Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][P:11](=[O:15])([CH3:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[ClH:16]>C(O)C.[Pd]>[ClH:16].[CH3:14][P:11]1(=[O:15])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CP1(=O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CP1(=O)CCNCC1
Reaction time: 4 h

Procedure:
1-Benzyl-4-methyl-[1,4]azaphosphinane 4-oxide was dissolved in ethanol (100 mL). 1 M HCl (100 mL) was added, along with palladium on carbon (10%, 2.6 g). The mixture was hydrogenated on a Parr shaker for 4 hours at 50 psi. The mixture was filtered through Celite and all solvents were removed under reduced pressure. The product was triturated in hot ethanol (50 mL) and cooled, and the solution was diluted with ether (300 mL). The white crystalline solid was filtered, washed with ether (2×50 mL), hexane (2×50 mL), and dried in vacuo. 4-methyl-[1,4]azaphosphinane 4-oxide hydrochloride was obtained as a white crystalline solid (9.46 g, 94%). 1H NMR (400 MHz, DMSO) δ 3.07 (m, 2H); 2.68 (m, 2H); 1.78 (m, 2H); 1.61 (m, 2H), 1.39 (3H, d, JH-C-P=13.6 Hz.); 31P NMR: δ 29 ppm; ESMS (m/z): (M+1)+ found, 134.
Reaction SMILES: Cl.[OH:2][C:3]1[C:36]([CH3:37])=[CH:35][C:6]([C:7]([NH:9][CH:10]2[CH2:14][NH:13][CH2:12][CH:11]2[O:15][C:16](=[O:34])[C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:33])[C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=3[OH:32])=[CH:19][CH:18]=2)=[O:8])=[CH:5][C:4]=1[CH3:38].C([N:41]([CH2:44]C)CC)C.C[N:47](C)C=O>>[NH2:47][C:44](=[NH:41])[N:13]1[CH2:14][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:35]=[C:36]([CH3:37])[C:3]([OH:2])=[C:4]([CH3:38])[CH:5]=2)[CH:11]([O:15][C:16](=[O:34])[C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:33])[C:24]3[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:25]=3[OH:32])=[CH:19][CH:18]=2)[CH2:12]1
Reactant: CCN(CC)CC
Reactant: COc1ccc(O)c(C(=O)c2ccc(C(=O)OC3CNCC3NC(=O)c3cc(C)c(O)c(C)c3)cc2)c1
Reactant: CN(C)C=O
Agent: Cl
Product: COc1ccc(O)c(C(=O)c2ccc(C(=O)OC3CN(C(=N)N)CC3NC(=O)c3cc(C)c(O)c(C)c3)cc2)c1
Temperature: 25 °C
Reaction time: 144 h

Procedure:
A mixture of 14 mg of 4-(2-hydroxy-5-methoxy-benzoyl)-benzoic acid (3RS,4SR)-4-(4-hydroxy-3,5-dimethylbenzoylamino)-pyrrolidin-3-yl ester hydrochloride (Example 70), 0.01 ml of triethylamine and 37 mg of formamidinesulphonic acid in 2 ml of dimethylformamide was stirred at room temperature for 6 days. The solvent was evaporated under reduced pressure and the residue was taken up in water, sonicated and filtered. After drying under reduced pressure there were obtained 8 mg of 4-(2-hydroxy-5-methoxy-benzoyl)-benzoic acid (3RS,4SR)-1-(amino-imino-methyl)-4-(4-hydroxy-3,5-dimethylbenzoyl amino)-pyrrolidin-3-yl ester as a yellow powder.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH3:19][N:20]([CH2:22][CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][NH:24]1)[CH3:21]>N1C=CC=CC=1>[CH3:19][N:20]([CH2:22][CH:23]1[NH:24][CH2:25][CH2:26][N:27]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]3[CH2:12][CH3:13])=[CH:4][C:3]=2[F:18])[CH2:28]1)[CH3:21]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: CN(C)CC1CNCCN1
Solvent: c1ccncc1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(CN(C)C)C3)cc21
Reaction time: 18 h
Yield: 15.7 %

