Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH:16]3[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.S([O-])([O-])(=O)=O.[Na+].[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(O)(=O)C.CN(C)C=O>[N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:20][CH2:19][CH2:18][N:17]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:16]3[CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NCCC1NCCCC1Nc1nccc(N2CCCCCC2)n1
Reactant: O=C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)NCCC1C(Nc2nccc(N3CCCCCC3)n2)CCCN1C1CCCCC1

Procedure:
The compound 20 (151 mg), dimethylformamide (3 mL), acetic acid (0.03 mL), cyclohexanone (0.37 mL), anhydrous sodium sulfate (800 mg) and sodium triacetoxyborohydride (765 mg) were stirred at room temperature for 1 day. The reaction solution was added aqueous 2N sodium hydroxide solution and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and then concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:methanol:triethylamine=80:10:1) to obtain the title compound (118 mg) having the following physical properties.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[NH:9]1[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:4]1[CH:3]=[C:2]([N:9]2[CH2:14][CH2:13][S:12](=[O:16])(=[O:15])[CH2:11][CH2:10]2)[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)c1
Reactant: O=S1(=O)CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=S1(=O)CCN(c2cccc(Br)c2)CC1
Temperature: 80 °C
Yield: 48.4 %

Procedure:
A mixture of 1,3-dibromobenzene (242 μL, 2.00 mmol), thiomorpholine 1,1-dioxide (270 mg, 2.00 mmol), Pd2(dba)3 (45.8 mg, 0.0500 mmol), rac-BINAP (96.3 mg, 0.150 mmol) and NaOtBu (231 mg, 2.40 mmol) in toluene was heated at 80° C. for 11 hours under nitrogen. After cooling to room temperature, the mixture was diluted with DCM and filtered through a Celite pad. The combined filtrate and washings were concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=90:10→80:20→75:25) to afford desired product (281 mg, 48.4%) as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CN=C1.[OH:14][CH2:15][C@@H:16]([CH3:48])[C@H:17]([NH:28][C:29]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:41]2[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>C(Cl)Cl>[Si:5]([O:14][CH2:15][C@@H:16]([CH3:48])[C@H:17]([NH:28][C:29]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=2[C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6]
Reactant: C[C@H](CO)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H](NC1(c2ccccc2)c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Reaction time: 14.25 h

Procedure:
TBDMS-Cl (48 mg, 0.312 mmol) followed by imidazole (28.8 mg, 0.423 mmol) were added to a CH2Cl2 (3 ml) solution of (2S,3S)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate (119.5 mg, 0.258 mmol), and the mixture was stirred at ambient condition for 14.25 hr. The reaction mixture was then diluted with CH2Cl2 (30 mL) and washed with water (15 mL), and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The resultant crude material was purified with a Biotage (40 g silica gel; 5% EtOAc/hexanes) to afford (2S,3S)-benzyl 4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate, contaminated with TBDMS based impurities, as a colorless viscous oil (124.4 mg). (2S,3R)-benzyl 4-hydroxy-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate was elaborated similarly to (2S,3R)-benzyl 4-(tert-butyldimethylsilyloxy)-3-methyl-2-(9-phenyl-9H-fluoren-9-ylamino)butanoate. (2S,3S)-silyl ether isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz), 7.82 (d, J=4.1, 1H), 7.80 (d, J=4.0, 1H), 7.38-7.07 (m, 16H), 4.70 (d, J=12.4, 1H), 4.42 (d, J=12.3, 1H), 3.28-3.19 (m, 3H), 2.56 (dd, J=10.1, 5.5, 1H), 1.61 (m, 1H), 0.90 (d, J=6.8, 3H), 0.70 (s, 9H), −0.13 (s, 3H), −0.16 (s, 3H). LC (Cond. 1, where the run time was extended to 4 min): RT=3.26 min; LC/MS: Anal. Calcd. for [M+H]− C37H44NO3Si: 578.31. found 578.40. (2S,3R)-silyl ether isomer: 1H NMR (DMSO-d6, δ=2.5 ppm, 400 MHz), 7.82 (d, J=3.0, 1H), 7.80 (d, J=3.1, 1H), 7.39-7.10 (m, 16H), 4.66 (d, J=12.4, 1H), 4.39 (d, J=12.4, 1H), 3.61 (dd, J=9.9, 5.6, 1H), 3.45 (d, J=9.5, 1H), 3.41 (dd, J=10, 6.2, 1H), 2.55 (dd, J=9.5, 7.3, 1H), 1.74 (m, 1H), 0.77 (s, 9H), 0.61 (d, J=7.1, 3H), −0.06 (s, 3H), −0.08 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:12][CH2:11][CH2:10][CH:4]([C:5]([O:7]CC)=[O:6])[CH2:3]1.[OH-].[Li+].Cl>O1CCOCC1.O>[CH3:1][N:2]1[CH2:12][CH2:11][CH2:10][CH:4]([C:5]([OH:7])=[O:6])[CH2:3]1
Reactant: CCOC(=O)C1CCCN(C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 1-methylnipecotate, 0.3 mL (1.65 mmol) in 10 mL of dioxane was added a solution of 118 mg (4.95 mmol) of lithium hydroxide in 10 mL of water. The solution was stirred for 1.5 hours at rt. then was acidified to pH=1 with 5N HCl. The mixture was concentrated to dryness and carried on without further purification. IS (MS) 144.1 (M+1).
Reaction SMILES: C(O)C.C(OC(=O)[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[N:12]=1)(C)(C)C.Cl>C(OCC)(=O)C>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([S:26]([CH:17]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:13]2[N:12]=[C:11]([NH2:10])[CH:16]=[CH:15][CH:14]=2)(=[O:28])=[O:27])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 71.8 %

