Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:10][C@H:9]2[C:11](N2C=CN=C2)=[O:12])=[CH:4][CH:3]=1.[CH3:18][C@@H:19]1[C@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:22][C:21](=[O:30])[NH:20]1.C1CCN2C(=NCCC2)CC1>CC#N>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([N:20]2[C@@H:19]([CH3:18])[C@@H:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:22][C:21]2=[O:30])=[O:12])=[CH:6][CH:7]=1
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Reactant: O=C([C@@H]1C[C@@H]1c1ccc(Br)cc1)n1ccnc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1C(=O)C1CC1c1ccc(Br)cc1

Procedure:
A mixture of (cis)-1-{[2-(4-bromophenyl)cyclopropyl]carbonyl}-1H-imidazole (1 eq) from Step 1, (4R, 5S)-(+)-4-methyl-5-phenyl-2-oxazolidinone (1.2 eq) or (−)-isomer and DBU (added at 0° C., 1.2 eq) in CH3CN (0.2M) was stirred at 0° C. for 4 h. The solvent evaporated and residue purified by flash chromatography (Hexane:EtOAc; 100:0 to 80:20) to afford each diastereoisomer.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[CH:4][N:3]=1.[CH2:9]([Sn](CCCC)(CCCC)C=C)[CH2:10]CC.C(OCC)(=O)C.[F-].[K+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[C:6]([CH:9]=[CH2:10])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cc(I)ccn1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C=Cc1ccnc(F)c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
A mixture of 2-fluoro-4-iodopyridine (2.23 g, 10.0 mmol), tributyl vinyl tin (3.8 g, 12 mmol), and Pd2Cl2(PPh3)2 (703 mg, 1.0 mmol) in dioxane (20 mL) was heated under nitrogen at 80° C. overnight. After cooled, ethyl acetate (40 ml) and saturated KF aqueous solution were added to the reaction mixture. The mixture was stirred for 30 min. The organic layer was separated and washed with water, dried (MgSO4), and concentrated. The resulting residue was purified by flash column chromatography eluting with hexane/ethyl acetate (20:1) to provide the title compound (463 mg, 38%). 1HNMR (500 MHz, CDCl3) δ ppm 5.55 (d, J=10.92 Hz, 1 H) 5.99 (d, J=17.47 Hz, 1 H) 6.67 (dd, J=17.47, 10.61 Hz, 1 H) 6.88 (m, 1 H) 7.17 (dt, J=5.30, 1.56 Hz, 1 H) 8.16 (d, J=5.30 Hz, 1 H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.Cl.[CH3:13][NH:14][O:15][CH3:16].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl.O>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:14]([O:15][CH3:16])[CH3:13])=[O:9])=[CH:10][CH:11]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(CO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)c1ccc(CO)cc1
Yield: 109.2 %

Procedure:
4-(Hydroxymethyl)benzoic acid (3.00 g, 19.7 mmol) and N,O-dimethylhydroxylamine hydrochloride (2.31 g, 23.7 mmol) in chloroform (30 mL) was stirred with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.54 g, 23.7 mmol), 1-hydroxybenzotriazole (3.20 g, 23.7 mmol) and N,N-diisopropylethylamine (8.04 mL, 47.3 mmol) at room temperature for one day. After addition of water, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a mixture containing the title compound as a colorless oil (4.20 g). The resulting mixture was used for the next step.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:19][CH2:20][CH3:21])[C@@H:5]([NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)[CH3:6])[CH3:2].[CH:22]1[C:34]2[CH:33]([CH2:35][O:36][C:37]([NH:39][C@@H:40]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[CH:47][CH:46]=3)[C:41](O)=[O:42])=[O:38])[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1>>[C:52]([O:51][C:48]1[CH:47]=[CH:46][C:45]([CH2:44][C@H:40]([NH:39][C:37](=[O:38])[O:36][CH2:35][CH:33]2[C:34]3[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:41]([N:7]([C@@H:5]([CH3:6])[CH:4]([O:3][CH2:1][CH3:2])[O:19][CH2:20][CH3:21])[CH2:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[O:42])=[CH:50][CH:49]=1)([CH3:55])([CH3:53])[CH3:54]
Reactant: CC(C)(C)Oc1ccc(C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Reactant: CCOC(OCC)[C@H](C)NCc1cccc2ccccc12
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OCC1c2ccccc2-c2ccccc21
Yield: 79.1 %

