Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13](O)=[CH:14][CH:15]=1.C1(C)C=CC=CC=1.[O-2:24].[Ba+2:25].[Ba]>O.C(O)CCCCCCC>[CH2:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[O-:24])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1].[Ba+2:25].[CH2:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=1[O-:24])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: [O-2]
Reactant: CCCCCCCCCc1ccc(O)cc1
Agent: [Ba+2]
Agent: [Ba]
Solvent: O
Solvent: CCCCCCCCO
Solvent: Cc1ccccc1
Product: CCCCCCCCCc1ccccc1[O-]

Procedure:
Nonylphenol 110 g (0.5 mole), toluene 80 g, octanol 20 g and barium oxide 115 g (0.75 mole) were stirred and treated with 13.5 g water. Reaction proceeded with exothermic heat, and was continued nder reflux for 1 hour. After cooling, the mixture was filtered and there was obtained a black-green liquid overbased barium nonylphenolate complex, which was analyzed to find barium: 28% metal ratio:6.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)=[C:11]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][CH:5]=1.Br[C:30]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O.O>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)=[C:11]([C:17]2[N:18]=[N:19][N:20]([C:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:21]=2)[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:9]=1
Reactant: BrC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 24 h
Yield: 63.7 %

Procedure:
To a suspension of 0.64 g (16 mmol) 50% sodium hydride in 7.5 mL of dry dimethylformamide was added 5.7 g (16 mmol) of ethyl 3,3-bis(4-fluorophenyl)-2-(1H-tetrazol-5-yl)-2-propenoate and the resultant mixture stirred for 30 minutes. To the resultant solution, 5.7 g (18 mmol) bromotriphenylmethane was added and the mixture stirred for 24 hours. The mixture was diluted to 200 mL with water and the insolubles collected by filtration. The product was recrystallized from ethyl acetate to give 6.1 g of the title compound; m.p.=161°-162° C. (dec).
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[CH3:5][N:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1>C(O)C.C[O-].[Na+]>[CH3:5][N:6]1[CH2:11][CH2:10][C:9]([CH2:4][N+:1]([O-:3])=[O:2])([OH:12])[CH2:8][CH2:7]1
Reactant: C[N+](=O)[O-]
Reactant: CN1CCC(=O)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CN1CCC(O)(C[N+](=O)[O-])CC1
Yield: 73.4 %

Procedure:
Nitromethane (6.6 mL, 122.0 mmol) and sodium methoxide (0.94 mL of 25 wt % in methanol, 4.1 mmol) were added to a solution of 1-methyl-4-piperidone (10 mL, 81.3 mmol) in ethanol (10 mL). After 30 minutes more ethanol (15 mL) was added to facilitate stirring. The reaction mixture was stirred at ambient temperature for 2 days and then filtered. The isolated solid was rinsed with ether to provide 10.39 g of 1-methyl-4-nitromethylpiperidin-4-ol as a white powder. An additional 1.18 g was isolated from the filtrate.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][CH:11]([C:15]1[O:16][C:17]2[C:22]([C:23](=[O:32])[C:24]=1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[CH:21][CH:20]=[C:19]([Cl:33])[CH:18]=2)[CH:12]([CH3:14])[CH3:13])(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:7][CH2:8][CH2:9][NH:10][CH:11]([C:15]1[O:16][C:17]2[C:22]([C:23](=[O:32])[C:24]=1[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[CH:21][CH:20]=[C:19]([Cl:33])[CH:18]=2)[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)C(NCCNC(=O)OC(C)(C)C)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NCCN)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Yield: 90.9 %

Procedure:
A solution of {2-[1-(3-benzyl-7-chloro-4-oxo-4H-chromen-2-yl)-2-methyl-propylamino]-ethyl}-carbamic acid tert-butyl ester (5.7 g, 12 mmol) in 4:1 methylene chloride/trifluoroacetic acid (250 mL) was maintained at room temperature for 1.5 hours, at which time it was concentrated. The residue was dissolved in methylene chloride (200 mL), washed with 10% sodium carbonate, saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and concentrated. The residue (4.2 g, 91% yield) was used without further purification.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([CH2:19][CH2:20][CH2:21][C:22](CC([O-])=O)=[O:23])[CH3:18]>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:22](=[O:23])[CH2:21][C:20]([CH2:19][CH2:17][CH3:18])=[N:16]2)=[CH:13][CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(NN)cc1
Reactant: CCCCCC(=O)CC(=O)[O-]
Product: CCCC1=NN(c2ccc(S(=O)(=O)NC(C)(C)C)cc2)C(=O)C1

