Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH2:9][CH:10]=O)=[CH:7][CH:6]=[CH:5][C:4]=1[C:12]1[S:16][C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH2:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=2)[C:22]#[N:23])=[N:14][N:13]=1)[CH3:2].[NH:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31]([OH:33])=[O:32].CC(O)=O.C([BH3-])#N.[Na+]>C(O)C>[C:22]([C:21]1[CH:24]=[C:17]([C:15]2[S:16][C:12]([C:4]3[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH2:10][N:29]4[CH2:36][CH2:35][CH2:34][C@H:30]4[C:31]([OH:33])=[O:32])[CH:7]=[CH:6][CH:5]=3)=[N:13][N:14]=2)[CH:18]=[CH:19][C:20]=1[CH2:25][CH:26]([CH3:28])[CH3:27])#[N:23]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CCc1c(CC=O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1c(CCN2CCC[C@H]2C(=O)O)cccc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 41.9 %

Procedure:
To a solution of 5-{5-[2-ethyl-3-(2-oxoethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(2-methylpropyl)benzonitrile (D31) (99 mg, 0.254 mmol) in Ethanol (15 mL) stirred at room temperature was added L-proline (117 mg, 1.017 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium cyanoborohydride (31.9 mg, 0.508 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was quenched with water and DCM was evaporated in vacuo. The mixture was extracted by EA/THF for 3 times. The combined organic solution was washed with brine, concentrated and purified by Mass Directed AutoPrep to afford 1-[2-(3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-ethylphenyl)ethyl]-L-proline (E59) (52 mg) as a off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.CCCCCC.[Li]CCCC.[C:19]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:27]1([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:26])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: Brc1cccnc1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
A solution of 3-bromopyridine (10 g, 0.063 mol) in dry THF (200 mL)/hexane (50 mL) was cooled to −90° C. To this cooled solution was added n-BuLi (2.2 M, 32 mL, 0.063 mol) slowly and allowed to stir for 30 min under N2 atmosphere. A solution of benzophenone (11.5 g, 0.063 mol) in dry THF (50 mL) was added to this at the same temperature over a period of 30 min. The reaction mixture was warmed slowly to RT and allowed to stir another 3 h at RT. The reaction mixture was cooled, quenched with water (200 mL) and extracted with ethyl acetate (2×100 mL). The organic layer was dried, concentrated under vacuum and the crude product was purified by column chromatography on silica gel (30% ethyl acetate in pet. ether) which gave the title compound (3.3 g).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li]CCCC.[CH3:15][C:16]1([CH3:24])[O:21][C:20](=[O:22])[CH:19]=[C:18]([CH3:23])[O:17]1.[F:25][C:26]([F:33])([F:32])[C:27]([O:29]CC)=[O:28].CC(O)=O>C1COCC1>[CH3:15][C:16]1([CH3:24])[O:21][C:20](=[O:22])[CH:19]=[C:18]([CH2:23][C:27]([OH:29])([OH:28])[C:26]([F:33])([F:32])[F:25])[O:17]1
Reactant: CC1=CC(=O)OC(C)(C)O1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C=C(CC(O)(O)C(F)(F)F)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
To a solution of hexamethyldisilazane (167 mL, 800 mmol) in THF (200 mL) at 0° C. was cannulated n-BuLi (500 mL, 800 mmol) and the mixture was stirred at 0° C. for 30 min, then cannulated into a solution of freshly distilled 2,2,6-trimethyl-1,3-dioxin-4-one (56.9 g, 400 mmol) in THF (400 mL) at −78° C., keeping the internal temperature below −60° C. Stirring was continued at −78° C. for 1 h, then a solution of ethyl 2,2,2-trifluoroacetate (52.5 mL, 440 mmol) in THF (100 mL) was added quickly (<1 min; internal temperature remained below −70° C.). The cooling bath was removed and stirring was continued at −78 to 0° C. for 2 h. Cooled to −45° C., then HOAc (57.3 mL, 1000 mmol) was added and the mixture was warmed to −10° C. Poured into ice cold 0.5 M HCl (pH 1), extracted with TBME, washed with sat. NaHCO3-sol., icecold 0.5 M HCl and brine, dried over Na2SO4. Removal of the solvent in vacuum (bath temperature below 40° C.) left a yellow oil, added THF (ca. 200 mL), toluene (ca. 50 mL) and H2O (ca. 20 mL) and evaporated to dryness to give the title compound as a light yellow solid (89.27 g, 87%). MS (ISN) 237.0 [(M−H)−].
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[O:15])[CH:10]=[CH:11][CH:12]=1.C(N(CC)CC)C>ClCCl>[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]([NH:16][C:14](=[O:15])[NH:13][C:9]2[CH:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:12]=[CH:11][CH:10]=2)=[CH:18][CH:19]=1
Reactant: Nc1cccc(NC(=O)Nc2ccnc3ccccc23)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(NC(=O)Nc2ccnc3ccccc23)c1
Reaction time: 16 h