Procedure:
To an ethanol (5 ml) solution of t-butyl[6-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]carbamate (370 mg, 0.748 mmol) was added concentrated hydrochloric acid (5 ml). The resulting mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure. To the residue thus obtained was added ethyl acetate. The resulting mixture was washed sequentially with saturated sodium bicarbonate and brine. The organic layer thus obtained was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (210 mg, 0.537 mmol, 71%) as a white powder.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([S:13]CC2C=CC(OC)=CC=2)[CH2:10][C@H:9]1[CH2:23][N:24]([CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:7])[CH2:2][CH2:3][CH3:4].C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([SH:13])[CH2:10][C@H:9]1[CH2:23][N:24]([CH2:34][C:35]([OH:37])=[O:36])[CH2:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1C[C@H](SCc2ccc(OC)cc2)C[C@H]1CN(CC(=O)OC(C)(C)C)Cc1cc(F)ccc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)N1C[C@H](S)C[C@H]1CN(CC(=O)O)Cc1cc(F)ccc1F
Yield: 48.6 %

Procedure:
250 mg (0.42 mmol) (2S,4R)-2-[[tert-butoxycarbonylmethyl-(2,5-difluoro-benzyl)-amino]-methyl]-4-(4-methoxy-benzylsulfanyl)-pyrrolidine-1-carboxylic acid butyl ester were treated with 670 μl (4.2 mmol, 10 eq) triethyl silane in 7.5 ml TFA at 80° C. for 1.5 h. The solvent was evaporated and the residue was redissolved in toluene and evaporated. The crude material was purified by flash chromatography yielding 85 mg (49%) (2S,4R)-2-[[carboxymethyl-(2,5-difluoro-benzyl)-amino]-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid butyl ester as light brown oil, MS: 417 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.N1CCC[C@@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:20]([O:27][C:28]1[CH:37]=[C:36](I)[CH:35]=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Cu]I.C(OCC)(=O)C.O.CS(C)=O>[CH2:20]([O:27][C:28]1[CH:37]=[C:36]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:35]=[CH:34][C:29]=1[C:30]([O:32][CH3:33])=[O:31])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1ccc(I)cc1OCc1ccccc1
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C(O)[C@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(-n2ccnc2)cc1OCc1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
1H-Imidazole (0.044 g), D-proline (0.013 g), potassium carbonate (0.15 g), and copper(I) iodide (0.010 g) were added to a dimethyl sulfoxide (1 mL) solution of methyl 2-(benzyloxy)-4-iodobenzoate (0.20 g), followed by stirring under a nitrogen atmosphere at 90° C. for 1 hour. The reaction mixture was cooled to room temperature, and then dimethyl sulfoxide (0.5 mL), D-proline (0.013 g), and copper(I) iodide (0.010 g) were added thereto, followed by stirring under a nitrogen atmosphere at 90° C. for 2 hours. After cooling the reaction mixture to room temperature, water and ethyl acetate were added thereto, and the insoluble substance was removed by filtration. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [Fuji Silysia Chemical Ltd., PSQ100B (spherical), eluent: 90-20% hexane/ethyl acetate] to obtain 0.13 g of methyl 2-(benzyloxy)-4-(1H-imidazol-1-yl)benzoate as a white solid.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=4[C:10]3=[N:9][C:8]=2[C:22]([NH2:24])=[O:23])[CH:5]=[CH:4][CH:3]=[N:2]1.BrC1C=CC2OCCN3C(CN4C=CN=C4C)=C(C(N)=O)N=C3C=2C=1.N1C=CC=N1.[CH3:55][C:56]([OH:60])([C:58]#[CH:59])[CH3:57]>>[N:1]1([CH2:6][C:7]2[N:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:20]=[CH:19][C:18]([C:59]#[C:58][C:56]([OH:60])([CH3:57])[CH3:55])=[CH:17][C:16]=4[C:10]3=[N:9][C:8]=2[C:22]([NH2:24])=[O:23])[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2n(c1Cn1cccn1)CCOc1ccc(Br)cc1-2
Agent: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: c1cn[nH]c1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(Cn3cccn3)n1CCO2
Yield: 14 %

