Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C@@H:24]1[CH2:27][CH2:26][N:25]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C@@H:24]1[CH2:27][CH2:26][N:25]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CON
Product: CC(C)(C)OC(=O)N1CC[C@H]1CONC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Yield: 82.5 %

Procedure:
Following a procedure analogous to Example 45, from the carboxylic acid (6b, 553 mg, 2.00 mmol) of Example 9 or 16 and (S)-tert-butyl 2-((aminooxy)methyl)azetidine-1-carboxylate (578 mg) described in Reference Example 21, 760.1 mg of the title compound was afforded (yield 83%).
Reaction SMILES: C([O:3][C:4]([CH:6]([N:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10](=[CH2:16])[C:9]1=[O:17])[CH3:7])=[O:5])C.[OH-].[Na+]>>[C:4]([CH:6]([N:8]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10](=[CH2:16])[C:9]1=[O:17])[CH3:7])([OH:5])=[O:3]
Reactant: C=C1CCCCCN(C(C)C(=O)OCC)C1=O
Agent: [Na+]
Agent: [OH-]
Product: C=C1CCCCCN(C(C)C(=O)O)C1=O

Procedure:
Hydrolyze 100 mg 1-(1-ethoxycarbonylethyl)-3-methyleneperhydroazocin-2-one, prepared in Example 1, with dilute sodium hydroxide. Carefully acidfy the hydrolysate to pH 2 and extract with ethyl acetate. Dry and concentrate to obtain 1-(1-carboxyethyl)-3-methyleneperhydroazocin-2-one.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]([CH3:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:19]1([CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=1)[OH:20]>CN(C=O)C>[CH3:12][N:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:4][CH2:3][CH2:2][O:20][C:19]1[CH:26]=[CH:25][C:23]([OH:24])=[CH:22][CH:21]=1
Reactant: CN(CCCBr)c1ccccc1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCCOc1ccc(O)cc1)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 24.4 %

Procedure:
A mixture of compound 9a (500 mg, 2.7 mmol), K2CO3 (740 mg, 5.4 mmol), and KI (445 mg, 2.7 mmol) in DMF (50 mL) was bubbled with argon for 10 min Hydroquinone (589 mg, 5.4 mmol) was added to the mixture under argon. The reaction mixture was heated and stirred at 80° C. for 6 hours. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 100 mLs water. The mixture was adjusted pH to ˜7 with diluted hydrochloric acid. The mixture was then extracted with CH2Cl2 and the combined organic layer was washed with water and then brine and was dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc to provide the compound 9 (170 mg, 0.66 mmol, 24% yield) as a white solid. HRMS (ESI, positive) m/z calcd. for C16H20NO2 [M+H]+: 258.14886, found: 258.14888. 1H NMR (400 MHz, Chloroform-d) δ 7.36-7.27 (m, 2H), 6.94-6.70 (m, 7H), 5.94 (broad s, 1H), 4.00 (t, J=5.9 Hz, 2H), 3.60 (t, J=7.0 Hz, 2H), 3.01 (s, 3H), 2.09 (p, J=6.2 Hz, 2H).
Reaction SMILES: C(Br)(Br)[Br:2].[CH3:5][CH:6]([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8]>O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)(Cl)Cl>[Br:2][C:6]([CH3:5])([C:11]([O:13][CH3:14])=[O:12])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(C)C(=O)OC
Reactant: BrC(Br)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)C(C)(Br)C(=O)OC
Yield: 89.4 %

Procedure:
Bromoform (1.01 g, 0.4 mol), 1.46 g dimethyl methylmalonate, 200 mg tetra-n-butylammonium fluoride trihydrate (0.632 mmol), and 5 mL carbon tetrachloride were mixed at 24° C. for 2 h. The solution was found to contain 2.01 g (89% yield) of dimethyl α-bromo-α-methylmalonate.
Reaction SMILES: F[C:2]1[C:3]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH:25]1[C@H:29]([OH:31])[CH3:30]>>[CH2:22]([S:19]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C:3]2[C:2]([N:24]3[CH2:28][CH2:27][CH2:26][C@@H:25]3[C:29](=[O:31])[CH3:30])=[CH:7][C:6]3[NH:8][C:29]([CH:25]4[CH2:26][CH2:27][CH2:28][NH:24]4)=[N:9][C:5]=3[CH:4]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20])[CH3:23]
Reactant: C[C@@H](O)C1CCCN1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc([N+](=O)[O-])c(N)cc2F)cc1
Product: CCS(=O)(=O)c1ccc(Oc2cc3nc(C4CCCN4)[nH]c3cc2N2CCC[C@@H]2C(C)=O)cc1

