Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.CN(C=O)C.[N+:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1)([O-:31])=[O:30]>O>[N+:29]([C:32]1[CH:33]=[CH:34][C:35]([C:36]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)[CH2:2][CH2:3]2)=[O:37])=[CH:39][CH:40]=1)([O-:31])=[O:30]
Reactant: O=C1CCc2cc(N3CCNCC3)ccc2N1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C1CCc2cc(N3CCN(C(=O)c4ccc([N+](=O)[O-])cc4)CC3)ccc2N1
Temperature: 25 °C
Yield: 56.1 %

Procedure:
6-(1-Piperazinyl)-3,4-dihydrocarbostyril (2.6 g) and 2 ml of pyridine were added to 40 ml of DMF. The mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 2.7 g of 4-nitrobenzoyl chloride. After completion of addition, the reaction mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol-chloroform to give 2.4 g of 6-[4-(4-nitrobenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 235.5°-236.5° C.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=O)=[C:16]3[N:15]=[C:14]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])[CH2:25][CH2:24]3)[C:13]=2[CH3:37])[CH2:10][CH2:9]1.N1CCCCC1>C(O)C.O>[CH:8]1([NH:11][C:12]2[N:17]3[N:18]=[CH:19][C:20]([CH:21]=[C:7]4[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1]4)=[C:16]3[N:15]=[C:14]([N:23]3[CH2:28][CH2:27][N:26]([C:29]4[N:36]=[CH:35][CH:34]=[CH:33][C:30]=4[C:31]#[N:32])[CH2:25][CH2:24]3)[C:13]=2[CH3:37])[CH2:9][CH2:10]1
Reactant: Cc1c(N2CCN(c3ncccc3C#N)CC2)nc2c(C=O)cnn2c1NC1CC1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: O
Solvent: CCO
Product: Cc1c(N2CCN(c3ncccc3C#N)CC2)nc2c(C=C3NC(=O)NC3=O)cnn2c1NC1CC1
Temperature: 80 °C
Yield: 15.5 %

Procedure:
Hydantoin (7.5 mg, 0.08 mmol) and 2-(4-(7-(cyclopropylamino)-3-formyl-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile (15 mg, 0.04 mmol) were dissolved in ethanol (0.5 mL) along with piperidine (8 uL, 0.08 mmol). The reaction was heated at 80° C. for 1 hour in the microwave. The reaction was then cooled to r.t., diluted with water, and the precipitate was collected and washed with water, 1:1 ethanol:water, then ethanol. The yellow solid was dried in vacuo to give 2-(4-(7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-6-methylpyrazolo[1,5-a]pyrimidin-5-yl)piperazin-1-yl)nicotinonitrile (3 mg, 17% yield). LCMS (M+1=485)
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([C:15]([OH:17])=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li].O/[N:20]=[C:21](/[C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[CH2:31][CH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29]2)=[CH:25][CH:24]=1)\[NH2:22].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl>CN(C=O)C>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]([C:15]3[O:17][N:22]=[C:21]([C:23]4[CH:24]=[CH:25][C:26]([CH2:27][N:28]5[CH2:29][CH:30]([C:32]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:33])[CH2:31]5)=[CH:39][CH:40]=4)[N:20]=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: CCCc1c(-c2ccccc2)noc1C(=O)O
Agent: On1nnc2ccccc21
Agent: [Li]
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1c(-c2ccccc2)noc1-c1nc(-c2ccc(CN3CC(C(=O)OC(C)(C)C)C3)cc2)no1
Temperature: 60 °C
Reaction time: 5 h
Yield: 43.9 %

Procedure:
A mixture of 3-phenyl-4-propylisoxazole-5-carboxylic acid, lithium salt (23.12 mg, 0.1 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate, Int.1 (30.5 mg, 0.1 mmol), HOBT (16.85 mg, 0.110 mmol), diisopropylethylamine (0.044 mL, 0.250 mmol) and EDC (23.00 mg, 0.120 mmol) was stirred in DMF (1 mL) at rt for 18 hr. Additional EDC (23.00 mg, 0.120 mmol) was added and the reaction mixture was stirred at 60° C. for 5 hr. The reaction mixture was partitioned between EtOAc (30 mL) and saturated sodium bicarbonate solution (30 mL). The organic layer was washed with water (2×25 mL), brine (25 mL), dried (MgSO4) and concentrated to afford an oil that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-50% EtOAc/Hex gradient. The essentially pure fractions containing product were concentrated to afford tert-butyl 1-(4-(5-(3-phenyl-4-propylisoxazol-5-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (22 mg, 0.044 mmol, 43.9% yield) as a colorless oil. HPLC retention time=1.84 minutes (PHENOMENEX® Luna 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1% TFA over a 2 minute gradient. MS: (M+H)=501.21.
Reaction SMILES: BrCCBr.[Mg].Br[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][C:8]=1[CH3:17].C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C>C1COCC1.O>[CH3:29][C:24]1([CH3:30])[C:25]([CH3:28])([CH3:27])[O:26][B:22]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][C:8]=2[CH3:17])[O:23]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1ccc2ccccc2c1Br
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Solvent: O
Product: Cc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Reaction time: 0.17 h

