Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17]O)=O)[N:10]=[C:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27].C1C=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:45]>CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([CH3:37])(=[O:36])=[O:35])[CH:29]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]2[S:45][CH2:17][C:16]([CH3:20])([CH3:19])[N:15]=2)[N:10]=[C:9]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CC(C)(CO)NC(=O)c1cn(-c2ccc(-c3cccc(S(C)(=O)=O)c3)cc2Cl)c(-c2ccccc2Cl)n1
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: CC1(C)CSC(c2cn(-c3ccc(-c4cccc(S(C)(=O)=O)c4)cc3Cl)c(-c3ccccc3Cl)n2)=N1
Yield: 18.9 %

Procedure:
To a N2 purged 50 mL round bottom flask attached with condenser was added 1-(3-chloro-3′-(methylsulfonyl)biphenyl-4-yl)-2-(2-chlorophenyl)-N-(1-hydroxy-2-methyl propan-2-yl)-1H-imidazole-4-carboxamide (361 mg, 646 μmol), anhydrous benzene (20 mL) and P2S5 (720 mg, 3.24 mmol). The reaction solution was stirred at reflux for 1.5 hr. The reaction solution was diluted with EtOAc (100 mL) and filtered through a Buchner funnel to remove excess P2S5. The filtrate was washed with aq. 0.1 N NaOH (60 mL) and H2O (100 mL). The partitioned organic phase was dried over Na2SO4, filtered, concentrated in vacuo, and chromatographed through a 12 g SiO2 column using a gradient of 100% hexane to 95% EtOAc to afford 68 mg (19% yield) of title compound. MS (ESI) 556.3, 558.3 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 8.10 (t, J=2.0 Hz, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.79 (br s, 1H), 7.66-7.70 (m, 2H), 7.55 (d, J=7.2 Hz, 1H), 7.43 (dd, J1 8.5=Hz, J2=2.0 Hz, 1H), 7.27-7.33 (m, 4H), 3.22 (s, 2H), 3.10 (s, 3H), 1.51 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[C:23]([OH:28])[CH:22]=3)=[N:19][N:20]=2)[C@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:29][CH2:30][CH2:31][C:32](Cl)=[O:33]>N1C=CC=CC=1.C(Cl)Cl>[C:32]([O:28][C:23]1[CH:22]=[C:21]([C:18]2[O:17][C:16]([C@H:12]([NH:11][C:8]3[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=3[CH3:10])[C@H:13]([O:15][C:16](=[O:17])[CH2:12][CH2:13][CH3:14])[CH3:14])=[N:20][N:19]=2)[CH:26]=[CH:25][C:24]=1[F:27])(=[O:33])[CH2:31][CH2:30][CH3:29]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccc(F)c(O)c3)o2)[C@@H](C)O)ccc(C#N)c1Cl
Reactant: CCCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC(=O)Oc1cc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@@H](C)OC(=O)CCC)o2)ccc1F
Reaction time: 23 h