Procedure:
A mixture of 480 mg of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 1.0 g of 2-dimethylaminomethylpiperazine and 5 ml of pyridine in a sealed flask flushed with argon was stirred at 120°-130° C. for 18 hours. The solvent was removed in vacuo. The residue was evaporated twice from toluene, giving a gum. The gum was added to a silica gel column and flash chromatographed with methanol:chloroform (1.5:8.5 saturated with water). Fractions 61 and 62 were combined, evaporated and dried, giving 105 mg of the desired product as a white solid, mp 148°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7](N)=[CH:6][C:5]=1[O:11][CH3:12].N([O-])=[O:15].[Na+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([OH:15])=[CH:6][C:5]=1[O:11][CH3:12]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1ccc(O)cc1OC
Yield: 64.4 %

Procedure:
4-Amino-2-methoxy benzoic acid methyl ester (15 g, 82.7 mmol) was dissolved in sulfuric acid (80 ml of a 25% solution). The solution was cooled in an ice bath and diazotized with saturated sodium nitrite solution (8.57 g, 124 mmol) maintaining the temperature below 5° C. The diazonium solution was poured slowly into boiling sulphuric acid (1L of a 3% solution) and the mixture was heated for an additional 5 mins. The mixture was then allowed to cool before being extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate and concentrated in vacuo to afford a brown solid (9.7 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]2[N:14]=[C:15]([C:17]3[CH:21]=[C:20]([CH3:22])[O:19][N:18]=3)[CH:16]=[C:4]2[N:3]=1.O.[NH2:24][NH2:25]>O1CCOCC1>[CH3:22][C:20]1[O:19][N:18]=[C:17]([C:15]2[CH:16]=[C:4]3[N:3]=[C:2]([NH:24][NH2:25])[CH:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:5]3[N:14]=2)[CH:21]=1
Reactant: Cc1cc(-c2cc3nc(Cl)cc(N4CCOCC4)n3n2)no1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cc3nc(NN)cc(N4CCOCC4)n3n2)no1
Reaction time: 3 h
Yield: 26 %

Procedure:
There was suspended, in 1,4-dioxane (20 mL), 5-chloro-2-(5-methylisoxazol-3-yl)-7-morpholin-4-yl-pyrazolo[1,5-a]-pyrimidine (0.82 g, 2.6 mM) prepared in the foregoing step 1, then hydrazine monohydrate (1.3 mL, 26 mM) was added to the suspension and the suspension was stirred for 3 hours while refluxing the same with heating. After the stirring operation, the reaction liquid was concentrated, the concentrate was then diluted with water and extracted with ethyl acetate. The resulting extracts were combined, dried over anhydrous sodium sulfate and the solvent was distilled off to thus give a crude product of the title compound (210 mg, yield: 26%). MS (ESI) m/z (M+H)+ 316.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:12]=[C:13]([C:21](Cl)=[O:22])[C:14]2[O:19][CH2:18][CH2:17][O:16][C:15]=2[CH:20]=1>C(C(C)=O)C>[ClH:10].[N:4]1([CH2:3][CH2:2][NH:1][C:21]([C:13]2[C:14]3[O:19][CH2:18][CH2:17][O:16][C:15]=3[CH:20]=[C:11]([Cl:10])[CH:12]=2)=[O:22])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C(Cl)c1cc(Cl)cc2c1OCCO2
Reactant: NCCN1CCCCC1
Solvent: CCC(C)=O
Product: Cl
Product: O=C(NCCN1CCCCC1)c1cc(Cl)cc2c1OCCO2
Yield: 129 %

Procedure:
150 ml of methyl ethyl ketone and 22 g of N-(aminoethyl)piperidine were introduced into a 500 ml balloon flask provided with an agitator and a thermometer. The mixture was cooled and then a suspension of 35 g of 7-chloro-1,4-benzodioxane-5-carbonyl chloride in 200 ml of methyl ethyl ketone was added at a temperature of from 15°-20° C. After agitation the crystals formed were dried off and then washed with methyl ethyl ketone. 35 g of N-[piperidino ethyl]-7-chloro-1,4-benzodioxane-5-carboxamide hydrochloride was produced (M.P.: 192° C.; yield: 64.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]4[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][CH:38]([NH:41][C:23]([C:21]2[CH:20]=[CH:19][C:13]3[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:27]=[CH:26][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:22]=2)=[O:24])[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[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: COCCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Yield: 61.2 %

