Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C@H:10]([C:14]([OH:16])=O)[C@H:11]([OH:13])[CH3:12])[C@@H:4]([CH3:9])[C:5]([O:7][CH3:8])=[O:6].C1OC1C.C1CCC(N=C=NC2CCCCC2)CC1>CO>[OH:13][C@@H:11]([C@@H:10]1[C@H:3]([C@@H:4]([CH3:9])[C:5]([O:7][CH3:8])=[O:6])[NH:2][C:14]1=[O:16])[CH3:12]
Reactant: COC(=O)[C@H](C)[C@@H](N)[C@H](C(=O)O)[C@@H](C)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1CO1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](C)[C@@H]1NC(=O)[C@@H]1[C@@H](C)O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
In 30 ml of anhydrous methanol was dissolved 510 mg of the hydrochloride of methyl (2R, 3R, 4S, 5R)-3-amino-4-carboxy-5-hydroxy-2-methyl-hexanoate (10), and 1 ml of propene oxide was added to the solution, and the mixture was heated under reflux for 10 minutes. The solution was allowed to cool and admixed with 450 mg of DCC, and the mixture was heated with stirring at 50° C. for 4 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was freed of the insoluble matter by filtration and concentrated under reduced pressure, and the residue was purified by silica-gel column chromatography. The eluate with benzene-ethyl acetate (1:1) yielded 310 mg of the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][CH:7]=[C:8]([C:10]([C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[O:11])[CH:9]=1)=[O:4].[H-].[Na+].I[CH3:28]>O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:28])[CH:7]=[C:8]([C:10]([C:12]2[C:13]([C:18]3[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[O:11])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(C(=O)c2c(-c3ccc(Br)cc3)noc2C)c[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(C(=O)c2c(-c3ccc(Br)cc3)noc2C)cn1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 66 %

Procedure:
A mixture of 212 mg (0.5 mmol) 4-[3-(4-bromo-phenyl)-5-methyl-isoxazole-4-carbonyl]-1H-pyrrole-2-carboxylic acid methyl ester (intermediate 2, step 2), 28 mg (0.66 mmol) NaH and 116 mg (0.65 mmol) iodomethane was stirred at room temperature for 24 h. The mixture was then diluted with water and the product extracted with ethyl acetate. The combined organic extracts were then dried with Na2SO4 and evaporated to yield 133 mg (61%) of the title compound as a light yellow solid after purification by chromatography on silica gel eluting with ethyl acetate/heptane. (m/e): 403.3/405.2 (M+H, 100%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.C1(C)C=CC(C([C@@](C(O)=O)(O)[C@@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1.[CH2:49]([N:56]1[CH2:61][CH2:60][C@@H:59]([CH3:62])[C@@H:58]([NH:63][CH3:64])[CH2:57]1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH2:49]([N:56]1[CH2:61][CH2:60][C@@H:59]([CH3:62])[C@@H:58]([N:63]([CH3:64])[C:2]2[C:3]3[CH:10]=[CH:9][N:8]([S:11]([C:14]4[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=4)(=[O:13])=[O:12])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:57]1)[C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Reactant: CN[C@H]1CN(Cc2ccccc2)CC[C@H]1C
Agent: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(N(C)[C@H]4CN(Cc5ccccc5)CC[C@H]4C)ncnc32)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 163.4 %