Procedure:
The entitled compound was obtained as a pale yellow solid in the same method as in Example 369 or in accordance with the method or by combining it with an ordinary method but using 4-(4-ethanesulfonyl-phenoxy)-5-fluoro-2-nitro-phenylamine obtained in Example 259 (step 1) and 1-(R)-pyrrolidin-2-yl-ethanol.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H][H]>C(O)C.[Ni]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CCO
Product: CN1CCN(C(=O)c2ccc(N)cc2)CC1

Procedure:
10.9 g of 4-(1-methyl-4-piperazinyl-carbonyl)-1-nitrobenzene are hydrogenated in 90 ml of ethanol with the addition of 1.1 g of Raney nickel for 35 minutes at ambient temperature under 50 psi of hydrogen atmosphere. The catalyst is removed by suction filtering, the filtrate is evaporated down, the residue is stirred with diethyl ether and dried.
Reaction SMILES: C(OC(N[C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][CH:13]=2)=O)(C)(C)C.N([O-])=O.[Na+].C(Cl)Cl.[BrH:28]>O>[Br:28][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[C:16]([O:19][CH3:20])[CH:15]=[CH:14][CH:13]=2
Reactant: Br
Reactant: COc1cccc2ncc(NC(=O)OC(C)(C)C)cc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cccc2ncc(Br)cc12
Reaction time: 1 h

Procedure:
To a solution of 3-(tert-butoxycarbonylamino)-5-methoxyquinoline (2.74 g, 10 mmol) in aqueous 48% HBr (40 mL), NaNO2 (2.1 g, 30 mmol) in water (20 mL) is added at 0° C. The reaction mixture is stirred 1 hour. The reaction mixture is extrated with CH2Cl2 (3×30 mL). After drying over MgSO4, dichloromethane is evaporated affording the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:29]=2[O:40][CH3:41])[C:24]([Cl:42])=[CH:23][N:22]=1>>[Cl:42][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:29]=2[O:40][CH3:41])=[N:26][C:21]([NH:1][C:2]2[CH:19]=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:17])[C:13]([F:16])([F:14])[F:15])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:22][CH:23]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCN(C[C@@H](O)C(F)(F)F)CC2
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCN(C[C@@H](O)C(F)(F)F)CC3)ncc1Cl

Procedure:
(R)-3-{7-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl}-1,1,1-trifluoro-propan-2-ol was prepared from (R)-3-(7-amino-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol and (2,5-dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 328. Product isolated as a white solid (85 mg, 52%). m.p.=174-175° C.; LCMS (m/e) 593 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.24 (d, 1H, J=8.7 Hz), 8.03 (s, 1H), 7.59 (s, 1H), 7.38 (s, 1H), 7.32-7.26 (m, 1H), 7.04 (d, 1H, J=8.1 Hz), 6.87 (s, 1H), 6.57 (s, 1H), 6.51 (d, 1H, J=8.7 Hz), 4.50-4.32 (m, 1H), 4.10-4.00 (m, 1H), 3.94 (s, 3H), 3.93-3.89 (m, 4H), 3.21-3.15 (m, 4H), 2.97-2.79 (m, 7H), 2.77-2.67 (m, 3H).
Reaction SMILES: C(=[N:14][C@@H:15]([CH2:19][CH:20]([CH3:23])[CH2:21][CH3:22])[C:16]([OH:18])=[O:17])(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:24].O1CC[CH2:27][CH2:26]1>>[ClH:24].[CH2:26]([O:18][C:16](=[O:17])[C@@H:15]([NH2:14])[CH2:19][CH:20]([CH3:23])[CH2:21][CH3:22])[CH3:27]
Reactant: C1CCOC1
Reactant: CCC(C)C[C@H](N=C(c1ccccc1)c1ccccc1)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@@H](N)CC(C)CC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
A solution of (S)-2-(benzhydrylidene-amino)-4-methyl-hexanoic acid (5.09 g, 15.1 mmol) in tetrahydrofuran (100 mL) was treated with a 2N aqueous hydrochloric acid solution (50 mL) and stirred at room temperature for 1.5 hr. The mixture was concentrated in vacuo and the residue partitioned between methyl t-butyl ether and water. The layers were separated and the aqueous phase was washed with methyl t-butyl ether. The organic phases were discarded and the aqueous phase neutralized with a 1N aqueous sodium hydroxide solution (150 mL) and extracted with methyl t-butyl ether. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The mixture was concentrated in vacuo and the residue was dissolved in diethyl ether (20 mL). The diethyl ether solution was treated with 3M hydrogen chloride in diethyl ether (10 mL) and the mixture concentrated in vacuo. The residue was triturated with diethyl ether and hexanes which afforded (S)-2-amino-4-methyl-hexanoic acid ethyl ester hydrochloride (2.30 g, 73%) as a white solid.
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(Cl)(Cl)(Cl)[Cl:21]>O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:21][C:3]([CH2:1][CH3:2])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOC(=O)C(CC)C(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Product: CCOC(=O)C(Cl)(CC)C(=O)OCC
Yield: 96 %