Procedure:
4-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (160 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carboxylic acid (180 mg), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (150 mg), HBTU (200 mg), and DIEA (1.2 mL) in DMF (2 mL).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P([O-])([O-])(O[CH2:11][C:12](C1C=CC=CC=1)([C:16]1C=CC=CC=1)[C:13](C)=[CH2:14])=O>C(=S)=S>[CH3:11][C:12]1([CH3:16])[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[O:7][CH2:14][CH2:13]1
Reactant: C=C(C)C(COP(=O)([O-])[O-])(c1ccccc1)c1ccccc1
Reactant: Oc1ccccc1
Solvent: S=C=S
Product: CC1(C)CCOc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a dry, ice-cooled flask containing 34.95 g (0.134 mol) of stannic chloride was added quickly under argon 63.0 g (0.669 mol) of phenol. The mixture was stirred at 0 degrees C. for 0.5 hour and then treated with 43.0 g (0.135 mol) of diphenyl-3-methyl-3-buten-1-yl phosphate (Compound 75), followed by a 5 ml carbon disulfide rinse. The mixture was stirred at room temperature for 21 hours and then quenched by pouring onto 700 g ice and 1 liter of 1.5N NaOH. The mixture was extracted with 1×600 ml and 2×300 ml ether. The combined ether fractions were washed with 2N NaOH, saturated NaCl and dried (MgSO4) Solvent was removed in vacuo and the residue purified by flash chromatography (silica; 2% ether in hexane) to give the title compound as a colorless oil. PMR (CDCl3) &: 1.34 (6H), 1.80-1.85 (2H, m)m 4.15-4.20 (2H, m), 6.80 (1H, dd, J~8.1 hz, 1.5 Hz), 6.87 (1H, td, J~8.1 Hz, 1.5 Hz), 7.07 (1H, td, J~8.1 Hz, 1.5 Hz), 7.26 (1H, dd, J~8.1 Hz, 1.5 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([CH2:13]O)[C:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24]COCC[Si](C)(C)C)=[C:20]([O:33][CH3:34])[CH:19]=3)=[O:16])=[N:9]2)=[CH:4][CH:3]=1.CS([Cl:39])(=O)=O.C(N(CC)CC)C>C(Cl)Cl>[Cl:39][CH2:13][C:11]1[C:10]([C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:33][CH3:34])[CH:19]=2)=[O:16])=[N:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(NC(=O)c2nn(-c3ccc(Cl)cc3)cc2CO)ccc1OCOCC[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)c2nn(-c3ccc(Cl)cc3)cc2CCl)ccc1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.9 %

Procedure:
To a mixture of 1-(4-chlorophenyl)-4-(hydroxymethyl)-N-(3-methoxy-4-((2-(trimethylsilyl)ethoxy)methoxy)phenyl)-1H-pyrazole-3-carboxamide (2.11 g, 4.19 mmol) in CH2Cl2 (40 mL) at room temperature under Ar was added methanesulfonyl chloride (0.424 mL, 5.44 mmol) and triethylamine. (1.20 mL, 8.61 mmol). The resulting solution was stirred at room temperature for 1.5 h. Solvent was evaporated. The crude product was diluted with EtOAc (150 mL), washed with H2O (30 mL). The organic layer was separated, dried over MgSO4 and concentrated to give a crude product which was further purified by ISCO automated chromatography (110 g, Hexane/EtOAc, 100:0 to 50:50 gradient) to give the products as beige solid (0.721 g, 44% yield). SEM group was deprotected during the process. LCMS (ES): m/z 392.0 [M+H]+.
Reaction SMILES: C(C1C=CC([C:11](=[O:13])C)=CC=1)C(C)C.Cl[CH2:15][C:16]#[N:17].[C:18]1(C)C=C[CH:21]=[CH:20][CH:19]=1>>[CH3:18][CH2:19][CH:20]([C:15]1([O:13][CH2:11]1)[C:16]#[N:17])[CH3:21]
Reactant: Cc1ccccc1
Reactant: CC(=O)c1ccc(CC(C)C)cc1
Reactant: N#CCCl
Product: CCC(C)C1(C#N)CO1