Procedure:
To a solution of 2-chloro-4-((1R,2R)-1-(5-(4-fluoro-3-hydroxyphenyl)-1,3,4-oxadiazol-2-yl)-2-hydroxypropylamino)-3-methylbenzonitrile (Example 41) (135.5 mg, 0.34 mmol) in pyridine (0.6 mL) and CH2Cl2 (4 mL) was added n-butyryl chloride (0.17 mL, 1.68 mmol). Upon complete addition the reaction mixture was stirred for 23 h, then quenched with 10% aqueous HCl (6 mL). The mixture was partitioned between H2O (40 mL) and CH2Cl2 (40 mL). The aqueous layer was extracted with CH2Cl2 (40 mL). The combined organic extracts were washed with NaHCO3 (45 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide a yellow oil, which was purified by flash chromatography over silica gel (20-25% EtOAc in hexanes) to provide the title compound as an off white solid (137.3 mg, 74%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 7.94 (ddd, J=2.2, 4.5, 8.6 Hz, 1H), 7.86 (dd, J=2.0, 7.0 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.52 (dd, J=8.8, 10.0 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 6.13 (d, J=8.8 Hz, 1H), 5.68 (pentet, J=6.5 Hz, 1H), 5.36 (dd, J=6.5, 8.4 Hz, 1H), 2.67 (t, J=7.2 Hz, 2H), 2.28-2.22 (m, 2H), 2.07-2.03 (m, 2H), 1.82-1.71 (m, 2H), 1.53 (d, J=6.5 Hz, 3H), 1.03 (t, J=7.2 Hz, 3H), 0.82 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[O:12][CH2:13][O:14][CH3:15].N1C=CC=CC=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.[Pd].O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH:6]=[CH:5][C:4]=1[O:12][CH2:13][O:14][CH3:15]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COCOc1ccc([N+](=O)[O-])cc1OC
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COCOc1ccc(NC(=O)C(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
To a solution of 2-methoxy-1-(methoxymethoxy)-4-nitrobenzene (1.2 g, 5.63 mmol) in ethyl acetate (30 ml) was added 10%-Pd/C (120 mg) at room temperature, and reaction was carried out under a hydrogen atmosphere. After 30 minutes, the mixture thus obtained was filtered by the use of Celite and the filtrate was concentrated under reduced pressure. To a solution of the resulting residue in ethyl acetate (30 ml) were added pyridine (0.546 ml, 6.75 mmol) and pivaloyl chloride (0.763 ml, 6.19 mmol) at 0° C., and the resulting mixture was warmed up to room temperature. After 15 hours, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution and the resulting mixture was poured into water (100 ml) and extracted with ethyl acetate (50 ml×2), and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain N-[3-methoxy-4-(methoxymethoxy)phenyl]-2,2-dimethylpropanamide (1.48 g, 98%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br.Br[CH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccncc1
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1Cc1ccncc1
Reaction time: 15.5 h
Yield: 50.4 %

Procedure:
A solution of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (163 mg, 0.609 mmol), 4-(bromomethyl)pyridine hyrdobromide (185 mg, 0.730 mmol), DIPEA (256 μL, 1.52 mmol) and KI (10 mg, 0.060 mmol) in CH3CN (6 mL) was warmed to 50° C. and stirred for 15.5 h according to General Procedure A. Purification by flash chromatography on silica gel using CH2Cl2/MeOH/NH4OH (94:5:1) afforded COMPOUND 74 (110 mg, 37%) as an orange oily solid. 1H NMR (CDCl3) δ 1.63-1.73 (m, 3H), 2.08-2.20 (m, 2H), 2.28-2.42 (m, 2H), 2.46 (s, 6H), 3.56 (s, 2H), 4.22 (d, 2H, J=11.8 Hz), 6.14 (d, 2H, J=5.3 Hz), 6.96 (dd, 2H, J=7.5, 4.8 Hz), 7.22 (d, 2H, J=7.9 Hz), 8.00 (d, 2H, J=4.4 Hz), 8.37 (d, 2H, J=4.4 Hz); ES-MS m/z 359 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH2:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][NH:12]1>C(O)(C)C>[N+:8]([C:5]1[C:4]([N:12]2[CH2:13][CH2:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:11]2)=[N:3][CH:2]=[CH:7][CH:6]=1)([O-:10])=[O:9]
Reactant: c1ccc2c(c1)CCNC2
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CC(C)O
Product: O=[N+]([O-])c1cccnc1N1CCc2ccccc2C1
Reaction time: 3 h

