Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cl-].[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][Zn+]>C1COCC1.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>[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: Fc1cccc(C[Zn+])c1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(Cc2cccc(F)c2)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 84.5 %

Procedure:
Methyl 2-chloroisonicotinate (5.6 g, 32.64 mmol) and Pd(PPh3)4 (0.754 g, 0.65 mmol) were dissolved in THF (100 mL) under nitrogen and (3-fluorobenzyl)zinc(II) chloride (0.5 M in THF) (100 mL, 50.00 mmol) was added. The brown solution was stirred at 60° C. for 4 h. The reaction was quenched by addition of methanol (50 mL), diluted with EtOAc and washed with NH4Cl. The organic layer was dried over Na2SO4, filtered and evaporated to yield a yellow oil. The compound was purified in 2 runs via Biotage, SNAP 340 g KP-SIL, eluent isocratic heptane/ethyl acetate 8:2 for 2 CV, then linear gradient heptane/ethyl acetate 8:2 to 5:5 over 5 CV to yield methyl 2-(3-fluorobenzyl)isonicotinate (6.766 g, 85%) as a yellow oil. 1H NMR (400 MHz, cdcl3) δ 3.93 (s, 3H), 4.21 (s, 2H), 6.88-7.00 (m, 2H), 7.02-7.07 (m, 1H), 7.22-7.30 (m, 1H), 7.66-7.73 (m, 2H), 8.68-8.73 (m, 1H). MS m/z 246 (M+H)+
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.C(Cl)(=O)C(Cl)=O.[CH3:17][CH:18]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[NH:21]1)[CH3:19].[Li]CCCC.[NH4+].[Cl-]>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH3:17][CH:18]([C@H:20]1[CH2:24][O:23][C:22](=[O:25])[N:21]1[C:6](=[O:8])[CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:10])[F:9])[CH3:19]
Reactant: O=C(O)CCCC(F)(F)F
Reactant: CC(C)[C@H]1COC(=O)N1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)[C@H]1COC(=O)N1C(=O)CCCC(F)(F)F
Temperature: 0 °C

Procedure:
To a stirred solution of 5,5,5-trifluoropentanoic acid (5.04 g, 32.3 mmol) in DCM (50 mL) and DMF (3 drops) was added oxalyl chloride (3.4 mL, 38.8 mmol) dropwise over 5 min. The solution was stirred until all bubbling subsided. The reaction mixture was concentrated under reduced pressure to give a pale yellow oil. To a separate flask charged with a solution of (4S)-4-(propan-2-yl)-1,3-oxazolidin-2-one (4.18 g, 32.4 mmol) in THF (100 mL) at −78° C. was added n-BuLi (13.0 mL, 32.5 mmol, 2.5M in hexane) dropwise via syringe over 5 min. After stirring for 10 min, the above acid chloride dissolved in THF (20 mL) was added via cannula over 15 min. The reaction mixture was warmed to 0° C., and was allowed to warm to room temperature as the bath warmed and stirred overnight. To the reaction mixture was added saturated NH4Cl, and then extracted with EtOAc (2×). The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (hexanes/EtOAc) to provide Preparation 1B (7.39 g, 86%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 4.44 (1H, dt, J=8.31, 3.53 Hz), 4.30 (1H, t, J=8.69 Hz), 4.23 (1H, dd, J=9.06, 3.02 Hz), 2.98-3.08 (2H, m), 2.32-2.44 (1H, m, J=13.91, 7.02, 7.02, 4.03 Hz), 2.13-2.25 (2H, m), 1.88-2.00 (2H, m), 0.93 (3H, d, J=7.05 Hz), 0.88 (3H, d, J=6.80 Hz).
Reaction SMILES: ClCCl.[OH:4][C:5]1[C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:9][C:8]([CH3:25])=[CH:7][N:6]=1.N1C(C)=CC=CC=1C.Br[C:35]([CH3:40])([CH3:39])[C:36](Br)=[O:37]>CN(C)C=O>[CH3:39][C:35]1([CH3:40])[O:4][C:5]2[N:6]=[CH:7][C:8]([CH3:25])=[CH:9][C:10]=2[N:11]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH2:13]2)[C:36]1=[O:37]
Reactant: Cc1cnc(O)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: CC(C)(Br)C(=O)Br
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: Cc1cnc2c(c1)N(C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
At room temperature, to a dichloromethane solution (15 ml) of tert-butyl 4-[(2-hydroxy-5-methylpyridin-3-yl)amino]piperidine-1-carboxylate (3.08 g) were added 2,6-lutidine (2.25 ml) and 2-bromoisobutyryl bromide (1.74 ml). After stirring at room temperature for 18 hours, N,N-dimethylformamide (15 ml) was added, and stirred at 70° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to afford tert-butyl 4-(3,3,7-trimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)piperidine-1-carboxylate (1.04 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[CH2:15][NH:16][S:34]([CH3:33])(=[O:36])=[O:35])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(CN)c2ccccc2F)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(CNS(C)(=O)=O)c2ccccc2F)CC1
Reaction time: 0.17 h
Yield: 97.8 %