Procedure:
To a clean, dry, nitrogen-purged reactor were charged 4-chloro-7-(4-methyl-benzenesulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (25.12 g, 0.082 mol), bis-(3R,4R)-(1-benzyl-4-methyl-piperidine-3-yl)-methylamine di-p-toluoyl-L-tartaric acid (40.31 g, 0.041 mol), potassium carbonate (34.2 g, 0.245 mol), and water (125.6 ml). The mixture was heated to 95-105° C. for a minimum of 10 hours, then cooled to 45-55° C. Acetonitrile (25 ml) was charged and the slurry was held at 45-55° C. for a minimum of 1 hour. The mixture was further cooled to 20-30° C. and stirred for a minimum of 5 hours. The resulting solids were isolated by filtration and washed with water (50 ml). After drying, 32.8 g (82.1%) of the title compound were isolated.
Reaction SMILES: C([O:5][C:6](=[O:31])[CH2:7][CH2:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][N:16]([CH2:21][CH2:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1)[C:15]2=[O:30])=[O:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:30]=[C:15]1[C:14]2[C:18](=[CH:19][CH:20]=[C:12]([C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:31])=[O:5])=[O:11])[CH:13]=2)[CH2:17][N:16]1[CH2:21][CH2:22][NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: CC(C)(C)OC(=O)CCNC(=O)c1ccc2c(c1)C(=O)N(CCNc1ccccn1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNC(=O)c1ccc2c(c1)C(=O)N(CCNc1ccccn1)C2

Procedure:
A solution of the ester (8) (252 mg, 0.60 mmol), TFA (4 ml) and CH2Cl2 (8 ml) was stirred at ambient temperature for 3 hours. The mixture was evaporated to dryness and the residue purified by flash chromatography (silica, EtOH/NH4OH 19:1) to provide (9) as off-white foam. NMR conforms to structure.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]([C:23]1[C:28]([C:29]2[O:30][C:31]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][NH:41][CH3:42])=[CH:36][C:35]=3[O:43][CH3:44])=[N:32][N:33]=2)=[N:27][C:26]([C:45]2[CH:50]=[CH:49][C:48]([S:51]([CH:54]([CH3:56])[CH3:55])(=[O:53])=[O:52])=[CH:47][CH:46]=2)=[CH:25][N:24]=1)C(=O)OC(C)(C)C)=O)(C)(C)C>C(Cl)Cl>[CH:54]([S:51]([C:48]1[CH:47]=[CH:46][C:45]([C:26]2[N:27]=[C:28]([C:29]3[O:30][C:31]([C:34]4[CH:39]=[CH:38][C:37]([CH2:40][NH:41][CH3:42])=[CH:36][C:35]=4[O:43][CH3:44])=[N:32][N:33]=3)[C:23]([NH2:15])=[N:24][CH:25]=2)=[CH:50][CH:49]=1)(=[O:53])=[O:52])([CH3:56])[CH3:55]
Reactant: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)o2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)o2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
TFA (393.7 mg, 266.0 μL, 3.453 mmol) was added to a solution of tert-butyl N-tert-butoxycarbonyl-N-[5-(4-isopropylsulfonylphenyl)-3-[5-[2-methoxy-4-(methylaminomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]carbamate (80 mg, 0.1151 mmol) CH2Cl2 (10 mL). The resulting mixture was stirred at room temperature for 1 h, and then concentrated in vacuo to leave an oil. The oil was re-dissolved in CH2Cl2 (10 ml), and evaporated to dryness. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3 CN) over 16 minutes at 25 mL/min]. The fractions were collected and freeze-dried to give the title compound as a yellow solid (27.1 mg, 39%); 1H NMR (400 MHz, DMSO) d 1.3 (d, 6H), 2.65-2.7 (m, 3H), 3.4-3.5 (m, 1H), 4.0 (s, 3H), 4.25-4.3 (m, 2H), 7.25 (d, 1H), 7.5 (s, 1H), 8.0 (d, 2H), 8.1 (d, 1H), 8.38 (d, 2H), 8.92 (br s, 2H) and 9.1 (s, 1H) ppm; MS (ES+) 495.3
Reaction SMILES: C(OC([NH:8][NH:9][C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH2:19][CH3:20])[CH:13]=1)=[O:11])=O)(C)(C)C.Cl>O1CCOCC1>[CH2:19]([C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([CH3:18])[N:15]=1)[C:10]([NH:9][NH2:8])=[O:11])[CH3:20]
Reactant: CCc1cc(C(=O)NNC(=O)OC(C)(C)C)cc(C)n1
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cc(C(=O)NN)cc(C)n1