Procedure:
According to the procedure described in the synthesis method of Compound III-1, (S)-1,1-diethoxy-N-(naphthalen-1-ylmethyl)propan-2-amine (Compound IX-2) 686 mg (2.4 mmol) was coupled with (S)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-tert-butoxyphenyl)propanoic acid 1.15 g (2.51 mmol) and purified on Buch silica gel column chromatography (n-hexane:ethyl acetate=7:3) to obtain the title compound 1.384 g (79%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][CH2:11][Si:12]([CH3:22])([CH3:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)(=O)C.C(OC(=O)C)C.Cl>C(OCC)C.O>[CH3:21][Si:12]([CH3:22])([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[CH2:11][OH:10]
Reactant: CC(=O)OC[Si](C)(C)Cc1cccc(F)c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: O
Product: C[Si](C)(CO)Cc1cccc(F)c1
Yield: 73.4 %

Procedure:
To a mixture of lithium aluminum hydride (0.06 g, 1.58 mmol) in diethyl ether (5 ml) is added dropwise acetoxymethyldimethyl-3-fluorobenzylsilane (0.38 g, 1.58 mmol) in diethyl ether (2 ml). The mixture is then allowed to react for 0.5 hours at room temperature, treated with ethylacetate (2 ml), hydrolyzed with 1N HCl (6.5 ml), and poured into water (20 ml) and diethyl ether (10 ml). The organic layer is washed with water, brine, dried over MgSO4 and the solvent removed in vacuo. Chromatography (silica gel, hexane/ether-60/40 affords the title compound (0.23 g, 73% yield).
Reaction SMILES: [NH2:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]3[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>O1CCOCC1.CC(C)=O>[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:1][CH:2]2[CH2:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:11]4[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=4)[CH:8]=3)[CH2:3]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: NC1Cc2ccc(C3=NNC(=O)CC3)cc2C1
Solvent: C1COCCO1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1CCC(c2ccc3c(c2)CC(NS(=O)(=O)c2ccc(F)cc2)C3)=NN1
Reaction time: 2 h

Procedure:
2.9 g (12.6 mmol) of 6-(2-amino-indan-5-yl)-4,5-dihydropyridazin-3(2H)-one are dissolved in a mixture of 30 ml of dioxan and 10 ml of acetone, and 1.42 g (14 mmol) of triethylamine and 2.8 g of p-fluorobenzenesulphonyl chloride are added. After 2 hours, the mixture is evaporated, water is added to the residue, and the reaction product is filtered off with suction and recrystallised from glacial acetic acid.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[C:5]([OH:10])(=[O:9])[C:6]([CH3:8])=[CH2:7]>>[C:1]([S:3][CH2:7][CH:6]([CH3:8])[C:5]([OH:10])=[O:9])(=[O:4])[CH3:2]
Reactant: C=C(C)C(=O)O
Reactant: CC(O)=S
Product: CC(=O)SCC(C)C(=O)O
Reaction time: 18 h

Procedure:
A mixture of thioacetic acid (50 g.) and methacrylic acid (40.7 g.) is heated on the steam bath for one hour and then stored at room temperature for 18 hours. After confirming by nmr spectroscopy that complete reaction of the methacrylic acid has been achieved, the reaction mixture is distilled in vacuo and the desired 3-acetylthio-2-methylpropanoic acid is separated in the fraction with boiling point 128.5°-131° (2.6 mmHg.), yield 64 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:16][O:17][CH2:18][C:19]2([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:38][N:39](C)C=O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C-]#N.[Zn+2].[C-]#N>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([C:38]#[N:39])[CH:3]=[C:4]([CH2:16][O:17][CH2:18][C:19]3([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:23][CH2:24]3)[CH:5]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(Br)cc(-c3ccc(C#N)cc3)c2)(c2ccccc2)CC1
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C#N)cc(-c3ccc(C#N)cc3)c2)(c2ccccc2)CC1
Temperature: 25 °C

