Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[OH:15])[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]=1[O:9][CH3:10]>CC(C)=O.[O-2].[O-2].[Mn+4]>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]([C:5]1[CH:6]=[C:7]([N+:11]([O-:13])=[O:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:15]
Reactant: COc1cc(C(O)c2ccccn2)cc([N+](=O)[O-])c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: CC(C)=O
Product: COc1cc(C(=O)c2ccccn2)cc([N+](=O)[O-])c1OC

Procedure:
7 g of manganese dioxide and added portionwise to 4.0 g of α-(3,4-dimethoxy-5-nitrophenyl)-2-pyridine-methanol dissolved in 100 ml of acetone while constantly heating under reflux over a period of 2.5 hours. Thereupon, the mixture is heated under reflux for an additional 2 hours. The manganese salts are subsequently filtered and the residue obtained after evaporation is recrystallized from ether/hexane. There is obtained 3,4-dimethoxy-5-nitrophenyl 2-pyridyl ketone of m.p. 113°.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:19][O:20][C:21]1[C:22]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[C:23]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:24]#[N:25]>ClCCl>[C:24]([C:23]1[C:22]([O:31][CH2:32][C:33]([F:34])([F:35])[F:36])=[C:21]([O:20][CH3:19])[C:28]([O:29][CH3:30])=[CH:27][C:26]=1[N+:1]([O-:4])=[O:2])#[N:25]
Reactant: COc1ccc(C#N)c(OCC(F)(F)F)c1OC
Reactant: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1cc([N+](=O)[O-])c(C#N)c(OCC(F)(F)F)c1OC
Yield: 73 %

Procedure:
Ammonium nitrate (2.82 g, 0.035 mol) and trifluoroacetic anhydride (12.4 ml, 0.088 mol) were added to a solution of 3,4-dimethoxy-2-(2,2,2,-trifluorethoxy)benzonitrile in dichloromethane. The temperature was maintained between 20° C. and 30° C. for 2 hours, after which time the reaction mixture was washed with saturated aqueous sodium bicarbonate solution. The organic layer was separated, dried (MgSO4) and evaporated under reduced pressure. Trituration with diethyl ether followed by filtration afforded a first crop of product. The filtrate was purified on silica gel, eluting with dichloromethane to afford the subtitle compound as a colourless solid (combined yield 6.56 g, 73%). Rf 0.31 (ethyl acetate:hexane 20:80, v/v). MS m/z 324 (MNH4)+.
Reaction SMILES: FC1C=CC(CN2[C@@H](C)CN(C3SC(C(OCC)=O)=C(C)N=3)C2=O)=CC=1.[F:27][C:28]1[CH:52]=[CH:51][C:31]([CH2:32][N:33]2[CH2:37][C@@H:36]([CH3:38])[N:35]([C:39]3[S:40][C:41]([C:45]([O:47]CC)=[O:46])=[C:42]([CH3:44])[N:43]=3)[C:34]2=[O:50])=[CH:30][CH:29]=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][C@@H:36]([CH3:38])[N:35]([C:39]3[S:40][C:41]([C:45]([OH:47])=[O:46])=[C:42]([CH3:44])[N:43]=3)[C:34]2=[O:50])=[CH:51][CH:52]=1
Reactant: CCOC(=O)c1sc(N2C(=O)N(Cc3ccc(F)cc3)C[C@H]2C)nc1C
Agent: CCOC(=O)c1sc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)nc1C
Product: Cc1nc(N2C(=O)N(Cc3ccc(F)cc3)C[C@H]2C)sc1C(=O)O