Procedure:
A solution of 17.2 g. of valeraldehyde (VII) and 16.5 g. of chloroacetonitrile in 20 ml. of toluene is treated with sodium t-amylate and worked up in the manner described in Example 3, above, to give a toluene solution of 3-butylglycidonitrile (I).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=2[NH2:13])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:18]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[C:1]1([S:7]([C:10]2[C:11]3[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:13][N:18]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccccc1CS(=O)(=O)c1ccccc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=S(=O)(c1ccccc1)c1n[nH]c2ccccc12
Reaction time: 0.5 h
Yield: 93 %

Procedure:
A stirred solution of 2-[(phenylsulfonyl)methyl]aniline (247 mg, 1.00 mmol) in 4N HCl (50 ml) is treated with a solution of NaNO2 (100 mg, 1.5 mmol) in water at ice-bath temperatures, stirred for 30 min., neutralized with 10% NaOH and filtered. The filtercake is dissolved in CH2Cl2, dried over MgSO4 and concentrated in vacuo to afford the title product as a tan solid, 240 mg (93% yield), mp 118° C., identified by mass spectral and HNMR analyses.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)C(C)C)(C)C.C(Cl)Cl.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:48])=[C:30]([C:32]2[CH:41]=[C:40]3[C:35]([CH:36]=[C:37]([NH:42][C:43]([CH:45]4[CH2:47][CH2:46]4)=[O:44])[N:38]=[CH:39]3)=[CH:34][CH:33]=2)[CH:31]=1.[NH:49]1[CH2:54][CH2:53][O:52][CH:51]([CH2:55][OH:56])[CH2:50]1>>[CH:45]1([C:43]([NH:42][C:37]2[N:38]=[CH:39][C:40]3[C:35]([CH:36]=2)=[CH:34][CH:33]=[C:32]([C:30]2[CH:31]=[C:26]([NH:25][C:2]([N:49]4[CH2:54][CH2:53][O:52][CH:51]([CH2:55][OH:56])[CH2:50]4)=[O:4])[CH:27]=[CH:28][C:29]=2[CH3:48])[CH:41]=3)=[O:44])[CH2:46][CH2:47]1
Reactant: OCC1CNCCO1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(NC(=O)N2CCOC(CO)C2)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.2 %

Procedure:
To a solution of triphosgene (22.7 mg, 0.0765 mmol) and N,N-diisopropylethylamine (0.20 mL, 1.1 mmol) in methylene chloride (4.0 mL, 62 mmol) was added a solution of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (59.9 mg, 0.189 mmol) and N,N-diisopropylethylamine (0.10 mL, 0.57 mmol) in methylene chloride (2.0 mL, 31 mmol). The resulting mixture was stirred at room temperature for 5 minutes, and then morpholin-2-ylmethanol (37.5 mg, 0.320 mmol) was added. The reaction mixture was stirred at room temperature for an additional 30 minutes, and then filtered through silica which was rinsed with ethyl acetate, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 34.6 mg (40%) of N-(3-(3-(cyclopropanecarboxamido)isoquinolin-7-yl)-4-methylphenyl)-2-(hydroxymethyl)morpholine-4-carboxamide. LCMS (ESI): RT (min)=3.964, M+H=461.2, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 9.18 (s, 1H), 8.56 (s, 1H), 8.47 (s, 1H), 7.98 (s, 1H), 7.91 (d, J=8.5 Hz, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.50-7.37 (m, 2H), 7.21 (d, J=8.2 Hz, 1H), 4.82 (t, J=5.5 Hz, 1H), 4.04 (d, J=12.9 Hz, 2H), 3.97-3.81 (m, 3H), 2.90 (t, J=6.0 Hz, 2H), 2.64 (dd, J=12.9, 10.0 Hz, 2H), 2.21 (s, 3H), 2.11-2.03 (m, 1H), 0.86 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N+:10]([O-])([O-:12])=[O:11].[Na+].Cl.C(OCC)(=O)C>O.CCOCC>[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[C:7]=1[N+:10]([O-:12])=[O:11]
Reactant: O=[N+]([O-])[O-]
Reactant: Cc1cc(C)cc(O)c1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 30 %