Procedure:
Methanesulphonyl chloride (27 ul) was added to 1-(3-aminophenyl)-3-quinolin-4-ylurea (0.08 g) in dichloromethane (25 ml) containing triethylamine (48 ul) and stirred for 16 h. The precipitate that formed was separated by filtration, washed with tetrahydrofuran and diethyl ether and dried to give the title compound (0.081 g).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Br:5][C:6]1[C:7]([CH3:15])=[N:8][CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1>C1COCC1>[Br:5][C:6]1[C:7]([CH3:15])=[N:8][CH:9]=[C:10]2[NH:12][CH:1]=[CH:2][C:11]=12
Reactant: C=C[Mg]Br
Reactant: Cc1ncc([N+](=O)[O-])cc1Br
Solvent: C1CCOC1
Product: Cc1ncc2[nH]ccc2c1Br
Temperature: 25 °C
Reaction time: 24 h
Yield: 0.9 %

Procedure:
To a stirred suspension of vinylmagnesium bromide (1 M in THF, 37.5 mL, 37.50 mmol) was added dropwise a solution of 3-bromo-2-methyl-5-nitropyridine (2.50 g, 11.52 mmol) in THF, under an atmosphere of nitrogen, at 0° C. The resulting solution was allowed to warm to RT and stirred for 1 day then quenched with saturated NH4Cl(aq). The resulting mixture was partitioned between EtOAc and water, the organic layer separated, dried (MgSO4) and evaporated to give a red crude oil, which was purified by column chromatography (Si—PCC, 50-100% EtOAc in cyclohexane) followed by reverse phase HPLC (Phenomenex Gemini 5u C18, 0.1% formic acid in water on a gradient of methanol 5-75%). The relevant HPLC fractions were loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH and the desired product eluted with 2 M NH3 in MeOH to give the title compound as a pale yellow solid (22 mg, 1%). LCMS (Method H): RT 2.23 min, [M+H]+ 211.1 (79Br), 213.1 (81Br)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>CCO.C1COCC1>[Cl:11][CH2:12][C:13]1[N:8]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[O:7][CH:15]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(F)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: Fc1ccc(-c2nc(CCl)co2)cc1
Temperature: 85 °C
Yield: 31.7 %

Procedure:
A mixture of 4-fluorobenzamide (2.5 g, 17.9 mmol) and 1,3-dichloroacetone (2.7 g, 21.6 mmol) in EtOH-THF (20 mL-10 mL) was heated to 85° C. for 24 h. The reaction mixture was cooled to room temperature and quenched with 10% NaHCO3 solution. The organic product was extracted with EtOAc and the organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 6-10% EtOAc in petroleum ether) to afford 4-(chloromethyl)-2-(4-fluorophenyl)oxazole (1.2 g, yield 32%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 8.07-8.02 (m, 2H), 7.70 (m, 1H), 7.19-7.13 (t, J=8.8 Hz, 2H), 4.58 (m, 2H). MS (ESI) m/z: Calculated for C10H7ClNO: 211.02. found: 212.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[N+:12]([C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH2:19][CH2:18]2)([O-:14])=[O:13]>C(O)CCC>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([N+:12]([O-:14])=[O:13])=[CH:23][CH:22]=3)[CH2:18][CH2:19]2)[N:3]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc2c(c1)CCN2c1nc(Cl)nc2[nH]cnc12
Reaction time: 72 h
Yield: 90.6 %

