Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]#[N:27])=[C:24]([C:28](=[O:32])[CH:29]([CH3:31])[CH3:30])[N:23]=[C:22]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26]#[N:27])=[C:24]([CH:28]([OH:32])[CH:29]([CH3:30])[CH3:31])[N:23]=[C:22]2[CH2:33][CH2:34][CH2:35][CH3:36])=[CH:16][CH:15]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCc1nc(C(=O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Yield: 59.2 %

Procedure:
Following a procedure similar to that described in Example 45(b), but using 500 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-isobutyrylimidazole-5-carbonitrile [prepared as described in step (a) above] and 25 mg of sodium borohydride in 10 ml of ethanol, 297 mg of the title compound were obtained as a viscous oil.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH:9]([N:11]2[CH2:16][CH2:15][CH:14]([C:17](=[O:26])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[CH2:13][CH2:12]2)[CH3:10])=[N:5][CH:6]=[CH:7][N:8]=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)C.Cl.C(OCC)(=O)C>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][C:17]([CH:14]1[CH2:13][CH2:12][N:11]([CH:9]([C:4]2[C:3](=[O:2])[NH:8][CH:7]=[CH:6][N:5]=2)[CH3:10])[CH2:16][CH2:15]1)=[O:26]
Reactant: COc1nccnc1C(C)N1CCC(C(=O)Cc2ccccc2F)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(c1ncc[nH]c1=O)N1CCC(C(=O)Cc2ccccc2F)CC1
Yield: 53.8 %

Procedure:
After dissolving 118 mg of 1-[1-[1-(3-methoxy-2-pyrazinyl)ethyl]piperidin-4-yl]-2-(2-fluorophenyl)ethanone in 2 ml of ethanol, 6 ml of 4N hydrogen chloride/ethyl acetate was added and the mixture was heated to reflux for 9 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: ethyl acetate/methanol), diethyl ether was added and the precipitate was filtered out to obtain the title compound (61 mg, 38% yield).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[S:9][CH:10]=1)=O)C.[BH4-].[Li+].CO.O>C(OCC)C>[OH:3][CH2:4][C:6]1[N:7]=[C:8]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]2)[S:9][CH:10]=1
Reactant: CCOC(=O)c1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(c2nc(CO)cs2)CC1

Procedure:
A mixture of 1,1-dimethylethyl 4-[4-(ethoxycarbonyl)-2-thiazolyl]-1-piperidinecarboxylate (i.e. the product of Example 1, Step A) (3.4 g, 10 mmol), lithium borohydride (0.33 g, 15 mmol) and methanol (607 μL, 15 mmol) in diethyl ether (40 mL) was heated at reflux for 16 h. The reaction mixture was cooled, treated with water (5 mL) and extracted with diethyl ether and dichloromethane. The combined organic layers were dried (MgSO4) and concentrated under reduced pressure and purified by silica gel chromatography using 50-100% ethyl acetate in hexanes as eluant to give 1.72 g of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][Si:5]([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6].[SH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C.O>[Si:5]([O:4][CH2:3][CH2:2][S:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17])([C:8]([CH3:11])([CH3:10])[CH3:9])([CH3:7])[CH3:6]
Reactant: O=C(O)c1cccc(S)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCSc1cccc(C(=O)O)c1
Reaction time: 2 h

Procedure:
(2-Bromoethoxy)(tert-butyl)dimethylsilane (1.48 mL) was added dropwise to a suspension of 3-mercaptobenzoic acid (1.07 g) and potassium carbonate (1.91 g) in DMF (15 mL). The resulting suspension was stirred for 2 h. The reaction was carefully acidified by dropwise addition of aqueous HCl (2M, 10 mL) and poured into water (100 mL). The resulting aqueous was extracted with ethyl acetate (3×100 mL). The combined organics were washed with brine (50 mL), dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a clear oil. Yield 2.8 g.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH:19]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)=[CH:25][CH:26]=3)[OH:20])=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[K+].O.[CH3:39]O>>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([CH:19]([O:20][CH3:39])[C:12]3[C:13]4[C:14](=[N:15][CH:16]=[CH:17][CH:18]=4)[NH:10][CH:11]=3)=[CH:22][N:23]=2)=[CH:30][CH:31]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(C(O)c2ccc(CNc3ccc(Cl)cc3)nc2)c2cccnc21
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(c1ccc(CNc2ccc(Cl)cc2)nc1)c1c[nH]c2ncccc12
Temperature: 50 °C

