Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH:16]1[O:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]3[N:28]=[C:27]([CH3:29])[O:26][C:23]3=2)[O:18][CH2:17]1.C=O.[C:32]([BH3-])#N.[Na+].C(O)(=O)C>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][CH2:13][N:14]([CH3:32])[CH2:15][CH:16]1[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]3[N:28]=[C:27]([CH3:29])[O:26][C:23]=3[C:24]=2[O:25]1
Reactant: [BH3-]C#N
Reactant: Cc1nc2ccc3c(c2o1)OC(CNCCCc1c[nH]c2ccc(F)cc12)CO3
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nc2ccc3c(c2o1)OC(CN(C)CCCc1c[nH]c2ccc(F)cc12)CO3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of [3-(5-fluoro-1H-indol-3-yl)-propyl]-(2-methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]napthalen-8-ylmethyl)-amine (0.05 g, 0.13 mmol) and formaldehyde (37 wt. % in water, 0.1 g, 1.3 mmol) in methanol (10 mL) was added sodium cyanoborohydride (0.014 g, 0.23 mmol) and acetic acid (0.01 g, 0.26 mmol) at room temperature. The mixture was stirred at room temperature under nitrogen overnight, then quenched with 1N NaOH (5 mL). The mixture was extracted with methylene chloride (3×40 mL). The organic layer was washed with water (3×30 mL), dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum. The crude oil was column chromatographed on silica gel (5% methanol-methylene chloride). The product-containing fractions were concentrated in vacuum to give 48 mg of the (S)-enantiomer of the title compound as a brown oil. The dihydrochloride salt was prepared in ethyl acetate as a white solid, m.p. 136-139° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15]#[N:16])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:17][OH:18]>>[Si:1]([O:8][CH2:9][C:10]1[S:14][C:13]([C:15](=[N:17][OH:18])[NH2:16])=[CH:12][CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C#N)s1
Reactant: NO
Product: CC(C)(C)[Si](C)(C)OCc1ccc(C(N)=NO)s1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 1 (1d) using 5-({[t-butyl(dimethyl)silyl]oxy}methyl)thiophene-2-carbonitrile (1.3 g, 5.0 mmol) that was obtained in Example 4 (4a) and a 40% aqueous solution of hydroxylamine (0.7 ml). Subsequently, the crude product of the title compound thus obtained was purified by recrystallization from a mixed solvent of ethyl acetate and hexane to afford the title compound (1.2 g) in a yield of 81% as a white crystalline solid.
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][C:19](N(OC)C)=[O:20])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][Mg]Br.[NH4+].[Cl-]>C1COCC1>[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][C:19](=[O:20])[CH3:25])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)COc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)COc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
To 208 mg (0.51 mmol) 2-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-N-methoxy-N-methyl-acetamide in 8 ml THF were added 0.51 ml 3M (1.53 mmol, 3 eq) methylmagnesiumbromide in THF at −75° C. The solution was slowly warmed to RT over night, a saturated aqueous solution of NH4Cl was added and the mixture stirred for 30 min. The phases were separated and the inorganic phase was extracted with EtOAc. The combined organic phases were dried over Na2SO4 and evaporated. Column chromatography on silica gel with EtOAc:hexane 1:4 yielded 109 mg (53%) 1-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propan-2-one as white solid, MS: 361 (M, 1Br).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[Cl:32])(=[O:24])=[O:23])[CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=2)[CH:6]=1.[OH-].[Li+]>C1COCC1.O>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[S:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([F:33])[CH:11]=3)[CH:6]=[C:5]([CH2:4][C:3]([OH:34])=[O:2])[C:14]=2[CH3:15])[CH2:17][CH2:18]1)(=[O:24])=[O:23]
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(=O)(=O)c3ccc(Cl)cc3Cl)CC2)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(CC(=O)O)cc2ccc(F)cc2c1C1CCN(S(=O)(=O)c2ccc(Cl)cc2Cl)CC1
Reaction time: 15 h
Yield: 98.9 %

