Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[C:2]1([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[CH:24]=2)[C:6]2[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:22])[CH3:21]>C(OCC)(=O)C.CCCCCC>[CH:29]([C:25]1[CH:24]=[C:23]([CH:2]2[C:6]3[CH:7]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=3[O:4][C:3]2([CH3:22])[CH3:21])[CH:28]=[CH:27][CH:26]=1)([CH3:30])[CH3:31]
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1cccc(C(C)C)c1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1cccc(C(C)C)c1
Yield: 65 %

Procedure:
Using N-(3-hydroxy-3-(3-isopropylphenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 245, the title compound was synthesized in the same manner as in Example 271. Yield: 65%. Melting point: 162-163° C. (ethyl acetate-hexane).
Reaction SMILES: Br.Br.[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[N:14]=1.C(N(C(C)C)C(C)C)C.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1>C(#N)C>[NH2:3][C:4]1[CH:5]=[N:6][C:7]2[CH2:13][CH2:12][N:11]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([Cl:24])=[CH:26][CH:27]=3)[CH2:10][CH2:9][C:8]=2[N:14]=1
Reactant: Nc1cnc2c(n1)CCNCC2
Reactant: ClCc1ccc(Cl)cc1
Agent: Br
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cnc2c(n1)CCN(Cc1ccc(Cl)cc1)CC2
Reaction time: 48 h

Procedure:
3.0 gm (9.2 mmols) of 2-amino-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepine dihydrobromide were suspended in 100 ml of acetonitrile, 7.5 ml of N-ethyl-diisopropylamine were added to the suspension, and the mixture was admixed dropwise with 1.5 gm (9.3 mmols) of p-chloro-benzyl-chloride. The reaction mixture was stirred for 48 hours and then evaporated, the residue was acidified with dilute hydrochloric acid, and the mixture was extracted with methylene chloride. The aqueous phase was made alkaline and then exhaustively extracted with methylene chloride, the extracts were evaporated, and the residue was column-chromatographically purified on silicagel with ethyl acetate as the mobile phase.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([NH2:37])[CH2:33][CH2:34][O:35][CH3:36]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:23]([F:25])([F:24])[F:26])[CH:17]=3)[CH2:13][CH:12]([C:27]3[O:28][N:37]=[C:32]([CH2:33][CH2:34][O:35][CH3:36])[N:31]=3)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1CC(c2cccc(OC(F)(F)F)c2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3cccc(OC(F)(F)F)c3)CN(C(=O)N3CCC(O)CC3)C2)n1

Procedure:
200 mg (0.48 mmol) of the compound from Example 194A and 113 mg (0.72 mmol) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 2. Yield: 182 mg (73% of theory)
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]=[N:10][OH:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.ClN1C(=O)CCC1=O.[CH2:20]([O:22][C:23](=[O:27])[C:24]#[C:25][CH3:26])[CH3:21].C(N(CC)CC)C>CN(C)C=O.C(OCC)C.O>[CH2:20]([O:22][C:23]([C:24]1[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][N:4]=2)=[N:10][O:11][C:25]=1[CH3:26])=[O:27])[CH3:21]
Reactant: ON=Cc1ncc(Cl)cc1Cl
Reactant: CC#CC(=O)OCC
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1c(-c2ncc(Cl)cc2Cl)noc1C
Yield: 38.6 %

Procedure:
Dissolve 3,5-dichloropyridine-2-carboxaldehyde oxime (0.70 g, 0.0037 mol) in N,N-dimethylformamide (10 mL). Add N-chlorosuccinimide (0.55 g, 0.004 mol) in small portions and sitr at ambient temperature until reaction is complete. Pour the mixture into water and extract with ethyl acetate. Wash with water and dry over sodium sulfate. Concentrate in vacuo and use without further purification. Combine this material with ethyl-2-butynoate (6.0 mL, 0.052 mol) under a nitrogen atmosphere. Add triethylamine (3.29 mL, 0.024 mol) in diethyl ether (10 mL) in a dropwise manner and stir overnight at ambient temperature. Quench with water and extract with ethyl acetate. Concentrate and elute over silica gel with dichloromethane to give the desired isoxazole (0.43 g, 39%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[O:13]=[C:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1.[OH-].[K+]>C1COCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Si:6]([O:5][CH2:4][CH2:3][CH2:2][N:19]1[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:15][C:14]1=[O:13])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1
Reaction time: 2 h
Yield: 80 %

