Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6])=[N+:2]=[N-:3].[Li+].CC([N-]C(C)C)C.[CH:21]1([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22]1.O>C1COCC1>[CH:21]1([CH2:26][CH2:27][C:28]([O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][N:1]=[N+:2]=[N-:3])=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: [N-]=[N+]=NCC(=O)c1ccccc1
Reactant: O=C(Cl)CCC1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: [N-]=[N+]=NC=C(OC(=O)CCC1CCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a stirred solution of α-azidoacetophenone (3.37 g, 20.9 mmol) in dry THF (50 mL) was added a solution of LDA (2.0 M in cyclohexane, 12.5 mL, 25 mmol) at -78° C. under nitrogen dropwise. After the reaction mixture was stirred for 1 h, a solution of 3-cyclopentylpropionyl chloride (5.04 g, 31.35 mmole, 1.5 eq.) was added to the dark red mixture, and after 10 min, the mixture was slowly warmed to room temperature. Stirring was continued for 1 h and the resultant yellow mixture was poured into water and extracted with ethyl acetate (3×50 mL). The combined organics were washed with water and brine, dried over magnesium sulfate, and filtered. Evaporation of solvent followed by column chromatography on silca gel (eluent: 2:1 ethyl acetate:hexanes) gave 4.0 g (71.5%) of the title compound: 1H NMR (400 MHz, CDCl3) ε 7.32-7.26 (m, 5H), 6.53 (s, 1H), 2.58 (t, 2H, J=7.5 Hz), 1.89-1.70 (m, 5H), 1,65-1.40 (m, 4H), 1.2 (m, 2H).
Reaction SMILES: [N+](=[CH:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[N-].[CH:9]([B:11]1[O:19][C:16]([CH3:18])([CH3:17])[C:13]([CH3:15])([CH3:14])[O:12]1)=[CH2:10]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:7]([O:6][C:4]([CH:3]1[CH2:10][CH:9]1[B:11]1[O:19][C:16]([CH3:18])([CH3:17])[C:13]([CH3:14])([CH3:15])[O:12]1)=[O:5])[CH3:8]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)C1CC1B1OC(C)(C)C(C)(C)O1
Reaction time: 2 h
Yield: 104.6 %

Procedure:
Ethyl diazoacetate (3.49 g, 61.3 mmol) was added over 20 minutes to a stirred suspension of palladium (II) acetate (61 mmol) and vinylboronic acid pinacol ester (1.9 g, 12.26 mmol) in diethyl ether (30 mL) and stirred for 2 hours. The reaction was concentrated in vacuo and the residues distilled under vacuum (100-140° C. at 0.5-1 mbar) to afford 2-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-cyclopropanecarboxylic acid ethyl ester (3.08 g, quant.) as a 4:6 mix of products, cis/trans isomers. 1H NMR 300 MHz (CHCl3-d): δ 4.26-4.25 (0.8 H, m), 4.12-4.12 (1.2 H, m), 1.83-1.82 (0.4 H, m), 1.76-1.75 (0.6 H, m), 1.28-1.27 (6 H, m), 1.26 (6 H, m), 1.22 (3 H, m), 1.16-1.05 (0.8 H, m), 1.01-1.00 (1.2 H, m), 0.58 (0.6 H, ddd, J=10.25, 7.44, 5.18 Hz), 0.41-0.41 (0.4 H, m)
Reaction SMILES: [Mg].Cl[CH:3]1[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]1.[Cl:10][C:11]1[C:16]2[CH:17]=[N:18][N:19]([CH2:20][CH3:21])[C:15]=2[N:14]=[C:13]2[C:22](=[O:31])[C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][CH2:26][C:12]=12>O1CCCC1>[Cl:10][C:11]1[C:16]2[CH:17]=[N:18][N:19]([CH2:20][CH3:21])[C:15]=2[N:14]=[C:13]2[C:22]([CH:3]3[CH2:8][CH2:7][N:6]([CH3:9])[CH2:5][CH2:4]3)([OH:31])[C:23]3[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=3[CH2:25][CH2:26][C:12]=12
Reactant: CCn1ncc2c(Cl)c3c(nc21)C(=O)c1ccccc1CC3
Reactant: CN1CCC(Cl)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCn1ncc2c(Cl)c3c(nc21)C(O)(C1CCN(C)CC1)c1ccccc1CC3