Procedure:
Similar to as described in General Procedure G, 3((1H-pyrazol-1-yl)methyl)-10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3-((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing 2-methylimidazole with pyrazole) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as a colorless solid (14 mg, 14%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[Cl:13][CH2:14][C:15](Cl)=[O:16].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[Cl:13][CH2:14][C:15]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:12])[NH:10]2)=[O:16]
Reactant: O=C1CCc2cccc(O)c2N1
Reactant: O=C(Cl)CCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C1CCc2c(C(=O)CCl)ccc(O)c2N1
Reaction time: 15 h
Yield: 37.7 %

Procedure:
13 g of 8-hydroxy-3,4-dihydrocarbostyril (VII) and 20 g of chloroacetyl chloride were dissolved in 100 ml of nitrobenzene, and 40 g of aluminum chloride was added slowly to the mixture followed by stirring for 15 hours at a temperature of 70° to 75° C. The mixture was then steam-distilled to remove nitrobenzene. After allowing the mixture to cool, the precipitated crystals were filtered, washed with hot water and recrystallized from methanol to give 7.2 g of 5-chloroacetyl-8-hydroxy-3,4-dihydrocarbostyril (IV) as light yellow crystals having a melting point of 189° to 190° C.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH:7]=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[C:28]([NH2:35])[CH:27]=2)[C:3]=1[C:4]#[N:5].[Cl:36][CH2:37][C:38](Cl)=[O:39]>C1COCC1>[NH2:1][C:2]1[C:3]([C:4]#[N:5])=[C:6]([C:26]2[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[C:28]([NH:35][C:38](=[O:39])[CH2:37][Cl:36])[CH:27]=2)[CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:9]=1
Reactant: COc1ccc(COc2ccccc2-c2cc(-c3ccc(N(C)C)c(N)c3)c(C#N)c(N)n2)cc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: COc1ccc(COc2ccccc2-c2cc(-c3ccc(N(C)C)c(NC(=O)CCl)c3)c(C#N)c(N)n2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a cooled (0° C.), stirred solution of 2-amino-4-[3-amino-4-(dimethylamino)phenyl]-6-{2-[(4-methoxybenzyl)-oxy]phenyl}nicotinonitrile (starting compound 4, 0.500 g, 1.724 mmol) in THF (7 mL) under an argon atmosphere was added chloroacetyl chloride (0.121 g, 1.074 mmol). The mixture was stirred at 0° C. for 15 minutes and then partitioned between ethyl acetate and saturated aqueous NaHCO3. The separated organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was suspended in ethyl acetate and ethanol. The resulting solid was collected by filtration, washed with ethanol, and dried under reduced pressure to give N-[5-(2-amino-3-cyano-6-{2-[(4-methoxybenzyl)oxy]-phenyl}-4-pyridinyl)-2-(dimethylamino)phenyl]-2-chloroacetamide as a yellow solid. (0.410 g, yield 70%)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:23][O:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([S:35](Cl)(=[O:37])=[O:36])=[CH:27][CH:26]=1>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH3:23][O:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([S:35]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([C:10]([OH:12])=[O:11])=[CH:2]2)(=[O:37])=[O:36])=[CH:27][CH:26]=1
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: COc1ccc(S(=O)(=O)Cl)c2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2cc(C(=O)O)c3ccccc32)c2ccccc12
Yield: 93 %

