Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([OH:10])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:14]1[C:15]2[CH:24]=[CH:23][N:22]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([CH3:32])=[CH:27][C:26]=3[CH3:33])[C:16]=2[C:17](=[O:21])[N:18]([CH3:20])[N:19]=1>CN(C=O)C.O>[C:26]1([CH3:33])[CH:27]=[C:28]([CH3:32])[CH:29]=[C:30]([CH3:31])[C:25]=1[N:22]1[C:16]2[C:17](=[O:21])[N:18]([CH3:20])[N:19]=[C:14]([O:10][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH3:9])[C:15]=2[CH:24]=[CH:23]1
Reactant: CCC(O)c1ccccc1
Reactant: Cc1cc(C)c(-n2ccc3c(Cl)nn(C)c(=O)c32)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCC(Oc1nn(C)c(=O)c2c1ccn2-c1c(C)cc(C)cc1C)c1ccccc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
To a solution of 1-phenyl-1-propanol (0.061 ml, 0.45 mmol) in DMF (1 ml) was added sodium hydride (60% in oil, 18 mg, 0.45 mmol). The mixture was stirred for 10 min before addition of 4-chloro-1-mesityl-6-methyl-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one (45.3 mg, 0.15 mmol). The mixture was stirred at 60° C. for 1 hour, then diluted with water (30 ml) and extracted with ethyl acetate (50 ml). The extract was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (5:1) to give 49.4 mg (82%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[NH:14][N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:32]([O:31][C:29]([N:23]1[CH2:28][CH2:27][N:26]([C:4](=[O:5])[C:3]2[CH:7]=[C:8]([CH2:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[NH:14][N:13]=3)[CH:9]=[CH:10][C:2]=2[F:1])[CH2:25][CH2:24]1)=[O:30])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F
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: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4ccccc34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)benzoic acid (100 mg, 0.33 mmol), tert-butyl piperazine-1-carboxylate (187.3 mg, 1.0 mmol), HATU (255 mg, 0.67 mmol), and DIPEA (0.5 ml, 3.0 mmol) were dissolved in DMF (25 ml) and stirred at room temperature for 24 h. The reaction mixture was partitioned between DCM and water (50 ml each), and the organic phase was washed with aqueous sodium bicarbonate and brine, dried over sodium sulphate, filtered, and concentrated to get the crude product. Then the crude product was purified by column chromatography on silica gel (Petroleum ether:Ethyl Acetate=1:3) to afford target compound (100 mg, 64%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:15]3[N:16]([C:20]([O:22]C(C)(C)C)=O)[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].Cl.C(OCC)(=O)C.[C:36]([O:43][CH2:44][CH3:45])(=[O:42])[CH2:37][CH2:38]C([O-])=O.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:28]=[CH:27][C:15]3[N:16]([C:20](=[O:22])[CH2:38][CH2:37][C:36]([O:43][CH2:44][CH3:45])=[O:42])[CH2:17][CH2:18][O:19][C:14]=3[CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)CCC(=O)[O-]
Reactant: CCc1[nH]c(C(=O)Nc2ccc3c(c2)OCCN3C(=O)OC(C)(C)C)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)CCC(=O)N1CCOc2cc(NC(=O)c3nc(Cl)c(CC)[nH]3)ccc21
Yield: 38.3 %

Procedure:
The same operation as in Example (93a) was performed using tert-butyl 7-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate obtained in Example (95c) (0.11 g, 0.27 mmol), a 4 N hydrochloric acid/ethyl acetate solution (8 ml, 32 mmol), monoethyl succinate (150 mg, 1 mmol), WSC hydrochloride (288 mg, 1.5 mmol), N,N-diisopropylethylamine (0.52 g, 4 mmol) and DMAP (10 mg). Purification by silica gel column chromatography (elution solvent: hexane/ethyl acetate=3/1, 2/1, 2/3, 0/1) gave 45 mg of the title compound as a light yellow solid (38%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[N:24]=[CH:23][CH:22]=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:44]=[C:35]5[CH2:36][N:37]([CH2:40][CH:41]([F:43])[F:42])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.ClCCl>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[C:18]([CH2:19][OH:20])=[C:21]([C:25]3[CH:30]=[C:29]([NH:31][C:32]4[CH:44]=[C:35]5[CH2:36][N:37]([CH2:40][CH:41]([F:43])[F:42])[CH2:38][CH2:39][N:34]5[N:33]=4)[C:28](=[O:45])[N:27]([CH3:46])[CH:26]=3)[CH:22]=[CH:23][N:24]=1)[N:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2cc3n(n2)CCN(CC(F)F)C3)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc3n(n2)CCN(CC(F)F)C3)c1=O
Reaction time: 1 h
Yield: 59.8 %