Procedure:
A Grignard reagent is prepared from 7.2 g. of magnesium turnings (0.3 mol.), 230 ml. of dry tetrahydrofuran and 40 g. of 4-chloro-1-methyl-piperidine (0.3 mol.). To this Grignard solution 31 g. of 4-chloro-1-ethyl-5,6-dihydrobenzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11(1H)-one (0.1 mol.), from example 1(e), dissolved in 230 ml. of dry tetrahydrofuran is added. Reaction and work-up according to the procedure of example 15 yields 4-chloro-1-ethyl-1,5,6,11-tetrahydro-11-(1-methyl-4-piperidinyl)benzo[5,6]cyclohepta[1,2-b]pyrazolo[4,3-e]pyridin-11-ol; m.p. 130°-132° (hexane, refrigerator).
Reaction SMILES: [Cl-].C(CC[N+:7]1[CH:12]=[CH:11][C:10](C#N)=[CH:9][CH:8]=1)(=O)N.[OH:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.[OH-].[Na+]>O>[OH:15][CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:10]2[CH:11]=[CH:12][N:7]=[CH:8][CH:9]=2)[CH2:21][CH2:20]1
Reactant: OCCCC1CCNCC1
Reactant: N#Cc1cc[n+](CCC(N)=O)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCCCC1CCN(c2ccncc2)CC1
Reaction time: 1 h
Yield: 40.3 %

Procedure:
A solution of N-(2-carbamoylethyl)-4-cyanopyridinium chloride (2.1 g) in water (5 ml) was added dropwise to a stirred mixture of 4-hydroxypropylpiperidine (2.4 g), water (10 ml) and 2.5M sodium hydroxide solution (4.6 ml) cooled in an ice-bath. The mixture was stirred at 0°-5° C. for 1 hour. 2.5M sodium hydroxide solution (7 ml) was added and the mixture heated at reflux for 3 hours. The mixture was cooled in an ice-bath and gummy solid separated out. The aqueous layer was decanted off and the gummy solid dissolved in dichloromethane (75 ml). The solution was washed with saturated sodium chloride solution (10 ml) and dried (MgSO4). The solvent was removed by evaporation to give a gummy solid (880 mg) which on trituration with ether gave a solid; NMR(d6 DMSO): 1.0-1.35(m,4H), 1.35-1.6(m,3H), 1.7(dd,2H), 2.70-2.88(dt,2H), 3.38(t,2H), 3.89(brd,2H), 4.35(brs,1H), 6.78(d,2H), 8.1(d,2H); mass spectrum(CI+): 221(M+H)+.
Reaction SMILES: O[CH:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[CH2:3]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[CH2:29]([N:31](CC)CC)[CH3:30].C(N)C.S(C1C=CC(C)=CC=1)([O-])(=O)=O>O1CCCC1>[CH2:29]([NH:31][CH:2]1[C:7]2[CH:8]=[C:9]([S:11]([NH2:14])(=[O:13])=[O:12])[S:10][C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[CH2:3]1)[CH3:30]
Reactant: CCN(CC)CC
Reactant: CN1CC(O)c2cc(S(N)(=O)=O)sc2S1(=O)=O
Agent: CCN
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: C1CCOC1
Product: CCNC1CN(C)S(=O)(=O)c2sc(S(N)(=O)=O)cc21
Reaction time: 18 h
Yield: 73 %

