Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[C:13]([F:16])([F:15])[F:14])[NH:9][C:8](=[O:17])[N:7]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[C:6]2=[O:23].[CH3:24][C:25]1(OC)[CH2:29][CH2:28][CH:27](OC)O1>CC(O)=O>[CH3:24][C:25]1[N:1]([CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][C:12]=2[C:13]([F:15])([F:16])[F:14])[NH:9][C:8](=[O:17])[N:7]([NH:18][S:19]([CH3:22])(=[O:20])=[O:21])[C:6]3=[O:23])[CH:27]=[CH:28][CH:29]=1
Reactant: COC1CCC(C)(OC)O1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc(C(F)(F)F)c(CN)cc2c1=O
Solvent: CC(=O)O
Product: Cc1cccn1Cc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1C(F)(F)F
Reaction time: 2 h
Yield: 72.6 %

Procedure:
To a solution of N-(6-aminomethyl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (150 mg, 0.43 mmol) in conc. CH3CO2H (10 mL) was added 2-methyl-2,5-dimethoxytetrahydrofurane (62.2 mg, 0.43 mmol) and the reaction mixture was stirred for 2 h at reflux temperature. Subsequently, the solvent was evaporated and the crude light-yellow residue was recrystallized from EtOAc/cyclohexane to yield N-[6-(2-methyl-pyrrol-1-ylmethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide (130 mg, 0.312 mmol, 73%) as a light-orange solid. 1H-NMR (DMSO-d6, 400 MHz) 3.11 ppm (s, 3H, SO2—CH3); LC-MS rt=3.994 nm; MS: m/z 416.9 [M+H]+ Column: SunFireC18, 4.6*50 nm, 3.5 um; Positive MS Water/Acetonitrile 95:5 to 5:95 in 5 min, Flow: 1.5 mL/min
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[F:12][C:13]1([F:28])[CH2:18][CH2:17][C:16]([CH2:26][NH2:27])([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:3]([F:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:27][CH2:26][C:16]1([C:19]2[CH:20]=[N:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:17][CH2:18][C:13]([F:12])([F:28])[CH2:14][CH2:15]1)=[O:7]
Reactant: O=C(O)c1cccc(Cl)c1F
Reactant: NCC1(c2ccc(F)nc2)CCC(F)(F)CC1
Product: O=C(NCC1(c2ccc(F)nc2)CCC(F)(F)CC1)c1cccc(Cl)c1F

Procedure:
From 3-chloro-2-fluorobenzoic acid and (4,4-difluoro-1-(6-fluoropyridin-3-yl)cyclohexyl)methanamine. LCMS (MH+): m/z=401.2, tR (minutes, Method D)=0.75
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].ClC1C=CC=CC=1C[N:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[N:13]=[C:12]1[CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:16][C:15]1[N:11]=[C:12]([CH2:18][NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[NH:13][C:14]=1[CH3:17]
Reactant: Cc1nc(CCl)n(Cc2ccccc2Cl)c1C
Reactant: CC(C)CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(CNCCC(C)C)[nH]c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 7 ml (60 mmol) of isoamylamine in 3 ml of acetonitrile is added slowly a solution of 1-(2′-chlorobenzyl)-4,5-dimethyl-2-chloromethylimidazole in 10 ml of acetonitrile followed by added 1.5 g (10.8 mmol) of potassium carbonate powder. The reaction mixture is stirred overnight at room temperature under nitrogen and excess isoamylamine is evaporated in vacuo. The residue is dissolved in 50 ml of ethyl acetate and 25 ml of water. The ethyl acetate layer is separated, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product is purified by preparative TLC [silica gel, chloroform-methanol-ammonium hydroxide (90:10:1)] to give 1.39 g (46%) of N-[(4,5-dimethylimidazol-2-yl)methyl]-(3-methylbutyl)amine as a yellow oil. MS m/z (M++1) 320; 1H-NMR 400 MHz(δ, CDCl3): 0.81 (6H, d, J=6.4 Hz), 1.25 (2H, m), 1.51 (1H, m), 1.96 (3H, s), 2.17 (3H, s), 2.56 (2H, m), 3.68 (2H, s), 5.21 (2H, s), 6.39 (1H, d, J=7.6 Hz), 7.13 (1H, m), 7.19 (1H, m), 7.37 (1H, m) ppm.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14][NH2:15])=[CH:6][C:5]=1[OH:16].[CH2:18]([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]1[CH:34]=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][O:14]/[N:15]=[CH:34]/[C:26]2[N:25]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:33]3[C:28]([CH:27]=2)=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:6][C:5]=1[OH:16]
Reactant: COC(=O)c1ccc(OCCCON)cc1O
Reactant: O=Cc1cc2ccccc2n1Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: COC(=O)c1ccc(OCCCO/N=C/c2cc3ccccc3n2Cc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.8 %