Procedure:
Following the procedure as described in Preparation 6, making variations as required to replace (S)-ethyl 2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate with (R)-ethyl 2-(3-(4-fluorobenzyl)-5-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid (73%): mp 184-186° C.; 1H NMR (300 MHz, DMSO-d6) δ 12.83 (s, 1H), 7.37-7.32 (m, 2H), 7.22-7.16 (m, 2H), 4.58-4.51 (m 1H), 4.46 (d, J=15.2 Hz, 1H), 4.38 (d, J=15.2 Hz, 1H), 3.61 (t, J=9.0 Hz, 1H), 3.03 (dd, J=9.0, 3.3 Hz, 1H), 2.50 (s, 3H), 1.38 (d, J=6.2 Hz, 3H); (ES+) m/z 349.7 (M+1).
Reaction SMILES: C([O-])(=O)CCCCCCCCCCCCCCCCC.[Zn+2:21].C([O-])(=O)CCCCCCCCCCCCCCCCC.[P:42](=[O:46])([OH:45])([OH:44])[OH:43].C([O:65][P:66](=[O:69])([OH:68])[OH:67])CCCCCCCCCCCCCCCCC.C(OP(=O)(O)OCCCCCCCCCCCCCCCCCC)CCCCCCCCCCCCCCCCC.[Zn].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Fe]>[P:42]([O-:46])([O-:45])([O-:44])=[O:43].[Zn+2:21].[P:66]([O-:69])([O-:68])([O-:67])=[O:65].[Zn+2:21].[Zn+2:21]
Reactant: CCCCCCCCCCCCCCCCCCOP(=O)(O)O
Reactant: O=P(O)(O)O
Agent: [Fe]
Agent: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: CCCCCCCCCCCCCCCCCCOP(=O)(O)OCCCCCCCCCCCCCCCCCC
Product: O=P([O-])([O-])[O-]
Temperature: 550 °C

Procedure:
A mixture of iron powder and zinc stearate and a mono, di or triester of phosphoric acid and long-chain alcohols, such as a mixture of phosphoric acid monostearyl ester and phosphoric acid distearyl ester having a melting point of 70° C., as antitack agent was pressed to form a molded article, the proportion of the antitack agents with respect to the weight of the iron powder being approximately 1.7% by weight, and the atomic ratio Zn:P being approximately 3:2. The molded article was heated in a nonreducing atmosphere, such as in nitrogen, to a maximum temperature of approximately 550° C., the antitack agents pyrolyzing to ZnO and P2O5, and the oxides reacting with each other to form zinc phosphate. As was determined, zinc phosphate has a high specific electrical resistance, adheres well to metals and protects especially iron from corrosion. The composite material obtained is suitable as a soft magnetic material for fast-acting electric valves.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[NH:6][C:7](=[O:17])[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)[CH3:4].[Li+].[Br-].[CH2:20]([O:22][CH:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38]Br)=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]>CN(C=O)C.O>[CH2:20]([O:22][CH:23]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:37][CH2:38][N:6]2[C:7](=[O:17])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH2:3][CH3:4])=[CH:34][CH:35]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]
Reactant: CCc1nc(-c2ccccc2)cc(=O)[nH]1
Reactant: CCOC(=O)C(Cc1ccc(OCCBr)cc1)OCC
Agent: [Br-]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCCn2c(CC)nc(-c3ccccc3)cc2=O)cc1)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20393.1 %

Procedure:
To a stirred suspension of NaH (300 mg, 0.0123 mmol, 60%) in dry DMF (20 mL) at 0° C. was added a solution of (±) 2-ethyl-4-phenyl-1,6-dihydropyrimidin-6-one (1.9 g, 0.0095 mmol) in dry DMF (5 mL). The solution was allowed to stir at room temperature for 20 min. after the effervescence cease. LiBr (1.0 g, 0.012 mmol) was added followed by ethyl 2-ethoxy-3-[4-(2-bromoethoxy)phenyl]propanoate (3.2 g, 0.0095 mmol) (disclosed in U.S. patent application Ser. No. 09/012,585), in dry DMF at room temperature. The reaction mixture was immersed in a preheated oil bath at 80° C. and stirred for 18 h and cooled to room temperature, poured into water and extracted with ethyl acetate (3×10 mL). The combined ethyl acetate layers were washed with brine, dried (Na2SO4) and concentrated. The crude compound was chromatographed over silica gel using ethyl acetate:per. ether (3:7) to yield the title compound as a liquid (900 mg, 21%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:17](O)=[O:18])[N:3]=1.C1COCC1.C(N1C=CN=C1)([N:32]1C=CN=C1)=O.N>CO.O.CN(C=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:5]=[C:4]([NH:13][C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[C:17]([NH2:32])=[O:18])[N:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(C(=O)O)cc1Nc1nc(N)n(-c2ccccn2)n1
Agent: N
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(N)=O)cc1Nc1nc(N)n(-c2ccccn2)n1
Reaction time: 1 h
Yield: 43 %