Procedure:
Under nitrogen, a stirred solution of the compound from Step E (5.00 g, 16.8 mmol) and p-toluenesulfonyl chloride (1.1 eq, 18.5 mmol, 3.30 g) in tetrahydrofuran (100 mL) was treated with triethylamine (1.1 eq, 2.78 mL). After 18 h at room temperature, TLC. indicated that starting material was still present so additional p-toluenesulfonyl chloride (0.4 eq, 1.3 g) and triethylamine (0.4 eq, 1.0 mL) was added. Stirring was continued for another 18 h, at which point TLC. indicated the absence of starting material. Ethylamine (18 g) was added to the reaction mixture and the flask was stoppered. After 18 h at room temperature, TLC. indicated that the intermediate tosylate was absent. At this point, the reaction mixture was combined with another 1.55 g run for workup. The mixture was partitioned between 1 M aqueous hydrochloric acid (100 mL) and diethyl ether (250 mL) and the acidic aqueous phase was separated. The organic phase was further extracted with 1 M aqueous hydrochloric acid (3×100 mL), and the combined aqueous layers were then back washed with ether (3×100 mL), basified using solid sodium bicarbonate, and extracted with ethyl acetate (4×250 mL). The combined organic ethyl acetate extracts were dried over MgSO4, treated with decolorizing carbon (Norite A), filtered through celite, and concentrated under reduced pressure, to provide 5.2 g (73%) of the sulfonamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C)C=O.[H-].[Na+].[CH2:29](Br)[CH:30]=[CH2:31]>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH2:31][CH:30]=[CH2:29])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C=CCBr
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione and 30 ml of dimethylformamide was added 0.6 g of approximately 55 % sodium hydride and the solution was stirred for 30 minutes at room temperature. To this was further added 3.6 g of allyl bromide, and the mixture was reacted for 2 hours at room temperature. Then, the solvent was distilled off from the resulting mixture under reduced pressure to leave a residue, to which was added water to precipitate a crude product. This product was recrystallized from methanol to yield 2.9 g of 1(m-nitrophenyl)-3 -allylquinazoline- 2,4(1H, 3H)-dione as light brown needles, melting at 165°-166° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1F)[C@@H:10](OS(C1C=CC(C)=CC=1)(=O)=O)[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([O-:36])(=[S:35])[CH3:34].[K+]>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH:10]([S:35][C:33](=[O:36])[CH3:34])[C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC([O-])=S
Reactant: COC(=O)[C@H](OS(=O)(=O)c1ccc(C)cc1)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1F
Agent: [K+]
Product: COC(=O)C(SC(C)=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Yield: 43.2 %

Procedure:
Methyl (2RS,3S)-3-tert-butoxycarbonylamino-2-acetylthio-3-(2-fluorophenyl) propionate may be prepared in a similar manner to that described in Example 1G, but starting with 30 g of methyl (2R,3S)-3-tert-butoxycarbonylamino-2-tosyloxy-3-(2-fluorophenyl)propionate and 17.2 g of potassium thioacetate. 9.8 g of methyl (2RS,3S)-3-tert-butoxycarbonylamino-2-acetylthio-3-phenylpropionate are thus obtained in the form of a red oil which is used without further purification in the subsequent syntheses.
Reaction SMILES: [CH:1]1[CH2:6][CH2:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:2]1([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:1][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: Nc1ccccc1
Reactant: C1=CCCC=C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C1=CC(Nc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.7 %

