Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1COCC1.[NH:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:7]([C:17]([OH:19])=O)[CH2:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:37][O:38][C:39]([C@@H:41]([NH2:51])[CH2:42][O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:40].Cl>CN(C=O)C>[NH:6]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:7]([C:17]([NH:51][C@H:41]([C:39]([O:38][CH3:37])=[O:40])[CH2:42][O:43][CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)=[O:19])[CH2:8][O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)COCc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 8 h
Yield: 875.5 %

Procedure:
THF (700 ml) and BOC-Ser(Bzl)-OH (23.6 g, 0.8 M) and HOBT (108 g, 0.8 M) were added to H-Ser(Bzl)-Ome.HCl (196.57 g, 0.8 M); and DMF (200 ml) was added to prepare a solution. WSCI (146 ml, 0.8 M) was added dropwise thereto at 0° C. and the mixture was stirred at 0° C. for one hour and at room temperature overnight. The reaction mixture was concentrated in vacuo, and ethyl acetate (1 l.) was added to the residue, which was then washed with 5% sodium bicarbonate solution, 1 N HCl and water, each three times, in that order. Hexane was added to the oily product, which was then crystallized by adding crystalline seed. The material was then recrystallized from ether-hexane to obtain the substance [28] (340.4 g, yield: 87.5%).
Reaction SMILES: [CH3:1][O-].[Na+].[CH3:4][O:5][C:6](=O)[CH2:7][O:8]C.COC=O.Cl.[CH3:16][S:17][CH2:18][C:19]([NH2:21])=[NH:20].Cl>CO.O>[CH3:16][S:17][CH2:18][C:19]1[N:21]=[CH:1][C:6]([O:5][CH3:4])=[C:7]([OH:8])[N:20]=1
Reactant: CSCC(=N)N
Reactant: C[O-]
Reactant: COCC(=O)OC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: COC=O
Product: COc1cnc(CSC)nc1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
5.4 g (0.1 mol) of solid sodium methylate were added in portions to a mixture of 10.4 g (0.1 mol) of methoxyacetic acid methyl ester and 6 g (0.1 mol) of formic acid methyl ester at 20°-25° C. and the mixture was subsequently stirred at room temperature for 5 hours. A further 5.4 g (0.1 mol) of sodium methylate, dissolved in 40 ml of methanol, were then added, 14.1 g (0.1 mol) of methylthioacetamidine hydrochloride were subsequently added to the mixture and the mixture was then stirred at room temperature for 24 hours. The solvent was now stripped off in vacuo, the residue was dissolved in 300 ml of water and the solution was brought to pH 6 by adding concentrated hydrochloric acid. The solution was then twice extracted by shaking with 150 ml of methylene chloride each time, the organic phase was dried over sodium sulphate and the solvent was distilled off in vacuo. 13 g (70% of theory) of 2-methylthiomethyl-6-hydroxy-5-methoxypyrimidine were obtained in this manner in the form of a light brown powder with a melting point of 102° C. ##STR9##
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@@H:7]1[CH2:14][C@H:13]2[C@H:9]([CH2:10][C@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:12]2)[C@H:8]1/[CH:23]=[CH:24]/[C:25](=[O:31])[CH2:26][CH2:27][C:28]#[C:29][CH3:30])(=[O:5])[CH3:4].CO>O1CCCC1>[C:3]([O:6][C@@H:7]1[CH2:14][C@H:13]2[C@H:9]([CH2:10][C@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:12]2)[C@H:8]1/[CH:23]=[CH:24]/[C@@H:25]([OH:31])[CH2:26][CH2:27][C:28]#[C:29][CH3:30])(=[O:5])[CH3:4]
