Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[CH2:12]([Li])CCC.CI.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:12])[C:10]#[N:11])=[CH:5][CH:4]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(CC#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc(C(C)C#N)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
14.7 g (0.10 mole) of p-methoxyphenylacetonitrile was dissolved in 250 ml of dry tetrahydrofuran and placed in a dry ice/isopropanol bath under N2. 69.0 ml of 1.6M n-butyl lithium (0.11 mole) was added dropwise over 30 minutes and the mixture stirred at -78° C. for one hour. The lithium salt of the nitrile precipitated as a yellow solid during this time. 71.0 g (0.50 mole) of methyl iodide was then added and stirring at -78° C. continued for an additional hour. The mixture was then poured into saturated ammonium chloride and the product extracted into diethyl ether, washed with saturated sodium chloride and dried over sodium sulfide. It was filtered and evaporated, redissolved in methylene chloride and passed through Florisel®. Evaporation gave 15.0 g of α-(p-methoxyphenyl)propionitrile as an orange oil.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:12]=[C:11]([C:22]([OH:24])=O)[CH:10]=1.[NH2:25][C@@H:26]([CH3:29])[CH2:27][OH:28].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O>>[OH:28][CH2:27][C@@H:26]([NH:25][C:22]([C:11]1[CH:10]=[C:9]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=2[F:1])[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=2)[CH:12]=1)=[O:24])[CH3:29]
Reactant: C[C@H](N)CO
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-c3cccc(F)c3F)c2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)N[C@@H](C)CO)cc(-c3cccc(F)c3F)c2)nc1
Temperature: 25 °C

Procedure:
A round bottom flask was charged with 2′,3′-difluoro-5-(5-methylpyridin-2-yl)biphenyl-3-carboxylic acid (30.00 mg, 0.09222 mmol), (2S)-2-Aminopropan-1-ol (8.3119 mg, 0.11066 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.087662 g, 0.23055 mmol), N,N-diisopropylethylamine (0.064252 mL, 0.36888 mmol), N,N-dimethylformamide (0.157 mL, 2.03 mmol) and the reaction stirred over night at room temperature. The solvent was removed under reduced pressure and the residue purified by prep HPLC to get the compound as white solid.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[OH:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30](O)=[O:31]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][C:30](=[O:31])[CH2:29][C:28]([OH:27])([CH3:34])[CH3:33])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CC(C)(O)CC(=O)O
Agent: Cl
Product: CC(C)(O)CC(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (65 mg, 61%), MS (ISP) m/z=429.4 [(M+H)+], mp 168° C., was prepared in accordance with the general method of example 1 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and 3-hydroxy-3-methyl-butyric acid.
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]([CH3:15])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:7]=1[CH3:8])=O.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[C:23]([NH:25][C:26]1[CH:27]=[C:28]([CH:32]2[CH2:33][CH2:34][N:35]([CH2:1][C:3]3[C:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:5]([CH3:15])[N:6]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:7]=3[CH3:8])[CH2:36][CH2:37]2)[CH:29]=[CH:30][CH:31]=1)(=[O:24])[CH:22]([CH3:38])[CH3:21]
Reactant: CCOC(=O)c1c(C=O)c(C)n(-c2ccccc2)c1C
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CCOC(=O)c1c(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c(C)n(-c2ccccc2)c1C

Procedure:
Prepared by Procedure F and Scheme R using ethyl 4-formyl-2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 502.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH:21]3[CH2:23][CH2:22]3)[CH2:16][CH2:15]2)=[C:10]([CH2:24][NH:25][CH3:26])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]([C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([Cl:27])=[CH:29][CH:30]=3)[CH:21]3[CH2:23][CH2:22]3)[CH2:16][CH2:15]2)=[C:10]([CH2:24][NH:25][CH3:26])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NC2CC2)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](N(C(=O)c2ccc(Cl)cc2)C2CC2)CC1