Procedure:
To (1-Benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-[(4-chloro-phenylamino)-methyl]-pyridin-3-yl-methanol (56, 120.0 mg, 0.24 mmol) in methanol (20.0 mL) were added potassium hydroxide (0.400 g, 7.13 mmol) and water (5.0 mL, 0.28 mol). The reaction was heated to 50° C. for 10 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give compound (57, 30 mg, 33.0%). MS (ESI) [M+H+]+=379.4.
Reaction SMILES: [H-].[Na+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH:12]3[C:24]4[NH:23][C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[C:16]=4[CH2:15][CH2:14][N:13]3[CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:6][C:5]=2[O:4]1.CN(C=[O:36])C>>[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH:12]3[C:24]4[NH:23][C:22]5[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=5[C:16](=[O:36])[C:15]=4[CH2:14][N:13]3[CH2:25][C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:6][C:5]=2[O:4]1
Reactant: c1ccc2c3c([nH]c2c1)C(c1ccc2c(c1)OCO2)N(Cc1ccncc1)CC3
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(Cc1ccncc1)C2

Procedure:
Following the same procedure as outlined in Example 21, sodium hydride (60% in mineral oil, 40 mg, 1.0 mmol) and 1-(3,4-methylened ioxyphenyl)-2-(pyridin-4-yl)methyl-2,3,4,9-tetrahydro-1H-β-carboline (192 mg, 0.50 mmol) (prepared as in Example 15) in DMF (10 mL, anhydrous) were reacted to yield the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:8][C:3]=1[NH:4]C(=O)C.Cl>C(O)C.O1CCCC1>[NH2:4][C:3]1[C:2]([Cl:1])=[CH:11][C:10]([F:12])=[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])[CH:8]=1
Reactant: CC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Temperature: 25 °C

Procedure:
A mixture of 2′-chloro-5′-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4′-fluoroacetanilide (24.42 g, 64.3 mmol) in ethanol is treated with 2N hydrochloric acid (200 ml), diluted with tetrahydrofuran, refluxed overnight, cooled to room temperature, partially concentrated in vacuo to remove ethanol and tetrahydrofuran, neutralized with 3N sodium hydroxide solution, and extracted with ethyl acetate. The organic extracts are combined, washed sequentially with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a light, brown solid (20.3 g, mp 132-135° C.).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:19])([F:18])[F:17])[C@@H:14]3[C@@H:20]([O:23][Si](C(C)(C)C)(C)C)[CH2:21][CH2:22][N:13]3[C:12]2=[O:31])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl-].[NH4+].CCOC(C)=O>C1COCC1>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C@H:15]([C:16]([F:18])([F:19])[F:17])[C@@H:14]3[C@@H:20]([OH:23])[CH2:21][CH2:22][N:13]3[C:12]2=[O:31])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1c(N2C(=O)N3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)N3CC[C@H](O)[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.6 %

Procedure:
To a solution of 75F (8.20 mg, 0.173 mmol) in THF (2 mL) was added a 1 M THF solution of TBAF (0.120 mL, 0.120 mmol). After stirring at rt for 1 h, saturated aqueous ammonium chloride and EtOAc were added and the layers were separated. The organic layer was washed with brine then dried (MgSO4), filtered and concentrated. The resulting residue was purified via preparative HPLC (YMC ODS C-18, 30×250 mm, eluting with 50-90% solvent B (A=90% H2O-10% MeOH and B=10% H2O-90% MeOH) over 15 min; Flow rate at 20 mL/min; UV detection at 220 nm) to provide the title compound (4.10 mg) as a white solid. MS: m/z 360 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[S:17][C:16]([N+:18]([O-])=O)=[C:15]([C:21]([NH2:23])=[O:22])[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O.NN>CO.[Fe](Cl)(Cl)Cl>[NH2:18][C:16]1[S:17][C:13]([C:10]2[CH:11]=[N:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][CH:9]=2)=[CH:14][C:15]=1[C:21]([NH2:23])=[O:22]
Reactant: NC(=O)c1cc(-c2ccc(N3CCOCC3)nc2)sc1[N+](=O)[O-]
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: NC(=O)c1cc(-c2ccc(N3CCOCC3)nc2)sc1N
Temperature: 65 °C

