Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N+:52]([C:55]1[CH:60]=[CH:59][C:58]([C:61]2[N:62]=[C:63]([NH2:66])[S:64][CH:65]=2)=[CH:57][CH:56]=1)([O-:54])=[O:53]>CN(C=O)C>[CH2:12]([O:11][C:9]([N:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3](=[O:5])[NH:66][C:63]1[S:64][CH:65]=[C:61]([C:58]2[CH:57]=[CH:56][C:55]([N+:52]([O-:54])=[O:53])=[CH:60][CH:59]=2)[N:62]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccc([N+](=O)[O-])cc2)cs1)C1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Z-Pro-OH (1.46 g, 5.85 mmol) and HATU (2.2 g, 5.85 mmol) were combined in 30 mL of dry DMF. To this solution was added DIEA(1.5 mL, 8.8 mmol). This solution was stirred at room temperature for 1 hour. To this solution was added 4-(4-nitro-phenyl)-thiazol-2-ylamine (1.0 g, 4.5 mmol). Reaction mixture was stirred at room temperature overnight. The crude material was purified using HPLC to yield 2-[4-(4-Nitro-phenyl)-thiazol-2-ylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester. MS: 453.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:18][C:19]([CH3:21])=[CH2:20])=[C:4]([OH:17])[C:5]([CH3:16])=[C:6]([CH3:15])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.C(=O)(O)[O-].[Na+]>CO>[CH3:20][C:19]1([CH3:21])[CH2:18][C:3]2[C:2]([CH3:1])=[C:7]([NH:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]([CH3:15])=[C:5]([CH3:16])[C:4]=2[O:17]1
Reactant: C=C(C)Cc1c(C)c(Nc2ccccc2)c(C)c(C)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1Nc1ccccc1)CC(C)(C)O2
Yield: 69.2 %

Procedure:
To a solution of 3,5,6-trimethyl-2-(2-methyl-2-propenyl)-4-phenylaminophenol (1.40 g, 4.98 mmol) in methanol 130 ml) was added conc. hydrochloric acid (10 ml) with ice-cooling and the mixture was heated with reflux in an argon atmosphere. The reaction mixture was cooled, neutralized with an aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed with a saturated saline solution and concentrated. The residue was recrystallized from isopropyl ether to obtain the desired compound (0.97 g, yield: 69.3%), m.p. 148°-150° C.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]1[CH:7]=[C:8]([C:23]([OH:25])=O)[CH:9]=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[C:11]=1[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH2:47]([NH:49][CH2:50][CH3:51])[CH3:48]>ClCCl>[CH2:47]([N:49]([CH2:50][CH3:51])[C:23](=[O:25])[C:8]1[CH:7]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:1])[C:11]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:10]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:9]=1)[CH3:48]
Reactant: CCNCC
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCNc1cc(C(=O)N(CC)CC)cc(S(N)(=O)=O)c1Oc1ccccc1
Reaction time: 0.08 h
Yield: 64.1 %

Procedure:
Bumetanide (1.16 g, 3.2 mmol) was dissolved in dichloromethane (10 mL) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, 690 mg, 3.6 mmol) was added. After 5 minutes N-hydroxybenzotriazole (HOBt, 498 mg, 3.6 mmol) was added and the solution was stirred for an additional 5 minutes. Diethylamine (332 uL, 3.2 mmol) was added and the reaction was stirred for 2 hours. The reaction was washed with saturated sodium bicarbonate, water and brine, and dried with magnesium sulfate. The dichloromethane was removed under reduced pressure to yield 860 mg (65%) of pure N,N-diethyl 3-aminosulfonyl-5-butylamino-4-phenoxybenzamide.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[N:12]([CH2:13][C:14]([OH:16])=[O:15])[C:11](=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([O:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C.Br[CH2:50][C:51]([O:53][CH3:54])=[O:52]>O.CN(C)C=O>[ClH:1].[O:2]=[C:3]1[N:12]([CH2:13][C:14]([O:16][CH2:50][C:51]([O:53][CH3:54])=[O:52])=[O:15])[C:11](=[O:17])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:23][CH2:24][CH:25]([O:28][CH:29]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:27]1
Reactant: COC(=O)CBr