Procedure:
Hydroamination of 1,3-Dienes with Arylamines: Sixteen examples of hydroamination of 1,3-dienes with arylamines are shown in Table 3 below (Entries 1-16). Typical reaction conditions are 0.5 mmol amine, 2 mmol cyclohexadiene, 2 mol % Pd(PPh3)4, 10 mol % TFA, toluene, 25° C., mixed for 24 hours. A typical procedure is given for Entry 1, Table 1: Pd(PPh3)4 (5.8 mg, 0.0050 mmol) was suspended in 0.1 mL of toluene in a screw-capped vial. 1,3-Cyclohexadiene (160 mg, 190 μL, 2.00 mmol) and aniline (46.6 mg, 45.6 μL, 0.500 mmol) were added to the reaction mixture. The vial was sealed with a cap containing a PTFE septum and removed from the drybox. Trifluoroacetic acid (5.7 mg, 3.9 μL, 0.050 mmol) was added to the reaction mixture by syringe. The reaction mixture was then stirred at room temperature for 24 h. All volatile compounds were evaporated under reduced pressure, and the residue was adsorbed onto silica gel. The product was eluted using 0.5% ethyl acetate/hexanes to give 85.5 mg (99%) of N-cyclohex-2-en-1-ylaniline as a colorless oil. Additional compounds were made in a similar fashion and analyzed as follows.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:33])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][C@@H:17]([CH2:21][NH:22]C(=O)OCC3C=CC=CC=3)[CH2:16]2)=[N:5][CH:4]=1>CO.[Pd]>[NH2:22][CH2:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:10]2[C:11]3[C:6](=[N:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH:7]=[CH:8][C:9]2=[O:33])[CH2:16]1
Reactant: COc1cnc2ccc(=O)n(CCN3CCC[C@@H](CNC(=O)OCc4ccccc4)C3)c2c1
Agent: [Pd]
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC[C@@H](CN)C3)c2c1
Yield: 107 %

Procedure:
To a solution of phenylmethyl [((3S)-1-{2-[7-(methyloxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]ethyl}-3-piperidinyl)methyl]carbamate (0.21 g, 0.44 mmol) in MeOH (30 mL) was added 10% Palladium on carbon (0.20 g) and the solution subjected to H2 at 50 PSI on a Parr shaker. The solution was filtered through a pad of Celite® and concentrated under reduced pressure to give desired product (0.149 g, 100%)
Reaction SMILES: OC1C(C2(CO)C3C(=CC=CC=3)N(CC[CH2:22][N:23]3[C:31](=[O:32])[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:24]3=[O:33])C2=O)=CC2OCOC=2C=1.C1([CH2:40][CH2:41][N:42]2[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]([C:53]3[C:61]([OH:62])=[CH:60][C:56]4[O:57][CH2:58][O:59][C:55]=4[CH:54]=3)([CH2:51]O)[C:43]2=[O:63])CC1>>[O:63]=[C:43]1[C:44]2([C:53]3=[CH:54][C:55]4[O:59][CH2:58][O:57][C:56]=4[CH:60]=[C:61]3[O:62][CH2:51]2)[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[N:42]1[CH2:41][CH2:40][CH2:22][N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33]
Reactant: O=C1N(CCC2CC2)c2ccccc2C1(CO)c1cc2c(cc1O)OCO2
Reactant: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Yield: 45 %