Procedure:
Under a nitrogen atmosphere, 3,5-dimethylphenol (40.9 mmoles) was dissolved in 40 mL water and 40 mL ether. To this was added 1.5 equivalents (61.4 mmoles) of sodium nitrate (NaNO3). The reaction was cooled in an ice bath and 50 mL concentrated HCl was slowly added to the reaction. The reaction was warmed to room temperature and followed by TLC (ethyl acetate:hexanes, 1:1) until the reaction was complete (0.5 hour). The reaction was extracted into ether (×3), washed with saturated NaHCO3, saturated NaCl, dried over MgSO4, filtered, rinsed with ether, and concentrated. The product was purified using silica-gel chromatography, yielding 3,5-dimethyl-4-nitro-phenol as a yellow solid(2.05 grams; 30% yield). The product was characterized by NMR (DMSO).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[C@@H:19]([CH2:20][C@@H:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:26]=2)[CH2:22][CH3:23])[CH2:18][O:17]C1(C)C)=O)(C)(C)C>O.C(#N)C.[OH-].[Na+]>[NH2:15][C@@H:19]([CH2:20][C@@H:21]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:26]=1)[CH2:22][CH3:23])[CH2:18][OH:17]
Reactant: CC[C@@H](C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)Oc1cccc(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC[C@@H](C[C@H](N)CO)Oc1cccc(OCc2ccccc2)c1
Temperature: 80 °C
Yield: 100.6 %

Procedure:
To a solution of trifluoroacetic acid (0.07 ml) in water (6 ml) was added dropwise a solution of (S)-4-[(S)-2-(3-benzyloxy-phenoxy)-butyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (135 mg) in acetonitrile (1 ml). The mixture was heated for 4 h at 80° C. with mechanical shaking. The mixture was then cooled to room temperature and diluted with 1 N aqueous sodium hydroxide solution. The mixture was extracted twice with ethyl acetate and the combined organic phases were dried over sodium sulphate and concentrated in vacuo to give (2S,4S)-2-amino-4-(3-benzyloxy-phenoxy)-hexan-1-ol (94 mg, quant.) as a light yellow viscous oil. MS (ISP): 316.1 ([M+H]+).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[NH:17][O:18][C:19](=[O:21])[N:20]=3)=[C:12]([Cl:22])[CH:11]=2)=[C:5]([CH3:7])[N:6]=1.[S:23]1[C:27](B(O)O)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O>[S:23]1[C:27]([C:2]2[S:3][C:4]([CH2:8][O:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[NH:17][O:18][C:19](=[O:21])[N:20]=4)=[C:12]([Cl:22])[CH:11]=3)=[C:5]([CH3:7])[N:6]=2)=[CH:26][C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2
Reactant: OB(O)c1cc2ccccc2s1
Reactant: Cc1nc(Br)sc1COc1ccc(-c2nc(=O)o[nH]2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc3ccccc3s2)sc1COc1ccc(-c2nc(=O)o[nH]2)c(Cl)c1
Temperature: 40 °C
Yield: 46.1 %

Procedure:
A mixture of 3-[4-(2-Bromo-4-methyl-thiazol-5-ylmethoxy)-2-chloro-phenyl]-2H-[1,2,4]oxadiazol-5-one (300 mg, 0.7 mmol), Benzo[b]thiophene-2-boronic acid (142 mg, 0.8 mmol) and cesium carbonate (730 mg, 2.2 mol) in dimethylformamide (5 mL) and water (1 mL) is degassed using a stream of argon for 15 min. Tetrakis-triphenylphosphine-palladium (0) (34 mg, 0.03 mmol) is added and the mixture is warmed to 40° C. for 4 hours. The solvent is removed under reduced pressure and the residue is taken up in water (10 mL) and ethylacetate (30 mL). The phases are separated and the water phase is additionally extracted two-times with ethylacetate. The combined organic phases are dried over MgSO4 and the solvent is removed under reduced pressure. The crude product is purified using reverse phase HPLC to obtain 147 mg 3-[4-(2-Benzo[b]thiophen-2-yl-4-methyl-thiazol-5-ylmethoxy)-2-chloro-phenyl]-2H-[1,2,4]oxadiazol-5-one as an amorphous lyophilisate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][S:13][C@H:12]2[CH2:16][CH2:17][CH2:18][C@@H:19]([C:20](O)=[O:21])[N:11]2[C:10]1=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(Cl)(=O)OCC(C)C.[NH2:39][NH2:40]>C(Cl)Cl.CCOC(C)=O>[NH:39]([C:20]([C@H:19]1[N:11]2[C@@H:12]([S:13][CH2:14][CH2:15][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]2=[O:23])[CH2:16][CH2:17][CH2:18]1)=[O:21])[NH2:40]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)O)N2C1=O
Reactant: NN
Agent: CC(C)COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCS[C@H]2CCC[C@@H](C(=O)NN)N2C1=O
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 99.4 %