Procedure:
To a colorless solution of {4-[1-(2,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (109 mg, 0.208 mmol) in THF (8.0 mL) was added a solution of an excess lithium hydroxide (100 mg, 4.18 mmol) in water (2.0 mL) at room temperature. The resulting light yellow solution was stirred for 15 hours. The reaction mixture was concentrated and the aqueous solution was diluted with water then neutralized with 1.0 N aqueous HCl. The resulting suspension was extracted into ethyl acetate (2×40 mL). The combined extracts were washed with brine and dried over anhydrous MgSO4, filtered, and concentrated to afford {4-[1-(2,4-dichloro-benzenesulfonyl)-piperidin-4-yl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid (105 mg, 99%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.32 (br. s, 1H), 8.06 (d, J=8.5 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H), 7.88 (dd, J=8.5, 6.8 Hz, 1H), 7.64-7.82 (m, 3H), 7.25-7.39 (m, 1H), 3.82-3.94 (m, 2H), 3.76 (br. s, 2H), 3.47-3.72 (m, 1H), 3.07 (br. s, 2H), 2.36 (s, 3H), 2.09-2.46 (m, 2H), 1.68 (d, J=12.0 Hz, 2H). MS cald. for C24H23Cl2FNO4S [(M+H)+] 510, obsd. 510.1.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:8]([C@@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=O)C)C=O)(=[O:3])[CH3:2].C[Si]([N:32]=[N+:33]=[N-:34])(C)C>C(Cl)Cl>[C:25]([O:24][C@H:23]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@@H:8]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[O:9][C@@H:10]1[N:32]=[N+:33]=[N-:34])(=[O:27])[CH3:26]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](C=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
About 2 ml. stannic chloride is added to a solution of 8 grams of D-mannose pentaacetate and 2.6 ml. trimethylsilyl azide in 180 ml. methylene chloride, and the resulting mixture is stirred at a temperature of about 25° C. for a period of approximately six hours. The reaction solution is diluted with an additional 100 ml. of methylene chloride, and the resulting methylene chloride solution is washed successively with water, with aqueous sodium bicarbonate solution, again with water, and dried over anhydrous sodium sulfate. The dry methylene chloride solution is evaporated in vacuo to a syrup which crystallizes upon standing to give approximately 7.6 grams of 2,3,4,6-tetra-O-acetyl-α-D-mannopyranosyl azide; m.p. 52°-53° C. (after recrystallization from 2-propanol); [α]D25 +116°, (c 1.02, chloroform).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:9]([O-])=O)=[N:5][CH:6]=[CH:7][CH:8]=1>CO.[Pd]>[CH3:1][O:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccnc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cccnc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
3-Methoxy-2-nitro-pyridine (53, 7.00 g, 45.4 mmol) in 100 mL of methanol, was degassed and palladium (0.7 g, 20%) was added. The reaction was stirred at room temperature for one day under a hydrogen balloon. The reaction was filtered through celite and the filtrate concentrated under vacuum to provide the desired compound (54, 5.555 g). MS (ESI) [M+H+]+=125.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.C(O)(=O)C.[Br:17]Br.[O-]S([O-])=O.[Na+].[Na+]>O.CC(=O)OCC.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([F:11])[C:7]([OH:10])=[C:8]([Br:17])[CH:9]=1
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(F)c(O)c(Br)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
3.9 g of 3-fluoro-4-hydroxy-benzoic acid methyl ester were dissolved using 25 ml of acetic acid and 25 ml of DCM. The mixture was cooled to 0° C. and 1.4 ml bromine added slowly (30 minutes) at 0° C. Stirring was continued at room temperature for 18 h. Then, 200 ml of EA and a solution of 7.6 g Na2SO3 in 50 ml of water were added and the resulting mixture was stirred for 10 minutes at room temperature. The layers were separated, and the organic layer was washed using first 50 ml of water and second 50 ml of a saturated aqueous NaCl-solution. The organic layer was dried using MgSO4 and evaporated to yield 5.0 g of the title compound that was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([F:22])=[CH:16][C:11]=1[C:12]([O:14]C)=[O:13].[OH-].[Na+].C(OCC)(=O)C.Cl>O1CCCC1.C(OCC)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:19]=[C:18]([O:20][CH3:21])[C:17]([F:22])=[CH:16][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1nc(Nc2ccc(F)cc2F)c(C(=O)O)cc1F
Yield: 73.3 %