Reactant: CC#CCCC(=O)/C=C/[C@@H]1[C@H]2C[C@H](CCCCC(=O)OC)O[C@H]2C[C@H]1OC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCC[C@H](O)/C=C/[C@@H]1[C@H]2C[C@H](CCCCC(=O)OC)O[C@H]2C[C@H]1OC(C)=O
Reaction time: 1 h

Procedure:
At -40°, 210 mg. of sodium borohydride is added in incremental portions to a solution of 390 mg. of (1S,5R,6R,7R,3S)-7-acetoxy-6-[(E)-3-oxo-1-octen-6-ynyl]-3-(4-methoxycarbonyl-1-butyl)-2-oxabicyclo[3,3,0]octane in 12 ml. of methanol and 5 ml. of tetrahydrofuran. The mixture is stirred for 1 hour at -40°, then combined with 0.5 ml. of glacial acetic acid, concentrated under vacuum, the residue mixed with methylene chloride, and the organic extract is shaken with 4% sodium bicarbonate solution and then washed neutral with water, dried over magnesium sulfate, and evaporated under vacuum. After chromatography of the residue on silica gel with ether/pentane (6+4), 110 mg. of the β-configured compound and 150 mg. of the title compound are obtained in the form of an oil.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(O[N:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)(=O)C1C=CC=CC=1>C1COCC1.CCOCC.[Cl-].[Cl-].[Zn+2]>[CH2:1]([C:9]1[CH:14]=[CH:13][C:12]([N:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:29][CH2:30]2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCN(OC(=O)c2ccccc2)CC1
Reactant: CCCCCCCCc1ccc(I)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To a solution of the product of Step A (0.32 g; 1.01 mmol) in anhydrous THF (2 ml) 2 M iPrMgCl in THF (0.56 ml; 1.11 mmol) was added at −15° C. under N2, followed 1.27 M solution of anhydrous ZnCl2 in THF (0.41 ml; 0.52 mmol), after stirring for 1 h at 0° C. The resulting mixture was stirred for 30 min on ice-bath under N2 and the solution of the product of Step B (0.16 g; 0.51 mmol) and CuCl2 (2.5 mol %) in anhydrous THF (10 ml) was added. The resulting mixture was allowed to warm up to room temperature and stirred for additional 10 min. This was diluted to 20 ml with Et2O and washed with 5% NaHCO3, H2O, brine, dried over anhydrous MgSO4 and filtered. The filtrate was evaporated under reduced pressure and the residue was purified by FCC (SiO2, hexane/EtOAc 9:1) to give the title compound (0.06 g; 31%), as a creamy syrup. 1H-NMR (CDCl3) 7.07 (d, 2H, J=8.6 Hz); 6.84 (d, 2H, J=8.6 Hz); 3.55 (t, 4H, J=5 Hz); 3.06 (t, 4H, J=5 Hz); 2.51 (t, 2H, J=7.94 Hz); 1.55-1.38 (m, 11H); 1.26 (m, 10H); 0.86 (t, 3H, J=6.93 Hz).
Reaction SMILES: B(Cl)(Cl)Cl.C([O:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[S:26][N:25]=[CH:24][N:23]=1)C1C=CC=CC=1.CO>C(Cl)Cl>[OH:12][N:13]1[C:19](=[O:20])[N:18]2[CH2:21][C@H:14]1[CH2:15][CH2:16][C@H:17]2[C:22]1[S:26][N:25]=[CH:24][N:23]=1
Reactant: O=C1N2C[C@@H](CC[C@H]2c2ncns2)N1OCc1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: O=C1N(O)[C@@H]2CC[C@@H](c3ncns3)N1C2
Temperature: 0 °C
Reaction time: 6 h
Yield: 81 %

Procedure:
BCl3 (1 M in DCM, 3.0 mL, 3.0 mmol) was added dropwise to a solution of (2S,5R)-6-(benzyloxy)-2-(1,2,4-thiadiazol-5-yl)-1,6-diazabicyclo[3.2.1]octan-7-one (190 mg, 0.60 mmol) in dry DCM (20 mL) at −78° C. The mixture was stirred at 0° C. for 6 hrs., then, MeOH (3 mL) was added slowly at −78° C. The solvents were evaporated under vacuum to give (2S,5R)-6-hydroxy-2-(1,2,4-thiadiazol-5-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (110 mg, 80%) as a yellow solid, which was directly used in the next step. ESI-MS (EI−, m/z): 227.1 [M−H]−.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>[OH-].[Na+]>[CH2:14]([O:13][C:11]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NCCCCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCNC(=O)OCc1ccccc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