Procedure:
To a solution of 4-(3-aminooxy-propoxy)-2-hydroxy-benzoic acid methyl ester (0.17 g, 0.69 mmol) and 1-benzyl-1H-indole-2-carbaldehyde (0.16 g, 0.69 mmol) in methylene chloride (10 mL) was added anhydrous magnesium sulfate (0.04 g). The mixture was allowed to stir at ambient temperature overnight, then heated to reflux for 1 hour and allowed to cool back to ambient temperature. The mixture was filtered and the filtrate was concentrated under reduced pressure. The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 20/80) to give 4-[3-({[(1E)-(1-benzyl-1H-indol-2-yl)methylidene]amino}oxy)propoxy]-2-hydroxybenzoic acid methyl ester (0.11 g, 36%) as a white solid. 1H NMR (400 MHz, CDCl3); δ 10.94 (s, 1H), 8.16 (s, 1H), 7.70 (d, 1H), 7.63 (d, 1H), 7.28-7.17 (m, 5H), 7.11 (t, 1H), 7.00 (d, 2H), 6.78 (s, 1H), 6.41 (s, 1H), 6.39 (d, 1H), 5.72 (s, 2H), 4.21 (t, 2H), 3.98 (t, 2H), 3.89 (s, 3H), 2.03 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([NH2:8])=[O:7].[CH2:9](O)[CH3:10].C(N(CC)CC)C.C(Br)C>C1(C)C=CC=CC=1>[CH2:9]([N:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([NH2:8])=[O:7])[CH3:10]
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: CCO
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: CCBr
Product: CCN1CCC[C@H]1C(N)=O

Procedure:
To a solution of (S)-2-pyrrolidine carboxamide (13.2 g, 116 mmol) in ethanol (140 ml) K2CO3 (17.6 g, 128 mmol) and triethylamine (1.2 ml, 8.6 mmol) were added. The mixture was heated to 30 C. and stirred vigorously. Then ethylbromide (10.4 ml, 138 mmol) were added during 0.5 hours. After 30 hours the mixture was diluted with toluene (50 ml) and washed with water (50 ml). The organic layer was concentrated at reduced pressure. The residue was dissolved in toluene (150 ml) and washed with a small amount of aqueous sodium hydroxide, dried with magnesium sulfate, and evaporated to dryness in vacuo. Yield 10.7 g (65%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9](=[O:16])[NH:8][N:7]=1.[N+:20]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])#[C-:21].CCCCCC.C(OCC)(=[O:37])C>C1COCC1>[CH2:26]([O:25][C:23](=[O:24])[CH:22]([NH:20][C:21]([NH:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]([CH2:5][C:6]2[C:15]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[NH:8][N:7]=2)[CH:3]=1)=[O:37])[CH3:28])[CH3:27]
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1
Reactant: [C-]#[N+]C(C)C(=O)OCC
Reactant: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)NC(=O)Nc1cccc(Cc2n[nH]c(=O)c3c2CCCC3)c1