Procedure:
To a solution of 4-[2-Amino-1-(2fluoro-phenyl)-ethyl]-piperazine-1-carboxylic acid tert-butyl ester (207) (0.71 g, 2.19 mmol) in THF (5 mL) at 0° C. was added diisopropylethylamine (0.42 mL, 2.42 mmol). The solution was allowed to stir for 10 min. Methansulfonyl chloride (0.17 mL, 2.19 mmol) was then added and the solution was allowed to stir at room temperature for 18 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with brine (50 mL) and H2O (50 mL). The organic phase was concentrated to dryness yielding 0.86 g (98%) product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([C:11](=[O:22])[CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[C:5]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[CH:4]=1.[OH-].[K+].Cl>CO>[C:25]([CH2:24][O:23][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[C:6]=1[C:11](=[O:22])[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)([OH:27])=[O:26]
Reactant: COC(=O)COc1cc(OC)cc(OC)c1C(=O)CCc1ccc(OC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CCC(=O)c2c(OC)cc(OC)cc2OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
Then, 6.05 g of 1-(4,6-dimethoxy-2-methoxycarbonylmethoxyphenyl)-3-(4-methoxyphenyl)-1-propanone was dissolved in 50 ml of methanol, and 30 ml of a 5% aqueous solution of potassium hydroxide was added to the solution and the mixture was stirred at room temperature for 30 minutes to effect reaction. After the reaction, the reaction mixture was made acidic by addition of dilute hydrochloric acid, extracted with diethyl ether and filtered, and the solvent was removed from the filtrate by distillation and the obtained residue was recrystallized from a mixed solvent of diethyl ether and n-hexane to obtain 5.0 g (yield=87.4%) of 1-(2-carboxymethoxy-4,6-dimethoxyphenyl)-3-(4-methoxyphenyl)-1-propanone in the form of a colorless prism.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:28][CH3:29])([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([CH2:25][CH3:26])([OH:24])[CH2:22][CH3:23])=[C:15]([CH3:27])[CH:14]=2)[CH2:11][CH3:12])=[CH:6][C:5]=1[CH3:30].[OH-].[Li+]>>[CH2:11]([C:10]([C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:31])=[O:2])=[C:5]([CH3:30])[CH:6]=1)([C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([CH2:22][CH3:23])([OH:24])[CH2:25][CH3:26])=[C:15]([CH3:27])[CH:14]=1)[CH2:28][CH3:29])[CH3:12]
Reactant: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)OC)c(C)c2)cc1C)CC
Agent: [Li+]
Agent: [OH-]
Product: CCC(O)(C#Cc1ccc(C(CC)(CC)c2ccc(C(=O)O)c(C)c2)cc1C)CC
Yield: 83.2 %