To a solution of 6-Amino hexanoic acid (50 grams, 379.65 mmol) in 1N Sodium hydroxide (95.3 ml) is cooled to 5 to 10° C. and simultaneously added from two separating funnels 4N Sodium hydroxide (190.6 ml) and Benzyl chloroformate (50% in Toluene, 196 grams) keeping the temperature at 5 to 10° C., later stirred at the same temperature for 2 hours and allowed to room temperature and stirred overnight. The reaction mixture is washed with Diisopropyl ether (3×200 ml), cooled to 10° C.; pH adjusted to 2 with dilute HCl, residue precipitated is filtered, dried and slurried in Diisopropyl ether to give pure 6-Benzyloxycarbonylamino hexanoic acid (38 grams) as white powder.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([N:22]3[C:27](=[O:28])[C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=5)=[CH:32][CH:31]=4)=[C:25]([CH2:44][CH2:45][CH2:46][CH3:47])[N:24]=[C:23]3[CH3:48])=[CH:21][C:16]=2[O:15][CH2:14]1>O.C(OCC)(=O)C>[O:13]1[C:17]2[CH:18]=[CH:19][C:20]([N:22]3[C:27](=[O:28])[C:26]([CH2:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=5[C:42]5[NH:3][C:4](=[O:7])[O:5][N:43]=5)=[CH:32][CH:31]=4)=[C:25]([CH2:44][CH2:45][CH2:46][CH3:47])[N:24]=[C:23]3[CH3:48])=[CH:21][C:16]=2[O:15][CH2:14]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(-c2ccc3c(c2)OCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccc3c(c2)OCO3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.45 g), sodium hydrogen carbonate (2.10 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[1-(1,3-benzodioxol-5-yl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.99 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.49 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.46 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.86 g, 77%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=3)[NH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].O.NN.N.C(Cl)Cl>CO.[Ni]>[CH2:1]([N:3]1[CH2:4][CH:5]=[C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=3)[NH:11][CH:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Ni]
Agent: N
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Yield: 98.9 %

Procedure:
A suspension of 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-5-nitro-1H-indole (0.375 g, 1.382 mmol) in dry methanol (10 mL) was treated with Raney-nickel (0.1 g, 0.351 mmol), followed by hydrazine hydrate (0.672 mL, 13.82 mmol) at room temperature. The resulting mixture was placed in a pre-heated oil bath and refluxed for 5 min. (TLC basis, 2 M NH3 in MeOH:CH2Cl2, 5:95). The reaction was brought to room temperature, filtered through celite bed and washed with methanol (3×5 mL). The combined methanol layer was evaporated and crude was purified by flash column chromatography (2 M NH3 in MeOH:CH2Cl2, 5:95) to obtain 3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-5-amine (0.33 g, 99%) as a foam. 1H NMR (DMSO-d6) δ 10.60 (s, 1H), 7.15 (d, 1H, J=2.7 Hz), 7.05 (d, 1H, J=8.4 Hz), 7.00 (d, 1H, J=1.5 Hz), 6.48 (dd, 1H, J=2.1, 8.5 Hz), 5.98 (s, 1H), 4.48 (s, 2H), 3.10-3.04 (m, 2H), 2.59 (t, 2H, J=5.4 Hz), 2.54-2.39 (m, 4H, merged with DMSO peak), 1.06 (t, 3H, J=7.2 Hz); EI-MS (m/z, %): 241 (M+, 100).