Procedure:
In 60 ml of tetrahydrofuran was dissolved 2.00 g of methyl 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinate, and 25.5 ml of 1N aqueous sodium hydroxide solution was added thereto at room temperature, after which the resulting mixture was subjected to reaction under reflux for 7 hours. Subsequently, the solvent was removed by distillation under reduced pressure, and to the residue thus obtained were added 100 ml of ethyl acetate and 100 ml of water, after which the pH of the resulting mixture was adjusted to 2.0 with 2N hydrochloric acid. The organic layer was washed successively with 50 ml of water and 50 ml of saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and to the crystalline material thus obtained was added 10 ml of diethyl ether, after which crystals were collected by filtration to obtain 1.40 g (yield 73.3%) of 2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinic acid having a melting point of 237°-240° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[C:20]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)=[CH:29][CH:30]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: CC(C)(C)c1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-tert-butylaniline were reacted to yield N2-(4-tert-butylphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.85 (d, 1H, J=3.6 Hz), 7.44 (bdd, 2H, J=6.3 Hz), 7.35-7.31 (m, 3H), 6.93 (dd, 1H, J=2.7 and 8.7 Hz), 6.83 (d, 1H, J=9 Hz), 6.80 (bs, 1H), 4.23 (s, 4H), 1.28 (s, 9H); LCMS: ret. time: 27.67 min.; purity: 98%; MS (m/e): 395 (MH+).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].CC(C)=O.[OH-].[Na+].[C:16]1([CH:23]=[CH:22][CH:21]=[C:19]([OH:20])[CH:18]=1)[OH:17]>O>[Cl:6][C:5]1([O:17][C:16]2[CH:23]=[CH:22][CH:21]=[C:19]([O:20][C:5]3([Cl:6])[N:4]=[C:2]([Cl:3])[N:1]=[CH:8][NH:7]3)[CH:18]=2)[N:4]=[C:2]([Cl:3])[N:1]=[CH:8][NH:7]1
Reactant: Oc1cccc(O)c1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: ClC1=NC(Cl)(Oc2cccc(OC3(Cl)N=C(Cl)N=CN3)c2)NC=N1
Reaction time: 4 h
Yield: 890.2 %

Procedure:
A 1 L jacketed reaction flask equipped with a gas inlet, a mechanical stirrer, two liquid inlets and a condenser is purged with argon and charged with 37.3 g (0.0200 mol) of cyanuric chloride and 300 mL of acetone. The stirred mixture is cooled below −15° C. and 30 mL of deionized water are added. A 10% aqueous sodium hydroxide solution (88 g) are added over a 66-minute period via a peristaltic pump. Six minutes after the sodium hydroxide addition is started, a resorcinol solution (11.0 g, 0.100 mol in 50 mL of water) addition is begun also via a peristaltic pump. The resorcinol solution is then added over a 60-minute period concurrent with the sodium hydroxide solution. A slight exotherm occurs causing the temperature to rise to −12° C. The mixture is then stirred for an additional four hours at between −15° C. and −20° C. A 200 mL poriton of water is added and the white solids formed are collected by vacuum filtration followed by washing with three 50 mL portions of water. The solids are dried at 60° C. under reduced pressure to afford 36.5 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([CH2:11][S:12](Cl)(=[O:14])=[O:13])#[N:10].O>CCOCC>[CH2:1]([NH:8][S:12]([CH2:11][C:9]#[N:10])(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCS(=O)(=O)Cl
Reactant: NCc1ccccc1
Solvent: O
Solvent: CCOCC
Product: N#CCS(=O)(=O)NCc1ccccc1
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 2.14 g of benzylamine in 10 ml of ether at 5° C. was slowly added a solution of 1.37 g of cyanomethylsulfonylchloride [Sammes, et al., J. Chem. Soc. (C), 2151, 1971] in 5 ml of ether. The resulting mixture was then stirred for another 30 minutes, poured into 50 ml of water and extracted with 50 ml of ethyl acetate. The organic layer was then washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude sulfonamide was then purified on a silica gel column (1:1 hexane/ethyl acetate) to provide 1.52 g of N-benzyl cyanomethylsulfonamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].O.[C:18]1([CH3:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH:21]2[CH2:22][CH2:23][CH:18]([CH2:24][CH2:3][CH2:2][CH2:7][CH3:6])[CH2:19][CH2:20]2)[CH:5]=[CH:6][C:7]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Cc1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCCCCC1CCC(c2ccc(-c3cccc(F)c3)c(F)c2)CC1
Temperature: 25 °C