Procedure:
To a solution of (4S,7S,10aS)-4-(tert-butoxycarbonylamino)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylic acid (121 mg, 0.351 mmol) and N-methylmorpholine (0.048 mL, 0.44 mmol) in DCM (2 mL) at 0° C. was added isobutyl carbonochloridate (0.053 mL, 0.40 mmol). The mixture was stirred at 0° C. for 40 min. Then, hydrazine (0.044 mL, 1.4 mmol) was added and the reaction was stirred at rt for 1 hr. The mixture was diluted with EtOAc and washed with water and saturated aqueous NaCl. The organic layer was separated, dried over MgSO4, filtered and concentrated to give tert-butyl (4S,7S,10aS)-7-(hydrazinecarbonyl)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (125 mg, 0.349 mmol, 99% yield) as a white solid. Anal. Calcd. for C15H26N4O4S m/z 358.4. found: 359.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]([F:17])([F:16])[S:3][C:4]1[N:8]=[CH:7][N:6]([C:9](=[O:15])[N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[N:5]=1.C(Cl)(Cl)(Cl)Cl.I([O-])(=O)(=O)=[O:24].[Na+].[OH2:29]>C(#N)C.O.[Ru](Cl)(Cl)Cl>[Br:1][C:2]([F:16])([F:17])[S:3]([C:4]1[N:8]=[CH:7][N:6]([C:9](=[O:15])[N:10]([CH2:11][CH3:12])[CH2:13][CH3:14])[N:5]=1)(=[O:24])=[O:29]
Reactant: CCN(CC)C(=O)n1cnc(SC(F)(F)Br)n1
Reactant: O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCN(CC)C(=O)n1cnc(S(=O)(=O)C(F)(F)Br)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
To a solution of 57 g (0.17 mol) 3-(bromodifluoromethylthio)-1-(N,N-diethylcarbamoyl)-1,2,4-triazole, prepared as above, in 100 ml acetonitrile were sequentially added 100 ml carbon tetrachloride, 200 ml water and 11 1.23 g (0.52 mol) sodium periodate. To the resulting suspension was added 20 mg (ca 5 mol %) ruthenium trichloride hydrate and the suspension was then stirred at room temperature for 24 h. The reaction mixture was then diluted with 500 ml water, extracted with dichloromethane (3×200 ml) and the combined resulting organic layers were sequentially washed with water, saturated sodium bicarbonate solution and brine. The dichloromethane solution was dried over MgSO4 and evaporated. Preparative LC purification of the residue with 40% ethyl acetate-hexane gave 53.31 g (85% yield) of the desired 3-(bromodifluoromethylsulfonyl)-1-(N,N-diethylcarbamoyl)-1,2,4-triazole as a white solid with melting point 74-75° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:21]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:12][CH2:11]3)=[CH:8][S:7][C:6]=2[CH:21]=1
Reactant: NCCCCN1CCN(c2csc3cc(F)ccc23)CC1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)NCCCCN1CCN(c2csc3cc(F)ccc23)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 43.9 %

Procedure:
To a 0° C. solution of 4-(6-fluorobenzo[b]thien-3-yl)-1-piperazine-butanamine (4.04 g, 13.1 mmol), triethylamine (1.89 g, 18.6 mmol), and dichloromethane (50 mL) under a nitrogen atmosphere was added isobutyryl chloride (1.63 g, 15.3 mmol) over 6 minutes. The reaction was stirred at 0° C. for 4 hours and then was diluted with dichloromethane (140 mL). The mixture was washed successively with 5% aqueous NaOH (100 mL) and water (100 mL), dried (K2CO3), and concentrated in vacuo to give an off-white solid. The crude product was chromatographed on silica gel with 10% methanol/dichloromethane as eluent to afford an off-white solid. Recrystallization from ethyl acetate/heptane gave 2.17 g (43%) of the title compound as beige needles: m.p. 130°-131° C. TLC (silica gel, 10% methanol/dichloromethane) Rf =0.37. The IR(CHCl3), 1H NMR (CDCl3, 200 MHz), and MS (M+ 377, EI, 70 eV) were consistent for the assigned structure.