Procedure:
4-{1-Ethyl-1-[4-(3-ethyl-3-hydroxy-pent-1-ynyl)-3-methyl-phenyl]-propyl}-2-methyl-benzoic acid methyl ester (2.20 g, 5.23 mmol) and lithium hydroxide (376 mg, 15.69 mmol) are reacted and purified analogous to Example 1I to give the title compound (1.77 g, 83%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:19](O)=[O:20])=[CH:17][C:18]=3[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[NH2:50][CH:51]1[CH2:56][CH2:55][N:54]([CH2:57][C:58]2[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][CH:59]=2)[CH2:53][CH2:52]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:1]([N:8]1[CH2:23][CH2:22][C:11]2[NH:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]([NH:50][CH:51]4[CH2:56][CH2:55][N:54]([CH2:57][C:58]5[CH:63]=[CH:62][C:61]([C:64]#[N:65])=[CH:60][CH:59]=5)[CH2:53][CH2:52]4)=[O:20])=[CH:17][C:18]=3[C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc2[nH]c3c(c2c1)CN(Cc1ccccc1)CC3
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CN2CCC(NC(=O)c3ccc4[nH]c5c(c4c3)CN(Cc3ccccc3)CC5)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a solution of 2-benzyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-8-carboxylic acid (50 mg, 0.2 mmol) in DMF (2 mL), HATU (O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) (75 mg, 0.2 mmol), 4-amino-1-(4-cyanobenzyl)piperidine dihydrochloride (47 mg, 0.2 mmol) and triethylamine (105 μL, 76 mg, 0.8 mmol) were added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into saturated sodium bicarbonate solution (30 mL) to give a white precipitate which was filtered and dried under vacuuo. The resulting solid was triturated with ethyl ether to yield Compound 4 as a white crystalline solid (80 mg, 97%). 1H NMR (DMSO-d6): δ 11.00 (1H, br s); 8.00 (1H, d, J=7.7 Hz); 7.82 (1H, s); 7.78 (2H, d, J=8.3 Hz); 7.53 (1H, d, J=11.8 Hz); 7.50 (2H, d, J=7.7 Hz); 7.39 (2H, d, J=6.6 Hz); 7.36 (2H, d, J=8.3 Hz); 7.32-7.23 (2H, m); 3.76 (3H, br s); 3.58 (4H, d, J=10.5 Hz); 2.89-2.73 (6H, m); 2.06 (2H, t, J=11.0 Hz); 1.76 (2H, d, J=9.9 Hz); 1.58 (2H, q, J=10.7 Hz). MS (M+H)+=504.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:17])[CH:9]([NH2:16])[CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.Cl.[CH2:19]([O:21][C:22]1[CH:32]=[C:31]([O:33][CH2:34][CH3:35])[CH:30]=[CH:29][C:23]=1[C:24](=N)OCC)[CH3:20].ClC1C=CC(C2NC(C3C=CC(OC)=CC=3OCC)=NC2CC2CCCC2)=CC=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:17][C:24]([C:23]3[CH:29]=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[CH:32][C:22]=3[O:21][CH2:19][CH3:20])=[N:16][CH:9]2[CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: CCOC(=N)c1ccc(OCC)cc1OCC
Reactant: NC(CC1CCCC1)C(N)c1ccc(Cl)cc1
Agent: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1
Agent: Cl
Product: CCOc1ccc(C2=NC(CC3CCCC3)C(c3ccc(Cl)cc3)N2)c(OCC)c1

Procedure:
5-(4-Chloro-phenyl)-4-cyclopentylmethyl-2-(2,4-diethoxy-phenyl)-4,5-dihydro-1H-imidazole was prepared from 1-(4-chloro-phenyl)-3-cyclopentyl-propane-1,2-diamine and ethyl 2,4-diethoxy-benzimidate hydrochloride in an analogous manner as described for the preparation of 5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-1H-imidazole (Example 9). HR-MS (ES, m/z) observed 427.2152, calculated for C25H32N2O2Cl [(M+H)+]427.2147.
Reaction SMILES: [OH:1][CH:2]1[CH:6]2[O:7][C:8](=[O:18])[CH:9]3[CH:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]1[CH2:4][CH:5]23.[Cl:19][CH2:20][C:21](Cl)=[O:22].N1C=CC=CC=1.O>O1CCCC1>[Cl:19][CH2:20][C:21]([O:1][CH:2]1[CH:6]2[O:7][C:8](=[O:18])[CH:9]3[CH:10]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH:3]1[CH2:4][CH:5]23)=[O:22]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2O
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)CCl
Yield: 94.3 %

Procedure:
In 1,000 ml of tetrahydrofuran were dissolved 163 g of tert-butyl 6-hydroxy-2-oxohexahydro-3,5-methano-2H-cyclopenta[b]furan-7-carboxylate and 86.9 g of 2-chloroacetic chloride. To this solution below 15° C., 58.3 g of pyridine was added dropwise. The reaction solution was stirred at room temperature for 2 hours, whereupon 250 ml of deionized water was added, followed by ordinary workup. Recrystallization from hexane yielded 200 g of the title compound. Yield 94%.
Reaction SMILES: N1CCC[C@H]1C(O)=O.[N:9]1[C:18]2[C:13](=[CH:14][C:15]([CH:19]([CH3:23])[CH2:20][CH:21]=[O:22])=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1.[Cl:24]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Cl:24][CH:20]([CH:19]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:9]=[CH:10][CH:11]=[CH:12]2)[CH3:23])[CH:21]=[O:22]
Reactant: CC(CC=O)c1ccc2ncccc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClC(Cl)Cl
Product: CC(c1ccc2ncccc2c1)C(Cl)C=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
L-Proline (5.8 mg, 0.050 mmol) was added to a solution of 3-quinolin-6-ylbutanal (50 mg, 0.25 mmol) in chloroform (0.5 mL) at 0° C. followed by addition of N-chlorosuccinimide (36.9 mg, 0.276 mmol). The mixture was stirred at RT for 2 h, diluted with hexanes and filtered. The filtrate was concentrated and purified by chromatography on silica gel with EtOAc in methylene chloride (0-10%) to afford the desired product (0.048 g, 82%). LCMS: (M+H)=234.1/236.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:20][CH2:17][CH2:18][CH3:19])(=[O:10])=[O:9])=[C:4]([O:12][C:13]([F:16])([F:15])[F:14])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CCCN
Solvent: ClCCl
Product: CCCNS(=O)(=O)c1ccc(Br)cc1OC(F)(F)F
Yield: 99.2 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethoxy-benzenesulfonyl chloride (0.35 g, 1.03 mmol) and propylamine (0.21 mL, 2.57 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-propyl-2-(trifluoromethoxy)benzenesulfonamide (0.37 g, 91%) was provided after purification. MS (ESI) m/z 362. HPLC purity 100.0% at 210-370 nm, 9.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[NH:11]1[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12]1>>[NH2:8][C:5]1[CH:4]=[N:3][C:2]([N:11]2[CH2:15][CH2:14][CH:13]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH2:12]2)=[N:7][CH:6]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ncc(N)cn2)C1
Yield: 65.2 %