Reactant: O=C(O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)COC(=O)Cn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A mixture of the hydrochloride of 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline-3-acetic acid obtained in Example 50 (0.58 g, 1.00 mmol), triethylamine (0.42 ml, 3.00 mmol) and N,N-dimethylformamide (2.0 ml) was stirred at 60° C. for 15 minutes, and methyl bromoacetate (0.11 ml, 1.20 mmol) was added dropwise. The reaction mixture was stirred at the same temperature for 6 hours, combined with an iced water, and then extracted with a solvent mixture of ethyl ether-ethyl acetate. After the extract was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluting with chloroform-methanol (20:1, v/v) to give a free form of the title compound (0.49 g, 80%) as an oil.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)c1ccc(O)cc1

Procedure:
Next, the 4-methoxybenzoic acid (IV) was digested with HBr (20 ml) and glacial acetic acid (40 ml) overnight. Most of the acetic acid was distilled off and the remaining mixture was diluted with water. The precipitated benzoic acid was extracted in ether; the ether layer was dried with anhydrous MgSO4, filtered and rotary evaporated to produce 11.0 g of the 4-hydroxybenzoic acid (V).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[C:14]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:13]=2[N:12]=1)[CH2:9][CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:13]2[N:12]=[C:11]([C@@H:8]([NH2:7])[CH2:9][CH3:10])[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:14]=2[CH:22]=1
Reactant: CC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of [(S)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)propyl]carbamic acid tert-butyl ester (557 mg, 1.5 mmol) in DCM (8 mL) was added TFA (4 mL) and the mixture stirred at RT for 1 h. The volatiles were removed in vacuo and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The crude material was used in the following step without further purification. Yellow oil (349 mg, 86%). LCMS (Method B): RT 1.75 min [M+H]+ 270.92.
Reaction SMILES: [N+:1]([CH:4]=[C:5]([NH:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)([O-:3])=[O:2].I([O-])(=O)(=O)=[O:27].[Na+]>O>[N+:1]([CH:4]=[C:5]([NH:16][CH2:17][CH2:18][S:19][CH2:20][C:21]1[S:22][CH:23]=[CH:24][N:25]=1)[NH:6][CH2:7][CH2:8][S:9]([CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)=[O:27])([O-:3])=[O:2]
Reactant: O=[N+]([O-])C=C(NCCSCc1nccs1)NCCSCc1nccs1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])C=C(NCCSCc1nccs1)NCCS(=O)Cc1nccs1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
1-Nitro-2,2-bis-[2-(2-thiazolylmethylthio)ethylamino]ethylene (4.5 g) was added to a stirred solution of an equivalent amount of sodium metaperiodate (2.3 g) in water (1600 ml), and the resulting solution was stirred at room temperature for 20 hours. Evaporation of the solvent and chromatographic purification of the residue on silica gel gave the title product as an oil. The structure of the product was confirmed by the 100 mHz n.m.r. spectrum in 2H6 -dimethylsulphoxide which showed the following resonances:
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:8]=2)[N:3]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][C:2]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-:33])=[O:32])[CH:26]=2)[N:5]=[C:4]([C:7]2[O:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=3)[N:8]=2)[N:3]=1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
A mixture of 5-(5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazole (Intermediate B, 2 g, 6.43 mmol), 1-(bromomethyl)-3-nitrobenzene (1.39 g, 6.43 mmol) and Cs2CO3 (4.2 g, 12.9 mmol) in DMF (40 mL) was stirred at RT for 16 h. The mixture was then diluted with H2O and extracted with EtOAc (3×200 mL). The combined organic extracts were washed with H2O (20 mL) and brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure to afford the title compound as a yellow solid (1.8 g, 56.4%). LC-MS (ES+) C19H13F3N6O4 requires: 446. found: 447 (M+H)+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@@H:6]1Br)(=O)C.O[Li].O.[CH3:28][N:29]1[C@@H:45]2[CH2:46][C:34]3=[CH:35][CH:36]=[C:37]([OH:48])[C:38]4[O:39][C@H:40]5[C@@H:41]([OH:47])[CH2:42][CH2:43][C@@H:44]2[C@:32]5([C:33]=43)[CH2:31][CH2:30]1.C(O)(=O)C>CO.O.C(Cl)(Cl)Cl>[C@@H:6]1([O:48][C:37]2[CH2:36][CH2:35][C:34]3[CH2:46][C@H:45]4[N:29]([CH3:28])[CH2:30][CH2:31][C@:32]56[C:33]=3[C:38]=2[O:39][C@H:40]5[C@@H:41]([OH:47])[CH:42]=[CH:43][C@@H:44]46)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)CC[C@H]3[C@H]1C5