Procedure:
5-(6-Morpholin-4-ylpyridin-3-yl)-2-nitrothiophene-3-carboxamide (2.77 g, 8.28 mmol), iron(III) chloride (0.03 g, 0.17 mmol), and hydrazine monohydrate (1.34 ml, 27.3 mmol) were combined in methanol (166 ml) and the reaction mixture was purged with nitrogen. The reaction was heated to 65° C. for 3 hours. After cooling to room temperature, the reaction mixture was filtered and solid was washed with methanol. Silica gel was added to the filtrate and the mixture was concentrated. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/methanol to give the title compound as an orange solid.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>[Cl-].[Zn+2].[Cl-].C1C=CC=CC=1>[CH2:8]([C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:1])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CCl
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: Cc1ccccc1Cc1ccccc1
Reaction time: 6 h
Yield: 88.9 %

Procedure:
A solution of 70 parts of o-xylyl chloride and 240 parts of benzene is added to a mixture of 250 parts of 75 percent strength by weight sulfuric acid and 30 parts of zinc chloride at from 75° to 80° C, whilst stirring thoroughly. After a further 6 hours, the organic phase is separated off and 80 parts (88.9% of theory) of o-benzyltoluene boiling at 98° C at 0.2 mm Hg are isolated by distillation.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH2:17][CH2:18][C:19]([OH:21])=O)[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]([CH2:17][CH2:18][C:19]([NH:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:21])[C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: COc1ccc(N(CCC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CN
Product: CCOC(=O)CNC(=O)CCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-3-(p-anisidino)propionic acid and ethyl glycinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-3-(p-anisidino)propionyl]glycinate (M.P. 87° to 89°), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-3-(p-anisidino)propionyl]glycine (M.P. 185° to 187°).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)=[C:9]([NH2:22])[N:8]=2)[CH2:3][CH2:2]1.[Br:23]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.ClCCl>[Br:23][C:12]1[N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][O:17]2)[C:14]2[C:10]([N:11]=1)=[C:9]([NH2:22])[N:8]=[C:7]([NH:6][CH2:5][CH2:4][CH:1]1[CH2:2][CH2:3]1)[N:15]=2
Reactant: Nc1nc(NCCC2CC2)nc2c1ncn2C1CCCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Nc1nc(NCCC2CC2)nc2c1nc(Br)n2C1CCCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N2-(2-cyclopropylethyl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2,6-diamine (4.17 g) in chloroform (46.0 ml) at 0° C., was added N-bromosuccinimide (2.58 g) to give a dark green suspension. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was taken up in dichloromethane (100 ml) and washed with water (1×100 ml). The organic layer was separated, dried by passing through a hydrophobic frit and concentrated in vacuo to give a green gum (5.50 g, 80% pure).
Reaction SMILES: C([O:5]O)(C)(C)C.[C:7]1([CH2:13][CH2:14][CH:15]=[CH:16][CH2:17][OH:18])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(Cl)Cl>[O:5]1[C@@H:15]([CH2:14][CH2:13][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C@@H:16]1[CH2:17][OH:18]
Reactant: CC(C)(C)OO
Reactant: OCC=CCCc1ccccc1
Solvent: ClCCl
Product: OC[C@@H]1O[C@H]1CCc1ccccc1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a 1 L 3-neck round-bottom flask equipped with a mechanical stirrer, thermocouple and nitrogen inlet was added CH2Cl2 (350 mL), dried 4 Å molecular sieves (30 g) and L-(+)-diethyl tartrate (7.62 g, 0.037 mol). The resulting mixture was cooled to -20° C. and treated with Ti(O-i-Pr)4 (9.2 mL, 0.031 mol), followed by the addition of t-butylhydroperoxide (4.0 M in CH2Cl2, 182 mL, 0.78 mol) at a rate to maintain the temperature 2 -20° C. Upon complete addition, the reaction mixture was stirred for another 30 min, and then treated with a solution of the allylic alcohol (15) (50 g, 0.31 mol) in CH2Cl2 (30 mL) at a rate to maintain the temperature at -20° C. The reaction was stirred at the same temperature for 5 h, then filtered into a solution of ferrous sulfate heptahydrate (132 g) and tartaric acid (40 g) in water (400 mL) at 0° C. The mixture was stirred for 20 min, then transferred to a separatory funnel and extracted with t-BuOMe (2×200 mL). The combined organic phase was stirred with 30% NaOH solution containing NaCl, for 1 h at 0° C. The layers were again separated, and the aqueous phase extracted with t-BuOMe. The combined organic phase was washed with brine, dried over MgSO4 and concentrated to yield the title compound (52.8 g) as an amber oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]1>>[CH3:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:27]4[CH2:32][CH2:31][CH:30]([NH:33][C:34](=[O:36])[CH3:35])[CH2:29][CH2:28]4)=[CH:4][CH:5]=3)[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: Cc1ccc(COc2ccn(CCc3ccc(CBr)cc3)c(=O)c2)nc1
Reactant: CC(=O)NC1CCNCC1
Product: CC(=O)NC1CCN(Cc2ccc(CCn3ccc(OCc4ccc(C)cn4)cc3=O)cc2)CC1