Procedure:
To a solution of 135e (100 mg, 0.158 mmol) in methanol/dichloromethane (4/4 mL) was added NaBH4 (18 mg, 0.475 mmol) at room temperature. After the reaction was stirred for 1 h, LCMS indicated the reaction was complete. The reaction mixture was quenched with water (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 135 (60 mg, 60%) as a white solid. MS-ESI: [M+H]+ 635.3. 1H NMR (500 MHz, CDCl3) δ 8.66 (d, J=5.0 Hz, 1H), 8.35 (d, J=2.5 Hz, 1H), 8.00 (d, J=2.5 Hz, 1H), 7.59-7.58 (m, 1H), 7.56-7.55 (m, 1H), 7.53-7.52 (m, 2H), 7.45 (s, 1H), 6.07-5.83 (m, 1H), 5.72 (s, 1H), 4.51-4.49 (m, 2H), 4.11-4.08 (m, 2H), 4.05-4.03 (m, 1H), 3.94 (s, 2H), 3.73 (s, 3H), 3.13-3.10 (m, 2H), 3.00-2.94 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)C.C(O)CO.[OH-].[K+]>O>[Cl:22][C:17]1[CH:16]=[C:15]([C:14]2[N:6]([CH2:5][C:4]([OH:3])=[O:24])[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[N:13]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Cl)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: O=C(O)Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21

Procedure:
A mixture of N-[3-[(3,4-dichlorobenzoyl)amino]-2-pyridinyl] glycine ethyl ester (33 g, 0.09 mole) and 167 ml of ethylene glycol was heated at reflux for 11/2 hr. After cooling, potassium hydroxide (8.4 g) in 40 ml of water was added and the reaction mixture was heated at reflux for 1 hr. The solution was filtered to remove yellow insoluble precipitate, the filtrate was diluted with 650 ml of water, and acidified with ethanolic hydrogen chloride. The solid, which formed, was collected by filtration, washed with water, and dried under high vacuum first at 50° C. overnight, then at 70° C. for 21/2 days to give 25.3 g (98%), mp 248°-49° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH2:23][CH3:24])[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]([CH3:22])=[C:18]([CH2:23][CH3:24])[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CCc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1C
Solvent: CN(C)C=O
Product: CCc1c(C)c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)n1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-ethyl-5-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate and dimethyl sulphate in dimethylformamide there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-ethyl-3,5-dimethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, 1H-NMR (CDCl3, 400 MHz) 7.82 ppm (d, 1H), 7.33 ppm (d, 1H), 5.23 ppm (m, 1H), 3.51 ppm (s, 3H), 2.71 ppm (m, 2H), 2.04 ppm (s, 3H), 1.35 ppm (d, 6H), 1.28 ppm (t, 3H),
Reaction SMILES: [C:1]([CH2:4][CH:5]1[C:9]2[C:10]([C:16]([NH:18][C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=3[Cl:26])=[O:17])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:8]=2[O:7][CH2:6]1)(O)=[O:2].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34]>>[Cl:25][C:24]1[CH:23]=[N:22][CH:21]=[C:20]([Cl:26])[C:19]=1[NH:18][C:16]([C:10]1[C:9]2[CH:5]([CH2:4][C:1]([NH:34][CH2:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)=[O:2])[CH2:6][O:7][C:8]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)=[O:17]
Reactant: NCc1ccccn1
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c1OCC2CC(=O)NCc1ccccn1
Yield: 56 %

Procedure:
Substantially the same procedure as in Example 13 was repeated using Compound 9 (0.30 g) obtained in Example 9 and 2-pyridylmethylamine to give Compound 24 (0.21 g, 56%) as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[C:9]([N+]([O-])=O)[CH:8]=[C:7]([O:14][CH3:15])[CH:6]=1)(=[O:4])=[O:3].[Cl-].[NH4+:17].CO>[Zn].O>[CH3:1][S:2]([C:5]1([NH2:17])[CH:6]=[C:7]([O:14][CH3:15])[CH:8]=[CH:9][CH2:10]1)(=[O:4])=[O:3]
Reactant: [NH4+]
Reactant: COc1cc([N+](=O)[O-])cc(S(C)(=O)=O)c1
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CO
Product: COC1=CC(N)(S(C)(=O)=O)CC=C1
Reaction time: 0.5 h
Yield: 75.9 %