Procedure:
(3-Bromopropoxy)-tert-butyldimethylsilane (2.53 g, 0.01 mol) in THF (10 ml) was added dropwise at room temperature to a stirred mixture of tert-butyl 3-oxopiperazine-1-carboxylate (2.0 g, 0.01 mol), powdered potassium hydroxide (0.67 g, 0.012 mol) and tetra-n-butylammonium bromide (0.63 g, 0.002 mol) in THF (15 ml). The reaction was stirred 2 hr then filtered and evaporated. The residue was purified by column chromatography on silica using ethyl acetate as eluent to give tert-butyl 4-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-3-oxopiperazine-1-carboxylate (2.98 g, 80%) as a colourless oil; NMR Spectrum:(CDCl3) 0.02 (s, 6H), 0.87 (s, 9H), 1.43 (s, 9H), 1.76 (quintet, 2H), 3.35 (m, 2H), 3.45 (t, 2H), 3.60 (m, 4H), 4.03 (s, 2H)
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:11][C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][NH2:20])[CH:15]=[CH:16][CH:17]=1)[CH2:8][CH2:9][CH3:10].[CH:21]1([CH:27]=[CH:28][C:29](Cl)=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.O>C(#N)C>[CH:21]1([CH:27]=[CH:28][C:29]([NH:20][CH2:19][CH2:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=2)=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCCCOc1cccc(CCN)c1
Reactant: O=C(Cl)C=CC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCOc1cccc(CCNC(=O)C=CC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
Powdered potassium carbonate (4.5 g) was added to a solution of 2-(3-butyloxyphenyl)ethylamine (4.12 g) in acetonitrile (55 cm3). A solution of 3-cyclohexylacryloyl chloride (3.66 g) in acetonitrile (20 cm3) was added dropwise over fifteen minutes and the reaction mixture was then stirred at room temperature for 2 hours. Following treatment with distilled water (75 cm3) and SVM (3 cm3), a white precipitate was formed. This was filtered off and sucked dry to give the product (3.76 g) m.p. 67°-71° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1>CCOC(C)=O>[ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: COc1ccccc1N1CCCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccccc1N1CCCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64 %