Procedure:
1,2-Dibromoethane (˜0.3 ml) was added to 6.10 g (250 mmol) magnesium turnings in 1000 cm3 of THF. This mixture was stirred for 10 min, and then 55.3 g (250 mmol) of 1-bromo-2-methylnaphthalene was added for 1 h by vigorous stirring at room temperature for 3.5 h. Thereafter, 46.5 g (250 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added in one portion. The resulting mixture was stirred for 15 minutes and then was poured into 1000 cm3 of cold water. The product was extracted with 3×300 ml of ethyl acetate. The organic layer was separated, washed by water, brine, then dried over MgSO4, and, finally; evaporated to dryness. The resulting white solid was washed by 2×75 ml of pentane and dried in vacuum. Yield 47.3 g (70%). Anal. calc. for C17H21BO2: C, 76.14; H, 7.89. Found: C, 76.31; H, 8.02. 1H NMR (CDCl3): 8.12 (m, 1H, 8-H), 7.77 (m, 1H, 5-H), 7.75 (d, J=8.4 Hz, 1H, 4-H), 7.44 (m, 1H, 7-H), 7.38 (m, 1H, 6-H), 7.28 (d, J=8.4 Hz, 1H, 3-H), 2.63 (s, 3H, 2-Me), 1.48 (s, 12H, CMe2CMe2).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14](I)[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:32][C@@H:33]([OH:36])[C:34]#[CH:35].CN(C=O)C>N(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([C:35]#[C:34][C@@H:33]([OH:36])[CH3:32])[CH:15]=[C:16]([CH2:21][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:29])[CH:11]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOCC3)cc(I)c21
Reactant: C#C[C@@H](C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Solvent: CN(C)C=O
Product: C[C@H](O)C#Cc1cc(CN2CCOCC2)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
To a solution of N-(4-chlorobenzyl)-8-iodo-1-methyl-6-(4-morpholinylmethyl)-4-oxo-1,4-dihydro-3-quinolinecarboxamide (300 mg), PdCl2(PPh3)2 (19.1 mg), and CuI (5.2 mg) in Et2NH (6.2 mL) is added (R)-(+)-3-butyn-2-ol (0.047 mL, 0.599 mmol). Anhydrous DMF (10 mL) is added to help solubilize the reactants (also requires sonication). The reaction is stirred at room temperature overnight, then condensed. The resulting residue is placed under high vac to remove residual DMF. The crude product is dissolved in CH2Cl2 and partitioned between CH2Cl2 and H20. The aqueous layer is extracted with CH2Cl2 (2×). The combined organic layers are dried over Na2SO4, filtered, and condensed. The crude product is adsorbed onto silica and chromatographed (eluent 100% CH2Cl2 (1L), 0.5% MeOH in CH2Cl2 (1L), 1% MeOH in CH2Cl2 (1L), 1.5% MeOH in CH2Cl2 (1L), and 2% MeOH in CH2Cl2 (4L)). Product-containing fractions are combined, concentrated, and recrystallized from hot acetonitrile to afford 90.7 mg (34%) of the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5](O)=O.[NH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[NH2:21]>P(Cl)(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]1[NH:21][C:20]2[CH:19]=[CH:18][N:17]=[CH:16][C:15]=2[N:14]=1
Reactant: COc1ccc(C(=O)O)c(OC)c1
Reactant: Nc1ccncc1N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2nc3cnccc3[nH]2)c(OC)c1