Procedure:
To a mixture of 1-methanesulfonyl-3-methoxy-5-nitro-benzene (1.5 g, 6.48 mmol), zinc dust (4.3 g, 64.87 mmol), and ammonium chloride (5.2 g, 97.31 mmol) were added methanol (20.32 mL) and water (9.9 mL) at room temperature. After addition of water, the reaction was exothermic. The suspension was stirred for 30 min and the reaction mixture was filtered through the Celite. The filter cake was washed with water and methanol. The filtrate was concentrated to remove methanol and the residue was extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to isolate 1-methanesulfonyl-5-methoxy-phenylamine (1.0 g, 76%) as a light yellow solid: ES(+)-HRMS m/e calcd for C8H12NO3S (M+H)+ 202.0533, found 202.0532.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([OH:13])=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=1.Cl[CH2:15][O:16][CH3:17]>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:15][O:16][CH3:17])=[C:8]([C:10](=[O:12])[CH3:11])[CH:9]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(Br)cc1C(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a slurry of sodium hydride (60% oily dispersion; 1.125 g, 28 mmol) in anhydrous DMF (80 mL), 1-(5-bromo-2-hydroxyphenyl)ethanone (4.67 g, 21.7 mmol) was added at 0° C. under a nitrogen atmosphere. After stirring for 1 h at the same temperature, methyl chloromethyl ether (tech, 90%; 2.35 g, 26 mmol) was added dropwise. The reaction mixture was allowed to gradually warm to room temperature and was stirred for 4 h. The reaction mixture was then quenched by pouring it onto saturated NH4Cl (aq) (100 mL). The reaction mixture was then extracted with 8:1 Et2O/EtOAc (2×150 mL). The combined organic layers were washed with water (4×80 mL), brine (60 mL), and dried over MgSO4. After purification by flash chromatography (9:1 hexane/EtOAc), the title compound (15) was obtained as colorless oil (4.44 g, 79% yield).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].[OH-].[Na+].[CH2:13]([OH:16])[CH2:14][OH:15]>O>[OH:15][CH2:14][CH2:13][O:16][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7]
Reactant: OCCO
Reactant: O=Cc1cccc(CBr)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1cccc(COCCO)c1
Temperature: 55 °C

Procedure:
A mixture of 1.99 g of 3-(bromomethyl)benzaldehyde, 0.80 g of sodium hydroxide and 8 ml of ethylene glycol was heated at 55° C. for 6 hours. After water was added, the mixture was extracted with chloroform and then washed with an aqueous saturated sodium chloride solution. After dried over anhydrous sodium sulfate and then concentration under reduced pressure, the resulting residue was subjected to silica gel column chromatography to obtain 0.79 g of oily 3-[(2-hydroxyethoxy)methyl]benzaldehyde [Compound No. (g)].
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[CH:15]=[N:16][N:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH3:34])=[CH:21][CH:20]=2)[CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40]>CN(C)C=O.O>[Si:1]([O:8][CH2:9][CH2:10][N:11]([C:12]([C:14]1[CH:15]=[N:16][N:17]([C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[CH3:34])=[CH:23][CH:24]=2)[CH:18]=1)=[O:13])[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)NCCO[Si](C)(C)C(C)(C)C)cn2)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CCCN1CCCOc1ccc(-n2cc(C(=O)N(CCO[Si](C)(C)C(C)(C)C)CC(=O)OC(C)(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 25.5 %