Procedure:
From the reaction of N-tert.-butyl-4-hydrazinobenzenesulfonamide and ethylbutyrylacetate, N-tert.-Butyl-4-(4,5-dihydro-3-propyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide is obtained. Subsequent reaction with 2-ethoxyaniline yields N-tert-butyl-4-(4-(2-ethoxyanilinomethylen)-4,5-dihydro-3-propyl-5-oxo-1H-pyrazol-1-yl)-benzenesulfonamide, Mp: 254° C.
Reaction SMILES: [C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28].[O-]S([O-])(=O)=O.[Mg+2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CO.C(Cl)Cl>[C:1]([C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:28][CH2:27][CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[F:19])=[CH:13][CH:12]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCC#Cc1ccc(C=O)cc1
Reactant: NCCc1ccccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCCCCC#Cc1ccc(CNCCc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-dec-1-ynylbenzaldehyde (24.2 mg, 0.1 mmol) in anhydrous THF (0.6 mL) was added the 2-(2-fluorophenyl)ethylamine (13.9 mg, 0.1 mmol) and anhydrous MgSO4 (50 mg). The mixture was stirred overnight at RT. The reaction mixture was filtered and evaporated to give an oily residue. This crude product was taken up in MeOH (0.5 mL) then the sodium triacetoxyborohydride (53 mg, 0.25 mmol) was added and the reaction mixture was stirred overnight at rt. The solvents were evaporated under vacuum to give a solid. This solid was suspended in DCM (0.75 mL) and eluted through a SCX column (Isolute, 1 g) with DCM (6 mL), then NH3 (2M in MeOH, 4 mL). The desired fractions (TLC monitoring) were concentrated under vacuum to afford the title product as a yellow oil. M+(LC/MS(ESI)): 366.3. HPLC (Condition A), Rt: 4.64 min (HPLC purity: 80.5%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][CH2:12][N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[N:6]=[C:5]3[C:18]4[C:24]([O:25][CH3:26])=[CH:23][CH:22]=[C:21]([O:27][CH3:28])[C:19]=4[S:20][C:3]=1[C:4]=23.Cl[CH2:30][CH2:31][N:32]1[CH2:36][CH2:35][O:34][C:33]1=[O:37]>>[CH2:14]([N:13]([CH2:16][CH3:17])[CH2:12][CH2:11][N:7]1[C:8]2[CH:9]=[CH:10][C:2]([NH:1][CH2:30][CH2:31][N:32]3[CH2:36][CH2:35][O:34][C:33]3=[O:37])=[C:3]3[S:20][C:19]4[C:21]([O:27][CH3:28])=[CH:22][CH:23]=[C:24]([O:25][CH3:26])[C:18]=4[C:5]([C:4]=23)=[N:6]1)[CH3:15]
Reactant: CCN(CC)CCn1nc2c3c(c(N)ccc31)Sc1c(OC)ccc(OC)c1-2
Reactant: O=C1OCCN1CCCl
Product: CCN(CC)CCn1nc2c3c(c(NCCN4CCOC4=O)ccc31)Sc1c(OC)ccc(OC)c1-2
Yield: 56.9 %