Procedure:
A mixture of 2,4 dimethoxybenzoic acid (2.5 g) and 3,4-diaminopyridine (1.5 g) was ground to a fine powder and added portionwise to phosphorus oxychloride (50 ml) with stirring. The mixture was stirred and heated under reflux for 2.5 hours before excess phosphorus oxychloride was removed in vacuo. The residue was cooled, water (20 ml) added and the pH adjusted to 7 with ammonium hydroxide to yield a pale yellow solid which was collected, washed with water and dried. The solid was recrystallised twice from aqueous ethanol to yield a cream coloured crystalline solid m.p. 195°-198°.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15](=[O:18])[NH:16][N:17]=[C:13]3[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11]([CH3:29])=[C:10]2[C:30]([NH2:32])=O)=[CH:5][CH:4]=1)#[N:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[C:15](=[O:18])[NH:16][N:17]=[C:13]3[N:12]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[C:11]([CH3:29])=[C:10]2[C:30]#[N:32])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC1=C(C(N)=O)C(c2ccc(C#N)cc2)n2c(n[nH]c2=O)N1c1cccc(C(F)(F)F)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2c(n[nH]c2=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38.5 %

Procedure:
Intermediate 13 (92 mg, 0.209 mmol) was dissolved in THF (8 mL), and Burgess reagent (150 mg, 0.63 mmol) was added. The reaction mixture was stirred at RT for 30 mins and was then partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer further extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated in vacuo. The resulting residue was purified by silica gel chromatography eluting with 80% EtOAc in cyclohexane as eluent to yield a white solid. Further purification was carried out by reverse phase HPLC using a gradient of 40-98% MeCN in water (+0.1% formic acid) to yield the title compound as a white solid (34 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:19]5[CH2:24][CH2:23][NH:22][CH:21]([CH3:25])[CH2:20]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:30]=O>C(O)=O>[CH:1]1([N:4]2[C:13]3[N:12]=[C:11]4[CH:14]=[C:15]([N:19]5[CH2:24][CH2:23][N:22]([CH3:30])[CH:21]([CH3:25])[CH2:20]5)[C:16]([F:18])=[CH:17][C:10]4=[CH:9][C:8]=3[C:7](=[O:26])[C:6]([C:27]([OH:29])=[O:28])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: C=O
Reactant: CC1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)CCN1
Solvent: O=CO
Product: CC1CN(c2cc3nc4c(cc3cc2F)c(=O)c(C(=O)O)cn4C2CC2)CCN1C

Procedure:
1-Cyclopropyl-8-(3,4-dimethyl-1-piperazinyl)- 7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid is prepared under the conditions of Reference Example 21 but starting from 1.9 g of 1-cyclopropyl-7-fluoro-8-(3-methyl-1-piperazinyl)-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid, 1.38 cm3 of formic acid and 3.30 cm3 of a 30% aqueous solution of formaldehyde. After recrystallizing crude product from 50 cm3 of ethanol, 1.3 g of 1the cyclopropyl-8-(3,4-dimethyl-1-piperazinyl)-7-fluoro-4-oxo-1,4-dihydro-benzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid melting at 219° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[C:17]([OH:19])[N:16]4[CH:20]=[CH:21][N:22]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[C:25](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.CN(C)C(=O)C.ClCCl>[CH3:25][N:1]1[CH2:2][CH2:3][CH:4]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:18]=[C:17]([OH:19])[N:16]4[CH:20]=[CH:21][N:22]=[C:15]4[CH:14]=3)=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Oc1nc(-c2ccc(C3CCNCC3)cc2)cc2nccn12
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: CN1CCC(c2ccc(-c3cc4nccn4c(O)n3)cc2)CC1
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a suspension of 7-(4-(piperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidin-5-ol (1.03 g, 3.50 mmol) in tetrahydrofuran (35 mL) and N,N-dimethylacetamide (2.5 mL) was added formaldehyde (5.21 mL, 70.0 mmol) followed by sodium triacetoxyborohydride (3.71 g, 17.5 mmol) and the reaction was allowed proceed at ambient temperature with stirring under nitrogen for 30 minutes. Aqueous saturated sodium bicarbonate was added slowly and gas evolution was observed. To the aqueous was added dichloromethane (100 mL) and a thick white precipitate was observed. The organic was collected and a second extraction with dichloromethane yielded a homogenous milky mixture. The biphasic mixture was filtered and the solid was washed with dichloromethane and retained. The biphasic mixture was separated and the aqueous was extracted with DCM. The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was triturated with diethyl ether and the resulting solids were collected by means of vacuum filtration. The two crops of solids were combined to afford 7-(4-(1-methylpiperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidin-5-ol (0.935 g, 3.03 mmol, 86.6% yield). MS (apci) m/z=309.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)[C:3]=1[C:4]#[N:5].ClC1C=CC=C(C(OO)=[O:31])C=1>ClCCl>[Cl:1][C:2]1[CH:9]=[N+:8]([O-:31])[CH:7]=[C:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:15]=2)[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(Cl)cncc1-c1ccc(Oc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: N#Cc1c(Cl)c[n+]([O-])cc1-c1ccc(Oc2ccccc2)cc1
Reaction time: 22 h
Yield: 63.1 %

