.88 (s, 2H), 3.68-3.79 (m, 2H), 2.85 (s, 7H), 1.55 (s, 6H).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@@H:7]([C@H:9]([CH2:11][O:12][S:13]([CH3:16])(=[O:15])=[O:14])[OH:10])[OH:8])(=[O:4])=[O:3].[CH2:17]=O.S(=O)(=O)(O)O>>[CH3:16][S:13]([O:12][CH2:11][C@:9]1([CH2:17][O:8][C@H:7]1[CH2:6][O:5][S:2]([CH3:1])(=[O:3])=[O:4])[OH:10])(=[O:15])=[O:14]
Reactant: CS(=O)(=O)OC[C@H](O)[C@@H](O)COS(C)(=O)=O
Reactant: C=O
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)OC[C@@H]1OC[C@]1(O)COS(C)(=O)=O
Yield: 63 %

Procedure:
L-threitol 1,4-bis(methanesulfonate) was reacted with formaldehyde and concentrated sulfuric acid as described in J. Med. Chem., 7, 14 (1964) to yield 2,3-O-methylene-L-threitol 1,4-bis-(methanesulfonate) in 63% yield.
Reaction SMILES: [C:1]([Si:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:44]1[C:48](=[O:49])[C:47]2=[CH:50][CH:51]=[CH:52][CH:53]=[C:46]2[C:45]1=[O:54].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([Si:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][N:44]1[C:48](=[O:49])[C:47]2[C:46](=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:45]1=[O:54])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](OCCCCO)(c1ccccc1)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCCCON1C(=O)c2ccccc2C1=O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.6 %

Procedure:
4-(tert-Butyl-diphenyl-silanyloxy)-butan-1-ol (10.0 g, 30.5 mmol), triphenylphosphine (8.0 g, 30 mmol), and N-hydroxyphthalimide (4.97 g, 30.5 mmol) were combined in anhydrous tetrahydrofuran (200 ml) att 0° C. and the resultant solution was stirred at 0° C. for 1 hour. Diethyl azodicarboxylate (5.31 g, 30.5 mmol) was added at 0° C., and the reaction mixture was allowed to gradually warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform. Precipitation ensued, and the white solid was removed by filtration. The filtrate was concentrated and purified with column chromatography (hexane/ethyl acetate (3/1)) to afford 2-[4-(tert-butyl-diphenyl-silanyloxy)-butoxy]-isoindole-1,3-dione (11.06 g, 77% yield) as colorless crystals: 1H NMR (400 MHz, DMSO-d6) δ 7.84 (4H, s), 7.59 (4H, dd, J=7.6, 1.0 Hz), 7.39-7.43 (6H, m), 4.13 (2H, t, J=6.4 Hz), 3.68 (2H, t, J=5.8 Hz), 1.67-1.78 (4H, m), 0.95 (9H, s).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5]2.[C:14]([C@@H:18]1[CH2:23][CH2:22][C@H:21](O)[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O.C1(C)C=CC=CC=1>[C:14]([C@H:18]1[CH2:23][CH2:22][C@H:21]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[CH:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5]3)[CH2:20][CH2:19]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: N#Cc1ccc2cc(O)ccc2c1
Reactant: CC(C)(C)[C@H]1CC[C@@H](O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C#N)ccc3c2)CC1
Reaction time: 15 h

Procedure:
To a vial charged with 6-hydroxy-2-naphthonitrile (3.38 g, 0.02 mol, 1.0 eq.), cis-4-tert-butylcyclohexanol (6.24 g, 0.04 mol, 2.0 eq.), PPh3 (10.5 g, 0.04 mol, 2.0 eq.) and toluene (20 mL), was added DIAD (12 mL, 0.06 mol, 3.0 eq.) under nitrogen atmosphere at r.t. and stirred for 15 h. Water was added and extracted with EtOAc. The organic layer was purified by silica gel chromatography (PE:EA=10:1) to give the title compound (9.0 g, 86%) as a slight yellow solid. EDI-MS (M+1)+: 308.0. 1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.78-7.73 (m, 2H), 7.54 (dd, 1H), 7.22 (dd, 1H), 7.14 (s, 1H), 4.33-4.30 (m, 1H), 2.29-2.25 (m, 2H), 1.93-1.90 (m, 2H), 1.48-1.26 (m, 2H), 1.25-1.10 (m, 3H), 0.91 (s, 9H).
Reaction SMILES: [CH:1]1[N:5]=[CH:4][N:3]([C:6](N2C=NC=C2)=[O:7])[CH:2]=1.[C:13]([O:17][C:18](=[O:25])[NH:19][CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14]>C1COCC1.C(Cl)Cl>[C:13]([O:17][C:18](=[O:25])[NH:19][CH:20]1[CH2:24][CH2:23][N:22]([C:6]([N:3]2[CH:2]=[CH:1][N:5]=[CH:4]2)=[O:7])[CH2:21]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)n2ccnc2)C1
Temperature: 57.5 °C
Yield: 88.1 %