Procedure:
A suspension of 2-chloro-5-nitro-pyridine (1.58 g, 10 mmol) in isopropanol (30 ml) was treated at rt with 1,2,3,4-tetrahydro-isoquinoline (2.6 g, 20 mmol). The resulting mixture was stirred for 3 hr. The precipitate was filtered, partitioned (AcOEt/H2O) and the organic phase dried (Na2SO4). After evaporation of the solvent the title compound was obtained as a yellow solid mass (1.4 g, 55%), MS: m/e=256 (M+H+).
Reaction SMILES: [NH2:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[N:4]=[N:3]1.[Br:12][CH2:13][CH2:14][C:15](Cl)=[O:16].C(N(CC)CC)C>C1C=CC=CC=1>[Br:12][CH2:13][CH2:14][C:15]([NH:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:5]=2[N:4]=[N:3]1)=[O:16]
Reactant: O=C(Cl)CCBr
Reactant: Cc1ccc2c(c1)nnn2N
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)nnn2NC(=O)CCBr
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 14.8 g (0.1 mol of 1-amino-5-methyl benztriazole in 200 ml of anhydrous benzene was placed under a nitrogen atmosphere and, over a period of 30 minutes, a solution of 18.9 g (0.11 mol) of β-bromopropionyl chloride in 25 ml of anhydrous benzene and 10.1 g (0.10 mol) of triethylamine were simultaneously added to the solution while stirring the latter. The addition was so made that the amount of acid chloride added was always greater than the amount of amine. The temperature of the mixture rose to above 40° C. Stirring was then continued for 1 hour without application of heat and was continued for a further hour with heating to 60° C. following by stirring for two further hours without application of heat. The organic phase was then poured off from a greasy deposit in the reaction vessel and was washed with water. The deposit was taken up in chloroform and was also washed with water. The organic phases obtained were dried over sodium sulphate, combined and completely concentrated by evaporation. 24 G of the intermediate product, 1-(β-bromopropionylamino)-5-methyl benztriazole were obtained as residue in the form of a frothy resin.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9]Br)[C:3]=1[Cl:11].[C-:12]#[N:13].[K+]>C(O)C.O>[Br:1][C:2]1[C:3]([Cl:11])=[C:4]([CH2:9][C:12]#[N:13])[C:5]([F:8])=[CH:6][CH:7]=1
Reactant: Fc1ccc(Br)c(Cl)c1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCc1c(F)ccc(Br)c1Cl
Reaction time: 16 h
Yield: 100.2 %

Procedure:
A solution of 1-bromo-3-bromomethyl-2-chloro-4-fluorobenzene (9.945 g) in absolute ethanol (40 mL) was added dropwise to a solution of potassium cyanide (2.38 g) in water (2 ml) under heating over a period of 30 minutes. The reaction mixture was heated to reflux for 7 hours. The reaction mixture was then allowed to cool and stored at ambient temperature for 16 hours. The mixture was filtered and the filtrate concentrated. The residue was dissolved in ethyl acetate, dried over magnesium sulfate and concentrated to give (3-bromo-2-chloro-6-fluoro-phenyl)-acetonitrile as a pale yellow oil (8.19 g).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[N:4]=[C:5]([CH:8]2[CH2:11][CH2:10][CH2:9]2)[S:6][CH:7]=1.[C:12]1([P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[Cl-:1].[CH:8]1([C:5]2[S:6][CH:7]=[C:3]([CH2:2][P+:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:4]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: ClCc1csc(C2CCC2)n1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [Cl-]
Product: c1ccc([P+](Cc2csc(C3CCC3)n2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 41.7 %

Procedure:
A mixture of 4.8 g of 4-chloromethyl-2-cyclobutyl-thiazole, 7.0 g of triphenylphosphine and 125 ml of toluene was heated to reflux for 16 hr and then cooled to room temperature. The mixture was then filtered to yield 4.8 g of [(2-cyclobutyl-4-thiazolyl)methyl]triphenylphosphonium chloride.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH2:36](Br)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:9][CH:10]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: BrCc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCOCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 1(g), by alkylating tert-butyl (3RS,4RS)-4-[4-(3-hydroxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate [Example 24(t)] with benzyl bromide therer was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless, amorphous solid, which was used in the next step without characterization.
Reaction SMILES: [CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].Br[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH2:1]([C@@H:4]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: BrCC1CCCC1
Reactant: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(CC2CCCC2)C1=O

Procedure:
The title compound was prepared from (3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 42, Step A) and (bromomethyl)cyclopentane as described in Example 44, Step A. Purification of the residue by silica gel prep plate (25% EtOAc/hexanes) provided the title compound as a colorless solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][CH:12]([CH3:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:15]([O:22][C:23]1[C:24]([C:40](O)=[O:41])=[N:25][C:26]([CH2:30][C:31]([CH3:39])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])=[N:27][C:28]=1[OH:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O=P(Cl)(Cl)Cl>O.N1C=CC=CC=1>[CH2:15]([O:22][C:23]1[C:24]([C:40]([N:11]([CH2:10][CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:12]([CH3:14])[CH3:13])=[O:41])=[N:25][C:26]([CH2:30][C:31]([CH3:32])([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH3:39])=[N:27][C:28]=1[OH:29])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)NCCO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(Cc1nc(O)c(OCc2ccccc2)c(C(=O)O)n1)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC(C)(C)c2ccccc2)nc(O)c1OCc1ccccc1
Temperature: -10 °C
Yield: 26 %