Procedure:
Diethyl ethylmalonate (1.88 g, 10 mmol), 1.38 g (10 mmol) of potassium carbonate, 0.1 g of tetra-n-butylammonium chloride hydrate, and 5 mL of carbon tetrachloride were mixed at 70° C. for 3 h. Gas chromatographic analysis of the mixture showed complete conversion of the diethyl ethylmalonate to yield 2.13 g of diethyl α-chloro-α-ethylmalonate (96% yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1.[CH3:12][NH:13][C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15]>CN1C(=O)CCC1>[CH3:12][N:13]([C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15])[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:11])=[N:9][N:10]=2)[N:7]=1
Reactant: CN[C@@H](C)c1ccccc1
Reactant: Cc1nnc2ccc(Cl)nn12
Solvent: CN1CCCC1=O
Product: Cc1nnc2ccc(N(C)[C@H](C)c3ccccc3)nn12
Temperature: 200 °C

Procedure:
6-Chloro-3-methyl-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.712 mmol; commercially available or prepared according to patent WO2006/039325A2), (S)-N-methyl-1-phenylethanamine (385 mg, 2.85 mmol) and anhydrous NMP (1 mL) were charged into a microwave tube equipped with a magnetic stirbar. After the vessel was sealed, the mixture was heated at 200° C. for 60 min using microwave irradiation. The reaction was purified by normal phase chromatography (10% CH2Cl2 in hexane then a gradient of 0% to 20% MeOH in CH2Cl2) and by reverse phase chromatography before being lyophilized to give the (S)-N,3-dimethyl-N-(1-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-amine (Compound 3) as an off-white solid (69 mg; 36% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.01 (d, J=10.1 Hz, 1H), 7.25-7.39 (m, 6H), 5.71 (q, J=6.9 Hz, 1H), 2.84 (s, 3H), 2.54 (s, 3H), 1.58 (d, J=6.9 Hz, 3H). LRMS [M+H]+: 268 m/z.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Reactant: Nc1ccccc1Cl
Product: CCOC(=O)c1cnc2ccnn2c1Nc1ccccc1Cl
Yield: 31.4 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (3.00 g, 14.5 mmol) and 2-chloroaniline (2.77 g, 21.7 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (1.44 g, 31%) was obtained.
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[C:13]([Cl:22])[CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17]([N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[O:18])=[C:13]([Cl:22])[CH:12]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: CN1CCNCC1
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1Cl
Product: CN1CCN(C(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2Cl)CC1
Yield: 92.5 %