Reaction SMILES: [C-]#N.[Na+].Cl.Cl.[N:6]12CCC(C[CH2:11]1)CN2.[Cl:14][C:15]([Cl:25])=[CH:16][CH:17]1[CH:19]([C:20](Cl)=[O:21])[C:18]1([CH3:24])[CH3:23].[O:26]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH:36]=[O:37])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O.CCCCCCC>[Cl:14][C:15]([Cl:25])=[CH:16][CH:17]1[CH:19]([C:20]([O:37][CH:36]([C:11]#[N:6])[C:35]2[CH:38]=[CH:39][CH:40]=[C:33]([O:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:34]=2)=[O:21])[C:18]1([CH3:24])[CH3:23]
Reactant: CC1(C)C(C=C(Cl)Cl)C1C(=O)Cl
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: C1CN2CCC1CN2
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: CCCCCCC
Solvent: O
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1
Reaction time: 0.67 h

Procedure:
A stirred mixture of sodium cyanide (18.1 g, 0.36 mole) and diazabicyclo[2.2.2]octane dihydrochloride (1.11 g, 0.006 mole) in 30 g of water was warmed to 40°. During a one hour period a solution of 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride (77.6 g, 0.33 mole) and 3-phenoxybenzaldehyde (61.5 g, 0.3 mole) in 102 ml of n-heptane was added to the reaction mixture. After complete addition, the reaction mixture was stirred for 40 minutes and an additional 3.5 g (0.015 mole) of the acyl chloride added. The reaction mixture was stirred for an additional 40 minutes and then washed with 100 g of a 10% aqueous sodium carbonate solution and then water. The organic phase was separated from the mixture and the solvent removed by distillation under reduced pressure to give α-cyano-3-phenoxybenzyl 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].Cl[C:6]1[C:11]([NH2:12])=[C:10](Cl)[N:9]=[C:8]([CH3:14])[N:7]=1.O1CC[CH2:17][CH2:16]1>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([C:6]1[C:11]([NH2:12])=[C:10]([CH2:1][CH3:2])[N:9]=[C:8]([CH3:14])[N:7]=1)[CH3:17]
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Product: CCc1nc(C)nc(CC)c1N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 100 mL, 300 mmol) was added to a stirred suspension of 4,6-dichloro-2-methylpyrimidin-5-amine (10.7 g, 60.1 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel(II) (3.26 g, 6.01 mmol) in tetrahydrofuran (400 mL) at 0° C., and the mixture was stirred at room temperature for 4 hr. The reaction was quenched by water, acidified by 1N hydrochloric acid and extracted with ethyl acetate. The aqueous layer was neutralized by 1N sodium hydroxide, extracted with ethyl acetate, and the combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a yellow wax (4.22 g, 25.5 mmol, 42%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].N1(C(N2C=CN=C2)=O)C=CN=C1.Cl.[CH3:26][O:27][NH:28][CH3:29].Cl>ClCCl.O1CCOCC1>[C:1]([N:4]1[CH2:5][CH2:6][CH:7]([C:10]([N:28]([O:27][CH3:26])[CH3:29])=[O:12])[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: CNOC
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1COCCO1
Product: CON(C)C(=O)C1CCN(C(C)=O)CC1
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a solution of 1-acetylpiperidine-4-carboxylic acid (58.50 g, 342 mmol) in dichloromethane (700 mL) was added di(1H-imidazol-1-yl)methanone (58.18 g, 359 mmol). After the addition the mixture was agitated for two hours and N-methoxymethanamine hydrochloride (35.00 g, 359 mmol) was added at once. The mixture was allowed to agitate overnight at ambient temperature and 4M HCl in dioxane (75 mL) was added slowly. The slurry was agitated for 30 minutes and then filtered. Filtrate was washed twice with sodium bicarbonate solution, dried and concentrated to give the title compound (59.10 g, 80.72% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([CH3:11])[C:8]([OH:10])=O)[CH2:2]1.Cl.CN(C)CCCN=C=NCC.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39]3[N:43]=[CH:42][N:41]([C:44]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)([C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[N:40]=3)=[CH:36][CH:37]=2)[C:32]([C:63]2[CH:64]=[C:65]([NH2:69])[CH:66]=[CH:67][CH:68]=2)=[N:31]1.CN(C)C=O>ClCCl>[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[N:30]1[C:38]2[C:33](=[CH:34][C:35]([C:39]3[N:43]=[CH:42][N:41]([C:44]([C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=4)([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[N:40]=3)=[CH:36][CH:37]=2)[C:32]([C:63]2[CH:64]=[C:65]([NH:69][C:8](=[O:10])[CH:7]([CH:3]3[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]3)[CH3:11])[CH:66]=[CH:67][CH:68]=2)=[N:31]1