Procedure:
N-[1-(4-{2-[4-(5-Methyl-pyridin-2-ylmethoxy)-2-oxo-2H-pyridin-1-yl]-ethyl}-benzyl)-piperidin-4-yl]-acetamide is prepared as example 13.1c from 55 mg (0.13 mmol) 1-[2-(4-bromomethyl-phenyl)-ethyl]-4-(5-methyl-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 13.1b) and 76 mg (0.53 mmol) N-piperidin-4-yl-acetamide.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1>C(=O)(OC)OC>[CH3:3][O:4][C:5](=[O:21])[CH:6]([C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)[C:5]([O:4][CH3:3])=[O:21]
Reactant: COC(=O)Cc1ccc(Oc2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COC(=O)OC
Product: COC(=O)C(C(=O)OC)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 90 °C

Procedure:
A suspension of sodium hydride (350 mg) in dimethyl carbonate (10 ml) is treated at room temperature with the product obtained in step D. The mixture is heated to 90° C. for 1 hour, cooled and poured into ice water and extracted with methylene chloride. The extract is dried and evaporated to yield 5.7 of the title compound as an oil.
Reaction SMILES: [NH2-].[Na+].C1(C)C=CC=CC=1.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[C:17]1([CH:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:24]2[CH2:27][CH:26](OS(C)(=O)=O)[CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O>[C:17]1([CH:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:24]2[CH2:27][CH:26]([O:16][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:25]2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Oc1ccccc1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 8.6 g. (0.22 mole) of sodium amide in 100 ml. of dry toluene was added 18.2 g. (0.2 mole) of phenol in 50 ml. of dry toluene. After stirring for 2 hrs. at 60° C. the pot temperature was raised to 80° C. and a solution of 1-diphenylmethyl-3-methylsulfonyloxyazetidine (63.4 g.; 0.2 mole) in 200 ml. of dry toluene was added dropwise. After an additional 2 hrs. at 80° C. the cooled mixture was treated with water, the toluene layer was extracted with dilute sodium hydroxide solution, dried and concentrated at reduced pressure. The residue was crystallized twice from a water-isopropanol mixture. The free base melted at 83°-85° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][C:5]=1[Br:12].[C:14]([C:18]1[CH:26]=[CH:25][C:21]([CH:22]=[N:23][OH:24])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:24]/[N:23]=[CH:22]/[C:21]2[CH:25]=[CH:26][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=2)=[CH:6][C:5]=1[Br:12]
Reactant: CC(C)(C)c1ccc(C=NO)cc1
Reactant: COC(=O)c1ccc(CBr)cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc(CO/N=C/c2ccc(C(C)(C)C)cc2)cc1Br
Yield: 81.8 %