Procedure:
from trans-4-(4-tert.butoxycarbonyl-methylaminomethyl-phenyl)-N-cyclopropylcyclohexylamine and 4-chlorobenzoyl chloride. Melting point: 151°-152° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH:26]([O:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][N:31]=1)([CH3:28])[CH3:27]>CN(C=O)C>[CH:26]([O:29][C:30]1[C:35]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)=[CH:34][CH:33]=[CH:32][N:31]=1)([CH3:28])[CH3:27]
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1Br
Reactant: CC(C)Oc1ncccc1B1OC(C)(C)C(C)(C)O1
Solvent: CN(C)C=O
Product: CC(C)Oc1ncccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 25, from N-(4-bromo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 25, intermediate a) and 2-isopropoxypyridine-3-boronic acid pinacol ester (CAS RN 848243-25-4) and using DMF as reaction solvent. Off-white solid (13%). MS (ESI): m/z=483.8 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([CH3:22])[C:3]=1[NH:23][C:24](=O)[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>ClC(Cl)C>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([CH3:22])[C:3]=1[NH:23][C:24](=[S:40])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1cc(N2CCc3cc(C(F)(F)F)ccc3C2)cc(C)c1NC(=O)CC(C)(C)C
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CC(Cl)Cl
Product: Cc1cc(N2CCc3cc(C(F)(F)F)ccc3C2)cc(C)c1NC(=S)CC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of N-[2,6-Dimethyl-4-(6-trifluoromethyl-3,4-dihydro-1H-isoquinolin-2-yl)-phenyl]-3,3-dimethyl-butyramide (200 mg, 0.48 mmol) in dichloroethane (10 mL) was added Lawesson's reagent (193 mg, 0.48 mmol) and the reaction mixture was stirred at reflux for 2 h. The mixture was then cooled to room temperature and concentrate. Purification by preparative thin layer chromatography (dichloromethane 100%) afforded the desired compound as a solid.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:32])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[OH-].[K+]>C(O)C.O>[CH:14]1([CH2:13][CH:12]([C:19]2[CH:20]=[CH:21][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:23][CH:24]=2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:33])=[O:2])=[CH:5][N:6]=2)=[O:32])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)nc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NC(=O)C(CC2CCCC2)c2ccc(Oc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
A solution of 6-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-nicotinic acid methyl ester (prepared in Example 30B-b, 102 mg, 0.23 mmol) in ethanol (10 mL) at 25° C. was treated with a solution of potassium hydroxide (40 mg, 0.69 mmol) in water (2.5 mL). This light yellow solution was stirred at 25° C. for 2 h and then concentrated in vacuo to remove ethanol. The resulting aqueous solution was acidified to pH=2 with a 1N aqueous hydrochloric acid solution and then extracted with methylene chloride (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 10/90 hexanes/ethyl acetate plus 1% acetic acid) afforded 6-[3-cyclopentyl-2-(4-phenoxy-phenyl)-propionylamino]-nicotinic acid (74 mg, 76%) as a white solid: FAB-HRMS m/e calcd for C26H26N2O4 (M+H)+ 431.1971, found 431.1987.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[N:19]=1>>[N:11]1([CH2:10][CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:17][C:18]3[O:22][N:21]=[C:20]([C:23]4[S:24][CH:25]=[CH:26][CH:27]=4)[N:19]=3)=[CH:3][CH:4]=2)[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: ClCc1nc(-c2cccs2)no1
Product: c1csc(-c2noc(COc3ccc(CCCn4ccnc4)cc3)n2)c1
Yield: 41 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was reacted with 5-chloromethyl-3-(2-thienyl)-1,2,4-oxadiazole to obtain 5-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]-3-(2-thienyl)-1,2,4-oxadiazole. The yield was 41%. Recrystallization from ethyl acetate-hexane gave pale yellow prisms, mp 118-119° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([F:34])=[C:30]([CH:33]=1)[CH2:31]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:31][C:30]2[CH:33]=[C:26]([Cl:25])[CH:27]=[CH:28][C:29]=2[F:34])[C:15]2[CH:24]=[CH:23][C:18]3[O:19][CH2:20][CH2:21][O:22][C:17]=3[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc3c(c2)OCCO3)CC1
Reactant: Fc1ccc(Cl)cc1CBr
Product: CC(C)(C)OC(=O)N1CCC(N(Cc2cc(Cl)ccc2F)c2ccc3c(c2)OCCO3)CC1
Yield: 94.5 %