Procedure:
To a suspension of CDI (3.8 g, 20.5 mmol) in THF (40 mL) was added pyrrolidin-3-yl-carbamic acid tert-butyl ester (3.99 g, 20.5 mmol) and the reaction mixture was heated at about 55-60° C. for about 4 h. The reaction mixture was cooled at ambient temperature and concentrated in vacuo to afford an yellow oil. The residue was dissolved in DCM (40 mL), washed with water (2×30 mL), and the organic portion was separated, dried over MgSO4, filtered, and concentrated in vacuo to give [1-(imidazole-1-carbonyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (5.06 g, 88%) as a yellow oil which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method d) Rt 2.08 min; m/z: (M+H)+ 281.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][CH3:13])[CH2:10][C@H:9]([NH:14][C:15]2[N:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=2)[C@@H:8]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:6])([CH3:3])[CH3:2].[H-].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1)[CH2:35]Br>CN(C=O)C>[CH:1]([O:4][C:5]([N:7]1[C@H:11]([CH2:12][CH3:13])[CH2:10][C@H:9]([N:14]([C:15]2[N:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=2)[CH2:35][C:34]2[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=[C:32]([Cl:31])[CH:33]=2)[C@@H:8]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:6])([CH3:2])[CH3:3]
Reactant: CC[C@@H]1C[C@H](Nc2ncc(Br)cn2)[C@H](Cc2ccccc2)N1C(=O)OC(C)C
Reactant: FC(F)(F)c1cc(Cl)cc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](N(Cc2cc(Cl)cc(C(F)(F)F)c2)c2ncc(Br)cn2)[C@H](Cc2ccccc2)N1C(=O)OC(C)C
Reaction time: 3.5 h
Yield: 73.2 %

Procedure:
To a suspension of (2S,3S,5R)-2-benzyl-3-(5-bromo-pyrimidin-2-ylamino)-5-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (0.064 mmol; 28.6 mg) and sodium hydride (60% dispersion in mineral oil, 0.19 mmol; 7.6 mg) in DMF (0.6 mL) is added 3-chloro-5-trifluoromethylbenzyl bromide (0.13 mmol; 35.6 mg) at room temperature under N2. After 3.5 hours, additional sodium hydride (60% dispersion in mineral oil, 0.19 mmol; 7.6 mg) is added to the suspension. The reaction mixture is stirred for 20 minutes, and quenched with water and saturated aqueous ammonium chloride solution. The product is extracted three times with EtOAc. The combined organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent: n-hexane/EtOAc) to give (2S,3S,5R)-2-Benzyl-3-[(5-bromo-pyrimidin-2-yl)-(3-chloro-5-trifluoromethyl-benzyl)-amino]-5-ethyl-pyrrolidine-1-carboxylic acid isopropyl ester (30.0 mg, 73%); ESI-MS m/z: 639 [M+1]+, Retention time 2.68 min (condition A).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[OH:13])[C:6]([O:8][CH3:9])=[O:7])=[O:2].[CH:14]1([Mg]Br)[CH2:16][CH2:15]1>C1COCC1>[CH:14]1([CH:1]([OH:2])[C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=2[OH:13])[C:6]([O:8][CH3:9])=[O:7])[CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(O)c(C=O)c1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(O)c(C(O)C2CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In an ice-bath, methyl 3-formyl-4-hydroxybenzoate T29.1 (900 mg, 5 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) was dissolved in 5 mL THF. Then cyclopropylmagnesium bromide, 0.5 m in THF (22000 μL, 11 mmol) (commercially available from Sigma-Aldrich, St. Louis, Mo., USA) was added slowly. The reaction was raised to room temperature immediately and stirred at room temperature for 2 hours. After quenching with 1N HCl 11 mL, the reaction was extracted with EtOAc and dried. Silica gel chromatography afforded 950 mg of the product T29.2 (85%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[Si:15]([O:22][C:23]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(N(CC)CC)C>ClCCl>[Si:15]([O:22][C:23]1([CH2:29][CH2:30][CH2:31][NH:32][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CC(C)(C)[Si](C)(C)OC1(CCCN)CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC1(CCCNc2c([N+](=O)[O-])cnc3ccccc23)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.6 %