Procedure:
37.8 g of 2,6-dichloropurine, 700 ml of butanol and 32.8 g of 5-nitroindoline are mixed and brought to a temperature of 90° C. for approximately 3 days. The mixture is allowed to return to ambient temperature. Partial drying, washing with ethyl ether and drying under vacuum at 50° C. are carried out and 57.3 g of expected product are obtained, in the form of beige crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5](P(OC)(OC)=O)[NH:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:4].[CH3:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[CH:29]=O.C1CCN2C(=NCCC2)CC1>ClCCl>[CH2:10]([O:9][C:7]([NH:6]/[C:5](=[CH:29]\[C:25]1[S:26][CH:27]=[CH:28][C:24]=1[CH3:23])/[C:3]([O:2][CH3:1])=[O:4])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccsc1C=O
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C(=C/c1sccc1C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
A stirred solution of N-(benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (5.01 g, 15.1 mmol) and 3-methylthiophene-2-carbaldehyde (7.5:1 mixture with 4-methylthiophene-2-carbaldehyde, 2.48 g, 19.6 mmol) in dry dichloromethane (100 mL), was cooled to 0° C. and treated dropwise with DBU (2.76 g, 18.1 mmol). The mixture was warmed to ambient temperature and stirred overnight. The solution was concentrated, taken up in ethyl acetate (150 mL) and washed with 5% hydrochloric acid (2×75 mL). The organic extract was washed with saturated aqueous sodium bicarbonate (2×75 mL), water (75 mL), dried (magnesium sulfate), filtered and evaporated. The residue was purified by flash chromatography (20-40% ethyl acetate/hexanes gradient) to afford the title compound (4.07 g, 81%) as an orange oil. The product is a mixture of 3- and 4-methylthiophene isomers (6.8:1). 1H NMR major isomer: (300 MHz, d6-DMSO) δ2.33 (s, 3H), 3.72, (s, 3H), 5.13 (bs, 2H), 7.01 (d, 1H, J=5.3 Hz), 7.18-7.52 (m, 5H), 7.60-7.85 (m, 2H), 8.83 (s, 1H). MS APCI, m/z=354(M+Na). LC/MS: 2.43 min.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:17]([OH:29])[C:18](=[O:28])[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])=O)C1C=CC=CC=1>[Pd].O.C(O)C>[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C@H:16]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH:17]([OH:29])[C:18](=[O:28])[NH:19][C@@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21]
Reactant: C[C@@H](NC(=O)C(O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: C[C@@H](NC(=O)C(O)[C@H](CCCCN)NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A slurry of palladium on carbon (1.5 g, 10% w/w) in water (3 mL) was added to a solution of tert-butyl (1S)-5-{[(benzyloxy)carbonyl]amino}-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate (15.28 g, 29.70 mmol) in ethanol (200 mL). The resulting slurry was stirred vigorously under a hydrogen atmosphere (45 psi) at 50° C. for 18 h. Catalyst was then filtered off, rinsing with ethanol (400 mL). Concentration of the filtrate under vacuum afforded tert-butyl (1S)-5-amino-1-(1-hydroxy-2-oxo-2-{[(1R)-1-phenylethyl]amino}ethyl)pentylcarbamate as a colorless oil that crystallized upon standing under vacuum (10.52 g, 93%). 1H NMR (300 MHz, DMSO-d6) δ 8.15 (d, J=8 Hz) and 8.08 (d, J=8 Hz) total 1H, 7.90-7.87 (m, ca 1H); 7.87-7.28 (m, 4H); 7.25-7.20 (m, 1H); 6.51 (d, J=9 Hz) and 6.17 (d, J=9 Hz) total 1H; 4.99-4.92 (m, 1H); 3.96 (d, J=4 Hz) and 3.90 (d, J=3 Hz) total 1H, 3.80-3.69 (m, 1H); 2.68-2.64 (m) and 2.53-2.57 (m) total 1H, 1.53-1.23 (m, 18H). ES-LCMS m/z 380 (M+H).
Reaction SMILES: [C:1]([Si:5]([CH3:45])([CH3:44])[O:6][C:7]1[CH:8]=[C:9]([O:36][Si:37]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:39])[CH3:38])[C:10]2[CH2:21][S:20][CH2:19][C@@H:18]([CH2:22]O)[NH:17][C:16](=[O:24])[C@@H:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:14][O:13][C:12](=[O:33])[C:11]=2[C:34]=1[CH3:35])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:47].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:47][CH2:22][C@@H:18]1[NH:17][C:16](=[O:24])[C@@H:15]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:14][O:13][C:12](=[O:33])[C:11]2[C:34]([CH3:35])=[C:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([CH3:45])[CH3:44])[CH:8]=[C:9]([O:36][Si:37]([C:40]([CH3:42])([CH3:43])[CH3:41])([CH3:38])[CH3:39])[C:10]=2[CH2:21][S:20][CH2:19]1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c2c1C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](CO)CSC2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)c2c1C(=O)OC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CBr)CSC2
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of 103 mg of tert-butyl (4R, 7S)-12, 14-bis (tertbutyldimethylsilyloxy)-1,3,4,5,6,7,8, 10-octahydro-4-hydroxymethyl-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate in 2 ml of methylene chloride was treated with 99 mg of carbontetrabromide and 79 mg of triphenylphosphine, and then stirred at 20° C. for 15 minutes. The solution was chromatographed on silica gel using ethyl acetate/hexane (1:3, v/v) as eluent to yield tert-butyl (4R, 7S)-4-bromomethyl-12,14-bis-(tert-butyldimethylsilyloxy)-1,3,4,5,6,7,8,10-octahydro-11-methyl-6,10-dioxo-9,2,5-benzooxathiaazacyclododecine-7-carbamate. This material was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 13 to yield, after crystallization from ethyl acetate/hexane, tert-butyl (4R, 7S)-4-bromomethyl- 1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy-11-methyl-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-7-carbamate as a white solid.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.[O-:12][C:13]#[N:14].[K+]>O>[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH:11][C:13]([NH2:14])=[O:12])[CH2:8][CH2:9][CH2:10][C:3]1=2
Reactant: NC1CCCc2sccc21
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)NC1CCCc2sccc21
Yield: 22.1 %