Procedure:
Following General procedure H, 2-chloro-5-nitropyrimidine (500 mg, 3.1 mmol) was reacted with tert-butyl pyrrolidin-3-ylcarbamate (632 mg, 3.5 mmol) followed by reduction to afford the desired product (565 mg, 65%) as a purple solid: ESI MS m/z 280 [C13H21N5O2+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:10][C:9]2=O.[CH2:32]([NH:34][CH3:35])[CH3:33]>>[CH3:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:2]([CH3:1])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:10]=[C:9]2[N:34]([CH2:32][CH3:33])[CH3:35]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: CCNC
Product: CCN(C)c1nc(-n2cc(C(=O)O)cn2)nc2ccc(NCc3c(C)cccc3C)cc12

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and N-ethyl-N-methylamine in step E. MS (ESI/CI): predicted mass C24H26N6O2, 430.2.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:18][CH2:17]1)=[O:15]>C(OCC)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][CH:19]2[CH2:18][CH2:17][N:16]([C:14](=[O:15])[CH2:13][NH:1][C:2]3[CH:11]=[CH:10][C:5]4[NH:6][C:7](=[O:9])[O:8][C:4]=4[CH:3]=3)[CH2:21][CH2:20]2)=[CH:28][CH:27]=1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Reactant: O=C(CCl)N1CCC(Oc2ccc(Cl)cc2)CC1
Solvent: CCOCC
Product: O=C(CNc1ccc2[nH]c(=O)oc2c1)N1CCC(Oc2ccc(Cl)cc2)CC1

Procedure:
The title compound is prepared from 6-amino-3H-benzoxazol-2-one and 2-chloro-1-[4-(4-chloro-phenoxy)-piperidin-1-yl]-ethanone according to the method described in Example 206. Melting Point: 180-183° C. (diethylether)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[C:5]2=[CH:4][N:3]=1.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][CH2:23][NH2:24]>>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:5]2[C:6](=[N:7][C:2]([NH:24][CH2:23][CH2:22][CH2:21][N:20]([CH3:25])[CH3:19])=[N:3][CH:4]=2)[NH:8][N:9]=1
Reactant: CN(C)CCCN
Reactant: COc1ccccc1-c1n[nH]c2nc(Cl)ncc12
Product: COc1ccccc1-c1n[nH]c2nc(NCCCN(C)C)ncc12
Yield: 12 %

Procedure:
The compound was prepared from 6-chloro-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-d]pyrimidine (Example 6) and 3-dimethylamino propylamine (Aldrich) in an analogous manner as described in Example 32 (120° C.) and 9.2 mg (12% yield) free base was obtained. Purification of the mother liquor with HPLC gave a TFA salt (50 mg, 49% yield) MS (M+H)+, 327.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6]/[CH:7]=[CH:8]\[CH2:9]N1[C@@H](COC(=O)NCCCCC)CCC1=O>[Pd].CO>[CH3:1][O:2][C:3](=[O:26])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCNC(=O)OC[C@H]1CCC(=O)N1C/C=C\CCCC(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCCCCCC(=O)OC
Reaction time: 5 h
Yield: 256 %