Procedure:
4-Chloro-3-nitroquinoline (0.700 g, 3.37 mmol) was added in two portions to a solution of 3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propan-1-amine (0.960 g, 3.54 mmol) and triethylamine (0.610 mL, 4.38 mmol) in dichloromethane (15 mL) at 0° C. After 30 min, the reaction was allowed to warm to rt and stir overnight. The mixture was diluted with dichloromethane (40 mL) and was washed with saturated aqueous sodium bicarbonate (30 mL). The aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to afford a yellow solid. The crude product was purified using HPFC (silica gel, gradient elution with 0-2% ethyl acetate/hexanes) to yield N-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl]-3-nitroquinolin-4-amine as a bright yellow solid (1.40 g, 93%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10](=[O:26])(=[O:25])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1)=[O:4].[NH2:27][CH2:28][C@@H:29]([C:31]1[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=1)[OH:30]>>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([NH:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:19][CH2:20][CH:21]([NH:27][CH2:28][C@H:29]([OH:30])[C:31]3[CH:32]=[CH:33][C:34]([OH:42])=[C:35]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH:36]=3)[CH2:22][CH2:23]2)=[CH:16][CH:17]=1)(=[O:25])=[O:26])=[O:4]
Reactant: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: CS(=O)(=O)Nc1cc([C@@H](O)CN)ccc1O
Product: COC(=O)c1sccc1S(=O)(=O)Nc1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1

Procedure:
The title compound was prepared from 3-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-thiophene-2-carboxylic acid methyl ester (which was obtained in Example 234) and N-[5-((1 R)-2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 10) according to the procedure of Example 278 as a pale yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20–1.40 (m, 2 H), 1.70–1.90 (m, 2 H), 2.50–2.75 (m, 5 H), 3.40–3.55 (m, 2 H), 3.89 (s, 2 H), 4.46 (dd, J=8.0, 4.2 Hz, 1 H), 6.75–6.85(m, 3 H), 6.90 (d, J=9.0 Hz, 2 H), 7.00 (dd, J=8.3, 2.0 Hz, 1 H), 7.16 (d, J=2.0 Hz, 1 H), 7.32 (d, J=3.3 Hz, 1 H), 7.89 (d, J=3.3 Hz, 1 H); MS (ES) m/z: 624.9 (MH+); HRMS Calcd. for C26H34N4O8S3 (MH+): 625.1455. Found: 625.1441.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[C:6](=[CH2:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.C12BC(CCC1)CCC2.[O:27]1CCCC1>>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[CH:6]([CH2:15][OH:27])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: C1CCOC1
Reactant: C=C1c2ccccc2C=Cc2cc(Cl)ccc21
Agent: B1C2CCCC1CCC2
Product: OCC1c2ccccc2C=Cc2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-chloro-5-methylene-dibenzo[a,d]cycloheptene (8.3 g) in dry tetrahydrofuran (30 ml). under an inert atmosphere, was added 9-borabicyclo [3.3.1]nonane (71 ml of a 0.5 molar solution in tetrahydrofuran) at ambient temperature and the reaction mixture was then refluxed for 3 h. After cooling. the reaction was quenched by the slow addition of 2N sodium hydroxide solution (180 ml) and 30% hydrogen peroxide (36 ml). After stirring vigorously at 0° C. for 45 minutes the reaction mixture was allowed to warm to room temperature over a 2 h period then extracted into diethyl ether (3×250 ml). The combined organic layers were washed with brine (1×150 ml), dried (Na2SO4), filtered and concentrated in vacuo to leave a residue which was purified by chromatography on flash silica with 40% ethyl acetate in hexane as eluent to give the title compound (8.1 g) as a colourless oil. δ (360 MHz, CDCl3) 3.80 (2H. d, J=7.9 Hz CH--CH2OH), 4.18 (1H, t, J= 7.9 Hz, CH--CH2OH), 6.76 (1H, d, J=11.9 Hz, CHA =CHB) 6.89 (1H, d, J=11.9 Hz, CHA =CHB), 7.24-7.38 (7H, m, ArH); m/e 258 and 256 (M+)
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]=[C:9]([C:15](O)=[O:16])[C:8]2=[O:18])(=[O:3])[CH3:2].S(Cl)([Cl:21])=O>>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[O:11][CH:10]=[C:9]([C:15]([Cl:21])=[O:16])[C:8]2=[O:18])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc2occ(C(=O)O)c(=O)c2c1
Product: CC(=O)Oc1ccc2occ(C(=O)Cl)c(=O)c2c1

Procedure:
In accordance with the procedure described in Example 5-a), 6-acetoxychromone-3-carboxylic acid (77 mg, 0.314 ml) was treated with thionyl chloride (0.1 ml, 1.4 mmol) to obtain 6-acetoxychromone-3-carbonyl chloride.