Procedure:
Following the procedure as described in EXAMPLE 1, and making non-critical variations using 2-{3-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-2-oxo-2,3-dihydro-1H-indol-1-yl]propyl}-1H-isoindole-1,3(2H)-dione to replace 1-(2-cyclopropylethyl)-3-(6-hydroxy-1,3-benzodioxol-5-yl)-3-(hydroxymethyl)-1,3-dihydro-2H-indol-2-one, the title compound was obtained in 45% yield: 1H NMR (300 MHz, CDCl3) δ 7.83-7.80 (m, 2H), 7.70-7.68 (m, 2H), 7.28-7.26 (m, 1H), 7.15 (d, 1H), 7.05-7.00 (m, 1H), 6.86 (d, 1H), 6.48 (s, 1H), 6.23 (s, 1H), 5.85-5.83 (m, 2H), 4.91 (d, 1H), 4.65 (d, 1H), 3.94-3.68-(m, 4H), 2.15-2.10-(m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.4, 168.2, 155.9, 148.8, 142.4, 141.9, 134.0, 132.5, 132.0, 128.9, 124.1, 123.4, 123.3, 119.4, 108.4, 103.2, 101.5, 93.6, 80.4, 58.2, 38.0, 35.6, 26.8; MS (ES+) m/z 469.3 (M+1), 491.3 (M+23).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:19][NH:20][O:21][CH3:22].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15](=[O:17])[N:20]([O:21][CH3:22])[CH3:19])[CH2:13][CH2:14]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 20 g (82.2 mmol) trans-4-tert-Butoxycarbonylamino-cyclohexanecarboxylic acid in 1.2 l CH2Cl2 was treated with 12.83 g (131.5 mmol) N,O-dimethyl-hydroxylamine hydrochloride, 10.85 ml (98.6 mmol) N-methylmorpholine and at 0° C. with 18.91 g (98.64 mmol) EDCI and 12.62 g (82.2 mmol) HOBT. The reaction mixture was stirred 2 h at room temperature and extracted with aqueous 10% KHSO4/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3, 10% NaCl and dried over Na2SO4 to yield 24.25 g (quantitative) trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexyl]-carbamic acid tert-butyl ester, mp: 130-140° C., slowly dec.; MS: 287 (MH+).
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[CH:29](=O)[CH2:30][CH2:31][CH2:32][CH2:33]C>>[CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[C:21]=4[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Reactant: CCCCCC=O
Product: CCCCCc1c2c(nc3cc(F)ccc13)-c1cc3c(c(=O)n1C2)COC(=O)C[C@]3(O)CC

Procedure:
The product of Example 84 is treated with hexanal according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[NH2:10][OH:11].[Na]>CO>[OH:11][NH:10][C:1](=[NH:2])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: N#Cc1cccnc1
Reactant: NO
Agent: Cl
Agent: [Na]
Solvent: CO
Product: N=C(NO)c1cccnc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89.2 %

Procedure:
3-Cyanopyridine (4.0 g) and hydroxylamine hydrochloride (3.2 g) were added to a solution of sodium (1.8 g) in MeOH (60 ml). The mixture was stirred 2.5 h at RT and refluxed 30 min. After cooling to RT, solids were filtered off. The solution was evaporated. White crystals (4.7 g) were obtained upon flash chromatography (125 g silica gel; CH2Cl2/MeOH 9:1) followed by a precipitation from heptan and ethyl acetate.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[C:6]([O:10][C:11](OC([O-])=O)=[O:12])([CH3:9])([CH3:8])[CH3:7]>C(Cl)Cl>[C:6]([O:10][C:11]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: NCCCO
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCO
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A solution of 3-aminopropanol (15 mL, 0.20 mol) in methylene chloride (50 mL) at rt was treated with t-butylpyrocarbonate (42.02 g, 1 equiv) in methylene chloride (25 mL), dropwise over 2 h. After stirring overnight the mixture was evaporated, flushed with heptane (3×), and dried in vacuo to give the product as a thick oil (34.31 g, 100%). 1H NMR δ 1.48 (s, 9H), 3.12 (br, 1H), 3.22 (q, J=7.5 Hz, 2H), 3.60 (q, J=7.8 Hz, 2H), 4.81 (br, 1H). MS (DCl) 176 (MH)+. Anal calcd for C8H17NO3: C-54.84, H-9.78, N-7.99. Found: C-54.80, H-9.82, N-7.97.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8](O)=[O:9])[N:3]=1.P(Cl)(Cl)([Cl:16])=O.CN(C)C=O>COCCOC>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([Cl:16])=[O:9])[N:3]=1
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 50.0 ml of 1,2-dimethoxyethane (DME), 10.0 g of 2- (5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 8.4 g of phosphorus oxychloride at 5° C. to a mixture of 20 ml of DME and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, the reaction mixture was poured into 160 ml of ice water to precipitate crystals. The resulting crystals were collected by filtration, washed with 200 ml of ice water and then stirred for 30 minutes in 120 ml of n-hexane. After filtration, the resulting crystals were dried under reduced pressure, whereby the title compound was obtained. Yield: 8.43 g (76.6%). Purity: 97.2%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:24][C:25](OC(C)=O)=[O:26]>C(Cl)Cl>[C:25]([N:21]1[CH2:20][CH2:19][N:18]([CH:15]2[CH2:14][CH2:13][N:12]([C:5]3[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:17][CH2:16]2)[CH2:23][CH2:22]1)(=[O:26])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(N2CCC(N3CCNCC3)CC2)ccc1[N+](=O)[O-]
Solvent: ClCCl
Product: COc1cc(N2CCC(N3CCN(C(C)=O)CC3)CC2)ccc1[N+](=O)[O-]
Yield: 92 %