Procedure:
N-(2-(tert-Butyldimethylsilyloxy)ethyl)propan-2-amine (8b) (98.0 mg, 451 μmol, Eq: 1.1, prepared as previously described) was added to 5-(benzyloxy)-6-hydroxy-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxylic acid (56) (155 mg, 410 μmol, Eq: 1.00), then pyridine (2.5 ml) was added, and the reaction mixture was cooled to −10° C. with stirring. POCl3 (188 mg, 115 μl, 1.23 mmol, Eq: 3) was added dropwise, then the reaction mixture was stirred at −10° C. for 1 hour, allowed to warm to 0° C. and stirred for one hour. 10 drops of water were added at 0° C., the reaction mixture was stirred for 5 min and the solvent was removed on a rotary evaporator to almost dryness. The mixture was placed on 12 g silica gel column and eluted with 5% to 50% ethyl acetate/hexane over 20 min. to give 5-(benzyloxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)-6-hydroxy-N-isopropyl-2-(2-methyl-2-phenylpropyl)pyrimidine-4-carboxamide (57) (62 mg, 26%).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]3[NH:12][CH:13]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=O)[C:5]([C:6]=23)=[N:4][NH:3]1.[CH:29]1([NH2:32])[CH2:31][CH2:30]1.[BH4-].[Na+]>CO>[CH:29]1([NH:32][CH2:18][C:17]2[CH:16]=[C:15]([CH:14]3[C:5]4=[N:4][NH:3][C:2](=[O:1])[C:11]5[CH:10]=[CH:9][CH:8]=[C:7]([C:6]=54)[NH:12][CH:13]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:31][CH2:30]1
Reactant: O=Cc1cccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)c1
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=c1[nH]nc2c3c(cccc13)NC(c1ccccc1)C2c1cccc(CNC2CC2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.3 %

Procedure:
A mixture of 3-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzaldehyde (70 mg, 0.19 mmol) and cyclopropanamine (32.55 mg, 0.57 mmol) in anhydrous methanol (10 mL) was stirred at room temperature for 1.5 h. Then the mixture was cooled to 0° C., sodium borohydride (10.82 mg, 0.286 mmol) was added portion-wise. After the addition, the mixture was stirred at this temperature for 2 hr. Methanol was removed under reduced pressure. The residue was dissolved in ethyl acetate (50 mL), extracted with 1N hydrochloric acid (20 mL), the aqueous layer was separated. The organic layer was washed with 1N hydrochloric acid (20 mL). The combined aqueous layers were adjusted to pH=9 with potassium carbonate, extracted with ethyl acetate (25 mL×4). The combined organic layers were dried over anhydrous sodium sulfate, and concentrated to give 9-(3-((cyclopropylamino)methyl)phenyl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (15 mg, yield 19%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.19-0.29 (m, 4H), 1.74-1.80 (m, 1H), 3.55 (s, 2H), 4.16-4.19 (d, J=8.8 Hz, 1H), 4.60-4.62 (d, J=8.8 Hz, 1H), 6.88-6.90 (d, J=7.6 Hz, 1H), 6.95 (s, 1H), 7.01-7.10 (m, 6H), 7.13-7.15 (m, 2H), 7.42-7.44 (d, J=7.6 Hz, 1H), 7.48-7.75 (t, J=8.0 Hz, 1H); LC-MS (ESI) m/z: 408(M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=S)[CH2:13][N:14]=1.[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25][NH2:26])[CH3:22]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[N:11]=[C:12]([NH:26][CH2:25][CH:24]([O:27][CH2:28][CH3:29])[O:23][CH2:21][CH3:22])[CH2:13][N:14]=1
Reactant: CCOC(CN)OCC
Reactant: CCc1cc2c(s1)NC(=S)CN=C2c1ccccc1Cl
Solvent: CCO
Product: CCOC(CNC1=Nc2sc(CC)cc2C(c2ccccc2Cl)=NC1)OCC
Yield: 87.9 %