Procedure:
Palladium on carbon (10 mol %, 5 mg) was added to a solution of alkene 27 (24 mg, 0.065 mmol) in MeOH (2.0 mL). The flask was evacuated and refilled with hydrogen (3×), and the reaction mixture was stirred vigorously under a balloon of hydrogen for 5 h. The mixture was then filtered through celite, washing with MeOH (5 mL) and the filtrate was concentrated in vacuo to afford 24 mg (99%) of the title compound (29).
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:20]=[C:21]([NH:25]C(=O)C)[CH:22]=[CH:23][CH:24]=4)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[OH-].[Na+]>Cl>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=4)[NH2:25])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1cccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c1
Temperature: 100 °C

Procedure:
A stirred mixture of N-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)1- piperidiny]propoxyl]phenyl]acetamide (9.2 g, 22 mmol), prepared as described in the previous example, in 15% hydrochloric acid (110 ml) was heated at 100° C. for 2.5 hours until a homogeneous solution resulted. The reaction was cooled to 0° C. in an ice bath and basified with 50% NaOH. The product was extracted with ethyl acetate (3×200 ml). The ethyl acetate solution was washed with water, brine, then dried over Na2SO4. The solvent was removed. The crude product was purified on a flash chromatography column. The product thus obtained was a solid: 6.6 g (80%). Recrystallization from hot ethanol (50 ml) gave 3-[3-[4-(6-fluoro-1,2-benzisoxazol- 3-yl)-1-piperidinyl]propoxy]-aniline as off white crystals; 3.46 g, m.p.=115°-117° C. ANALYSIS: Calculated for C2H24 FN3O3 68.27%C. 6.55%H 11.37%N; Found: 68.34%C. 6.53%H 11.31%N
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].[H-].[Na+].S(OC)(O[CH3:18])(=O)=O>C1COCC1>[CH3:18][O:1][CH:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5]
Reactant: N#CC(=CO)c1ccccc1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC=C(C#N)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Hydroxy-2-phenylacrylonitrile (12.3 g, 84.7 mmol) was dissolved in dry THF (100 ml) in a reaction vessel, and then NaH (4.1 g, 169.4 mmol) was slowly added thereto. The mixture was stirred at room temperature for 2 hr. Thereafter, dimethyl sulfate (13.7 ml, 144.0 mmol) was added, followed by stirring at 40° C. for 12 hr. After completion of the reaction, the reaction mixture was washed with distilled water and concentrated under reduced pressure. The concentrate was diluted with EtOAc and extracted with EtOAc together with distilled water. The organic layer was dried over anhydrous MgSO4 and filtered. The filtrate was concentrated under reduced pressure to give 17.9 g (112.5 mmol, quant.) of the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][N:6]1[C:10]([S:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)=[C:9]([CH2:20]O)[N:8]=[C:7]1[CH3:22]>>[Cl:3][CH2:20][C:9]1[N:8]=[C:7]([CH3:22])[N:6]([CH3:5])[C:10]=1[S:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=1
Reactant: Cc1cc(C)cc(Sc2c(CO)nc(C)n2C)c1
Reactant: O=S(Cl)Cl
Product: Cc1cc(C)cc(Sc2c(CCl)nc(C)n2C)c1
Temperature: 70 °C
Yield: 73 %

Procedure:
To 1.9 ml of thionyl chloride was added 370 mg (1.4 mmol) of [1,2-dimethyl-5-(3,5-dimethylphenylthio)-1H-imidazol-4-yl]methanol (42b), and the mixture was heated at 70° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. Ice-water and then a saturated aqueous sodium hydrogen carbonate solution were added to the reaction mixture to neutralize, and extracted with diethyl ether. The organic layer was washed with water and dried over sodium sulfate, and the solvent was concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate) to give 288 mg of 4-chloromethyl-1,2-dimethyl-5-(3,5-dimethylphenylthio)imidazole (42c) as oil (yield 73%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH:10]=1)[NH:7][C:6]([C:19]1[S:20][CH2:21][C@@H:22]([CH2:24][CH2:25]O)[N:23]=1)=[CH:5]2.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH2:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[CH:10]=1)[NH:7][C:6]([C:19]1[S:20][CH2:21][C@H:22]([CH2:24][CH2:25][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:23]=1)=[CH:5]2
Reactant: C1COCCN1
Reactant: Cc1cc(NCC2CCOCC2)c2[nH]c(C3=N[C@H](CCO)CS3)cc2c1
Product: Cc1cc(NCC2CCOCC2)c2[nH]c(C3=N[C@@H](CCN4CCOCC4)CS3)cc2c1

Procedure:
2-((R)-2-{5-methyl-7-[(tetrahydro-pyran-4-ylmethyl)-amino]-1H-indol-2-yl}-4,5-dihydro-thiazol-4-yl)-ethanol prepared in Step B and morpholine were reacted according to the same procedure as Example 156 to give the title compound.