Procedure:
To a solution of 1H-indole-3-carboxylic acid (0.5 g, 3.1 mmol) in tetrahydrofuran (20 cm3 at 0° C. was added sodium bis(trimethylsilyl)amide (6.2 cm3, 6.2 mmol) dropwise under nitrogen. The solution was stirred at 0° C. for 30 m before addition of 4-methoxy-1-naphthyl sulfonyl chloride (0.8 g, 3.1 mmol) and the resultant solution was stirred at room temperature for 18 h. The solution was diluted with saturated aqueous sodium bicarbonate solution and washed with ethyl acetate. The aqueous layer was acidified to pH 1 with 5N hydrochloric acid and the product extracted into ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and the filtrate evaporated under reduced pressure to give the title compound (A) (1.1 g, 93%).
Reaction SMILES: C(O[C:5]1([NH:21][O:22][CH3:23])[C:17]2[C:12](=[C:13]([CH3:20])[C:14]([CH3:19])=[CH:15][C:16]=2[CH3:18])[O:11][C:7]2([CH2:10][CH2:9][CH2:8]2)[CH2:6]1)(=O)C.[OH-].[Li+].C(OCC)(=[O:28])C>CO>[CH3:23][O:22][NH:21][CH:5]1[C:17]2[C:12](=[C:13]([CH3:20])[C:14]([CH3:19])=[C:15]([OH:28])[C:16]=2[CH3:18])[O:11][C:7]2([CH2:8][CH2:9][CH2:10]2)[CH2:6]1
Reactant: CCOC(C)=O
Reactant: CONC1(OC(C)=O)CC2(CCC2)Oc2c(C)c(C)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CONC1CC2(CCC2)Oc2c(C)c(C)c(O)c(C)c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (4-(methoxyamino)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-4-yl acetate) (80 mg) in methanol (8 mL) was added lithium hydroxide (4%) water solution under nitrogen. The solution was stirred at room temperature for 2 hours. Ethyl acetate was added. The organic layer was washed with ammonium hydrochloride water solution, water and brine. The solution was evaporated and chromatographed (silica gel, hexane-ethyl acetate 2% to 8%) to give 70 mg of 4-(methoxyamino)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].[N:6]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][CH2:10]N[CH2:8][CH2:7]1>O1CCOCC1>[NH2:4][S:1]([N:5]1[CH2:10][CH2:11][N:6]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:7][CH2:8]1)(=[O:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: NS(N)(=O)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(S(N)(=O)=O)CC1
Yield: 70 %

Procedure:
Sulfamide (5 eq) was added to a solution of tert-butyl piperazine-1-carboxylate in dioxane (0.12 M). The reaction was stirred at reflux overnight. The solvent was removed in vacuo, the residue taken up in EtOAc and washed with H2O, brine, before being dried (Na2SO4), filtered and concentrated in vacuo to give the crude material. Purification was by automated FC (EtOAc:PE:Et3N 40:60:0.02) to afford the title compound (70%). 1H NMR (300 MHz, DMSO-d6, 300 K) δ 1.39 (s, 9H), 2.88-2.90 (m, 4H), 3.37-3.39 (m, 4H), 6.78 (s, 2H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH2:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[BH4-].[Na+].[C:22](O)(=[O:24])[CH3:23]>C(O)C.[OH-].[Na+]>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][CH2:11][C:12]([O:24][CH2:22][CH3:23])([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: C=C(COC1CCN(C(C)=O)CC1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(C)(COC1CCN(C(C)=O)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-Acetyl-4-(2-phenylallyloxy)piperidine (7.0 g.) (prepared as in Example BB) in ethanol (10 ml.) was added to a stirred suspension of mercuric acetate (9.2 g.) in ethanol (50 ml.) at room temperature. The mixture was stirred at room temperature for one hour then cooled to 0° C. Sodium hydroxide solution (20 ml., 5 N) followed by sodium borohydride (1.03 g.) in sodium hydroxide solution (20 ml., 5 N) were added to the stirred suspension and after 10 minutes glacial acetic acid was added to pH 6. The suspension was filtered, the filtrate concentrated and the residue partitioned between chloroform and water. The organic layer was dried (Na2SO4) and the solvent evaporated in vacuo. Gas-liquid chromatographic (GLC) analysis of the product indicated incomplete conversion to the desired product therefore the oxymercuration process was repeated as above to give N-acetyl-4-(2-ethoxy-2-phenyl-n-propoxy)piperidine (7.4 g.), 84% pure by GLC. The product in ethanol (100 ml.) and sodium hydroxide solution (30 ml.) was heated under reflux for 11 hours. The organic solvent was evaporated and the aqueous solution was extracted with chloroform (3×30 ml.). The combined chloroform extracts were dried (Na2SO4) and the solvent evaporated in vacuo to give 4-(2-ethoxy-2-phenyl-n-propoxy)piperidine as an oil (3.8 g.). A sample was converted to the oxalate salt which was recrystallized twice from ethyl acetate then acetone and had an m.p. of 126°-127° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:37]=[CH:36][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)\[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C.CCCCCC>[CH3:8][C:7]1[S:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:4][C:3]=1[CH2:2][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:20][O:21]/[N:22]=[C:23](/[C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)\[CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:36][CH:37]=1
Reactant: Cc1sc(-c2ccccc2)nc1CCl
Reactant: COC(=O)CC/C(=N\OCc1ccc(O)cc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)sc2C)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.4 %