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: CN1CC[C@]23C4=C5CCC(O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O)=C4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reaction time: 1 h
Yield: 24.5 %

Procedure:
2,3,4,6-Tetra-O-acetyl-α-D-glucopyranosyl bromide (1.20 g, 3.0 mmol) was added in one portion to a stirred solution of LiOH·H2O (0.15 g, 3.5 mmol) and dihydromorphine (1.0 g, 3.0 mmol) in dry methanol (10 mL) at room temperature. The resulting mixture was stirred for 1 hr, a solution of LiOH·H2O (0.42 g, 10.0 mmol) in water (10 mL) was added dropwise to the mixture, and the mixture allowed to stir for an additional 3 hr. The resulting suspension was acidified to pH 7 with acetic acid (0.5 mL) and 20 mL of chloroform was added. The resulting precipitate was removed by filtration and washed with ethanol (20 mL) following by acetone (20 mL), to provide a crude product. The crude product was dissolved in 50% aqueous methanol (12 mL), recrystallized at 0° C., filtered, and dried under reduced pressure (10 mm Hg, 50° C.) to provide 0.33 g (30%) of 3-O—β-glucosyldihydromorphine.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:12]=[CH:13][CH:14]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:15]3[C:19]=2[N:18]=[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=32)[O:6]1)=[O:4].[OH-].[Na+].Cl>O1CCCC1.CO.O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH:14]2[C:15]3=[C:16]4[CH2:23][CH2:22][CH2:21][CH2:20][C:17]4=[N:18][C:19]3=[C:11]([O:10][C:7]3[O:6][C:5]([C:3]([OH:4])=[O:2])=[CH:9][CH:8]=3)[CH:12]=[CH:13]2)=[CH:26][CH:27]=1
Reactant: COC(=O)C1CCC(OC2=C3N=c4ccccc4=C3C(Cc3ccc(F)cc3)C=C2)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(OC2=C3N=C4CCCCC4=C3C(Cc3ccc(F)cc3)C=C2)o1
Yield: 83.8 %

Procedure:
A solution of 5-[[9-[(4-fluorophenyl)methyl]-1,2,3,4-tetrahydro-9H-dibenzo[b,d]pyrrol-6-yl]oxy]-2-furancarboxylic acid methyl ester (2.1 g) from Example 123 in tetrahydrofuran (20 mL) and methanol (10 mL) was treated with 1N sodium hydroxide solution (6 mL) and refluxed for 90 minutes. The reaction mixture was diluted with water, treated with excess 2N hydrochloric acid (4 mL) and the product extracted with dichloromethane. The organic layer was washed with water, dried over anhydrous sodium sulfate, evaporated in vacuo, and crystallized from dichloromethane-hexane to provide 1.7 g (84%) of 5-[[9-[(4-fluorophenyl)methyl]-1,2,3,4-tetrahydro-9H-dibenzo[b,d]pyrrol-6-yl]oxy]-2-furancarboxylic acid as a colorless crystalline material, mp at 161° C. with decomposition.
Reaction SMILES: [N+:1]([CH2:4][C@@H:5]([C@@H:7]([C@H:9]([C@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6])([O-])=O.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[C:25]1([NH:31]N)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[OH-].[Na+].O.C(O)(=O)C>[C:25]1([NH:31][N:1]=[CH:4][C@@H:5]([C@@H:7]([C@H:9]([C@H:11]([CH2:13][OH:14])[OH:12])[OH:10])[OH:8])[OH:6])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NNc1ccccc1
Reactant: O=[N+]([O-])C[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)CO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: OC[C@H](O)[C@H](O)[C@@H](O)[C@@H](O)C=NNc1ccccc1
Reaction time: 8 h

Procedure:
1-Deoxy-1-nitro-L-mannitol (20 g.) was dissolved in 2 N sodium hydroxide (60 ml.), and the solution was immediately added dropwise to a stirred solution of sulfuric acid (30 ml.) in water (36 ml.) at room temperature. Some cooling (ice bath) was used to keep the reaction mixture at 22°±5°. The solution was then diluted to 400 ml. with water, just neutralized with solid sodium hydrogen carbonate, and a solution of phenylhydrazine (12 ml.) in glacial acetic acid (28 ml.) added. The mixture was stirred overnight at 5° and then filtered, and the L-mannose phenylhydrazone was washed with cold water, ethanol, and ether. Recrystallization from ethanol gave pure L-mannose phenylhydrazone, m.p. 198°-199°, [α]D -33.5° (c 2.5, pyridine) compared with m.p. 199°-200°, [α]D +34° for the D-isomer, p. 240).