Procedure:
A mixture of 50 grams of 4,5,6,7-tetrahydrobenzo-[b]thiophen-4-amine hydrochloride (about 45 grams real, based on 90% purity) in 100 ml. of water is stirred at about 15° C., and a solution of 23.1 grams of potassium cyanate in 100 ml. of water is added dropwise. After completion of the addition, the mixture is warmed slowly to 70° C. to 75° C. and held for an hour. The mixture is cooled, and the white solid is collected by filtration and washed with water. The solid is air-dried, pulverized, and washed with acetonitrile. On drying, this gives 37.3 grams of crude product, which on treatment with about 1200 ml. of hot acetone gives 11.45 grams, melting point 200° C. to 204° C. of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]([CH:14]3[CH2:16][CH2:15]3)[C:11]([C@@H:17]([NH:19]C(OC(C)(C)C)=O)[CH3:18])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:27])=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]([CH:14]3[CH2:16][CH2:15]3)[C:11]([C@@H:17]([NH2:19])[CH3:18])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:27])=[O:4]
Reactant: COC(=O)c1c(F)ccc2nc([C@H](C)NC(=O)OC(C)(C)C)n(C3CC3)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1c(F)ccc2nc([C@H](C)N)n(C3CC3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-((S)-1-tert-butoxycarbonylaminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazole-4-carboxylic acid methyl ester (698 mg, 1.85 mmol) in DCM (3 mL) was added TFA (3 mL) and the reaction mixture stirred at RT for 2 h. The crude mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford 2-((S)-1-aminoethyl)-3-cyclopropyl-5-fluoro-3H-benzoimidazole-4-carboxylic acid methyl ester as a yellow oil. The resulting residue was treated with 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (486 mg, 2.03 mmol) and DIPEA (970 μL, 5.55 mmol) in n-butanol (3 mL). The reaction mixture was heated in a sealed vial for 20 h at 100° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) to afford the title compound (780 mg, 88% over 2 steps). LCMS (Method C): RT 2.91 min [M+H]+ 480.22.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:19]1([CH:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl.CCOCC>[CH:25]([CH:26]1[N:10]([CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C@H:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:2][O:1]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)CN[C@H](CO)c1ccccc1
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1C(C(c2ccccc2)c2ccccc2)OC[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 114.1 %