Procedure:
Excess HCl in EtOAc was added dropwise to a solution of intermediate 28 (396 mg, 1.29 mmol) in EtOAc and the reaction mixture was stirred at rt for 1.5 h. Filtration gave 1-(2-methoxyphenyl)-1,4-diazepane hydrochloride (intermediate 29) (200 mg, 64%) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:37][CH2:38][O:39][CH3:40])=[C:13]([CH:36]=1)[C:14]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15]>CC(C)=O>[CH3:40][O:39][CH2:38][O:37][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:36][C:13]=1[C:14]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:15]
Reactant: COCOc1ccc(CBr)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Reactant: C1CCNCC1
Solvent: CC(C)=O
Product: COCOc1ccc(CN2CCCCC2)cc1C(=O)Nc1cc(-c2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, piperidine (0.094 mL) was added to an acetone (1.5 mL) suspension of tert-butyl 2-(5-(bromomethyl)-2-(methoxymethoxy)benzamido)-4-phenylbenzoate (0.10 g), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and a saturated aqueous solution of sodium bicarbonate and ethyl acetate were added to the residue. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Kanto Chemical Co., Inc., silica gel 60 (spherical), eluent: 100-95% chloroform/methanol] to obtain 0.080 g of tert-butyl 2-(2-(methoxymethoxy)-5-((piperidin-1-yl)methyl)benzamido)-4-phenylbenzoate.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH:10]=[CH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.N(C(OCC)=O)=NC(OCC)=O.[Cl:31][CH2:32][CH2:33][CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:31][CH2:32][CH2:33][CH2:34][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH:11]=[CH:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: Oc1ccccc1C=Cc1cccc2[nH]ccc12
Reactant: OCCCCl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ClCCCOc1ccccc1C=Cc1cccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under an inert atmosphere, 235 mg of 2-[(1H-indol-4-yl)-ethenyl]-phenol in 20 ml of tetrahydrofuran with 0.15 ml of diethyl azodicarboxylate, 0.1 ml of 3-chloro-1-propanol, and 262 mg of triphenylphospine were stirred for 5 hours. Then 0.1 ml of 3-chloro-1-propanol, 0.15 ml of diethyl azodicarboxylate and 262 mg of triphenyl phospine were added, and after 15 hours of stirring at ambient temperature, the mixture was concentrated to dryness. The residue was purified by chromatography on silica (eluent: benzene) to obtain 310 mg of 4-[2-[2-(3-chloropropoxy)-phenyl]-ethenyl]-1H-indol.
Reaction SMILES: [OH-].[Na+].C(O)(=O)C(O)=O.[F:9][C:10]1[CH:11]=[C:12]([CH:42]=[CH:43][CH:44]=1)[CH2:13][O:14][C:15]1[CH:41]=[CH:40][C:18]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]3[CH:30]=[N:31][CH:32]=[C:33]([CH2:35][O:36]C(=O)C)[CH:34]=3)=[O:27])[CH2:22][CH2:21]2)=[CH:17][CH:16]=1.Cl>C1COCC1>[F:9][C:10]1[CH:11]=[C:12]([CH:42]=[CH:43][CH:44]=1)[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH:29]3[CH2:34][CH:33]([CH2:35][OH:36])[CH2:32][NH:31][CH2:30]3)=[O:27])[CH2:22][CH2:21]2)=[CH:40][CH:41]=1
Reactant: CC(=O)OCc1cncc(OC(=O)N2CCC(Oc3ccc(OCc4cccc(F)c4)cc3)CC2)c1
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OC1CNCC(CO)C1)N1CCC(Oc2ccc(OCc3cccc(F)c3)cc2)CC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
An aqueous 1 M sodium hydroxide solution (7.65 ml) was added to a THF (20 ml) solution containing 5-[(acetoxy)methyl]pyridin-3-yl 4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate oxalate (1.10 g), followed by stirring at 65° C. for 3 hours. The reaction liquid was neutralized with 1 M hydrochloric acid, followed by extraction with chloroform and drying over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform:methanol=12:1 (v/v)) to obtain 5-(hydroxymethyl)piperidin-3-yl 4-{4-[(3-fluorobenzyl)oxy]phenoxy}piperidine-1-carboxylate (770 mg).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[N:11]([CH2:24][CH2:25][CH3:26])[N:12]=[C:13]2[C:22]=1[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:15]=[C:14]2[NH2:23].C(N(CC)CC)C.Cl.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CO>[NH2:23][C:14]1[C:13]2=[N:12][N:11]([CH2:24][CH2:25][CH3:26])[C:10]([CH2:9][C:8]([NH:7][C:3](=[O:4])[CH:2]([CH3:6])[CH3:1])([CH3:28])[CH3:27])=[C:22]2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: CC(C)C(=O)Cl
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.9 %

Procedure:
2-Methylpropanoyl chloride (786 μL, 7.50 mmol) was added to a 0° C. stirred solution of 1-(2-amino-2-methylpropyl)-2-propyl-2H-pyrazolo[3,4-c]quinolin-4-amine (prepared as described in Example 64, 892 mg, 3.00 mmol) and triethylamine (1.32 mL, 9.5 mmol) in dichloromethane (26.7 mL). After 10 minutes at 0° C., the solution was stirred for 2 hours at ambient temperature. The solution was concentrated to afford a white solid that was dissolved in methanol (20 mL) and concentrated hydrochloric acid (4 mL). The solution was heated at reflux for 3.5 hours, then was left to stand at ambient temperature overnight. To the solution was added 2 M aqueous sodium carbonate until the pH was basic. The mixture was concentrated under reduced pressure to remove the methanol. The mixture was extracted with chloroform four times. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated to yield an off-white solid that was purified by IFC (silica gel, eluted with CMA in chloroform). The appropriate fractions were combined and concentrated under reduced pressure to yield a white foam that was crystallized from 50% ethyl acetate in hexanes. The solid was isolated by filtration, washed with 50% ethyl acetate in hexanes, and dried to yield 815 mg of N-[2-(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)-1,1-dimethylethyl]-2-methylpropanamide as a white solid, mp 177-178.5° C.
Reaction SMILES: [CH2:1]=[CH:2][CH3:3].O=O.[C:6]([OH:9])(=[O:8])[CH3:7]>C(OC(=O)C)(=O)C>[C:6]([O:9][CH2:1][CH:2]([O:9][C:6](=[O:8])[CH3:7])[CH3:3])(=[O:8])[CH3:7]
Reactant: CC(=O)O
Reactant: C=CC
Agent: O=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OCC(C)OC(C)=O
Temperature: 140 °C