Procedure:
tert-Butyl 4-(((5-bromo-4′-cyanobiphenyl-3-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (52 mg, 0.09 mmol), tetrakis(triphenylphosphine) palladium(0) (14 mg, 0.01 mmol), and zinc cyanide (12 mg, 0.1 mmol) were combined in dimethylformamide (1.5 mL). The reaction mixture was degassed repeatedly using the freeze-pump-thaw method. After warming to room temperature, the reaction was heated at 90° C. for 1 h, cooled to room temperature, and concentrated. Flash chromatography on silica gel (30% ethyl acetate/hexanes) gave 15 mg (33%). 1H-NMR (CDCl3, 300 MHz) δ 7.78-7.75 (m, 3H), 7.52-7.55 (m, 2H), 7.31-7.33 (m, 4H), 7.20-7.23 (m, 2H), 4.41 (s, 2H), 3.70-3.77 (m, 2H), 3.43 (s, 2H), 2.97-3.06 (m, 2H), 2.17-2.21 (m, 2H), 1.78-1.88 (m, 2H), 1.40 (s, 9H). Mass spec.: 508.28 (MH)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.CCCCCC.[Li]CCCC.[CH:33]([N:36]=[C:37]=[O:38])([CH3:35])[CH3:34]>C(OCC)C>[CH:33]([NH:36][C:37]([C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1)=[O:38])([CH3:35])[CH3:34]
Reactant: CC(C)N=C=O
Reactant: CN(C)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)NC(=O)c1cc(N(C)C)cc(Oc2cccc(C(F)(F)F)c2)n1
Reaction time: 0.17 h

Procedure:
0.75 g (0.0021 mol) of 2-bromo-4-dimethylamino-6-{3-(trifluoromethyl)phenoxy} pyridine was suspended in about 15 ml of diethyl ether. While cooling the obtained suspension in a dry ice-acetone bath in an argon atmosphere, 1.4 ml of a 1.65M-hexane solution of BuLi (0.0021×1.1 mol) was added thereto, followed by stirring the suspension for about 10 minutes. After 0.35 g (0.0021×2.0 mol) of isopropyl isocyanate dissolved in about 10 ml of diethyl ether was added to the reaction solution, the obtained solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 5 ml of a 1N-hydrochloric acid aqueous solution, and then distributed in ethyl acetate-saturated sodium bicarbonate water, followed by washing with saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane) and reversed phase column (Lobor LiCHroprep RP-10; eluting solution: acetonitrile/water), thereby obtaining an aimed product.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:20]([CH2:26]Br)[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:13]1([CH2:12][N:11]2[CH2:10][CH2:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:26][CH:20]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(Br)CBr
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
To a solution of 1 (N,N'-dibenzylethylenediamine, 76.8 g, 0.296 mol) in toluene (240 mL) at 40° C. with mechanical stirring was added dropwise a solution of 2 (ethyl 2,3-dibromopropionate, 71.0 g, 0.296 mol) and triethylamine (84 mL, 0.60 mol) in 75 mL of toluene such that the temperature remained below 80° C. The mixture was stirred at 80° C. for 2.5 hours, then cooled. The resulting mixture was filtered, and the filtrate partitioned with 200 mL of water. The organic extract was dried with Na2SO4, and solvent removed in vacuo to yield an amber oil (3, 105 g, 100% yield). This material was used as is in the subsequent step, thus analysis was not obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][NH:19][O:20][CH3:21].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CCOCC>[CH3:21][O:20][N:19]([CH3:18])[C:14]([CH:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCOC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of (±)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (1.51 g, 6.53 mmol), N,O-dimethylhydroxylamine hydrochloride (0.83 g, 8.49 mmol) and i-Pr2NEt (3.1 mL, 17.6 mmol) in CH2Cl2 (30 mL) was added solid HATU (3.01 g, 7.85 mmol). The mixture was stirred at rt for 3 d, diluted with ether (175 mL), washed with 5% aq HCl (2×50 mL) and satd aq NaHCO3 (50 mL) and dried over MgSO4. Removal of the solvent left (±)-tert-butyl 2-(methoxy(methyl)carbamoyl)morpholine-4-carboxylate (1.73 g, 96%) as an oil.
Reaction SMILES: C([N:8]1[CH2:25][C:12]2([CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)[O:11][CH:10]([CH:26]=[CH2:27])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[CH2:26]([CH:10]1[O:11][C:12]2([CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17]2)[CH2:25][NH:8][CH2:9]1)[CH3:27]
Reactant: C=CC1CN(Cc2ccccc2)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCC1CNCC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 55 °C
Yield: 96 %