Procedure:
A suspension of 3-(5-Amino-1-pyridin-2-yl-1H-[1,2,4]triazol-3-ylamino)-4-methoxy-benzoic acid (108 mg, 0.8 mmol) in a mixed solvent of THF (50 mL) and DMF (15 mL) was treated with 1,1′-carbonyldiimidazole (194 mg, 1.2 mmol) at room temperature. After 1 h, ammonia in MeOH (7.0M, 1 mL) was added. The reaction mixture was stirred at 50 C for 16 h, poured into water. Precipitate was collected by filtration and further purified by HPLC to give 3-(5-Amino-1-pyridin-2-yl-1H-[1,2,4]triazol-3-ylamino)-4-methoxy-benzamide (112 mg). FIA-MS: m/e=326.1 (M+1). Rt=2.65 min (Method A). 1H-NMR (500 MHz, DMSO(d6): 8.65 (d, 1H), 8.43 (dd, 1H), 8.02 (td, 1H), 7.98 (m, 1H), 7.83 (m, 1H), 7.73 (d, 1H), 7.70 (m, 1H), 7.47 (dd, 1H), 7.27 (ff, 1H), 7.14 (m, 1H), 7.04 (d, 1H), 3.90 (s, 1H).
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[CH2:11][CH:10]=[CH:9][CH2:8][C@@H:7]1[CH2:12][O:13]C(=O)C)(=[O:3])[CH3:2].P([O-])([O-])([O-])=O.[OH-].[Na+].[OH-]>>[C:1]([O:4][CH2:5][C@@H:6]1[CH2:11][CH:10]=[CH:9][CH2:8][C@@H:7]1[CH2:12][OH:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1CC=CC[C@H]1COC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)OC[C@@H]1CC=CC[C@@H]1CO

Procedure:
A suspension of cis-1,2-diacetoxymethylcyclohex-4-ene (10 mmol), pH 7 phosphate buffer (25 mL) porcine pancreatic lipase (200 mg, Sigma Type II) was vigorously stirred. The reaction was kept constant by addition of 1M sodium hydroxide from a pH controller and syringe pump. After 16 hours addition of 1 eq hydroxide was complete and the mixture was filtered through a pad of Celite. The Celite was washed with ether and the filtrates were washed with ether (×3). The combined ether washes were washed with brine, dried and concentrated to yield the desired compound as a slightly yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][N:20]2[C@@H:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][O:22][C:21]2=[O:31])[CH:6]=1.[OH-].[Li+].Cl>C1COCC1>[Br:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:32])=[O:2])[CH:10]=[CH:9][CH:8]=2)=[C:13]([CH2:19][N:20]2[C@@H:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:23][O:22][C:21]2=[O:31])[CH:14]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)OC[C@@H]2c2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cccc(Oc2ccc(Br)cc2CN2C(=O)OC[C@@H]2c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
To {3-[4-bromo-2-((S)-2-oxo-4-phenyl-oxazolidin-3-ylmethyl)-phenoxy]-phenyl}-acetic acid methyl ester (0.043 g, 0.09 mmol) in THF (2 mL) was added 1N aqueous lithium hydroxide (2 mL), and the reaction was stirred at room temperature for 3 hours, until no starting material was seen by analytical LCMS. The mixture was acidified with 1N aqueous HCl and extracted three times with EtOAc, and the combined organic layers were dried and concentrated. The residue was purified by silica gel chromatography to give the desired product (0.027 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:19]#[N:20])=[CH:11][C:12]([N+:16]([O-])=O)=[C:13]([CH3:15])[CH:14]=2)=[CH:5][CH:4]=1.[CH3:21]N(C(N(C)C)N(C)C)C.Cl>C1(C)C=CC=CC=1.O.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]3[C:12](=[CH:11][C:10]=2[C:19]#[N:20])[NH:16][CH:21]=[CH:15]3)=[CH:5][CH:4]=1
Reactant: CN(C)C(N(C)C)N(C)C
Reactant: COc1ccc(-c2cc(C)c([N+](=O)[O-])cc2C#N)cc1
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc3cc[nH]c3cc2C#N)cc1
Yield: 32 %