Procedure:
To a solution of tert-butyl (S)-(2-hydroxy-1-phenyl-ethylamino)-acetate (2.5 g, 10 mmole, obtained from Reference Example 9) in anhydrous methylene chloride (35 ml) were added diphenylacetaldehyde (2.16 g, 11 mmole) and magnesium sulfate (1.2 g, 10 mmole) under nitrogen. The resulting mixture was stirred at room temperature under nitrogen for 15 h, and diluted with ether. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness in vacuo. The oily residue was solidified upon standing, and recrystallized from ether/hexanes to give tert-butyl ((4R)-2-benzhydryl-4-phenyl-oxazolidin-3-yl)-acetate as a white solid (4.9 g, 98%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10](=[O:23])(=[O:22])[N:9]=2)=[CH:4][CH:3]=1.[NH:24]1[CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:20][CH2:19][CH2:18][O:17][C:15]2[CH:14]=[CH:13][C:12]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=4)=[N:9][S:10](=[O:23])(=[O:22])[C:11]=3[CH:16]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: O=S1(=O)N=C(c2ccc(Br)cc2)c2ccc(OCCCBr)cc21
Reactant: C1CNC1
Product: O=S1(=O)N=C(c2ccc(Br)cc2)c2ccc(OCCCN3CCC3)cc21

Procedure:
According to the method in example 9, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole 1,1-dioxide and azetidine were converted to yield 6-(3-Azetidin-1-yl-propoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole 1,1-dioxide as yellow solid, MS: 435 (MH+, 1Br).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].Br[CH:15]([CH3:28])[C:16]([C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)=O>O1CCCC1>[C:3]1([C:2]2[NH:9][C:15]([CH3:28])=[C:16]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(Br)C(=O)c1ccc2ccccc2c1
Reactant: N=C(N)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2ccccc2)nc1-c1ccc2ccccc2c1

Procedure:
Benzamidine hydrochloride and an equimolar amount of sodium methylate were heated under reflux in tetrahydrofuran for 1 hour. After cooling, a tetrahydrofuran solution of an equimolar amount of 2-bromo-2′-propionaphthone was added dropwise thereto so that the temperature did not exceed 30° C., and then an equimolar amount of sodium methylate was further added, followed by heating under reflux for 1 hour. After removal of the solvent by distillation under reduced pressure, the residue was washed with water and subjected to recrystallization from acetonitrile to obtain grayish blue crystals.
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([OH:15])=O)[C:8]([CH3:11])=[CH:9][N:10]=1.[F:24][C:25]([F:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:26][NH2:27]>>[F:34][C:25]([F:24])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:26][NH:27][C:13](=[O:15])[CH2:12][N:7]1[C:8]([CH3:11])=[CH:9][N:10]=[C:5]([NH:4][CH2:3][C:2]([F:1])([F:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:6]1=[O:16]
Reactant: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)O
Reactant: NCC(F)(F)c1ccccn1
Product: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)NCC(F)(F)c1ccccn1

Procedure:
5-1 was prepared from [3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-acetic acid and 2,2-difluoro-2-(2-pyridyl)ethyl amine essentially according to the procedure of Example 1, Step K. Mass Spectrum: Found: (M+1)465.2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[CH:22]([N:25]([CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[C:32]([O:39][CH3:40])[CH:31]=1)[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][C:30]([CH2:29][N:25]([CH:26]([CH3:27])[CH3:28])[CH:22]([CH3:24])[CH3:23])=[CH:31][C:32]=3[O:39][CH3:40])[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: COc1cc(CN(C(C)C)C(C)C)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(CN(C(C)C)C(C)C)ccc1C(=O)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
To a solution of 1-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride(100 mg), 4-diisopropylaminomethyl-2-methoxybenzoic acid (77 mg), triethylamine (35 mg) and HOBt (43 mg) in DMF (10 ml) was added WSC hydrochloride (61 mg) under ice-cooling, and the solution was stirred at room temperature for 4 hours and concentrated. To the residue were added ethyl acetate and sodium bicarbonate solution. The organic layer was separated, washed with water and extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution and extracted with dichloromethane. The extract was dried and concentrated and the residue was crystallized with ether to give colorless crystals of the title compound (99 mg).