Procedure:
To a solution of 4-(3-amino-benzyl)-5,6,7,8-tetrahydro-2H-phthalazin-1-one (4) (0.472 mg, 1.850 mmol) in dry THF (25 ml) was added a solution of ethyl 2-isocyanopropionate (266 mg, 1.850 mmol) in 2 ml of THF. The resultant solution was then stirred for 4 hours and then concentrated in vacuo to afford a brown oil. The crude oil was subjected to flash chromatography eluent 4:1, hexane:ethyl acetate. (Rf=0.14 neat ethyl acetate). Main peak in LC-MS, (7.20 g, 98% purity); m/z (LC-MS, ESP), RT=3.20 mins (M+H 389.4).
Reaction SMILES: [CH:1]1([C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:5]=2[O-:6])[CH2:3][CH2:2]1.[Na+].CS(C)=O.[OH:17][C:18]1[CH:23]=[C:22]([Cl:24])[N:21]=[N:20][C:19]=1Cl.C1(C2C=CC=C(C)C=2O)CC1>C1CCCCC1.O>[Cl:24][C:22]1[N:21]=[N:20][C:19]([O:6][C:5]2[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:18]([OH:17])[CH:23]=1
Reactant: Cc1cccc(C2CC2)c1[O-]
Reactant: Oc1cc(Cl)nnc1Cl
Agent: Cc1cccc(C2CC2)c1O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Solvent: CS(C)=O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a mixture of 29.8 g (purity: 93.6%; 163 mmol) of sodium 2-cyclopropyl-6-methylphenoxide and 5 g of dimethyl sulfoxide was added 10.0 g (purity: 90%; 54.6 mmol) of 4-hydroxy-3,6-dichloropyridazine at room temperature. Then, the resultant mixture was heated from room temperature to 140° C. to effect a reaction for 28 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, and 300 g of pure water and 200 g of cyclohexane were added to the cooled mixture, and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. Then, the resultant aqueous phase containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 13.3 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 87.9%) and 60.4 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.4%) were obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH2:64])[CH:59]=2)=[CH:54][C:53]=1[CH3:65]>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:57]=[CH:56][C:55]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=2)=[CH:54][C:53]=1[CH3:65]
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: COc1ccc(-c2cccc(N)c2)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)cc1C
Temperature: 25 °C
Yield: 79.1 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.016 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-3′-methyl-biphenyl-3-ylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 78% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[N:7]([N:11]([CH3:17])C(=O)OCC)[CH:8]=[CH:9][CH:10]=1)=[O:5].[OH-].[Na+].[CH2:24](O)C>>[Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[CH:18][C:3]=1[C:4]([C:6]1[N:7]([NH:11][CH3:17])[C:8]([CH3:24])=[CH:9][CH:10]=1)=[O:5]
Reactant: CCO
Reactant: CCOC(=O)N(C)n1cccc1C(=O)c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Product: CNn1c(C)ccc1C(=O)c1ccccc1Cl

Procedure:
A solution containing [2-(2-chlorobenzoyl)-1H-pyrrol-1-yl]-methyl-carbamic acid, ethyl ester (29.4 g, 91 mmol) and sodium hydroxide (11 g, 275 mmol) in 50% aqueous ethanol was heated under reflux for 16 hours. The excess ethanol was evaporated and the solution was adjusted to pH 7 with 10% HCl. The resultant slurry was extracted with three 100 ml portions of DCM, dried (MgSO4), filtered, and evaporated to give 22 g of solid. This solid was charcoaled and recrystallized from ether-hexane to give 21 g (93%) of powder, m.p. 107°-108°.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:19][NH:20][NH2:21].[OH:22][CH2:23][CH2:24][NH:25][NH2:26]>>[CH3:19][N:20]1[C:15](=[O:17])[CH2:14][CH2:13][C:12]([C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:11][CH:10]=2)=[N:21]1.[OH:22][CH2:23][CH2:24][N:25]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)=[CH:7][CH:8]=2)=[N:26]1
Reactant: CNN
Reactant: NNCCO
Reactant: O=C(O)CCC(=O)c1ccc(-n2ccnc2)cc1
Product: CN1N=C(c2ccc(-n3ccnc3)cc2)CCC1=O
Product: O=C1CCC(c2ccc(-n3ccnc3)cc2)=NN1CCO

Procedure:
Using the procedure of this Example, reaction of 4-(1H-imidazol-1-yl)-γ-oxobenzenebutanoic acid with methyl hydrazine and 2-hydroxyethyl hydrazine gives 4,5-dihydro-2-methyl-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone and 4,5-dihydro-2-(2-hydroxyethyl)-6-[4-(1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone respectively.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[C:3](=[CH:4][CH:5]=[C:6]([OH:10])[CH:7]=2)[O:2]1.[Br:11]Br>C(O)(=O)C>[Br:11][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:9][C:8]2=[CH:7][C:6]=1[OH:10]
Reactant: BrBr
Reactant: Oc1ccc2c(c1)OCO2
Solvent: CC(=O)O
Product: Oc1cc2c(cc1Br)OCO2
Temperature: 0 °C