Procedure:
A mixture of 4′-methoxy-5-methyl-4-nitro-biphenyl-2-carbonitrile (118.0 mg, 0.44 mmol) and tris(dimethylamino) methane (128.0 mg, 0.88 mmol) in toluene (15 mL) was heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in EtOH (1 mL) and water (0.10 mL), and treated with iron powder (64.0 mg, 1.15 mmol), followed by concentrated HCl (28.0 mg, 0.29 mmol). The reaction mixture was heated to reflux for an additional 16 hours, and quenched with 1 N aqueous NaOH (0.288 mL). The solution was filtered through celite and rinsed with EtOH (10 mL). The filtrate was concentrated in vacuo to give the title compound (35 mg, 49% yield). MS (ES−) 247.1 (M−1)−. 1H NMR (400 MHz, DMSO-d6) δ 7.95 (s, 1 H), 7.68 (d, J=2.73 Hz, 1 H), 7.66 (s, 1 H), 7.48 (d, J=8.59 Hz, 2 H), 7.05 (d, J=8.59 Hz, 2 H), 6.58 (d, J=2.73 Hz, 1 H), 3.82 (s, 3 H).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:33])[N:6]2[CH2:28][C:29]([F:32])([F:31])[F:30].[CH3:34]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.IC>CN(C)C=O>[NH2:1][C:2]1[N:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:8]=[C:7]2[C:3]=1[N:4]([CH3:34])[C:5](=[O:33])[N:6]2[CH2:28][C:29]([F:32])([F:31])[F:30]
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2c1[nH]c(=O)n2CC(F)(F)F
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CC(F)(F)F)c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 36.3 %

Procedure:
80 mg (0.175 mmol) of the compound from example 36 and 48 mg (0.175 mmol) of BEMP were initially charged in 10 ml of dimethylformamide, and a solution of 25 mg (0.175 mmol) of iodomethane in 2 ml of dimethylformamide was added dropwise at 0° C. within 10 min. The mixture was stirred at 0° C. for 20 min. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: methanol/water, gradient 30:70→90:10). 30 mg of the title compound were obtained (35% of theory).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:13]2=[O:24])=[CH:2]1.C(N(CC)CC)C.[C:32](Cl)(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCCC1>[C:32]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[C:13](=[O:24])[CH:14]1[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOC(=O)CC1NCCN(CCc2c[nH]c3ccccc23)C1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1C(=O)N(CCc2c[nH]c3ccccc23)CCN1C(=O)c1ccccc1
Temperature: 25 °C

Procedure:
22.4 g of the product of Step C were dissolved in 225 ml of tetrahydrofuran and 14.3 ml of triethylamine and the mixture was cooled to 5° C. 7.9 ml of benzoyl chloride were slowly added and then stirring was maintained for 1 hour at ambient temperature. The insoluble part was separated and the filtrate was evaporated to dryness to obtain 28.4 g of the expected product melting at 144° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH:34]([CH3:36])[CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][C:38]1=[O:43]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30]([N:40]3[CH2:41][CH2:42][NH:37][C:38](=[O:43])[CH2:39]3)=[O:31])[C@H:13]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH:34]([CH3:35])[CH3:36])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CNCCN1
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
4-[(4S,5R)-2-(4-tert-Butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-2-one was prepared from (4S,5R)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12i) and 2-piperazinone (Avocado Organics) in an analogous manner as described in example 25. LR-MS: 607.4 [(M+H)+]
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:17]=1[CH:18]=O.Cl.Cl.[CH:28]([C@H:41]1[N:46]2[CH2:47][CH2:48][CH2:49][C@H:45]2[CH2:44][NH:43][CH2:42]1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C)C=O>[CH:28]([C@H:41]1[N:46]2[CH2:47][CH2:48][CH2:49][C@H:45]2[CH2:44][N:43]([CH2:18][C:17]2[C:20]([O:24][CH3:25])=[CH:21][CH:22]=[CH:23][C:16]=2[Cl:15])[CH2:42]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2CNC[C@@H]3CCCN32)cc1
Reactant: COc1cccc(Cl)c1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Cl)c1CN1C[C@@H]2CCCN2[C@H](C(c2ccccc2)c2ccccc2)C1
Yield: 49.1 %