Procedure:
The compound (T-31; 20.0 g), 3-fluorophenyl boronic acid (8.20 g), potassium carbonate (22.1 g), Pd/C (NX type; 0.114 g), toluene (100 ml), Solmix A-11 (100 ml), and water (100 ml) were put in a reaction vessel under a nitrogen atmosphere, and heated under reflux for 5 hours. The reaction mixture was cooled to 25° C., and then poured into water (300 ml) and toluene (300 ml) and mixed. Then, the mixture was allowed to stand to be separated into two layers of organic and aqueous layers, and the extraction to an organic layer was carried out. The obtained organic layer was fractionated, washed with water, and then dried over anhydrous magnesium sulfate. The obtained solution was concentrated under reduced pressure, and the residue was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder. The product was further purified by recrystallization from a mixed solvent of heptane/Solmix A-11 and dried, whereby 14.2 g of 2,3′-difluoro-4-(4-pentylcyclohexyl)-1,1′-biphenyl (T-32) was obtained. The yield based on the compound (T-31) was 78%.
Reaction SMILES: [N:1]([C:4]1[CH:36]=[CH:35][C:7]2[NH:8][C:9]([C:14]3[C:15](=[O:34])[N:16]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C@@H:17]4[C@H:22]([C:23]=3[OH:24])[C@@H:21]3[CH2:25][C@H:18]4[CH2:19][CH2:20]3)=[N:10][S:11](=[O:13])(=[O:12])[C:6]=2[CH:5]=1)=[N+]=[N-]>CO.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:36]=[CH:35][C:7]2[NH:8][C:9]([C:14]3[C:15](=[O:34])[N:16]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[C@@H:17]4[C@H:22]([C:23]=3[OH:24])[C@@H:21]3[CH2:25][C@H:18]4[CH2:19][CH2:20]3)=[N:10][S:11](=[O:12])(=[O:13])[C:6]=2[CH:5]=1
Reactant: [N-]=[N+]=Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)[C@@H]3[C@H]4CC[C@H](C4)[C@@H]3N(Cc3ccc(F)cc3)C1=O)N2
Temperature: 25 °C
Yield: 48.2 %

Procedure:
(1R,2S,7R,8S)-5-(7-Azido-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.348 g, 0.684 mmol) was dissolved in a 1:1 mixture if methanol and ethyl acetate (15 mL) at 25° C. Palladium on carbon (0.40 g, 5%, “wet”) was added, resulting in a black suspension. The reaction was maintained under a hydrogen atmosphere (balloon) at 25° C. for 6 h, and then was filtered through Celite. The Celite was washed with ethyl acetate (2×30 mL) and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 50 to 100% ethyl acetate in hexanes) to afford the desired product, (1R,2S,7R,8S)-5-(7-amino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-(4-fluoro-benzyl)-6-hydroxy-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (0.159 g, 0.330 mmol, 48%), as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ: 1.08-1.19 (3H, m), 1.40-1.57 (3H, m), 2.99 (1H, d, J=7.2 Hz), 3.31 (3H, s), 3.36-3.37 (1H, m), 3.50 (1H, d, J=7.8 Hz), 4.39 (1H, d, J=14.6 Hz), 4.93 (1H, d, J=14.5 Hz), 6.86-6.91 (3H, m), 7.13-7.15 (2H, m), 7.21 (1H, d, J=8.8 Hz), 7.30 (2H, bs), 13.79 (1H, s). LC-MS (ESI) calcd for C24H23FN4O4S 482.14, found 483.4 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH:15]([CH3:17])[CH3:16])[CH2:13][NH2:14])=[N:7][C:6]=12.C(N(C(C)C)C(C)C)C.N1([C:32](N2C=CN=C2)=[O:33])C=CN=C1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:12]([CH:15]([CH3:17])[CH3:16])[CH2:13][NH:14][C:32]3=[O:33])=[N:7][C:6]=12
Reactant: CC(C)[C@@H](CN)Nc1ccn2ncc(Br)c2n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)[C@H]1CNC(=O)N1c1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of (S)—N2-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-3-methylbutane-1,2-diamine (0.75 g, 2.52 mmol) in DMF was added N-ethyl-N-isopropylpropan-2-amine (1.38 ml, 7.55 mmol) and di(1H-imidazol-1-yl)methanone (0.816 g, 5.03 mmol) and the reaction stirred overnight at ambient temperature. The reaction was poured into water and extracted into EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by chromatography, eluting with 2% MeOH/dichloromethane, to yield (S)-1-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-5-isopropylimidazolidin-2-one (0.48 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([O-])(O)=O.[Na+].[C:15](Cl)(Cl)=[S:16]>C(Cl)(Cl)Cl.O>[N:1]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH3:9])=[C:15]=[S:16]
Reactant: S=C(Cl)Cl
Reactant: COc1ccncc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccncc1N=C=S
Reaction time: 4 h