Procedure:
To a solution of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}piperazine (Example 57, step C) (0.500 g, 1.56 mmol) in DCM (20 mL) was added Ac2O (0.22 mL, 2.34 mmol). TEA (0.33 mL, 2.34 mmol) was then added dropwise and the resultant mixture was stirred at rt overnight. TLC indicated that the reaction had gone to completion. The reaction mixture was evaporated onto silica gel and purified by flash chromatography to afford the title compound of step A (0.52 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J=9.6 Hz, 1H), 6.57 (dd, J=9.5, 2.5 Hz, 1H), 6.48 (d, J=2.6 Hz, 1H), 4.07-4.00 (m, 2H), 3.88 (s, 3H), 3.41-3.34 (m, 4H), 2.99-2.89 (m, 2H), 2.43-2.36 (m, 2H), 1.95 (s, 3H), 1.85-1.78 (m, 2H), 1.48-1.38 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:18]=[N:19][N:20]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:21]=3[C:22]([F:25])([F:24])[F:23])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:5]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.33 h
Yield: 37.6 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-VII, 40 mg, 0.093 mmol), tert-butyl 2-aminoacetate (18.29 mg, 0.139 mmol), HATU (45.9 mg, 0.121 mmol), and 4-methylmorpholine (37.6 mg, 0.372 mmol) were added to DMF (1 mL). It was stirred for 20 min and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 15 min, 20 mL/min, 220 nM, product retention=16.4 min) to provide (R/S)-tert-butyl 2-(2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)acetate (20 mg, 0.035 mmol, 37.9% yield): LCMS=488.1 [M+H−C4H9]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.46 (1 H, s), 8.12 (2 H, d, J=8.35 Hz), 7.50-7.75 (7 H, m), 5.17 (1 H, s), 3.90 (2 H, s), 1.44 (9 H, s); HPLC peak RT=9.1 min (Method A).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([CH:39]([CH3:44])[C:40]([O:42][CH3:43])=[O:41])=[C:35]([CH2:45][CH3:46])[CH:34]=2)=[CH:29][CH:28]=1)(C(C)(C)C)(C)C.O>O1CCCC1>[CH2:45]([C:35]1[CH:34]=[C:33]([C:30]2[CH:31]=[CH:32][C:27]([OH:26])=[CH:28][CH:29]=2)[CH:38]=[CH:37][C:36]=1[CH:39]([CH3:44])[C:40]([O:42][CH3:43])=[O:41])[CH3:46]
Reactant: CCc1cc(-c2ccc(O[Si](C)(C)C(C)(C)C)cc2)ccc1C(C)C(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(-c2ccc(O)cc2)ccc1C(C)C(=O)OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 0.1 %

Procedure:
A tetra-n-butylammonium fluoride-11.0M tetrahydrofuran solution (0.39 ml, 0.391 mmol) was added to a solution of methyl 2-(4′-{[tert-butyl(dimethyl)silyl]oxy}-3-ethyl-1,1′-biphenyl-4-yl)propionate (104 mg, 283 mmol) obtained in Example (103-1) in tetrahydrofuran (5 ml), and the mixture was stirred at room temperature for 1.5 hours. After water was added to the reaction mixture and the mixture was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (developing solvent: hexane/ethyl acetate=3/1) to give methyl 2-(3-ethyl-4′-hydroxy-1,1′-biphenyl-4-yl)propionate (76 mg, 1009).