Procedure:
A mixture of 2.2 g (0.0055 mol) of 5-amino-N,N-diethyl-7,10-dimethoxy-2H[1]benzothiopyrano[4,3,2-cd]indazole-2-ethanamine and 1.6 g (0.011 mole) of 3-(β-chloroethyl)-2-oxazolidinone was treated in the manner described in Example 42 to furnish 1.6 g of the title compound, mp greater than 250° C. dec.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([NH:13][C@H:14]([CH2:18][O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[C:5]([CH3:24])[C:4]=1[CH3:25].[CH3:26][Si](C=[N+]=[N-])(C)C>CO.C(Cl)Cl>[CH3:26][O:16][C:15](=[O:17])[C@H:14]([NH:13][S:10]([C:6]1[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:25])[C:5]=1[CH3:24])(=[O:12])=[O:11])[CH2:18][O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: COc1cc(C)c(S(=O)(=O)N[C@H](COC(C)(C)C)C(=O)O)c(C)c1C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H](COC(C)(C)C)NS(=O)(=O)c1c(C)cc(OC)c(C)c1C
Reaction time: 0.75 h

Procedure:
To a solution of 2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-tert-butoxypropionic acid (2.79 g, 7.5 mmol) in 70% methanol/methylene chloride (50 mL) at 0° C. was added 1M trimethylsilyldiazomethane in hexanes (22.5 mL, 23 mmol). After 45 min., the reaction mixture was concentrated and chromatographed using preparative chromatography (9% ethyl acetate-hexanes) to afford 2(R)-(4-methoxy-2,3,6-trimethyl-benzenesulfonylamino)-3-tert-butoxypropionic acid methyl ester (2.4 g).
Reaction SMILES: [P:1]([O:19][C:20]1([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:39]=[CH:38][N:37]=[C:36]([S:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:43][CH:42]=4)[C:35]3=[O:52])=[CH:30][C:29]=2[O:53][CH3:54])[CH2:23][C:22]([F:25])([F:24])[CH2:21]1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].C(=O)(O)[O-].[Na+:59]>C(O)(C(F)(F)F)=O.C(#N)C.O>[P:1]([O-:11])([O-:3])([O:19][C:20]1([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH:39]=[CH:38][N:37]=[C:36]([S:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][C:48]([F:51])([F:50])[F:49])=[CH:45][CH:46]=4)[C:35]3=[O:52])=[CH:30][C:29]=2[O:53][CH3:54])[CH2:23][C:22]([F:25])([F:24])[CH2:21]1)=[O:2].[Na+:59].[Na+:59]
Reactant: COc1cc(-n2ccnc(Sc3ccc(OC(F)(F)F)cc3)c2=O)ccc1OCC1(OP(=O)(OCc2ccccc2)OCc2ccccc2)CC(F)(F)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc(-n2ccnc(Sc3ccc(OC(F)(F)F)cc3)c2=O)ccc1OCC1(OP(=O)([O-])[O-])CC(F)(F)C1
Yield: 103.3 %

Procedure:
To a solution of dibenzyl 3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutyl phosphate (79 mg, 0.100 mmol) in TFA (2 mL) was stirred at RT for 3.5 hours. The mixture was concentrated. The crude product was purified by prep-HPLC (Phenomenex, Luna 5 micron 25×250 mm, flow rate=30 ml/min., gradient=20% A to 100% B in 10 min., A=90% H2O/10% MeOH/0.1% TFA, B=10% H2O/90% MeOH/0.1% TFA). Yield 46 mg, 0.075 mmol as yellow gum. The yellow gum in ACN (2 ml) was added 0.5 N aqueous sodium bicarbonate (302 μl, 0.151 mmol), the mixture was diluted with water (5 ml). The solution was then lyophilized. Yield sodium 3,3-difluoro-1-((2-methoxy-4-(2-oxo-3-(4-(trifluoromethoxy)phenylthio)pyrazin-1(2H)-yl)phenoxy)methyl)cyclobutyl phosphate (51.08 mg, 0.078 mmol, 78% yield) as off-white powder. MS (M+H=611). 1H NMR (400 MHz, MeOD) δ ppm 7.54-7.63 (2H, m), 7.19-7.33 (3 H, m), 7.02-7.17 (3H, m), 6.91 (1H, dd, J=8.44, 2.39 Hz), 4.28 (2H, s), 3.80 (3H, s), 3.13-3.32 (2H, m), 2.75-2.90 (2H, m).
Reaction SMILES: C1(C2C(OCC3(C(F)(F)F)CCCCC3)=CC(F)=C(C=2)C(O)=O)CC1.[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:46][CH2:45][C:44]([F:48])([F:47])[CH2:43][CH2:42]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([OH:36])=O)[CH2:28][CH2:27]1.CS(N)(=O)=O.[CH3:54][O:55][CH2:56][CH2:57][S:58]([NH2:61])(=[O:60])=[O:59]>>[CH:26]1([C:29]2[C:30]([O:39][CH2:40][CH:41]3[CH2:42][CH2:43][C:44]([F:47])([F:48])[CH2:45][CH2:46]3)=[CH:31][C:32]([F:38])=[C:33]([CH:37]=2)[C:34]([NH:61][S:58]([CH2:57][CH2:56][O:55][CH3:54])(=[O:60])=[O:59])=[O:36])[CH2:27][CH2:28]1
Reactant: COCCS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Product: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC2CCC(F)(F)CC2)cc1F