Procedure:
This compound was produced using similar methods as those used in Step 5, example 27, starting with 2-bromo-4-bromomethyl-benzoic acid methyl ester (0.40 g, 1.30 mmol), 4-tert-butyl-benzaldehyde oxime (0.24 g, 1.36 mmol) and cesium carbonate (1.69 g, 5.20 mmol) in acetone (50 mL). The crude material was purified by flash chromatography through silica gel using ethyl acetate/hexanes (0/100 gradient to 6/94) to give 2-bromo-4-[({[(1E)-(4-tert-butylphenyl)methylidene]amino}oxy)methyl]benzoic acid methyl ester (0.43 g, 83%) as a clear, colorless oil. 1H NMR (400 MHz, CDCl3); δ 8.13 (s, 1H), 7.78 (d, 1H), 7.69 (s, 1H), 7.49 (d, 2H), 7.39-7.36 (m, 3H), 5.18 (s, 2H), 3.92 (s, 3H), 1.32 (s, 9H).
Reaction SMILES: [CH:1]1([NH:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:28][C:29]([F:32])([F:31])[F:30])(=O)=O.C(N(CC)C(C)C)(C)C>ClCCl>[CH:1]1([N:4]([CH2:28][C:29]([F:32])([F:31])[F:30])[CH2:5][CH2:6][CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:18])(=[O:16])=[O:17])=[CH:11][C:10]=2[N+:19]([O-:21])=[O:20])[CH2:3][CH2:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: NS(=O)(=O)c1ccc(NCCCNC2CC2)c([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(NCCCN(CC(F)(F)F)C2CC2)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
To a solution of EXAMPLE 308A (314 mg) in dichloromethane (6 mL) was added 2,2,2-trifluoroethyl trifluoromethanesulfonate (255 mg) and N,N-diisopropylethylamine (258 mg). The mixture was stirred overnight. The mixture was diluted with dichloromethane (300 mL) and washed with aqueous NaHCO3, water, brine and dried over Na2SO4. Filtration and evaporation of solvent gave the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:10]=[CH:11]/[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[BH4-].[Na+].O.C(OCC)(=O)C>CO.[Ni](Cl)Cl>[OH:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]
Reactant: Cc1cccc(/C=C/C(=O)OC(C)(C)C)c1CO
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cccc(CCC(=O)OC(C)(C)C)c1CO
Reaction time: 4 h
Yield: 99.3 %

Procedure:
To a solution of 789 mg of tert-butyl (2E)-3-[2-(hydroxymethyl)-3-methylphenyl]acrylate in 16 ml of methanol was added 82 mg of nickel chloride (II). Then, 240 mg of sodium borohydride was added thereto under ice-cooling, followed by stirring for 4 hours under ice-cooling. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 790 mg of tert-butyl 3-[2-(hydroxymethyl)-3-methylphenyl]propanoate.
Reaction SMILES: [Li]CCCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[CH:12](=[O:18])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].CC([Si](Cl)(C)C)(C)C>CCOCC>[OH:18][CH:12]([C:7]1[S:8][CH:9]=[CH:10][N:11]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Brc1nccs1
Reactant: CCCCCC=O
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCCC(O)c1nccs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
n-BuLi (4.0 mL, 6.4 mmol, 1.6M) was added dropwise to a -78° C. solution of 2-bromothiazole (1.0 g, 6.1 mmol) in dry Et2O (12 mL). After stirring at -78° C. for 1 h, hexanal (0.77 mL, 6.4 mmol) was added and the solution stirred for 30 min. before a solution of TBDMSCl (1.1 g, 7.3 mmol) in dry Et2O (5 mL) was added. The solution was allowed to warm to rt while stirring for 16 h. The reaction was quenched with water, the layers separated and the aqueous extracted with EtOAc. The combined extracts were dried (MgSO4) and condensed. The crude material was purified by flash chromatography using 30% EtOAc/hexane to give 0.70 g (62%) of 2-(1-hydroxyhexyl)thiazole.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].N1C=CC=CC=1.Cl.[CH3:23][N:24]([CH3:32])[C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=1)[NH2:28]>C(OCCO)C>[CH3:23][N:24]([CH3:32])[C:25]1[CH:26]=[C:27]([NH:28][C:2]2[C:11]3[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:29]=[CH:30][CH:31]=1
Reactant: COc1cccc2c(Cl)c(C#N)cnc12
Reactant: CN(C)c1cccc(N)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cccc2c(Nc3cccc(N(C)C)c3)c(C#N)cnc12
Temperature: 100 °C

Procedure:
Using an analogous procedure to that described in Example 274. A reaction mixture of 250.0 mg (1.1 mmol) of 4-chloro-8-methoxy-3-quinolinecarbonitrile, 273.3 mg (3.0 mmol) of pyridine and 261.4 mg (1.25 mmol) of 3-dimethylaminoaniline hydrochloride in 10 mL of 2-ethoxyethanol was heated at 100° C. for 1.5 hr. The work up gave 294.8 mg (73.4%) of the product as a deep greenish yellow solid, m.p. 222-225° C., mass spectrum (electrospray, m/e): M+H 319.0.