Procedure:
Using general procedure H, 4-(2,3-dihydro-benzo[1,4]dioxin-6-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (see EXAMPLE 188) (502 mg, 1.50 mmol) and 5-chloro-2-fluoro-benzyl bromide (80%, 630 mg, 2.26 mmol) gave 4-[(5-chloro-2-fluoro-benzyl)-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as a pale yellow foam (676 mg, 94%).
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([O:22][CH3:23])=[CH:17][CH:18]=2)[N:13]=1.[H-].[Na+].Cl[CH2:27][C:28]([N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)=[O:29]>CN(C)C=O>[CH3:23][O:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([N:3]3[CH:2]([O:1][CH2:27][C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[O:29])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[C:4]3=[O:11])=[N:13]2)=[CH:18][CH:17]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3O)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)N3CCOCC3)nc2n1
Yield: 11.5 %

Procedure:
The procedure is as in Example 26, but starting with 3-hydroxy-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (12.3 g) in dimethylformamide (150 cc), an oily suspension (50% by weight; 2.4 g) of sodium hydride and N-chloroacetylmorpholine (8.2 g). The residue obtained is purified initially by chromatography on silica (0.063-0.2 mm; 180 g) contained in a column 4 cm in diameter [eluant: methylene chloride/methanol mixture (95:5 by volume)], collecting 100-cc fractions. Fractions 190 to 210 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is purified again by flash chromatography on silica (0.040-0.063 mm; 82 g) contained in a column 3 cm in diameter (eluant: methylene chloride/methanol [98:2 by volume)], collecting 10-cc fractions. Fractions 220 to 235 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. The solid obtained is recrystallized successively in acetonitrile and in ethanol. 2-(7-Methoxy-1,8-naphthyridin-2-yl)-3-(2-morpholino-2-oxoethoxy)-1-isoindolinone (2 g), m.p. 192° C., is thereby obtained.
Reaction SMILES: CCCCCC.[H-].[K+].[Cl:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[CH:15][NH:16]2)=[CH:12][CH:11]=1.[CH:19]([N:22]=[C:23]=[S:24])([CH3:21])[CH3:20]>C1COCC1>[CH:19]([NH:22][C:23]([N:16]1[C:17]2[C:13](=[CH:12][CH:11]=[C:10]([Cl:9])[CH:18]=2)[CH:14]=[CH:15]1)=[S:24])([CH3:21])[CH3:20]
Reactant: CC(C)N=C=S
Reactant: Clc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)NC(=S)n1ccc2ccc(Cl)cc21
Reaction time: 1 h
Yield: 62.6 %