Procedure:
Following the procedure as described in Example 158 step 5, and making variations as required to replace 5-cyclopropyl-2-fluoro-4-((1-(trifluoromethyl)-cyclohexyl)methoxy)-benzoic acid with 5-cyclopropyl-4-((4,4-difluorocyclohexyl)-methoxy)-2-fluorobenzoic acid and to replace methanesulfonamide with 2-methoxyethanesulfonamide, the title compound was obtained (0.072 g, 26%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ8.70-8.58 (m, 1H), 7.63-7.53 (m, 1H), 6.63-6.51 (m, 1H), 3.93-3.83 (m, 4H), 3.83-3.75 (m, 2H), 3.31 (s, 3H), 2.27-2.09 (m, 2H), 2.08-1.66 (m, 6H), 1.61-1.42 (m, 2H), 0.99-0.88 (m, 2H), 0.71-0.60 (m, 2H); MS (ES+) m/z 450.0 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.[CH3:22]I>CN(C)C=O.O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[N:9]1[CH3:22]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3Cl)c(=O)c12
Reactant: CI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c2c(c(=O)n1-c1ccccc1Cl)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 80 °C
Yield: 4.4 %

Procedure:
A mixture of (4S,7R)-2-(2-chloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 10; 5.11 g, 16.9 mmol) and methyl iodide (1.05 mL, 16.9 mmol) in N,N-dimethylformamide (20 mL) was heated to 80° C. for 2 h. The reaction mixture was diluted with water (50 mL) and saturated sodium bicarbonate (150 mL) and extracted with ethyl acetate (2×200 mL). The organic extracts were combined, washed with brine, dried (sodium sulfate), filtered, evaporated, and purified using an ISCO CombiFlash® Sg100c chromatography system eluting with 10-100% ethyl acetate/hexanes to give (4S,7R)-2-(2-chloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (233 mg, 4%). ES(+)-MS (M+H) 317.
Reaction SMILES: [Si:1]([O:8][C@H:9]([CH3:35])[C@@H:10]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([Cl:34])[CH:27]=1)[C:11]([NH:13][NH:14][C:15](=O)[C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[CH:18][CH:17]=1)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.CCN(CC)CC>C(Cl)Cl>[Si:1]([O:8][C@H:9]([CH3:35])[C@@H:10]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[C:28]([Cl:34])[CH:27]=1)[C:11]1[O:12][C:15]([C:16]2[CH:17]=[CH:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=2)=[N:14][N:13]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c(Cl)c1)c1nnc(-c2ccc(C#N)cc2)o1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 100.6 %