Procedure:
A solution of crude N′-(2-ethyl-6-methyl-pyridine-4-carbonyl)-hydrazinecarboxylic acid tert-butyl ester in dioxane (10 mL) is treated with 4M HCl in dioxane (4 mL) for 6 h. The mixture is evaporated, the residue taken up in MeOH and the 2-ethyl-6-methyl-isonicotinic acid hydrazide hydrochloride is precipitated from Et2O as white foam; 1H NMR (CD3OD): δ 8.16 (s, 1 H), 8.14 (s, 1 H), 3.15 (q, J=7.6 Hz, 2 H), 2.87 (s, 3 H), 1.46 (t, J=7.6 Hz, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:32]2[CH2:36][CH2:35][C@H:34]([NH:37]C(=O)OC(C)(C)C)[CH2:33]2)[CH:5]=[CH:6][C:7]=1[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:9]([C:11]1[S:12][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)=[O:10]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:37][C@H:34]1[CH2:35][CH2:36][N:32]([C:4]2[CH:3]=[CH:2][C:7]3[N:8]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[C:9](=[O:10])[C:11]4[S:12][C:13]([C:16]5[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=5)=[CH:14][C:15]=4[C:6]=3[CH:5]=2)[CH2:33]1
Reactant: COc1ccc(-c2ccc(C(=O)N(COCC[Si](C)(C)C)c3ccc(N4CC[C@H](NC(=O)OC(C)(C)C)C4)cc3Br)s2)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Product: COc1ccc(-c2cc3c(s2)c(=O)n(COCC[Si](C)(C)C)c2ccc(N4CC[C@H](N)C4)cc32)cc1
Yield: 16.5 %

Procedure:
Following Step 3 from General Procedure A, (S)-tert-butyl 1-{3-bromo-4-[5-(4-methoxyphenyl)-N-{[2-(trimethylsilyl)ethoxy]methyl}thiophene-2-carboxamido]phenyl}pyrrolidin-3-ylcarbamate (210 mg, 0.29 mmol) was reacted with bis(tri-tert-butylphosphine)palladium (15 mg, 0.029 mmol) to afford the desired product (25 mg, 14%): ESI MS m/z 622 [C28H35N3O3SSi+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([N+]([O-])=O)=[N:18][CH:19]=1.CC([O-])(C)C.[K+]>CN(C=O)C>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N+:10]([O-:12])=[O:11])=[N:18][CH:19]=1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Nc2ccc(Br)cn2)c([N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
A mixture of 4-methoxy-2-nitrobenzenamine (8 g, 47.62 mmol), 5-bromo-2-nitropyridine (7.2 g, 35.47 mmol), and potassium 2-methylpropan-2-olate (6 g, 53.57 mmol) in DMF (180 ml) was allowed to stir for 5 hours at 30° C. and overnight at 60° C. After being cooled down to room temperature, the reaction mixture was quenched by the addition of H2O (200 mL) and the resulting solution was extracted three times with 400 ml of EtOAc, washed with 200 ml of H2O and 200 ml of brine. The mixture was dried and concentrated under reduced pressure. The crude material such obtained was purified by solvating gas chromatography (SGC) using 1:10-1:5 EtOAc/PE as eluents to provide 800 mg (5%) of (5-Bromo-pyridin-2-yl)-(4-methoxy-2-nitro-phenyl)-amine (z) as a red solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[CH:13]2.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]=[CH:13]3)[CH:7]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: Clc1cc(Cl)ncn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(Nc2ccc3[nH]ccc3c2)ncn1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 37.5 %