Procedure:
A stirred slurry of hexane washed potassium hydride (0.56 g, 13.9 mmol) in 25 mL of dry THF was treated portionwise with 6-chloroindole (2.0 g, 13.9 mmol). The mixture was heated at reflux until a clear solution was obtained. A solution of isopropyl isothiocyanate (1.4 g, 13.9 mmol) in 5 mL THF was slowly added and stirring was continued for 1 hour. The solvent was evaporated and the residue partitioned between EtOAc and 1N HCl. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residual amber solids were recrystallized from EtOH to provide 2.2 g of the title compound as a cream colored solid, m.p. 92-93° C. (63% of theory).
Reaction SMILES: F[C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].[Br:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[C:16]([Cl:18])[CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:11][C:12]1[CH:13]=[C:14]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:19][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Oc1cc(Cl)cc(Br)c1
Reactant: Cc1ccnc(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccnc(C#N)c1Oc1cc(Cl)cc(Br)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 3-fluoro-4-methylpyridine-2-carbonitrile (11-1; 2.1 g, 15.43 mmol), 3-bromo-5-chlorophenol (3.68 g, 17.74 mmol) and cesium carbonate (5.03 g, 15.43 mmol) in DMF (30 mL) was heated to 70° C. for 1 hour and then to 80° C. for 1 hour. After this time, the reaction mixture was partitioned between water (300 mL) and ethyl acetate (2×500 mL). The combined extracts were washed with water (100 mL) and then brine (100 mL), dried over MgSO4, filtered and the solvent removed in vacuo. The residue was chromatographed using a RediSep column (330 g) and eluted with a gradient of 0-10% EtOAc/CH2Cl2 and the pure fractions combined and concentrated on the rotary evaporator to give the title compound. LRMS (M+1)=324.9.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([CH2:19][C:20]3[C:25]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=[CH:22][C:21]=3[N:32]([CH3:34])[CH3:33])[CH2:15][CH2:14]2)[C:9]2[C:4](=[CH:5][C:6]([O:37][CH3:38])=[C:7]([O:35][CH3:36])[CH:8]=2)[N:3]=1.[NH2:39][CH2:40][CH2:41][CH2:42][OH:43]>>[CH3:33][N:32]([CH3:34])[C:21]1[CH:22]=[CH:23][CH:24]=[C:25]([O:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[C:20]=1[CH2:19][N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:37][CH3:38])=[C:7]([O:35][CH3:36])[CH:8]=3)[N:3]=[C:2]([NH:39][CH2:40][CH2:41][CH2:42][OH:43])[N:11]=2)[CH2:14][CH2:15]1
Reactant: NCCCO
Reactant: COc1cc2nc(Cl)nc(NC3CCN(Cc4c(OCCN(C)C)cccc4N(C)C)CC3)c2cc1OC
Product: COc1cc2nc(NCCCO)nc(NC3CCN(Cc4c(OCCN(C)C)cccc4N(C)C)CC3)c2cc1OC

Procedure:
Following General Procedure D, Compound 75 (0.25 g, 0.10 mmol) and 3-amino-1-propanol (0.12 mL, 1.61 mmol) were converted into compound 207 as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:10]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=1)#[N:2].[N:25]([Sn](C)(C)C)=[N+:26]=[N-:27]>C1(C)C=CC=CC=1>[NH:25]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[C:9]2[C:10]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:2][N:27]=[N:26]1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#Cc1ccccc1-c1ccccc1C(=O)OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)c1ccccc1-c1ccccc1-c1nnn[nH]1
Yield: 85.6 %

Procedure:
To a solution of benzyl 2′-cyano-2-bipheylcarboxylate (560 mg) in toluene (10 ml), azidotrimethyltin (810 mg) was added. The mixture was refluxed for 12 hours. The reaction mixture was concentrated. 5% aqueous solution of potassium fluoride (4 ml) was added to the residue. The solution was filtered. The filtrate was diluted with ethyl acetate, and the solution was washed with a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=2:1→chloroform:methanol=10:1) to give the title compound (545 mg) having the following physical data.
Reaction SMILES: [NH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[NH2:2].[CH:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl>>[CH:13](=[N:2][NH:1][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][N:4]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: NNC1=NCCc2ccccc21
Agent: Cl
Product: C(=NNC1=NCCc2ccccc21)c1ccccc1

Procedure:
In a manner similar to that of Example 4, condensation of 1-hydrazino-3,4-dihydroisoquinoline (7 g.) and benzaldehyde (5.5 g.) and treatment of the reaction mixture with hydrochloric acid gave a solid, which was recrystallized from ethanol-ether, affording 1-(2-benzylidenehydrazino)-3,4-dihydroisoquinoline (I: X=C6H5, X'=Y=Y'=Z=Z'=H) hydrochloride (11.6 g., m.p. 226°-228° C.).
Reaction SMILES: [K].[C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)#[N:3].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br>>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])=[CH:6][CH:5]=1)#[N:3]
Reactant: BrCCCCCCBr
Reactant: N#Cc1ccc(O)cc1
Agent: [K]
Product: N#Cc1ccc(OCCCCCCBr)cc1