Procedure:
To a solution of tert-butyl 10-benzyl-8-vinyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (3.10 g, 8.32 mmol) in methanol (60 mL) was added Pd(OH)2 (1.40 g, 9.99 mmol) and ammonium formate (10.5 g, 166 mmol) and the mixture heated at 55° C. for 20 min. The reaction mixture was filtered, concentrated to −10 mL, then diluted with dichloromethane and saturated sodium bicarbonate solution. The organic layer was separated and the aqueous layer extracted with dichloromethane (5×20 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to provide tert-butyl 4-ethyl-5-oxa-2,9-diazaspiro[5.5]undecane-9-carboxylate (2.27 g, 7.99 mmol, 96%). ESI-MS m/z calc. 284.21. Found 285.1 (M+1)+; Retention time: 1.09 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][C:22](O)=[O:23])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:66][O:67][C:68](=[O:71])[CH2:69][NH2:70]>CN(C=O)C.CCOCC>[CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[C:17]([CH2:21][C:22]([NH:70][CH2:69][C:68]([O:67][CH3:66])=[O:71])=[O:23])[CH:18]=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]
Reactant: COC(=O)CN
Reactant: COCc1cc(-c2nc(-c3cccc(CC(=O)O)c3)no2)ccc1-c1ccccc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COCc1cc(-c2nc(-c3cccc(CC(=O)NCC(=O)OC)c3)no2)ccc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of crude (3-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}phenyl)acetic acid (308 mg; 0.74 mmol) in DMF (6 mL) at 0° C. was added DIEA (267 4, 1.5 mmol) and HATU (282 mg; 0.74 mmol). After 10 min, a solution of glycine methyl ester hydrochloride (93 mg; 0.74 mmol) in DMF (2 mL) was added and the reaction mixture stirred at RT overnight. Et2O was added and the mixture was washed with water. The organic phase was then dried over MgSO4, filtered and concentrated in vacuo. The crude was purified by preparative HPLC affording the title compound as a white solid. LC/MS (Method B): 484.4 (M−H)−, 486.3 (M+H)+. HPLC (Method A) Rt 5.40 min (Purity: 99.1%).
Reaction SMILES: [F:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[C:8]([F:13])[CH:7]=[CH:6][C:3]=1[CH:4]=O.FC(F)(F)C(O)=O.[CH:21]([C:24]1[S:25][CH:26]=[C:27]([C:29]([N:31]2[CH2:36][C:35]3([CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[O:34][CH2:33][CH2:32]2)=[O:30])[N:28]=1)([CH3:23])[CH3:22].C(O)(=O)C>CN1CCCC1=O>[F:1][C:2]1[C:9]([CH2:10][CH2:11][OH:12])=[C:8]([F:13])[CH:7]=[CH:6][C:3]=1[CH2:4][N:39]1[CH2:40][CH2:41][C:35]2([O:34][CH2:33][CH2:32][N:31]([C:29]([C:27]3[N:28]=[C:24]([CH:21]([CH3:22])[CH3:23])[S:25][CH:26]=3)=[O:30])[CH2:36]2)[CH2:37][CH2:38]1
Reactant: O=Cc1ccc(F)c(CCO)c1F
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4ccc(F)c(CCO)c4F)CC3)C2)cs1
Reaction time: 1 h

Procedure:
2,4-Difluoro-3-(2-hydroxyethyl)benzaldehyde (example 45, step b) (0.35 g) was added to a solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.67 g) and acetic acid (0.09 mL) in N-methyl-2-pyrrolidinone (1 mL). The resulting mixture was stirred for 1 h then quenched by portionwise addition of sodium triacetoxyborohydride (0.335 g) over 5 min. The resulting mixture was stirred overnight, diluted with acetonitrile (20 mL) and applied to a SCX cartridge (10 g Varian, pre-wetted with acetonitrile, (50 mL)). The cartridge was washed with acetonitrile (50 mL) and eluted with 10% ‘880’ aqueous ammonia in acetonitrile solution (50 mL). The eluent was evaporated, azeotroped with toluene and purified by silica gel chromatography eluting with 77.5:17.5:5 isohexane:ethyl acetate:triethylamine to 95:5 ethyl acetate:triethylamine gradient to give the subtitled compound as a yellow gum. Yield 0.74 g.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)(=O)[CH3:2].C(=O)(O)O.[NH2:17][NH:18][C:19]([NH2:21])=[NH:20].[ClH:22]>CO.CCOC(C)=O>[ClH:22].[NH2:20][C:19]([NH2:21])=[N:18]/[N:17]=[C:1](/[C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)\[CH3:2]
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: C/C(=N\N=C(N)N)c1ccc(C(=O)O)cc1
Temperature: 20 °C