Procedure:
4,6-Dichloropyrimidine (5.89 g, 40 mmol), 5-aminoindole (6.27 g, 47 mmol) and N,N-diisopropylethylamine (20.6 ml, 0.12 mol) were dissolved in N-methylpyrrolidone (80 ml), and the reaction mixture was stirred at 50° C. for 2.5 hours. The reaction mixture was partitioned between ethyl acetate and water; the aqueous layer was subjected to re-extraction with ethyl acetate; and the combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure; a small amount of ethyl acetate was added to the residue to crystallize; and the crystals were filtered off, washed with diethyl ether, and dried under aeration to yield the title compound (3.70 g, 15 mmol, 38%) as white crystals.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)=[N:5][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:8]=1[CH3:9].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)(C)C>[CH3:9][C:8]1[N:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)[C:3]=1[CH2:2][N:29]1[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]1
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CBr
Reactant: CN1CCNCC1
Solvent: CC(C)O
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1CN1CCN(C)CC1

Procedure:
A mixture of 5-bromomethyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (1.5 g), N-methylpiperazine (1.17 g) in isopropyl alcohol (15 ml) was refluxed for 6 hours. After evaporating the solvent, the residue was dissolved in chloroform, washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The filtrate was evaporated under reduced pressure, and the residue was subjected to column chromatography on alumina (100 g) eluting with chloroform. The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from diethyl ether to give 6-methyl-5-(4-methylpiperazin-1-ylmethyl)-4-(3-nitrophenyl)-2-phenylpyrimidine. (0.30 g).
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[CH3:28][N:29]1[C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32][CH:31]=[N:30]1>>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([S:20][C:11]2[C:12]3[C:13]([C:33]4[N:29]([CH3:28])[N:30]=[CH:31][CH:32]=4)=[CH:14][C:15]([F:18])=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:26][CH:25]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(F)cc12
Product: Cn1nccc1-c1cc(F)cc2c1c(Sc1ccc(Cl)cc1)c1n2CCC1CC(=O)O

Procedure:
Starting from (+/−)-methyl{8-bromo-9-[(4-chlorophenyl)thio]-6-fluoro-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl}acetate (Example 7, Step 9, 200 mg, 0.43 mmol) and 1-methyl-5-(tributylstannyl)-1H-pyrazole (239 mg, 0.64 mmol), the title compound was synthesized following the procedures described in Example 42 and Step 10 of Example 7.
Reaction SMILES: C([C@H](NC(=O)C1C=C(C2C=CC=CC=2)C=C(N2CCCC2=O)C=1)[C@@H](O)C[C@H](C(=O)NCCC(C)(C)C)C)C1C=CC=CC=1.[O:44]=[C:45]1[N:49]([C:50]2[CH:51]=[C:52]([CH:56]=[CH:57][CH:58]=2)[C:53]([OH:55])=O)[CH2:48][CH2:47][O:46]1.[CH:59]12[CH2:65][CH:62]([CH2:63][CH2:64]1)[CH2:61][CH:60]2[NH:66][C:67](=[O:82])[C@H:68]([CH3:81])[CH2:69][C@H:70]([OH:80])[C@@H:71]([NH2:79])[CH2:72][C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1>>[CH2:72]([C@H:71]([NH:79][C:53](=[O:55])[C:52]1[CH:56]=[CH:57][CH:58]=[C:50]([N:49]2[CH2:48][CH2:47][O:46][C:45]2=[O:44])[CH:51]=1)[C@@H:70]([OH:80])[CH2:69][C@H:68]([C:67](=[O:82])[NH:66][CH:60]1[CH2:61][CH:62]2[CH2:65][CH:59]1[CH2:64][CH2:63]2)[CH3:81])[C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=1
Reactant: O=C(O)c1cccc(N2CCOC2=O)c1
Reactant: C[C@H](C[C@H](O)[C@@H](N)Cc1ccccc1)C(=O)NC1CC2CCC1C2
Agent: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cc(-c2ccccc2)cc(N2CCCC2=O)c1)C(=O)NCCC(C)(C)C
Product: C[C@H](C[C@H](O)[C@H](Cc1ccccc1)NC(=O)c1cccc(N2CCOC2=O)c1)C(=O)NC1CC2CCC1C2