Procedure:
The intermediate 6-(4-cyanophenoxy)hexyl bromide was prepared from the potassium salt of 4-cyanophenol and 1,6-dibromohexane.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(O)(C)(C)C.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH:47]([CH3:49])[CH3:48])[C:36]=2[CH2:50][OH:51])=[CH:31][CH:30]=1>C(Cl)Cl>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[C:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:38]=[C:37]([CH:47]([CH3:49])[CH3:48])[C:36]=2[CH:50]=[O:51])=[CH:31][CH:30]=1
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CC(C)(C)O
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A solution of Dess-Martin periodinane (1.54 gm, 3.63 mmol) in dry CH2Cl2 (17 ml) was treated with t-butanol (267 mg, 3.60 mmol) and stirred for 15 minutes at room temperature. A solution of 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinemethanol (895 mg, 2.78 mmol) in CH2Cl2 (12 ml) was then added and stirring was continued 30 minutes, after which time the mixture was quenched by the addition of Et2O (70 ml) and 1N NaOH (35 ml). The biphasic mixture was stirred for 10 minutes and the layers were separated. The organic layer was washed with 1N NaOH, H2O and brine, then dried (Na2SO4), filtered and stripped. The solid residue was chromatographed (Flash, Merck SiO2, 10% EtOAc in hexane) to afford pure 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (782 mg, 88%) as a white solid. Analytically pure material was obtained by recrystallization of the solid from a minimum amount of hot hexane.
Reaction SMILES: [CH:1]([C@H:14]1[CH2:20][C@@H:19]2[C@@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH:1]([C@@H:14]1[O:15][CH2:16][C@@H:17]([OH:18])[C@@H:19]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)[C@H]2C[C@H]3O[C@H]3CO2)cc1
Reactant: NCc1ccccc1
Product: O[C@@H]1CO[C@@H](C(c2ccccc2)c2ccccc2)C[C@@H]1NCc1ccccc1

Procedure:
(1S,4R,6R)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]heptane 28d (0.019 g, 0.071 mmol) was reacted with benzylamine (0.15 g, 1.43 mmol) (Procedure E) to yield (3S,4S,6R)-6-benzhydryl-4-benzylamino-tetrahydropyran-3-ol, (+)-29h, 0.023 (85%, [α]D=(+)70.1, c=1, MeOH).
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]2[CH2:9][CH2:10][CH2:11][N:5]2[CH2:4]1.[C:12]([O-:15])(=[O:14])[CH3:13].[K+]>CN(C)C=O>[C:12]([O:15][CH2:2][C@H:3]1[O:8][CH2:7][C@@H:6]2[CH2:9][CH2:10][CH2:11][N:5]2[CH2:4]1)(=[O:14])[CH3:13]
Reactant: ClC[C@@H]1CN2CCC[C@H]2CO1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OC[C@@H]1CN2CCC[C@H]2CO1
Yield: 96.9 %

Procedure:
(3S,8aS)-3-(Chloromethyl)hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine (2.30 g, 13.1 mmol) and potassium acetate (12.8 g, 131 mmol) were stirred in dimethylformamide (25 mL) at 140° C. for 20 h. The mixture was partitioned between ethyl acetate and water. The organic portion was washed twice with water, then with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford (3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl acetate as a brown oil (2.53 g, 12.7 mmol, 97% yield). 1H NMR (400 MHz, CDCl3): 4.14-4.02 (m, 3H), 3.81-3.72 (m, 1H), 3.37-3.31 (m, 1H), 3.09 (dt, 1H), 3.00 (dd, 1H), 2.21-2.00 (m, 3H), 2.10 (s, 3H), 1.90-1.67 (m, 3H), 1.39-1.24 (m, 1H); MS (EI) for C10H17NO3: 200 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[Cl:11].[H-].[Na+].S(OC)(O[CH3:19])(=O)=O>O1CCOCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:19])=[CH:6][C:5]=1[Cl:11]
Reactant: COC(=O)c1ccc(O)cc1Cl
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc(OC)cc1Cl
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
To a solution of compound of example 163 (2.8 g, 15 mmol) in dry dioxane (50 mL) was added NaH (50%, 1.44 g, 30 mmol) and dimethyl sulfate (3.78 g, 30 mmol). It was stirred at 60-65° C. for 1 h. It was poured into ice water and extracted with EtOAc (2×100 mL). The organic extract was washed with brine, dried (anhydrous Na2SO4) and concentrated to obtain the title compound.