Procedure:
A mixture of 4-(chloromethyl)-5-methyl-2-phenylthiazol (394 mg), methy E-4-(4-hydroxybenzyloxyimino)-4-phenylbutyrate (500 mg), potassium carbonate (442 mg) and N,N-dimethylormamide (10 ml) was stirred at room temperature for 72 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was subjected to silica gel chromatography to obtain methy E-4-[4-(5-methyl-2-phenyl-4-thiazolylmethoxy) benzyloxyimino]-4-phenylbutyrate (570 mg, yield 71%) as a colorless oil from an ethyl acetate-hexane (1:5, v/v)-eluted fraction.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][C:18]3C=CC=CC=3)[CH2:12][CH2:11][C:10]=2[CH:9]=[N+:8]([O-])[C:7]=1[OH:25])=[O:5])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][C:4]([C:6]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:17][CH3:18])[CH2:12][CH2:11][C:10]=2[CH:9]=[N:8][C:7]=1[OH:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2c(c[n+]([O-])c1O)CCN(Cc1ccccc1)CC2
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)c1c(O)ncc2c1CCN(CC)CC2

Procedure:
Prepared from 4-ethoxycarbonyl-3-hydroxy-7-benzyl-6,7,8,9-tetrahydro-5H-pyrido[3,4-d]azepine 2-oxide by hydrogenation in ethanol at 130° C. in the presence of Raney nickel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([O:14]C)=[O:13])[NH:7]2.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[C:6]([C:12]([OH:14])=[O:13])[NH:7]2
Reactant: COC(=O)c1cc2c(OC)cccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: COc1cccc2[nH]c(C(=O)O)cc12
Yield: 99.6 %

Procedure:
The carboxylate (3a) (4 g, 19.49 mmol, 1 eq) obtained in (2-1) was added to aqueous solution of sodium hydroxide (2M, 98 mL, 0.20 mmol, 10 eq). The suspension was stirred and heated until the reaction mixture was uniform, and then refluxed for 30 minutes with heating. The mixture solution was acidified, and the resulting precipitate was extracted three times with ethyl acetate (100 mL). The extracts were combined, washed with water, dried over magnesium sulfate, and concentrated to give white solid of the title compound (4a) (3.71 g, yield 99%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]2.[F:15][C:16]1[CH:17]=[C:18]([OH:31])[CH:19]=[C:20]([C@@:22]2([O:29][CH3:30])[CH2:27][CH2:26][O:25][C@@H:24]([CH3:28])[CH2:23]2)[CH:21]=1>>[F:15][C:16]1[CH:17]=[C:18]([O:31][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]([CH3:13])[C:8](=[O:14])[CH:7]=[CH:6]3)[CH:19]=[C:20]([C@@:22]2([O:29][CH3:30])[CH2:27][CH2:26][O:25][C@@H:24]([CH3:28])[CH2:23]2)[CH:21]=1
Reactant: Cn1c(=O)ccc2cc(CBr)ccc21
Reactant: CO[C@]1(c2cc(O)cc(F)c2)CCO[C@@H](C)C1
Product: CO[C@]1(c2cc(F)cc(OCc3ccc4c(ccc(=O)n4C)c3)c2)CCO[C@@H](C)C1
Yield: 66 %

Procedure:
Using the procedure described in Example 1, 6-bromomethyl-1,2-dihydro-1-methylquinolin-2-one was reacted with (2S,4R)-4-(5-fluoro-3-hydroxyphenyl)-4-methoxy-2-methyltetrahydropyran to give (2S,4R)-4-[5-fluoro-3-(1,2-dihydro-1-methyl-2-oxoquinolin-6-ylmethoxy)phenyl]-4-methoxy-2-methyltetrahydropyran in 66% yield, m.p. 91°-93° C.