Procedure:
The title compound was prepared from 2-(4-(adamantan-1-yl)-2-chlorophenoxy)acetic acid (0.2 g, 0.62 mmol), prepared from the step 4, and 1-methylpiperazine (0.062 g, 0.62 mmol) according to the example 1, which was given 2-(4-(adamantan-1-yl)-2-chlorophenoxy)-1-(4-methylpiperazin-1-yl)ethanone as a white solid (0.231 g, 92.0% yield).
Reaction SMILES: [C:1]1([CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:9]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OC1CCCNC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: c1ccc(C(OC2CCCNC2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
The starting material is prepared as follows. The mixture of 8.28 g of diphenylmethanol, 5.05 g of 3-hydroxypiperidine and 9.5 g of p-toluene sulfonic acid monohydrate is heated to 160°-165° while evacuating the evolving water rapidly. After the water emission ceases, the mixture is heated to said temperature for 3 hours. It is allowed to cool to room temperature and is partitioned between 2 N aqueous sodium hydroxide and diethyl ether. The organic solution is separated, washed with water and saturated aqueous sodium chloride, dried and evaporated. The residue is taken up in diethyl ether, the solution extracted with 0.1 N hydrochloric acid, the extract washed with diethyl ether and made basic with saturated aqueous ammonia. It is re-extracted with diethyl ether, the extract dried and evaporated, to yield the 3-diphenylmethoxypiperidine as an oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)[O:18][CH2:17][CH2:16][O:15]1.[C:28]([O:32][C:33]([NH:35][CH:36](O)[CH3:37])=[O:34])([CH3:31])([CH3:30])[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:28]([O:32][C:33]([NH:35][CH2:36][CH2:37][O:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:14]2([CH3:13])[O:18][CH2:17][CH2:16][O:15]2)=[CH:22][CH:23]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(O)NC(=O)OC(C)(C)C
Reactant: CC1(COc2ccc(O)cc2)OCCO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1ccc(OCC2(C)OCCO2)cc1
Reaction time: 64 h
Yield: 56 %

Procedure:
Diethyl azodicarboxylate (3.8 ml) was added dropwise to a stirred solution of 4-[(2-methyl-1,3-dioxolan-2-yl)methoxy]phenol (3.4 g), N-t-butoxycarbonylaminoethanol (5.2 g) and triphenylphosphine (6.3 g) in anhydrous tetrahydrofuran (100 ml), at ice-bath temperature, under argon. The reaction mixture was left for 64 hours at 25° C. and then the solvent was removed under reduced pressure. The residue was dissolved in ether (100 ml) and the ethereal solution washed with 2N aqueous sodium hydroxide (2×50 ml), water (2×50 ml) and saturated brine (50 ml). The aqueous washings were in turn extracted with ether (50 ml). The ethereal solutions were combined, dried, and the ether removed under reduced pressure. The residue was purified by chromatography using 11/2% tetrahydrofuran in dichloromethane as eluent. The appropriate fractions were combined and evaporated to yield 1-t-butoxycarbonylamino-2-[4-((2-methyl-1,3-dioxolan-2-yl)-methoxy)phenoxy]ethane as a light yellow solid (3.2 g) m.p. 80°-82° C. (from cyclohexane); microanalysis: found C, 61.3; H, 7.7; N, 3.8%; required for C18H27NO6 : C, 61.2; H, 7.6; N 4.0%.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][C:8](N(OC)C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH:14]([Mg]Br)=[CH2:15]>C1COCC1>[C:1]([N:5]1[CH2:15][CH2:14][C:8](=[O:9])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CON(C)C(=O)CCNC(C)(C)C
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(C)N1CCC(=O)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.5 %

Procedure:
3-(t-Butyl-amino)-N-methoxy-N-methyl-propanamide (5 g, 26.6 mmol, 1.0 equiv) was dissolved in dry THF (50 mL) under Ar. The solution was cooled to −78° C. and a 1 M solution of vinylmagnesium bromide (66.5 mL, 66.5 mmol, 2.5 equiv) was added dropwise over a 20 min period. The reaction was then stirred at −78° C. for 30 min and at 0° C. for 30 min at which time the reaction solution was transferred via a double-ended cannula into ice-cold saturated sodium bicarbonate solution under Ar. The mixture was stirred for 10 min and the crude product was extracted 2×150 mL EtOAc. The organic extracts were combined and concentrated in vacuo to a red oil. Purification was done by flash chromatography on silica using 100% CH2Cl2 through 4, 8, and 16% MeOH in CH2Cl2. The product was isolated as an orange oil (1.3 g, 32%); MS, m/z 156=M+1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].Cl[C:11]([O:13][CH2:14][CH3:15])=[O:12].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:11](=[O:12])[O:13][CH2:14][CH3:15]
Reactant: NCc1ccccc1Cl
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)NCc1ccccc1Cl
Reaction time: 0.67 h