Procedure:
[b] A mixture of 20 g of 5-o-chlorophenyl-7-ethyl-1,2-dihydro-3H-thieno[2,3-e][1,4]diazepine-2-thione and 9.6 g of aminoacetaldehyde diethylacetal is added to 200 ml of ethanol, and the whole mixture is refluxed for 2.5 hours. While the reaction mixture is hot, an activated carbon is added to the reaction mixture. The whole mixture is filtered and the filtrate is cooled. The crystals formed are collected by suction filtration and washed with a small amount of ethanol to give 23 g of 5-o-chlorophenyl-2-(2,2-diethoxyethylamino)-7-ethyl-3H-thieno[ 2,3-e][1,4]diazepine melting at 143° - 146°C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[C:14]([O:16][CH2:17]C)=[O:15])[CH2:9]1.C[O-].[Na+]>CO>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[C:14]([O:16][CH3:17])=[O:15])[CH2:9]1
Reactant: CCOC(=O)C1C2CC(OC3CCCCO3)CC21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1C2CC(OC3CCCCO3)CC21

Procedure:
Gas-liquid chromatographic analysis of the ethyl 3-[(tetrahydropyran-2-yl)oxy]bicyclo[3.1.0]hexane-6-carboxylate (VIII) obtained as above shows that the product is a mixture of exo and endo isomers in a 4:1 ratio. A solution of 2.8 g. of the above mixture of isomers and 150 mg. of sodium methoxide in 50 ml. of methanol is heated under reflux for 4 hrs. The mixture then is evaporated, the residue extracted with diethyl ether, and the diethyl ether extract evaporated to give the exo isomer of methyl 3-[(tetrahydropyran-2-yl)oxy]bicyclo[ 3.1.0]-hexane-6-carboxylate as an oil; b.p. 130°-133° at 1.1 mm.; homogenous as to the exo isomer by gas-liquid chromatographic analysis and by thin layer chromatographic analysis (silica, developed with benzene-ether 5:1).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([O:25][CH3:26])=[O:24])=[CH:13][CH:12]=2)[C:8]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:7][C:6]=1[Cl:31])=[N+]=[N-]>CO.[Pd]>[NH2:1][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([O:25][CH3:26])=[O:24])=[CH:15][CH:16]=2)[C:8]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:7][C:6]=1[Cl:31]
Reactant: CCCCc1nc(Cl)c(CN=[N+]=[N-])n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1nc(Cl)c(CN)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
5-Azidomethyl-2-butyl-1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-4-chloroimidazole (3.48 g) was hydrogenated at 1 atm in methanol (100 mL) over 10% palladium/carbon (0.5 g). After 1 hour, the mixture was filtered through Celite® and the solvent removed in vacuo to give product (2.80 g) as an oil. NMR (200 MHz, CDCl3) δ7.84 (d, 1H, J=7 Hz); 7.52 (t, 1H, J=7 Hz); 7.40 (t, 1H, J=7 Hz); 7.30 (d, 1H, J=7 Hz); 7.26 (d, 2H, J=8 Hz); 7.02 (d, 2H, J=8 Hz); 5.27 (s, 2H); 3.74 (s, 2H); 3.65 (s, 3H); 2.60 (t, 2H, J=7 Hz); 1.67 (t of t, 2H, J=7,7 Hz); 1.36 (t of q, 2H, J=7,7 Hz); 0.86 (t, 3H, J=7 Hz). Anal. Calcd. for C23H26ClN3O2.(DMSO)0.5 : C, 63.91; H, 6.48; N, 9.32. Found: C, 63.78; H, 6.30; N, 9.14.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:4]=1[CH2:5][N:6]1[C:10](=[O:11])[C@@H:9]([CH3:12])[C@H:8]([C:13]([OH:15])=O)[CH2:7]1.[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[NH:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[CH2:22]([C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[N:30]1[C:13]([C@H:8]1[C@H:9]([CH3:12])[C:10](=[O:11])[N:6]([CH2:5][C:4]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[CH:19][C:3]=2[O:2][CH3:1])[CH2:7]1)=[O:15])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: COc1ccc(CN2C[C@@H](C(=O)O)[C@H](C)C2=O)c(OC)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2C[C@@H](C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)[C@H](C)C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.8 %

Procedure:
To a solution of the crude product of (trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carboxylic acid (14.0 g) in chloroform (60 ml) were sequentially added (R)-4-benzyl-2-oxazolidinone (8.15 g), WSC.HCl (9.70 g), 4-dimethylaminopyridine (2.81 g), and the mixture was stirred overnight at room temperature. This reaction solution was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=4/1 to 1/3) to give the titled compound (low-polarity component 11.4 g, high-polarity component 10.1 g).