Procedure:
Prepared in an analogous manner to E6, from 3-(2-oxooxazolidin-3-yl)benzoic acid (D19) and (2R,4S,5S)-5-amino-4-hydroxy-2-methyl-6-phenylhexanoic acid (bicyclo[2.2.1]hept-2-yl)amide (D29).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.Br[CH:10]([CH2:16][CH2:17][CH2:18][CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12].[H-].[Na+].[Br-].[Li+]>>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH:10]([CH2:16][CH2:17][CH2:18][CH3:19])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(I)cc[nH]1
Reactant: CCCCC(Br)C(=O)OCC
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Product: CCCCC(C(=O)OCC)n1ccc(I)cc1=O

Procedure:
500 mg (2.3 mmol) of 4-iodopyridin-2(1H)-one and 706 mg (3.2 mmol) of ethyl 2-bromohexanoate (racemate) in the presence of 1.15 eq. of sodium hydride and 2.3 eq. of lithium bromide were reacted according to General Method 4C. Yield: 352 mg (43% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[CH3:13])=[N:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:25][N:24]=[CH:23][C:22]=2[CH2:26][CH2:27][C:28](O)=[O:29])=[CH:17][CH:16]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[CH3:13][C:9]1[N:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:28](=[O:29])[CH2:27][CH2:26][C:22]3[CH:23]=[N:24][O:25][C:21]=3[C:18]3[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=3)=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: Cc1nccn1-c1ccc(N)cn1
Reactant: O=C(O)CCc1cnoc1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nccn1-c1ccc(NC(=O)CCc2cnoc2-c2ccc(Cl)cc2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
A mixture of 5-amino-2-(2-methyl-1-imidazolyl)pyridine (0.40 g), 3-[5-(4-chlorophenyl)-4-isoxazolyl]propionic acid (0.58 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.45 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.54 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-[6-(2-methyl-1-imidazolyl)-3-pyridyl]-3-[5-(4-chlorophenyl)-4-isoxazolyl]propionamide (0.59 g, yield 63%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from acetone-hexane. melting point: 193–194° C.
Reaction SMILES: [P:1]([O-:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C1COCC1.[CH3:22][C:23]([CH3:25])=[O:24]>>[O:2]([P:1]([C:23]([OH:24])([CH3:25])[CH3:22])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)=O
Reactant: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(O)P(=O)(Oc1ccccc1)Oc1ccccc1
Temperature: 50 °C

Procedure:
To a one liter four-inlet flask equipped with a temperature controller, a reflux condenser, a nitrogen feed and a mechanical stirrer, 1 mole (234 g) diphenyl phosphite (DPP) and 500 ml THF were added. The mixture was heated to 50° C. and then stirred. The mixture was heated to a temperature of 90° C. and the stirring was continued until DPP was dissolved completely. To this solution was added slowly 1.0 mole (58 g) acetone within two hours, and the temperature thereof was increased to 70° C. and maintained at that temperature for four hours after the addition of acetone was completed. The mixture was then cooled to room temperature to obtain solid, which was then filtered, and purified with THF to yield 2-(diphenoxy phosphoryl) propan-2-ol [DPOP; (II)]. Yield, 96%; m.p. 70-72° C. Anal. Calcd. for C15H17PO4: C, 61.64; H, 5.82; O, 21.92; P, 10.62. Found: C, 61.52; H, 5.96; O, 21.78; P, 10.74. EIMS, m/z: 292 (92. M+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH3:21])[CH2:15][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CNC
Reactant: O=CC1(c2ccc(C(F)(F)F)cc2)CCCCC1
Product: CN(C)CC1(c2ccc(C(F)(F)F)cc2)CCCCC1
Yield: 32.9 %