Procedure:
2-Chlorobenzylamine (1.7734 g) was dissolved in pyridine (10 ml), and to the solution was added dropwise ethyl chloroformate (1.437 ml) during 20 minutes under ice-cooling. After the mixture was stirred for 40 minutes, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and then saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title compound (2.715 g, quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].Cl.[Cl-].[I-].[Na+].[C:16](#[N:18])[CH3:17]>>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:17][C:16]1[CH:4]=[CH:3][CH:2]=[CH:7][N:18]=1
Reactant: CC#N
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Agent: Cl
Agent: [Cl-]
Agent: [I-]
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 52 %

Procedure:
2-chloro-4-nitro phenol 10 g (57.6 mmol, 1 eq), 2-pycolyl chloride hydrogen chloride 9.45 g (57.6 mmol, 1 equiv) cesium carbonate 41.3 (126.8 mmol, 2.2 equiv) and sodium iodide 8.64 g (57.6 mmol, 1 equiv) were suspended in 200 mL acetonitrile. The reaction mixture was stirred at 60° C. for 5 h. The resulted suspension was filtered and washed with 400 mL water, yielding 2-(2-chloro-4-nitro-phenoxymethyl)-pyridine (8 g, 52%) as a red solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])[C:5]([CH3:21])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([OH:38])[CH:33]=1.[H-].[Na+]>CN1CCCC1=O>[CH3:21][C:5]1[C:6]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[N:7][C:2]([O:38][C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)=[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:4]=1
Reactant: Oc1cccnc1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Oc2cccnc2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of example 20, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with pyridin-3-ol and sodium hydride in 1-methyl-pyrrolidin-2-one at reflux to give the title compound as colorless oil. MS: 511.4 (MH+).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[C:11]([C:20]2[N:25]3[N:26]=[CH:27][N:28]=[C:24]3[N:23]=[C:22]([CH2:29][CH3:30])[CH:21]=2)=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.O>C(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][CH:29]([C:22]1[CH:21]=[C:20]([C:11]2[C:10]([Cl:9])=[CH:15][C:14]([C:16]([F:17])([F:19])[F:18])=[CH:13][N:12]=2)[N:25]2[N:26]=[CH:27][N:28]=[C:24]2[N:23]=1)[CH3:30]
Reactant: CCc1cc(-c2ncc(C(F)(F)F)cc2Cl)n2ncnc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(Br)c1cc(-c2ncc(C(F)(F)F)cc2Cl)n2ncnc2n1
Reaction time: 8 h
Yield: 62.5 %

Procedure:
4.47 g of N-bromosuccinimide and 50 mg of azobisisobutylonitrile (AIBN) were added to a solution having 5.76 g of 7-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-5-ethyl-[1,2,4]triazolo[1,5-a]pyrimidine dissolved in 30 mL of chloroform, followed by stirring overnight under reflux with heating. After completion of the reaction, water was added to the reaction liquid, followed by extraction with ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/2) to obtain 4.47 g of the desired product as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:30][N:31]1CCCC1=O>[C-]#N.[Zn+2].[C-]#N.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.O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([C:30]#[N:31])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1
Reactant: CN1CCCC1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(C#N)ccc2c(=O)n1Cc1ccccc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 2-benzyl-6-bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), zinc cyanide (50 mg), tetrakis(triphenylphosphine)palladium(0) (35 mg) and 1-methyl-2-pyrrolidone (6 ml) was stirred at 100° C. under an argon atmosphere for 2 hrs. Water was added to the reaction mixture, and the mixture was extracted with a mixture of ethyl acetate and THF. The organic layer was washed with aqueous ammonia, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized (ethyl acetate-hexane) to give the title compound (230 mg).