Reaction SMILES: C1(O[C:8](=[S:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:35]2[CH2:34][CH2:33][N:32]([C:26]3[CH:25]=[C:24]([O:23][CH3:22])[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=3)[CH2:37][CH2:36]2)=[S:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=S)Oc2ccccc2)c(OC)nc1C
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Product: CCc1cc(NC(=S)N2CCN(c3cc(OC)cc(OC)c3)CC2)c(OC)nc1C
Yield: 85 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridine-3-yl)thiocarbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [P:1](=[O:7])([NH2:6])([S:4][CH3:5])[O:2][CH3:3].N1C=CC=CC=1.Cl[S:15][N:16]([CH:23]([CH3:25])[CH3:24])[C:17](=[O:22])[O:18][CH2:19][CH2:20][CH3:21].Cl.N1C=CC=CC=1.S(Cl)Cl>C(Cl)Cl>[CH2:19]([O:18][C:17]([N:16]([CH:23]([CH3:24])[CH3:25])[S:15][NH:6][P:1](=[O:7])([S:4][CH3:5])[O:2][CH3:3])=[O:22])[CH2:20][CH3:21]
Reactant: CCCOC(=O)N(SCl)C(C)C
Reactant: COP(N)(=O)SC
Agent: Cl
Agent: ClSCl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCOC(=O)N(SNP(=O)(OC)SC)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of 4.0 g (0.028 mol) O,S-dimethyl phosphoramidothioate, 2.2 g pyridine (0.028 mol) and 15 ml of anhydrous methylene chloride, chilled to 0°-5° C., was added dropwise 6.0 g (0.028 mol) propyl (chlorosulfenyl)(isopropyl)carbamate over a period of 15 minutes. Pyridine hydrochloride forms immediately during addition of the sulfenyl chloride. The reaction mixture was stirred for an additional half hour at room temperature after the addition of the sulfenyl chloride.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[O-]CC.[Na+].O=[C:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][C:14]1=[CH:26]N(C)C>C(O)C>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][C:13]2[N:6]=[CH:5][N:7]=[CH:26][C:14]=2[CH2:15]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: N=CN
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2ncncc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Formamidine acetate (472 mg, 4.52 mmol) in 15.0 mL of absolute ethanol was treated with sodium ethoxide (21 wt % solution in ethanol; 1.7 mL). After 30 min, a solution of the product from Step A above (1.15 g) in 8 mL of absolute ethanol was added, and the mixture was warmed at reflux for 18 h. The dark solution was cooled to room temperature and concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated to an orange oil. Purification by flash chromatography (silica gel; 2% methanol/dichloromethane as eluant) afforded the title compound as a light yellow gum.
Reaction SMILES: Cl.[Cl-].[Ca+2].[Cl-].[NH2:5][C:6]([CH3:15])([CH3:14])[CH2:7][NH:8][CH2:9][C:10]([NH2:13])([CH3:12])[CH3:11].[Cl-].[Na+].[C:18](=S)=S.S(=O)(=O)(O)O.S.C([O-])(=O)C.[Pb+2].C([O-])(=O)C>C1(C)C=CC=CC=1.[OH-].[K+]>[CH3:12][C:10]1([CH3:11])[CH2:9][N:8]2[CH2:7][C:6]([CH3:15])([CH3:14])[N:5]=[C:18]2[NH:13]1
Reactant: CC(C)(N)CNCC(C)(C)N
Reactant: S=C=S
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC1(C)CN2CC(C)(C)NC2=N1
Yield: 61.8 %

Procedure:
A 1 L three-necked flask was fitted with a condenser, which was then vented through an empty flask into a bubbler filled with 1 M KOH. A hydrogen chloride gas generation apparatus was also connected to the reaction flask through a sparging tube. The gas generation apparatus consisted of a 100 mL three-necked flask with an additions funnel and an outlet to a drying tube filled with calcium chloride. A purified nitrogen supply was fed into the top of the additions funnel. Into the reaction flask, 3.073 g (19.3 mmol) of di-(2-aminoisobutyl)amine was placed. This was dissolved in 900 mL of toluene and stirred magnetically. The gas generation apparatus was charged with 18.8 g (322 mmol) of sodium chloride, also stirred magnetically. The system was purged with nitrogen for approximately thirty minutes. Carbon disulfide (1.5 mL, 24.8 mmol) was added to the reaction solution which caused a clouding of the solution. The solution was then stirred at room temperature for four hours and twenty minutes. Production of hydrogen chloride started after 15 mL (280 mmol) of concentrated sulfuric acid was placed in the additions funnel. This was added dropwise to the sodium chloride over the course of ten minutes. The reaction solution was then brought to reflux and heated overnight. The evolution of hydrogen sulfide was followed by the reaction of the effluent gas with lead acetate. The reaction flask was then cooled in an ice bath and filtered to remove the product. The flask was rinsed with approximately 300 mL of methylene chloride to collect any remaining product, this solution was dried and combined with the filtered product. The crude weight was 3.133 g, and this was placed in a vacuum desiccator for several days to remove adsorbed toluene. The dried weight was 2.837 g, giving a yield of 61.8%. NMR (CDCl3) s 1.37 ppm, s 3.47 ppm. The acid salt was neutralized in aqueous potassium hydroxide and the water was then removed by evaporation Extraction of the residue into methyl ethyl ketone yielded the free base but often with many waters of hydration. HRMS calculated 168.1501. found 168.1499. NMR (CD3OD) 2.45 (s, 4H), 1.10 (s, 12H).