Procedure:
The title compound was prepared from 1-(4-(trifluoromethyl)phenyl)cyclohexane-carbaldehyde (128 mg, 0.50 mmol) and dimethylamine (2.0 M in THF, 0.5 ml, 1.0 mmol) according to General Procedure H2.The crude product was purified by silica gel column chromatography (MeOH/CH2Cl2, MeOH from 0% to 15%) to give N,N-dimethyl-1-(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (47 mg, 33%). 1H NMR (CDCl3): δ 1.29-1.38 (m 3H), 1.48-1.57 (m, 3H), 1.62-1.68 (m, 2H), 1.97 (s, 6H), 2.13-2.18 (m, 2H), 2.35 (s, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H). 13C NMR (CDCl3) δ 22.4, 26.7, 34.4, 37.5, 43.9, 48.6, 72.8, 123.3, 125.0, 125.1, 126.0, 127.6, 127.9, 128.3, 150.8.ESI MS m/z 286.
Reaction SMILES: C([C:3]([N:17]1CCCCC1)([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH2:4][CH:5]([CH3:10])[C:6](OC)=[O:7])#N.C(C(C1C=CN=CC=1)(N1CCCC1)CC(C)C(OC)=O)#[N:24].C(C(N1CCOCC1)(C1C=CN=CC=1)CC(C)C(OCC)=O)#N.C(C(C1C=CN=CC=1)(N1CCOCC1)CC(C)C(OCCC)=O)#N>>[CH3:10][CH:5]1[CH2:4][C:3]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[N:17][NH:24][C:6]1=[O:7]
Reactant: COC(=O)C(C)CC(C#N)(c1ccncc1)N1CCCCC1
Reactant: COC(=O)C(C)CC(C#N)(c1ccncc1)N1CCCC1
Agent: CCCOC(=O)C(C)CC(C#N)(c1ccncc1)N1CCOCC1
Agent: CCOC(=O)C(C)CC(C#N)(c1ccncc1)N1CCOCC1
Product: CC1CC(c2ccncc2)=NNC1=O

Procedure:
Following the above procedure described above for preparing methyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate but using in place of 2-(4-morpholinyl)-2-(4-pyridinyl)ethanenitrile and methyl methacrylate molar equivalent quantities respectively of the appropriate 2-(BN)-2-(4-pyridinyl)ethanenitrile and lower-alkyl methacrylate, it is contemplated that there can be obtained the following corresponding lower-alkyl 4-cyano-2-methyl-4-(BN)-2-(4-pyridinyl)butanoates: methyl 4-cyano-2-methyl-4-(1-piperidinyl)-4-(4-pyridinyl)butanoate; methyl 4-cyano-2-methyl-4-(4-pyridinyl)-4-(1-pyrrolidinyl)butanoate; ethyl 4-cyano-2-methyl-4-(4-morpholinyl)-4-(4-pyridinyl)butanoate; and, n-propyl 4-cyano-4-(4-pyridinyl)-2-methyl-4-(4-morpholinyl)butanoate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:9][C:10]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)=[CH:11][CH:12]=1)(=O)=O.[C:30]([C@:32]1([OH:40])[CH:37]2[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]2)[CH2:33]1)#[CH:31].C(N(CC)CC)C>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.CN(C)C=O>[CH2:21]([C:8]1[C:7]([C:31]#[C:30][C@:32]2([OH:40])[CH:37]3[CH2:38][CH2:39][N:34]([CH2:35][CH2:36]3)[CH2:33]2)=[CH:12][CH:11]=[C:10]([O:13][CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:9]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: O=S(=O)(Oc1ccc(OCC2CCCCO2)nc1Cc1ccccc1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O[C@]1(C#Cc2ccc(OCC3CCCCO3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 90 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A mixture of 428 mg of 2-benzyl-6-[(tetrahydro-4H-pyran-2-yl)methyloxy]-3-pyridyl trifluoromethanesulfonate, 180 mg of (3R)-3-ethynyl-3-quinuclidinol, 57.3 mg of tetrakis(triphenylphosphine)palladium(0), 1.9 mg of cuprous iodide, 415 μl of triethylamine and 5 ml of N,N-dimethylformamide was stirred at 90° C. for 3 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution, and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 305 mg of the target compound.