Procedure:
To a solution of 0.18 mol (25 g) of 4,5-methylenedioxyphenol in 125 ml of glacial acetic acid, a solution of 0.16 mol (29 g) of bromine in 145 ml of glacial acetic acid is added slowly, the temperature of the reaction medium being maintained at between 15° and 25° C. When the addition is complete, the reaction medium is poured into 1.5 liters of ice-cold water. The expected product precipitates. After being drained, it is washed with water until the solvent has been removed. After being dried under vacuum in the presence of potassium hydroxide, it is recrystallized from a petroleum ether/ethyl acetate mixture or from cyclohexane. It melts at 84° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13](Br)[C:12]([NH:17][C:18](=[O:48])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:47])[CH:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])=[CH:33][C:32]=3[C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])[CH2:28][CH3:29])[CH:20]=2)=[N:11]1.[CH3:49][C:50]1[CH:51]=[N:52][NH:53][CH:54]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([C:51]2[C:50]([CH3:49])=[CH:54][NH:53][N:52]=2)[C:12]([NH:17][C:18](=[O:48])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:26](=[O:47])[CH:27]([O:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]([CH2:40][CH3:41])([CH3:39])[CH3:38])=[CH:33][C:32]=3[C:42]([CH2:45][CH3:46])([CH3:44])[CH3:43])[CH2:28][CH3:29])[CH:20]=2)=[N:11]1
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2Br)c1
Reactant: Cc1cn[nH]c1
Solvent: CCOC(C)=O
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2c2n[nH]cc2C)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
45 g of 1-(2,4,6-trichlorophenyl)-3-{3-[2-(2,4-di-tert-amylphenoxy)butyramido]benzamido}-4-bromo-5-oxo-2-pyrazoline and 19 g of 4-methylpyrazole were mixed with each other, then stirred for 2 hours under heating at 90° C. To the reaction mixture was added 500 ml of ethyl acetate, followed by washing several times with water. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated. Upon crystallization of the residue from a solvent mixture of 100 ml of acetonitrile and 20 ml of benzene, 19 g of Coupler (2) was obtained. The melting point of the coupler was 142° to 145° C.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.Cl[CH2:15][CH2:16][C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18].O>CN(C=O)C>[C:3]1([O:13][CH2:15][CH2:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[OH:18])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Oc1cccc2ccccc12
Reactant: O[C@@H](CCCl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O[C@@H](CCOc1cccc2ccccc12)c1ccccc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
To a mixture of 8 ml of DMF and 0.44 g of 60% sodium hydride in mineral oil at 5° C. in an ice bath was added dropwise a solution of 1.44 g of 1-naphthol in 8 ml of DMF. The reaction mixture was stirred at 5° C. for two hours and a solution of 1.71 g of (S)-(-)-3-chloro-1-phenyl-1-propanol in 5 ml of DMF was added. After stirring overnight at room temperature, the reaction mixture was poured into 150 ml of water and extracted with ethyl acetate (3×50 ml). The combined extracts were combined and washed with water and 1N sodium hydroxide solution and dried over sodium sulfate. Yield: 2.56 g (92%). The crude product can be recrystallized from 95:5 hexane/ethyl acetate to give 1.5 g (54%) of purified (S)-(+)-3-(1-naphthalenyloxy)-1-phenyl-1-propanol, mp 76°-78° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[C:9]2([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=O)=[CH:12][CH:11]=3)[CH:5]1[CH2:6][N:7]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]2.S(C)C.CO>C1COCC1>[CH3:1][O:2][CH2:3][CH:4]1[C:9]2([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[CH2:20][CH2:19][CH2:18][CH2:17]4)=[CH:14][CH:15]=3)[CH:5]1[CH2:6][N:7]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:8]2
Reactant: COCC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(N2CCCC2=O)cc1
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: COCC1C2CN(C(=O)OC(C)(C)C)CC12c1ccc(N2CCCC2)cc1
Yield: 83.2 %

Procedure:
To a solution of tert-butyl 6-(methoxymethyl)-1-(4-(2-oxopyrrolidin-1-yl)phenyl)-3-aza-bicyclo[3.1.0]hexane-3-carboxylate (500 mg, 1.29 mmol) obtained in Step 2 of Example XXXIII, in dry THF (10 mL), was added BH3.Me2S complex (3.23 mL, 6.47 mmol, 2M in THF) at 0° C. under nitrogen atmosphere. The reaction mixture was refluxed for 4 h. After completion of the reaction as confirmed by TLC, methanol (20 mL) was added and the reaction mixture was heated to reflux for 1 h. The solvents were removed in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 3:7 EtOAc:Pet. ether) to afford the title compound (400 mg, 86%) as a viscous oil.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([N:10](CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>C(Cl)(Cl)Cl>[Cl:15][CH2:16][C:17]([NH2:1])=[O:18].[Cl:15][CH2:16][C:17]([NH2:10])=[O:18].[NH:1]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)CCl
Reactant: CCN(CC)CC
Agent: C1CNCCNC1
Solvent: ClC(Cl)Cl
Product: NC(=O)CCl
Temperature: -30 °C
Reaction time: 8 h