Procedure:
To a solution of N-{2-(tert-butyldimethylsilyloxy)ethyl}-1-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-1H-pyrazole-4-carboxamide prepared in Example 67-(1) (0.700 g) in N,N-dimethylformamide (5.0 mL), sodium hydride (55% in mineral oil, 0.058 g) was added and stirred at room temperature for 20 minutes. To the reaction mixture, tert-butyl 2-bromoacetate (0.281 g) was added and stirred for 30 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=1:1) to give the titled compound (0.220 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[CH2:10][C:9]1=[O:15])[C:4]([O:6][CH3:7])=[O:5].[CH3:17][C:18]([CH3:20])=[O:19].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]([CH3:16])=[C:3]([N:8]1[C@H:11]([CH2:12][CH:13]=[CH2:14])[C@@H:10]([C:18]([OH:19])([CH3:20])[CH3:17])[C:9]1=[O:15])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)=O
Reactant: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC[C@@H]1[C@@H](C(C)(C)O)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
1.55M Butyl lithium-hexane solution (2.82 ml) was added to a solution of N-isopropylcyclohexylamino (0.72 ml) in tetrahydrofuran (6 ml) at -70° C., and the mixture was stirred for 20 minutes at -70° C. This mixture was added to a solution of methyl 3-methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (247 mg) in tetrahydrofuran (6 ml) at -70° C. and the mixture was stirred for 1 hour at -70° C., and for 30 minutes at -30° C. Acetone (0.12 ml) was added to the reaction mixture at -70° C., and the mixture was stirred for 1 hour at -70° C. and for 30 minutes at -30° C.--15° C. 3N Hydrochloric acid was added to the reaction mixture at -70° C. and the mixture was diluted with ethyl acetate (200 ml). The solution was washed with water, brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. Triethylamine (0.15 ml) was added to a solution of the residue in dichloromethane (3 ml) at 0° C. and the mixture was stirred overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate (20 ml) and the solution was washed with 0.1N hydrochloric acid (15 ml) brine, aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (10 g) eluting with a mixture of benzene and acetone (10:1-2:1) to give methyl 3-methyl-2-[(3S,4R)-3-(1hydroxy-1-methylethyl)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (100 mg);
Reaction SMILES: [OH:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:12]([O:14][CH3:15])=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.N1C=CC=CC=1.[Cl:22][C:23](Cl)([O:25]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:22][C:23]([O:1][CH:2]1[CH:9]2[CH2:10][C:5]3([C:12]([O:14][CH3:15])=[O:13])[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2)=[O:25]
Reactant: COC(=O)C12CC3CC(C1)C(O)C(C3)C2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C12CC3CC(C1)C(OC(=O)Cl)C(C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 272.7 %

Procedure:
A stirred solution of methyl 4-hydroxyadamantane-1-carboxylate (1.01 g, 4.8 mmol) and pyridine (0.38 mL, 4.8 mmol) in CH2Cl2 (25 mL) was cooled in an ice bath and a solution of triphosgene (0.48 g, 1.6 mmol) in CH2Cl2 (10 mL) was added dropwise over 15 min. The ice bath was allowed to melt and the mixture was stirred for 3 h at rt.* The mixture was evaporated to dryness and the residue was triturated with EtOAc (100 mL). The filtrate was concentrated to afford 1-(methoxycarbonyl)-4-adamantyl chloroformate (1.19 g, 91%) as an oil. [* In some experiments the solution of 1-(methoxycarbonyl)-4-adamantyl chloroformate was used directly.]
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH2:5][NH2:6].[OH-].[Na+].[N:9]1([CH2:15][C:16]2[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.ClCCCN>C1C=CC=CC=1.CS(C)=O>[NH2:6][CH2:5][CH2:4][CH2:3][O:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:9]1[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: NCCCCl
Reactant: Oc1cccc(CN2CCCCC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 130 °C
Yield: 86 %

Procedure:
3-Chloropropylamine hydrochloride (VI) (0.2 mol, 39 g) was dissolved into 3N sodium hydroxide solution (containing 10% sodium chloride) and extracted with 300 ml of benzene. The benzene layer was dried over anhydrous magnesium sulfate. Separately, 3-piperidinomethylphenol (V) (0.2 mol, 38.2 g), sodium hydroxide (0.25 mol, 10 g), 100 ml of dimethylsulfoxide, and 70 ml of benzene were charged to a flask equipped with a water quantitative measurement tube, and heated at 130° C. for 3 hours while stirring to remove water produced by the tube, followed by continued stirring for 2 hours at 140°-150° C. To the resulting reaction mixture was dropwise added said benzene solution of 3-chloropropylamine at 150° C. while stirring over 4 hours. The reaction mixture was allowed to stand still to cool to room temperature to separate deposited sodium chloride by filtration. The filtrate was concentrated under reduced pressure and vacuum distilled to obtain 42.7 g of N-[3-(3-aminopropoxy)benzyl] piperidine (VII) (yield: 86.0%). m.p. 148°-151° C./0.25 mmHg.
Reaction SMILES: [C:1]([N:5]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25]I.Cl>CN(C)C=O.O>[CH3:25][N:6]([C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:15](=[O:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)N(NC(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccccc1)N(C(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of N'-t-butyl-N,N'-dibenzoylhydrazine (2.5 g, 0.008M) in dimethylformamide (DMF) (30 ml) at room temperature under nitrogen was added portionwise sodium hydride (60% oil dispersion) (0.4 g, 0.009M). The mixture was stirred at room temperature for 0.5 hours, and then methyl iodide (1.0 g, 0.008M) was added dropwise. The reaction mixture was allowed to stir for 1 hour. The mixture was then diluted with water (50 ml), neutralized with 10% HCl and the product extracted into methylene chloride (50 ml). The methylene chloride layer was washed with water (5×20 ml), dried over anhydrous magnesium sulfate and the methylene chloride removed under vacuum to afford N-methyl-N'-t-butyl-N,N'-dibenzoylhydrazine as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH2:10]([O:12][C:13](=[O:22])[CH:14]=[CH:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH3:11].C(OCC)C.Cl>ClCCl>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[C:4]2[C:3]=1[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:22])=[N:5]2
Reactant: CCOC(=O)C=CCC(=O)OCC
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(=O)OCC)c2c(Cl)cc(Cl)cc2n1
Yield: 10.4 %