Reactant: CC(C(=O)O)C1CCCNC1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)C1CCCNC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3-piperidyl propanoic acid (0.125 g, 0.796 mmol) in 7 mL of dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethyl carbodimide hydrochloride (0.190 g, 0.99 mmol). After 10 min at room temperature, 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.200 g, 0.59 mmol) was then added as a solid followed by 2 mL of dimethyl formamide. The reaction mixture was stirred at room temperature overnight. The completion of the reaction mixture was achieved after reacting an additional equivalent of reagents and stirring at room temperature for 24 hours. The crude mixture was partitioned between water and dichloromethane. The crude was not purified (yield not calculated). ES-MS (m/z) 742 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>ClC1C=CC=CC=1Cl>[CH2:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccccc1Cc1ccccc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3ccccc3Cc3ccccc3)c2cc1OC
Temperature: 180 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (230 mg) and 2-benzylphenol (254 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 180° C. overnight. The reaction solution was cooled to room temperature, and water was added thereto. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was then removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using ethyl acetate-hexane to give the title compound (40 mg, yield 10%).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([CH2:20][C:21](OCC)=[O:22])[CH2:4]1)[CH3:2].O/[N:27]=[C:28](\[NH2:31])/[CH2:29][OH:30].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CO>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C@@H:5]([CH2:20][C:21]2[O:22][N:31]=[C:28]([CH2:29][OH:30])[N:27]=2)[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C[C@H]1C[C@@H](CC)[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Reactant: N/C(CO)=N\O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@H](Cc2nc(CO)no2)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 130 °C
Yield: 20 %

Procedure:
To a solution of ethyl 2-((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)acetate (0.195 g, 0.571 mmol, Example #38, Step H) in toluene (1.00 mL) and MeOH (1.000 mL) were added (Z)-N′,2-dihydroxyacetimidamide (0.515 g, 5.71 mmol, Tyger) and K2CO3 (0.195 g, 1.41 mmol). The reaction was heated in a CEM microwave at about 130° C. twice at about 45 min each (250 psi maximum pressure, 1 min ramp, 300 max watts). (Z)-N′,2-dihydroxy acetimidamide (0.200 g, 2.22 mmol, Tyger) was added and the reaction mixture was heated in a CEM microwave at about 140° C. for about 45 min (250 psi maximum pressure, 1 min ramp, 300 max watts). (Z)-N′,2-dihydroxyacetimidamide (0.200 g, 2.22 mmol, Tyger) and K2CO3 (0.100 g, 0.725 mmol) were added, and the reaction mixture was heated in a CEM microwave at about 140° C. for about 45 min (250 psi maximum pressure, 1 min ramp, 300 max watts). The solvent was removed under reduced pressure. The residue was dissolved with water (20 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (5×50 mL). The combined organic layers were dried over anhydrous MgSO4, filtered, and concd to give a yellow residue. The crude material was purified via flash chromatography on silica gel eluting with a gradient of 0-10% MeOH in EtOAc to afford (5-(((1S,3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)methyl)-1,2,4-oxadiazol-3-yl)methanol (0.042 g, 20%) as a yellow solid: LC/MS (Table 1, Method a) Rt=1.67 min; MS m/z: 368 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH3:14])([CH3:13])[CH:8]([CH3:15])[C:7]2([CH3:17])[CH3:16])=O.[C:18](O)(=O)C.[CH:22]([NH2:24])=[NH:23]>C(O)CCC>[CH3:13][C:9]1([CH3:14])[C:10]2[C:6](=[CH:5][C:4]([C:2]3[CH:1]=[CH:18][N:24]=[CH:22][N:23]=3)=[CH:12][CH:11]=2)[C:7]([CH3:17])([CH3:16])[CH:8]1[CH3:15]
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)C(C)C2(C)C
Reactant: N=CN
Reactant: CC(=O)O
Solvent: CCCCO
Product: CC1C(C)(C)c2ccc(-c3ccncn3)cc2C1(C)C
Temperature: 120 °C
Yield: 37.5 %

Procedure:
A 5 L reaction vessel was charged with 1,1,2,3,3-pentamethyl-5-indanyl methyl ketone (460 g, 2.0 mol) (commercially available at IFF), formamidine acetate (675 g, 6.4 mol), and butanol (1.0 L). The reaction mixture was heated to 120° C. for 10 hours and then cooled to 25° C. The reaction mixture was washed twice with brine (1 L) and purified by vacuum distillation to afford 4-(2,3-dihydro-1,1,2,3,3-pentamethyl-1H-inden-5-yl)-pyrimidine (200 g) having a boiling point of 153° C. at a pressure of 2.0 mmHg.