Procedure:
4-Acetylbenzoic acid (L1) (1.041 g, 6.34 mmol), amino guanidine bicarbonate (1.12 g, 8.2 mmol, 1.3 eq) and c.HCl (0.7 ml, 7.0 mmol) in MeOH (30 mL) was refluxed for 1 h. The reaction mixture was diluted with EtOAc cooled to 20° C. and the resulting precipitate was filtered and recrytallized from MeOH/EtOAc to give L2 (887 mg, 55%), mp (MeOH/EtOAc)>300° C.; 1H NMR ([(CD3)2SO] δ 7.97-7.89 (m, 4H, ArH), 6.75 (br, 4H, 2×NH2), 2.25 (s, 3H, CH3), mass APCl+221.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1[C:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][CH:6]=1.C(=S)=S.O=[C:22]([CH:24]=[C:25]([CH3:27])[CH3:26])[CH3:23]>O>[CH3:9][C:17]1([CH3:16])[C:6]2[CH:5]=[C:17]3[C:9]([C:10]4[CH:11]=[C:12]5[C:22]([CH3:23])=[CH:24][C:25]([CH3:27])([CH3:26])[C:13]5=[CH:14][C:15]=4[CH2:16]3)=[CH:8][C:7]=2[C:6]([CH3:7])=[CH:5]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=O)C=C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: O
Product: CC1=CC(C)(C)c2cc3c(cc21)-c1cc2c(cc1C3)C(C)(C)C=C2C
Reaction time: 0.25 h

Procedure:
To a 300-ml three-neck flask, 25.8 g of anhydrous aluminum chloride, 5.18 g of fluorene, and 200 ml of carbon disulfide were charged under nitrogen atmosphere. 6.18 g of mesityl oxide was added dropwise thereto over 15 minutes in a water bath, and the mixture was stirred for 10 hours under reflux. After standing to cool, 100 ml of water was added thereto, and the organic layer was separated. The aqueous layer was extracted with 300 ml of hexane, and the separated organic layer was combined, and washed with water and a saturated aqueous solution of sodium chloride. After the solution was dried over magnesium sulfate, the solvent was distilled off, and the obtained product was purified by column chromatography, and recrystallized with a mixed solvent of ethanol/hexane. The yield was 1.14 g. Identification was performed by 1H-NMR spectrum. The measurement results are shown as follows.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21].CCOC(C)=O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:20](=[O:22])[CH3:21])[N:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)n1ncc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
Step 1) Dissolve commercially available 5-nitroindazole (100 g, 613 mmoles) in 2 L of THF and then add triethylamine (260 mL; 1.87 moles). Stir the solution at room temp until all the solid went into the solution, and then add acetic acid anhydride (94 g; 927 mmoles). After 2 h at room temperature, add 2 L of EtOAc and extract the mixture with 1 N HCl (2×800 mL). Wash the organic layer with aqueous sodium bicarbonate followed by saturated aqueous NaCl. Dry the organic layer with magnesium sulfate and concentrate to a thick slurry. Add t-Butyl methyl ether (300 mL) and filter the slurry. Collect the solid, rinse with t-butyl methyl ether, and dry under vacuum to afford 113 g (90%) of 1-(5-nitro-indazol-1-yl)-ethanone a pale yellow solid. 1H NMR (500 MHz, CDCl3) δ 8.70 (d, 1H, J=2.0 Hz), 8.58 (d, 1H, J=9.5 Hz), 8.44 (dd, 1H J=7.0, 2.0 Hz), 8.31 (s, 1H), 2.84 (s, 1H).
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@H]2C3C(=CC=CC=3)C[C@@H]2OC)=NC=1CC.[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[C:40]([C:58]([O:60][CH3:61])=[O:59])=[N:41][C:42]([NH:47][C@@H:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][C@@H:49]2[OH:57])=[C:43]([O:45][CH3:46])[N:44]=1>>[Cl:31][C:32]1[CH:37]=[C:36]([Cl:38])[CH:35]=[CH:34][C:33]=1[C:39]1[C:40]([C:58]([O:60][CH3:61])=[O:59])=[N:41][C:42]([NH:47][C@@H:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][C@@H:49]2[O:57][CH2:2][CH3:3])=[C:43]([O:45][CH3:46])[N:44]=1
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@H]1c2ccccc2C[C@@H]1OC
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(OC)nc1-c1ccc(Cl)cc1Cl
Product: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(C(=O)OC)c(-c2ccc(Cl)cc2Cl)nc1OC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-3,6-diethyl-N-[(1S,2S)-2-methoxy-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine but substituting methyl 3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}-5-methoxypyrazine-2-carboxylate and making non-critical variations provided the title compound as a solid: 1H NMR (CDCl3) δ 1.13-0.20, 3.15, 3.55-3.58, 3.66-3.70, 3.76, 4.02, 4.41, 5.75-5.79, 6.16, 7.25-7.34, 7.48, 7.59-7.61; MS (ESI+) for C24H23Cl2N3O4 m/z 488 (M+H)+.