Procedure:
A 1M solution of sodium triacetoxyborohydride in N,N-dimethylformamide (75 μl) was added portionwise to a mixture of 2-chloro-6-methoxybenzaldehyde (9.4 mg) and a solution of (4R,8aS)-4-benzhydryloctahydropyrrolo[1,2-a]pyrazine dihydrochloride (18.3 mg) in N,N-dimethylformamide (50 μl) at 25° C. and the whole was stirred at room temperature for 2 hours. The mixture was purified by high pressure liquid chromatography eluting with aqueous 0.1% trifluoroacetic acid solution-acetonitrile (90:10→10:90). The solution was concentrated in vacuo. To the residue was added ethyl acetate and aqueous 5% potassium carbonate solution. The mixture was applied on liquid/liquid extraction cartridge (CE1000M, VARIAN) and eluted with ethyl acetate. The eluate was concentrated in vacuo to give (4R,8aS)-4-benzhydryl-2-(2-chloro-6-methoxybenzyl)octahydropyrrolo[1,2-a]pyrazine (11.0 mg)
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:5]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>ClCCl.C(#N)C>[NH2:1][C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:31]([NH:30][C:27]3[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)=[O:32])[CH2:18][CH2:17]2)[C:5]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)c1csc2nc(N)nc(N3CCNCC3)c12
Reactant: COc1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1csc2nc(N)nc(N3CCN(C(=O)Nc4ccc(OC)cc4)CC3)c12
Reaction time: 8 h
Yield: 58.1 %

Procedure:
To a solution of Example 20 (70 mg, 0.23 mmol) in dichloromethane (2 mL) and acetonitrile (2 mL) was added 4-methoxyphenyl isocyanate (31 μL, 0.24 mmol). The reaction mixture was stirred overnight. The solvents were evaporated in vacuo and the crude residue was purified by flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually increasing from 1% to 3% methanol in dichloromethane), yielding the title compound (61 mg) as a white powder. 13C NMR δ (75 MHz, CD3OD) 171.65, 162.60, 160.54, 159.64, 155.32, 154.73, 133.60, 127.71, 124.13, 121.41 (2C), 113.30 (2C), 106.19, 60.79, 54.73, 47.93 (2C), 43.38 (2C), 13.73. MS (m/z) 457 [M+H]+.
Reaction SMILES: ClC1C=CC(OC2C=CC(NC)=CN=2)=C(C)C=1.ClC1C=CC=CC=1C(Cl)=O.[Cl:28][C:29]1[CH:53]=[CH:52][CH:51]=[C:50](Cl)[C:30]=1[C:31]([N:33]([C:35]1[CH:36]=[N:37][C:38]([O:41][C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=2[CH3:49])=[CH:39][CH:40]=1)[CH3:34])=[O:32]>>[Cl:28][C:29]1[CH:53]=[CH:52][CH:51]=[CH:50][C:30]=1[C:31]([N:33]([C:35]1[CH:36]=[N:37][C:38]([O:41][C:42]2[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:43]=2[CH3:49])=[CH:39][CH:40]=1)[CH3:34])=[O:32]
Reactant: Cc1cc(Cl)ccc1Oc1ccc(N(C)C(=O)c2c(Cl)cccc2Cl)cn1
Agent: CNc1ccc(Oc2ccc(Cl)cc2C)nc1
Agent: O=C(Cl)c1ccccc1Cl
Product: Cc1cc(Cl)ccc1Oc1ccc(N(C)C(=O)c2ccccc2Cl)cn1