Procedure:
To a stirred mixture of 3-amino-4-methoxypyridine (2.01 g, 16.2 mmol) and NaHCO3 (4.08 g, 48.6 mmol) in CHCl3 and water (1:1, 50 mL) at 4° C. was added thiophosgene (1.5 mL, 19.6 mmol) dropwise. After completion of the addition, the ice bath was removed. The mixture was stirred for 4 hours, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2. The combined organic phases were washed with water, dried over Na2SO4, filtered, and concentrated to give the title compound as brown solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[S:12])([CH3:3])[CH3:2].[CH2:13]([NH:15][CH2:16][C:17](O)=[O:18])[CH3:14].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:13]([N:15]1[CH2:16][C:17](=[O:18])[N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]([CH3:3])[CH3:2])[C:11]1=[S:12])[CH3:14]
Reactant: CCNCC(=O)O
Reactant: CC(C)c1ccccc1N=C=S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN1CC(=O)N(c2ccccc2C(C)C)C1=S
Yield: 42.9 %

Procedure:
The title compound was prepared by the procedure described in Example 16 using 15.42 g of 2-isopropylphenyl-isothiocyanate, 16.05 g of N-ethyl glycine, 12 g of triethyl amine, and 200 mL of chloroform. Purification was achieved by flash chromatography on silica gel (5-20 % ethyl acetate in hexane) Crystallization from ethanol afforded the title compound (9.8 g) as a white solid, m.p. 125°-127° C. Anal. Calcd. for. C14H18N2O S: C, 64.09; H, 6.91; N, 10.68. Found: C, 64.19 H, 6.93; N, 10.71. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(#N)C.CS(O[CH:17]1[CH2:20][N:19]([CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18]1)(=O)=O>>[CH:21]([N:19]1[CH2:20][CH:17]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:18]1)([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: Nc1ccc(F)cc1
Solvent: CC#N
Product: Fc1ccc(NC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-fluoro aniline (0.412 ml, 4.296 mmol) in acetonitrile (10 ml) potassium carbonate (771 mg, 5.584 mmol) was added followed by addition of 1-benzhydrylazetidin-3-yl methanesulfonate (D19) (1.5 g, 4.72 mmol). The reaction mixture was stirred at 100° C. for 5 minutes under microwave irradiation. Solvents were evaporated under vacuo and the residue was taken in with diethylether (50 ml) then water (50 ml) was added. The aqueous layer was extracted with diethylether (2×30 ml). The organics after solvent evaporation were purified by Biotage SNAP-Si cartridge (25 g) eluting with cyclohexane/ethylacetate from 100-0 to 85/15. Collected fractions, after solvent evaporation afforded the title (D24) (0.5 g)
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:16].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>ClCCl>[Br:16][CH2:14][C:13]([C:10]1[CH:9]=[N:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:12][CH:11]=1)=[O:15]
Reactant: CC(=O)c1cnc(-c2ccccc2)nc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Product: O=C(CBr)c1cnc(-c2ccccc2)nc1
Temperature: 40 °C
Yield: 79.4 %

Procedure:
To a solution consisting of 1-(2-phenylpyrimidin-5-yl)ethanone (Step A, 700 mg, 3.5 mmol) in dichloromethane (25 mL) was added tetrabutylammonium tribromide (1.87 g, 3.90 mmol). The reaction mixture was sealed with a screw top and warmed at 40° C. for 5 hours and allowed to cool to room temperature over a weekend. The pale yellow precipitate formed was collected on a filter and washed with 1:1 dichloromethane-hexane to afford the title intermediate (770 mg, 79%); Rf 0.31 with 9:1 v/v hexanes-ethyl acetate; MS (ESI+) m/z 279, 277 (M+1, Br isotopes).
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)(=[O:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:1]([O:4][CH2:5][CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1CCC(O)CC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)OCC1CCC(=O)CC1

Procedure:
The 4-(acetoxymethyl)cylohexan-1-ol obtained above is oxidized with 3.0 equivalents of pyridinium dichromate in refluxing methylene chloride to afford 4-(acetoxymethyl)cyclohexan-1-one.