Procedure:
1 g of tantalum-V-chloride was dissolved in 400 ml of glacial acetic acid and 50 ml of acetic acid anhydride. After saturation with propylene and the further introduction under pressure of about 10 atmospheres of propylene, 20 atmospheres of oxygen were additionally added and the mixture was heated to about 140° C. After cooling, the batch was distilled. 20 g of propylene glycol diacetate were formed.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH:11]=O)[CH:3]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([C@H:40]([NH2:42])[CH3:41])=[CH:36][CH:35]=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C@@H:8]2[CH2:9][CH2:10][CH2:11][N:42]2[C@H:40]([C:37]2[CH:38]=[CH:39][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[CH3:41])[CH:3]=1
Reactant: O=CCCC(=O)c1cc(Br)ccn1
Reactant: COc1ccc([C@@H](C)N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc([C@H](C)N2CCC[C@H]2c2cc(Br)ccn2)cc1
Temperature: -70 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 4-(4-bromo-pyridin-2-yl)-4-oxo-butyraldehyde (3) (720 mg, 2.97 mmol) in CH2Cl2 at −70° C. is added acetic acid (8.93 mg, 0.15 mmol), NaBH(OAc)3 (1.58 g, 7.44 mmol) and (R)-(+)-1-(4-methoxyphenyl)ethylamine (540 mg, 3.6 mmol). The reaction mixture is stirred at −70° C. for 1 hour, then warmed up to room temperature by removing the ice bath and letting it stir for another 2 hours. The reaction mixture is quenched by adding water (25 mL) is washed with 4×20 mL of water. The combined organic layers is concentrated and purified by flash column chromatography (hexane 70%, EtOAc 30%) to yield 4-bromo-2-{(1S,2S)-1-[1-(4-methoxy-phenyl)-ethyl]-pyrrolidin-2-yl}-pyridine (4) (386 mg, 36% yield) as a yellow solid: MS ES+363.10.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([C:8]([O:10]C)=O)=[N:6][CH:7]=1.O.[NH2:13][NH2:14]>CCO>[Br:1][C:2]1[CH:7]=[N:6][C:5]([C:8]([NH:13][NH2:14])=[O:10])=[N:4][CH:3]=1
Reactant: NN
Reactant: COC(=O)c1ncc(Br)cn1
Solvent: O
Solvent: CCO
Product: NNC(=O)c1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a slurry of methyl 5-bromopyrimidine-2-carboxylate (1.0 g, 4.6 mmol) in EtOH (3.6 mL) was added hydrazine monohydrate (0.46 mL, 9.2 mmol). The reaction mixture was stirred at rt for 1 h. The mixture was filtered, and the collected solid was washed with additional EtOH to provide the desired product as a beige solid (720 mg, 72%). MS (ESI): mass calcd. for C5H5N4O, 216.0; m/z found, 217.0 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 10.15 (s, 1H), 9.18-9.08 (s, 2H), 4.67 (s, 2H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH:19]1([NH2:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1CCCCC1
Reactant: Fc1ccc(-c2ccc3ncnc(Cl)c3c2)cc1
Product: Fc1ccc(-c2ccc3ncnc(NC4CCCCC4)c3c2)cc1
Yield: 78 %