Procedure:
2-Chloro-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide was prepared from 2-(4-Chloro-2-methyl-phenoxy)-5-(N-methylamino)pyridine and 2-chlorobenzoyl chloride in the same manner as 2,6-Dichloro-N-(6-(4-chloro-2-methyl-phenoxy)-pyridin-3-yl)-N-methyl-benzamide was prepared.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][O:8][C:9]([NH:11][C@@H:12]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:27][C@H:26]([CH2:28][N:29]5[CH:33]=[CH:32][N:31]=[N:30]5)[O:25][C:24]4=[O:34])=[CH:19][C:18]=3[F:35])[CH2:13]2)=[O:10])[CH2:4][O:3]1.Cl.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][O:8][C:9]([NH:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][C@H:26]([CH2:28][N:29]4[CH:33]=[CH:32][N:31]=[N:30]4)[O:25][C:24]3=[O:34])=[CH:19][C:18]=2[F:35])[CH2:13]1)=[O:10]
Reactant: CC1(C)OC[C@@H](COC(=O)N[C@@H]2CCN(c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)C2)O1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1)OC[C@@H](O)CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.9 %

Procedure:
(5R)-3-(4-((3R)-3-((4S)-2,2-Dimethyl-1,3-dioxolan-4-ylmethoxycarbonylamino)pyrrolidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (240 mg, 0.48 mM) in tetrahydrofuran (5 ml) was treated with hydrochloric acid (2M, 2 ml) and stirred at ambient temperature for 18 hours. Solid potassium carbonate was added to neutralise, and the mixture filtered, and the filtrate evaporated to dryness. The residue was purified by chromatography on a 10 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 10% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (170 mg).
Reaction SMILES: O.[OH-].[Li+].C([O:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([C:24]#[N:25])[CH:15]=2)[N:12]=[N:11][N:10]=1)(=O)C>C(O)C.O.CCOC(C)=O>[OH:7][CH2:8][C:9]1[N:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([CH:15]=2)[C:24]#[N:25])[N:12]=[N:11][N:10]=1
Reactant: CC(=O)OCc1nnnn1-c1ccc(C(F)(F)F)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: N#Cc1cc(-n2nnnc2CO)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 27.7 %

Procedure:
Lithium hydroxide monohydrate (1.35 g, 32.2 mmol) was added to a solution of {1-[3-cyano-4-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl acetate (Intermediate 39, 5.0 g, 16.1 mmol) in a mixture of ethanol and water (2:1) at 0° C. The reaction mixture was stirred for 6 h at room temperature. The reaction mixture was diluted with EtOAc and washed with ice-water. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude compound. This was purified by column chromatography (100-200 mesh silica gel), eluting with 20%-60% EtOAc/pet.ether to give the title compound (1.2 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].I[CH2:26][CH3:27]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([CH2:26][CH3:27])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1CN(Cc2ccccc2)CCC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 11.7 %

Procedure:
To a −78° C. solution of 1-benzyl-piperidin-4-one (3.79 g, 20 mmol) in anhydrous THF (20 mL) was added lithium hexamethyldisilazide (21 mL, 21 mmol of a 1.0 M solution in THF). After being stirred at −78° C. for 30 min, a solution of iodoethane (1.7 mL, 21 mmol) in THF (5 mL) was added to the reaction mixture. The resultant solution was stirred at 25° C. for 2 h and quenched with water. The aqueous layer was extracted with CH2Cl2. The organic extracts were combined, washed with brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give the crude product. The crude material was purified by flash column chromatography (hexane/EtOAc) to provide 0.51 g (11.5% yield) of 1-benzyl-3-ethyl-piperidin-4-one, which was converted into 1-benzyl-3-ethyl-piperidin-4-ylamine (3) using the same procedure as in Scheme 1-1. ((±)-cis:(±)-trans=1:1) LCMS m/z: 219 (M+H)+. This material was used without further purification.