Procedure:
A solution of N′-((2R,3R)-3-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyanophenylamino)butanoyl)-4-cyanobenzohydrazide (1.02 g, 1.98 mmol) in CH2Cl2 (30 mL) was added to a pre-cooled (0° C.) mixture of PPh3 (1.04 g, 3.97 mmol), iodine (1.01 g, 3.97 mmol) and Et3N (1.11 mL, 7.94 mmol). The reaction mixture was warmed to room temperature, stirred for 25 min and quenched with sat. aq. sodium thiosulfate (300 mL). The solution was extracted with CH2Cl2 (200 mL). The organic extract was washed with sat. aq. sodium thiosulfate (2×150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a brown oil, which was purified by flash chromatography over silica gel (20% EtOAc in hexanes) to provide the title compound as a light yellow oil (984 mg, 100%): 1H NMR (400 MHz, acetone-d6, δ in ppm) 8.22 (dm, J=8.6 Hz, 2H), 8.03 (dm, J=8.8 Hz, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 6.92 (dd, J=2.3, 8.8 Hz, 1H), 6.67 (d, J=9.0 Hz, 1H), 5.10 (dd, J=7.2, 9.2 Hz, 1H), 4.52 (dq, J=6.1, 7.2 Hz, 1H), 1.45 (d, J=6.1 Hz, 3H), 0.75 (s, 9H), 0.09 (s, 3H), −0.07 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=[O:4].[CH2:8]([N:15]1[CH2:22][C:19]2([CH2:21][CH2:20]2)[NH:18][CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:8]([N:15]1[CH2:22][C:19]2([CH2:21][CH2:20]2)[N:18]([C:3](=[O:4])[C:2]([F:7])([F:6])[F:1])[CH2:17][CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(CN2CCNC3(CC3)C2)cc1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C(N1CCN(Cc2ccccc2)CC12CC2)C(F)(F)F
Reaction time: 1 h
Yield: 102.1 %

Procedure:
Anhydrous trifluoroacetic acid (8.50 ml, 61.1 mmol) was added dropwise to a methylene chloride (200 ml) solution of the compound (10.3 g, 50.9 mmol) obtained in Step 3 above and triethylamine (17 ml, 122 mmol) with ice cooling and the resulting mixture was stirred at the same temperature for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture, the resulting mixture was diluted with chloroform, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (15.5 g, 100%) as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:26])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]1=[O:25])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+]>O1CCCC1.O>[CH3:7][CH:6]([CH3:8])[CH2:5][C@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[C:24]3[CH2:23][CH2:22][CH2:21][CH2:20][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[CH:11][C:10]1=[O:25])[C:3]([OH:26])=[O:2]
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc3c2CCCC3)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc3c2CCCC3)=CC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
A mixture of (S)-4-methyl-2-[2-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (94 mg, 0.26 mmol) in tetrahydrofuran (1.5 mL) and water (0.5 mL) was treated with lithium hydroxide monohydrate (14 mg, 0.33 mmol). The reaction was stirred at 25° C. for 3 h. At this time, the reaction was concentrated in vacuo. The residue was diluted with water (25 mL) and was extracted with diethyl ether (1×25 mL). The aqueous layer was then acidified with a 1N aqueous hydrochloric acid solution and then extracted with 10% methanol/dichloromethane (2×25 mL). The organics were then dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo to afford (S)-4-methyl-2-[2-oxo-4-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid (61 mg, 67%) as an orange solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.3 Hz, 3H), 0.93 (d, J=6.3 Hz, 3H), 1.36-1.84 (m, 7H), 2.53-2.61 (m, 2H), 2.68-2.83 (m, 2H), 4.12 (d, J=17.8 Hz, 1H), 4.24 (d, J=17.8 Hz, 1H), 4.62 (dd, J=11.2, 4.2 Hz, 1H), 4.66 (s, 1H), 6.99-7.07 (m, 2H), 7.18 (t, J=7.8 Hz, 1H), 12.84 (br. s., 1H).
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([NH:15][NH2:16])=[O:14])=[N:5]1)([CH3:3])[CH3:2].Cl.[CH:18]1([N:22]2[CH2:27][CH2:26][CH:25]([CH2:28][C:29](O)=O)[CH2:24][CH2:23]2)[CH2:21][CH2:20][CH2:19]1.P(Cl)(Cl)(Cl)=O>>[CH:18]1([N:22]2[CH2:23][CH2:24][CH:25]([CH2:28][C:29]3[O:14][C:13]([C:6]4[C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=4)=[N:15][N:16]=3)[CH2:26][CH2:27]2)[CH2:19][CH2:20][CH2:21]1
Reactant: O=C(O)CC1CCN(C2CCC2)CC1
Reactant: CC(C)n1nc(C(=O)NN)c2ccccc21
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)n1nc(-c2nnc(CC3CCN(C4CCC4)CC3)o2)c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 29.7 %