Procedure:
This compound was synthesized from 4-chloro-6-(4-fluorophenyl)-quinazoline and cyclohexylamine in 78% yield, using the procedure described for example 37. The product was characterized by its mass spectrum as follows: MS (m/z): 322 ([M+H]+, 100).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[OH:18])=[CH:9][CH:8]=1)(=O)=O.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][C:41]=1[C:42]([O:44][CH3:45])=[O:43].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.O.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>[C:29]([O:28][C:26]([N:15]([CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[OH:18])[CH2:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:38]2[CH:39]=[CH:40][C:41]([C:42]([O:44][CH3:45])=[O:43])=[C:36]([F:35])[CH:37]=2)=[CH:8][CH:9]=1)=[O:27])([CH3:31])([CH3:32])[CH3:30]
Reactant: COC(=O)c1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(OS(=O)(=O)C(F)(F)F)cc1)C[C@H](O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccc(Cl)c3)C(=O)OC(C)(C)C)cc2)cc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of 4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]phenyl trifluoromethanesulfonate (300 mg) in 1,2-dimethoxyethane (5 ml) was added [3-fluoro-4-(methoxycarbonyl)phenyl]boronic acid (125 mg), tetrakis(triphenylphosphine)palladium (53 mg) and aqueous solution of sodium carbonate (2M, 0.6 ml), and the mixture was stirred at 80° C. for 2 hours under nitrogen. The mixture was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=3/1) to give methyl 4′-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]-3-fluoro-1,1′-biphenyl-4-carboxylate (230 mg).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:25])[C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH3:16])C1C=CC=CC=1.[Li+].[BH4-].[OH-].[Na+].COC1C=CC=CC=1[C@H](C)CNC1C=C(C2C=NC(N3CCN(C)CC3)=CC=2)N=CN=1>C1COCC1.CO>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C@H:15]([CH3:16])[CH2:14][OH:25]
Reactant: COc1ccccc1[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: COc1ccccc1[C@H](C)CNc1cc(-c2ccc(N3CCN(C)CC3)nc2)ncn1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccccc1[C@H](C)CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
As shown in step 5-iii of Scheme 5, to an ice-cooled solution of (4S)-4-benzyl-3-[(2S)-2-(2-methoxyphenyl)-propanoyl]oxazolidin-2-one (3.10 g, 9.13 mmol) in THF (183 mL) and MeOH (1.24 mL) was added LiBH4 (9.13 mL of 2.0 M solution, 18.3 mmol) and the reaction was stirred at 0° C. for 2 hours, then warmed to room temperature over 18 hours. A solution of NaOH (18.6 mL of 2.0 M solution) was added and the reaction stirred until both layers were clear. The layers were separated and the aqueous layer was extracted with Et2O (2×). The organic extracts were combined and washed with H2O, brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (0 to 20% EtOAc in hexanes) to give (2S)-2-(2-methoxyphenyl)propan-1-ol (Compound 2016, 1.49 g, 95.4% yield) as a clear, colorless liquid: 1H NMR (300 MHz, CDCl3) δ 7.30-7.19 (m, 2H), 6.98 (td, J=7.5, 1.0 Hz, 1H), 6.95-6.86 (m, 1H), 3.85 (s, 3H), 3.83-3.63 (m, 2H), 3.56-3.38 (m, 1H), 1.84 (s, 1H), 1.30 (d, J=7.1 Hz, 3H); [α]D25.7+4.18 (c 1.11, CHCl3). This optical rotation compares with the rotation for Compound 2016 as described by Denmark S E et al. in J. Am. Chem. Soc. Vol. 132, pages 3612-3620 (2010) and by Matsumoto T et al., in Bull. Chem. Soc. Jpn. Vol. 58, 340-345 (1985).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[N:14]=[N:13][C:12]([NH:15][NH2:16])=[CH:11][C:10]=1[CH:17]1[CH2:19][CH2:18]1.[N:20]#[C:21]Br>>[Cl:8][C:9]1[C:10]([CH:17]2[CH2:19][CH2:18]2)=[CH:11][C:12]2[N:13]([C:21]([NH2:20])=[N:16][N:15]=2)[N:14]=1
Reactant: N#CBr
Reactant: NNc1cc(C2CC2)c(Cl)nn1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc2cc(C3CC3)c(Cl)nn12

Procedure:
(6-Chloro-5-cyclopropylpyridazin-3-yl)hydrazine trifluoroacetic acid salt (W3.012; 400 mg) was converted and worked up analogously to W2.008, except that, instead of 0.5, one further equivalent of cyanogen bromide solution was added. 260 mg of the title compound were obtained in sufficient purity.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH2:30]([NH-:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCc1ccccc1
Agent: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Solvent: Cc1ccccc1
Product: [NH-]Cc1ccccc1
Temperature: 80 °C

Procedure:
A mixture of Lovastatin (50 g, 0.124 mol) and benzylamine (46.32 g, 0.432 mol) was mixed with toluene (25 ml) and heated to 80° C. under nitrogen atmosphere for 1 hour. Absence of Lovastatin was monitored by HPLC. Excess benzylamine and toluene were distilled off at 85-90° C. under reduced pressure (5-10 mm Hg). The residue was mixed with xylenes (50 ml) and distilled again at 85-90° C. under reduced pressure (5-10 mm Hg) to get product, lovastatin benzylamide, as light brown viscous liquid. Yield: 67.5 g.