Procedure:
3.5-Dichloraniline (10.95 g) and diethylglutaconate (13.5 g) were dissolved in dry dichloromethane and heated at reflux for 14 h. Diethyl ether, saturated with hydrogen chloride (10 ml) was added and the reaction mixture was heated at reflux for a further 24 h. After this time the solution was filtered and the filtrate was washed with saturated sodium hydrogen carbonate solution, dried (Na2SO4), filtered and concentrated in vacuo to give an oily residue which was purified by silica gel chromatography using 15% ethyl acetate in hexane as the eluent to give as a colourless solid, 5,7-dichloro-2,4-diethoxycarbonylquinoline (2.4 g, m.p. 104°-106° C.); δ (360 MHz, CDCl3), 1.44 (3H, t, J=7.2 Hz, CH3CH2), 1.49 (3H, t, J=7.2 Hz, CH3CH2), 4.51 (2H, q, J=7.2 Hz, CH3CH2), 4.56 (2H, q, J=7.2 Hz, CH3CH2), 7.77 (1H, d, J=1.9 Hz, 6-H or 8-H), 8.17 (1H, s, 3-H) and 8.32 (1H, d, J=1.9 Hz, 6-H or 8-H); m/z 342 (M+1), 269 (100%, M+1 -CO2Et); Found: C, 52.58; H, 3.87; N, 4.04. C15H13Cl2NO4 requires C, 52.65; H, 3.83; N, 4.09% and 5,7-dichloro-4-(3,5-dichloroanilino)-2,4-diethoxycarbonyl-1,2,3,4-tetrahydro-quinoline (0.23 g, m.p. 153°-154° C.; δ (360 MHz, CDCl3) 1.29 (6H, t, J=7.2 Hz, CH3CH2 ×2), 2.34 (1H, dd, J=14.4 and 2.9 Hz, CHAHB -CHC), 2.65 (1H, dd, J=14.4 and 12.3 Hz, CHAHB -CHC), 4.27 (5H, m, CH3CH2 ×2 and HC), 4.91 (1H, br, NH), 5.54 (1H, br, NH), 6.28 (2H, d, J=1.8 Hz, ortho anilino protons), 6.60 (1H, t, J=1.8 Hz, para anilino proton), 6.64 (1H, d, J=2.1 Hz, 6-H or 8-H), 6.68 (1H, d, J=2.1 Hz, 6-H or 8-H); m/z 506 and 504 (M+), 433 (100%, M-CO2Et); Found: C, 49.95; H, 4.07; N, 5.51. C21H20Cl4N2O4 requires C, 49.83; H, 3.98; N, 5.53%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([O:19][CH:20]([CH3:22])[CH3:21])=[C:3]1[C:23]([O:25]C(C)(C)C)=[O:24].[OH-].[Na+].O>COCCO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:8][CH:9]=2)[C:4]([O:19][CH:20]([CH3:22])[CH3:21])=[C:3]1[C:23]([OH:25])=[O:24]
Reactant: CC(C)Oc1c(C(=O)OC(C)(C)C)n(C)c2ccc(OCc3ccccc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: CC(C)Oc1c(C(=O)O)n(C)c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
A suspension of 1,1-dimethylethyl 1-methyl-3(1-methylethoxy)-5-(phenylmethoxy)-1H-indole-2-carboxylate (5.6 g, 14 mmol) in 80 mL of 2-methoxyethanol is treated with a solution of 50% aqueous sodium hydroxide (5.0 g, 63 mmol) followed by the addition of 15 mL of water. The mixture is stirred at reflux for 3 hours, then cooled and added to 700 mL of water. The mixture is heated on a hot plate until nearly one phase and filtered hot. The warm filtrate is immediately treated with 50 mL of 4.0N HCl. After cooling to room temperature, followed by 1 hour in an ice bath, the precipitated solid is filtered and washed with 25% methanol in water to give 4.2 g (88%) of product suitable for further synthesis. A sample recrystallized from ethyl acetate-hexane has mp 136° C.-dec.