Procedure:
A solution of 3-chloro-5-(4-phenoxyphenyl)isonicotinonitrile (0.495 g, 1.614 mmol) and 77% 3-chloroperbenzoic acid (1.808 g, 8.07 mmol) in dichloromethane (20 mL) was stirred at room temperature. After 22 h at room temperature, the mixture was diluted with dichloromethane (100 mL), washed with 1 M sodium sulfite (25 mL), 1 N NaOH (2×25 mL), brined (25 mL), dried (MgSO4) and concentrated. Silica gel chromatography, loading with dichloromethane and eluting with 20-50% ethyl acetate in hexanes, gave 3-chloro-4-cyano-5-(4-phenoxyphenyl)pyridine 1-oxide as white solid (328.8 mg, 63% yield). 1H NMR (400 MHz, CDCl3) δ ppm 8.25 (1H, δ, J=1.51 Hz), 8.16 (1H, δ, J=1.51 Hz), 7.46-7.58 (2H, m), 7.36-7.45 (2H, m), 7.21 (1H, t, J=7.40 Hz), 7.03-7.16 (4H, m); MS (ES+) m/z: 323 (M+H); LC retention time: 3.863 min (analytical HPLC Method A).
Reaction SMILES: [CH2:1]([N:3]([CH2:31][CH3:32])[C:4](=[O:30])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28]C)[CH:23]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].B(Br)(Br)Br.C(=O)(O)[O-].[Na+]>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:31]([N:3]([CH2:1][CH3:2])[C:4](=[O:30])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:32]
Reactant: CCCN1CCC(N(Cc2cccc(OC)c2)c2ccc(C(=O)N(CC)CC)cc2)CC1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCCN1CCC(N(Cc2cccc(O)c2)c2ccc(C(=O)N(CC)CC)cc2)CC1
Temperature: 25 °C
Reaction time: 21 h
Yield: 9 %

Procedure:
A solution of N,N-diethyl-4-[3-methoxybenzyl(1-propylpiperidin-4-yl)amino]benzamide (Compound 1) in 20 mL of dry dichloromethane was cooled to −78° C. under Argon. A solution of boron tribromide (6.44 mL, 6.44 mmol, 1.0 M) in dichloromethane was added dropwise. The reaction mixture was allowed to warm to ambient temperature overnight. After 21 h of stirring, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution (30 mL). The layers were separated, and the aqueous solution was extracted twice (30 mL) with dichloromethane. The organic extracts were combined and dried (Na2SO4). Evaporation of the solvent afforded a yellow-brown glass. This material was suspended in 50 mL of saturated aqueous sodium carbonate solution and refluxed 20 h. After cooling, the reaction mixture was poured into a separatory funnel and extracted three times with chloroform. The organic extracts were combined and dried (Na2SO4). Evaporation of the solvent afforded a brown foam. This material was purified by preparative thin layer chromatography on two 20 cm×20 cm tapered silica gel plates with 3% methanol-chloroform. After three solvent runs, 0.04 g (9%) of N,N-diethyl-4-[3-hydroxybenzyl(1-propylpiperidin-4-yl)amino]benzamide was obtained as a yellow solid. MS (ES), m/z 424 (MH+). 300 MHz 1H NMR (CDCl3) δ0.89 (t, J=7.3 Hz, 3H), 1.18 (t, J=7.0 Hz, 6H), 1.43-1.61 (m, 2H), 1.67-1.88 (m, 4H), 1.95-2.14 (m, 2H), 2.28-2.39 (m, 2H), 3.01 (br d, J=11.3 Hz, 2H), 3.26-3.54 (br m, 2H), 3.69-3.86 (br m, 1H), 4.37 (br s, 2H), 6.52-6.66 (m, 4H), 6.70 (d, J=7.6 Hz, 1H), 7.12 (t, J=7.7 Hz, 1H), 7.16-7.29 (m, 2H).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[C:10](=[O:12])[CH2:11][C:5]=2[CH:4]=1.[BH4-].[Na+].O.C(Cl)(Cl)Cl>C(O)C>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH:10]([OH:12])[CH2:11][C:5]=2[CH:4]=1
Reactant: O=C1Cc2cc(C(F)(F)F)ccc2Sc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCO
Product: OC1Cc2cc(C(F)(F)F)ccc2Sc2ccccc21
Temperature: 30 °C