Procedure:
Homopiperazine (10 g; 100 mmol) was dissolved in chloroform (150 mL) and triethylamine (28 mL; 200 mmol) was added to the mixture. The solution was cooled to -30° C. under nitrogen and chloroacetyl chloride (17 mL, 213 mmol) was added over a period of 1 hour. The solution was stirred at -30° C. for 1 hour, at 0° C. for 2 hour and at ambient temperature overnight. The solution was washed with water (4×50 mL), dried over anhydrous MgSO4, filtered and concentrated. The oily residue was purified by column chromatography on silica gel (5% methanol in chloroform) to yield the title product as an oil which solidified on prolonged standing (10.3 g; 41%). 1H NMR (CDCl3): 4.04 (m, 4 H), 3.62 (m, 8 H), and 1.94 (m, 2 H).
Reaction SMILES: [OH:1][C@@H:2]([C@H:7]1[CH2:11][NH:10][CH2:9][C@@H:8]1[OH:12])[C@H](O)CO.C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22].O1CCCC1>CN(C)C(=O)C>[CH2:24]([O:23][C:21]([N:10]1[CH2:9][C@H:8]([OH:12])[C@@H:7]([CH2:2][OH:1])[CH2:11]1)=[O:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OC[C@@H](O)[C@@H](O)[C@H]1CNC[C@@H]1O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: O=C(OCc1ccccc1)N1C[C@H](CO)[C@@H](O)C1
Reaction time: 1 h

Procedure:
Process B: (3R,4S)-4-[(1S,2R)-1,2,3-Trihydroxypropyl]pyrrolidin-3-ol (0.76 g) and triethylamine (0.60 mL) were dissolved in N,N-dimethylacetamide (12 mL). While this solution was chilled in an ice water bath, benzyl chloroformate (0.58 mL) was added dropwise and the mixture was stirred for 1 hour, followed by addition of tetrahydrofuran (12 mL) and further stirring for 30 min. The insoluble material in the reaction mixture was then filtered and washed with a 1:1 mixture of N,N-dimethylacetamide and tetrahydrofuran. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting residue was dissolved in a mixture of ethanol (32 mL) and water (7 mL), followed by addition of sodium periodate (1.85 g) and stirring at room temperature for 1 hour. The insoluble material in the reaction mixture was filtered and washed with ethanol. The filtrate and the washings were combined and sodium borohydride (242 mg) was added. This was followed by stirring at room temperature for 1 hour, addition of acetone (2 mL) and concentration under reduced pressure. The resulting residue was dissolved in ethyl acetate (100 mL), washed with saturated brine (2×20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate:methanol=20:1) to give (3R,4R)-(1-benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl)methanol as a milky white syrup (828 mg).
Reaction SMILES: [CH3:1][P:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1)([CH3:4])=[O:3].[Cl-].[NH4+]>CO.O.[Fe]>[CH3:4][P:2]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[NH2:11])([CH3:1])=[O:3]
Reactant: CP(C)(=O)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CP(C)(=O)c1cccc(N)c1
Yield: 100.1 %

Procedure:
To a solution of compound 286 (1.5 g, 7.5 mmol) in methanol (62 ml) and water (12 ml) under nitrogen at room temperature was added ammonium chloride (0.604 g, 11.3 mmol) and iron (1.68 g, 30.1 mmol). The resulting mixture was heated to reflux for 30 min then filtered through celite. The celite pad was rinsed with methanol. The filtrate and washings were combined and concentrated and the residue was purified via Biotage (linear gradient 0-20%, methanol/dichloromethane; 25M column) to afford compound 287 as a yellow solid (1.27 g, 7.51 mmol, quantitative). MS (m/z): 170.1 (M+H).
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:20]([CH2:19][C:18]1[CH:21]=[CH:22][C:15]([CH3:14])=[CH:16][CH:17]=1)[CH2:11]2
Reactant: Cc1ccc(CN)cc1
Reactant: COC(=O)c1c(I)cccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(CN2Cc3cccc(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 31.5 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.245 g, 0.7 mmol), 4-methyl-benzylamine (0.102 mL, 0.8 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(4-methyl-benzyl)-2,3-dihydro-isoindol-1-one (0.080 g, 31%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.35 (s, 3H), 4.14 (s, 2H), 4.76 (s, 2H), 7.11-7.38 (m, 6H), 7.91 (d, 1H). GC-MS: m/z 363 (M)+.