Reaction SMILES: [F:1][C:2]1[C:10]([NH:11][S:12](=[O:18])(=[O:17])[NH:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=[C:7]([F:19])[C:3]=1[C:4]([OH:6])=O.[CH3:20][O:21][C:22]1[C:30]2[C:25](=[N:26][CH:27]=[C:28]([NH2:31])[CH:29]=2)[NH:24][N:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[C:10]([NH:11][S:12](=[O:18])(=[O:17])[NH:13][CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=[C:7]([F:19])[C:3]=1[C:4]([NH:31][C:28]1[CH:29]=[C:30]2[C:22]([O:21][CH3:20])=[N:23][NH:24][C:25]2=[N:26][CH:27]=1)=[O:6]
Reactant: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reactant: COc1n[nH]c2ncc(N)cc12
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCNS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(OC)c3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
2,6-Difluoro-3-(N-propylsulfamoylamino)benzoic acid (0.095 g, 0.32 mmol), 3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-amine (0.053 g, 0.32 mmol), HOBt (0.044 g, 0.32 mmol), and EDCI (0.062 g, 0.32 mmol) were dissolved in DMF (1.6 mL) and stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (30 mL) and washed with a mixture of 1:1:1 water:bicarbonate:brine (3×20 mL). The organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via column chromatography eluting with 1:1 then 8:2 EtOAc:hexanes to provide 2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(N-propylsulfamoylamino)benzamide (0.090 g, 0.20 mmol, 63% yield). 1H NMR (400 MHz, CD3OD) δ 8.57-8.60 (m, 1H), 8.47-8.49 (m, 1H), 7.63-7.70 (m, 1H), 7.04-7.11 (m, 1H), 4.07 (s, 3H), 2.94-3.30 (m, 2H), 1.45-1.56 (m, 2H), 0.85-0.90 (m, 3H); m/z (APCI-pos) M+1=441.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([CH:22]=1)[C:7]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:8].C1(C)C=CC=CC=1.CO>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([C@H:7]([OH:8])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10]2)[CH:22]=1
Reactant: Cc1ccc(F)cc1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccc(F)cc1[C@H](O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: -15 °C
Reaction time: 1 h
Yield: 29.4 %

Procedure:
To a solution of (R)-tert-butyl 3-(5-fluoro-2-methylbenzoyl)piperidine-1-carboxylate (10.5 g, 0.0336 mol) in anhydrous THF (150 mL) at −15° C. under nitrogen was added dropwise a solution of 1 M R-CBS-oxazaborolidine in toluene (3 mL, 3 mmol, 0.09 eq). After stirring for 1 hr at −15° C., a solution of 10 M BH3 in THF (17 mL, 0.0336 mol, 1 eq) was added dropwise. After addition, the reaction mixture was stirred for 2 hr at −15° C. Methanol (80 mL) was added dropwise carefully at −15° C. The solvent was removed under reduced pressure, the residue was purified by column chromatography on silica gel eluting with AcOEt/hexane (1:30→1:15) to provide the light yellow oil (95 g, HPLC≧70%, ratio≧3:1). The mixture was dissolved in a minimum volume of EtOAc, the solvent was removed on the rotary evaporator until crystals appeared. The solution was cooled to rt and stood for 1-2 h. To the solution was added hexane and then filtered, the crystals were washed with cool hexane and re-crystallized an additional two times to afford the pure isomer (R)-tert-butyl 3-((R)-(5-fluoro-2-methylphenyl)(hydroxy)methyl)piperidine-1-carboxylate (3.2 g, ee≧99%). 1H NMR (CDCl3) δ 7.1 (m, 2H), 6.85 (m, 1H), 4.7 (m, 1H), 2.3 (s, 3H), 1.45 (s, 9H), 1.25 (m, 4H).