Procedure:
12 g of 10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]thiepin-10-one are dissolved in 110 ml of absolute ethanol and treated with 4 g of sodium borohydride. The mixture is held at reflux for 12 minutes, cooled to 30° C and treated with 350 ml of water and 100 ml of chloroform. After equilibration, the organic phase is washed with aqueous sodium chloride solution, dried over sodium sulphate and evaporated under reduced pressure. There is obtained 10,11-dihydro-2-trifluoromethyl-dibenzo[b,f]thiepin-10-ol in the form of yellow crystals which melt at 122°-123° C.
Reaction SMILES: B(O[O-])=O.[OH2:5].[Na+].[CH3:7][O:8][C:9](=[O:25])[C:10]1[CH:15]=[C:14]([S:16][CH2:17][CH2:18][CH3:19])[N:13]=[C:12]([NH:20][C@H:21]([CH2:23][CH3:24])[CH3:22])[CH:11]=1>C(O)(=O)C>[CH3:7][O:8][C:9](=[O:25])[C:10]1[CH:15]=[C:14]([S@:16]([CH2:17][CH2:18][CH3:19])=[O:5])[N:13]=[C:12]([NH:20][CH:21]([CH2:23][CH3:24])[CH3:22])[CH:11]=1
Reactant: CCCSc1cc(C(=O)OC)cc(N[C@@H](C)CC)n1
Reactant: O
Agent: O=BO[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC[S@](=O)c1cc(C(=O)OC)cc(NC(C)CC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
Add sodium perborate monohydrate (0.133 g, 1.33 mmol) to a cooled solution of (S)-2-sec-butylamino-6-propylsulfanyl-isonicotinic acid methyl ester (0.396 g, 1.40 mmol) in acetic acid (4 mL). Stir at room temperature overnight and concentrate. Dissolve the residue in ethyl acetate and wash the solution with aqueous sodium bicarbonate, saturated aqueous sodium chloride, dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 30:70 ethyl acetate:hexanes) to give the title compound (0.230 g, 55%).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]2[O:11][N:10]=[C:9]([NH2:12])[CH:8]=2)=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:21]=1[C:22]([N:24]=[C:25]=[O:26])=[O:23].CN(C=O)C>O>[Cl:19][C:20]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:21]=1[C:22]([NH:24][C:25]([NH:12][C:9]1[CH:8]=[C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:2][CH:3]=2)[O:11][N:10]=1)=[O:26])=[O:23]
Reactant: Nc1cc(-c2ccc(-c3ccccc3)cc2)on1
Reactant: O=C=NC(=O)c1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NC(=O)c1c(Cl)cccc1Cl)Nc1cc(-c2ccc(-c3ccccc3)cc2)on1

Procedure:
5-(4-Biphenylyl)-3-aminoisoxazole (450 mg.) was mixed with excess 2,6-dichlorobenzoyl isocyanate in 50 ml. of DMF and the reaction mixture stirred overnight (about 18 hours) at room temperature. The reaction mixture was then poured into water and the product separated by filtration and recrystallized from ethanol, m.p. 225°-227° C.
Reaction SMILES: [OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:47])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[C:34]1=[O:46])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][NH:4][NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])=[O:7].[CH:48](=O)[C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[OH:1][C@H:2]([C@@H:18]([NH:26][C:27](=[O:47])[C@@H:28]([N:33]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([CH3:45])[N:40]=2)[C:34]1=[O:46])[C@@H:29]([CH3:32])[CH2:30][CH3:31])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][N:4]([CH2:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=1)[NH:5][C:6]([C@@H:8]([NH:13][C:14](=[O:17])[O:15][CH3:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])=[O:7]
Reactant: COc1ccc(C=O)cc1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NNC[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H]([C@@H](C)CC)N1CCN(Cc2cccc(C)n2)C1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)NN(Cc1ccc(OC)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H]([C@@H](C)CC)N1CCN(Cc2cccc(C)n2)C1=O
Yield: 58.3 %

Procedure:
A solution of Example 283A (50 mg, 0.45 mmol) in 1,2-dichloroethane (1 mL) and treated with p-anisaldehyde (16 mg, 1.5 equivalents), acetic acid (5 μL, 2 equivalents), and sodium triacetoxy borohydride (32 mg, 2 equivalents) at 25° C. for 16 hrs. The mixture was quenched with 10% NaHCO3 (2 mL) and CHCl3. The organic layer was separated, dried over sodium sulfate, filtered and the solvents were evaporated. The residue was purified using 5% methanol/CHCl3 to give 53 mg (90%) of the title compound.