Procedure:
To the mixture of 1-isopropyl-1H-indazole-3-carboxylic acid hydrazide (120 mg, 0.55 mmol) and (1-cyclobutyl piperidin-4-yl) acetic acid hydrochloride (147 mg, 0.74 mmol, obtained in preparation 6) cooled at 0° C., was added phosphoryl chloride (1.5 mL). The reaction temperature was gradually raised to 100° C. and stirred was 2 hours. Upon completion of the reaction, it was cooled to 0° C. and triturated with hexanes (3×25 mL). The crude product was cooled to 0° C., basified with aqueous sodium hydroxide solution and extracted with 5% methanol in dichloromethane. The combined organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 3-[5-(1-cyclobutyl piperidin-4-yl methyl)-[1,3,4]oxadiazol-2-yl]-1-isopropyl-1H-indazole (62 mg)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[C:6]([N+:18]([O-])=O)[CH:5]=1.[NH4+].[Cl-]>CCO.CCOC(C)=O.[Fe]>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[C:6]([NH2:18])[CH:5]=1
Reactant: COC(=O)c1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(Sc2ccc(O)cc2)c(N)c1

Procedure:
A suspension of 4-(4-hydroxy-phenylsulfanyl)-3-nitro-benzoic acid methyl ester (5.60 g, 18 mmol), Fe powder (5.34 g, 92 mmol) and NH4Cl (4.91 g, 92 mmol) in aqueous EtOH [prepared from EtOH (50 mL) and H2O (50 mL)] was gradually heated to reflux and refluxed for 45 minutes. The reaction mixture was diluted with AcOEt (50 mL) and filtered through celite pad. The filtrate was evaporated and the aqueous residue was portioned between AcOEt and 10% NaHCO3. The organic layer was separated, washed with H2O and brine, dried over MgSO4 and evaporated to give pale yellow solid. The resulting solid was washed with i-Pr2O and dried at 40° C. for 3 days under reduced pressure to give the title compound as slightly yellow crystal (4.50 g, 90% by 2 steps).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].OS(O)(=O)=O.[N+:16]([O-])([OH:18])=[O:17]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:16]([O-:18])=[O:17])=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9]
Reactant: CC(=O)c1ccccc1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(=O)c1cc([N+](=O)[O-])ccc1F
Temperature: -15 °C
Reaction time: 0.25 h

Procedure:
2′-Fluoroacetophenone (11.04 g) was dropwise added to concentrated H2SO4 (46 mL) at −20° C. After the addition was complete, a thoroughly mixed solution of fuming nitric acid (6.4 mL) and concentrated H2SO4 (18 mL) was added dropwise at −15° C. The reaction mixture was stirred at −15° C. for 15 minutes and then poured into 500 g of ice. The resulting solid was collected, washed with and dissolved in CH2Cl2. The organic layer was washed with water, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel flash chromatography (25% ethyl acetate in hexane) to give 8 g of the title compound as a solid.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)(=[O:8])[CH3:7].O>ClCCl>[C:6]([N:9]1[CH2:10][CH2:11][CH:12]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:20][CH:21]=2)[CH2:13][CH2:14]1)(=[O:8])[CH3:7]
Reactant: CC(=O)N1CCC(Cc2ccccc2)CC1
Reactant: O=S(=O)(O)Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC(Cc2ccc(S(=O)(=O)Cl)cc2)CC1

Procedure:
To chlorosulfonic acid (92 mL), a solution of 1-acetyl-4-benzylpiperidine (60.00 g) in dichloromethane (100 mL) was dropwise added for an hour at 0° C. under stirring, and the mixture was stirred at 0° C. for 30 minutes and at room temperature for 1.5 hours. The reaction mixture was poured into ice-cooled water (1 L) and extracted with dichloromethane (500 mL, 250 mL). The organic phase was washed with an aqueous solution of 5% sodium carbonate (500 mL×2) and saturated brine (250 mL). The organic phase was dried over magnesium sulfate (anhydrous), and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel 250 g, ethyl acetate). The objective fraction was concentrated under reduced pressure to give the title compound as a white solid (54.22 g).