Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]3[N:14]=[N:15][N:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[C:17]=3[CH3:18])[CH:10]=2)[C:5]1=[O:27])([CH3:3])[CH3:2].C([O-])(=[O:30])C.[Na+].O.C(=O)(O)O.C(OCC)(=O)C>C(O)(=O)C.BrBr>[CH:1]([N:4]1[C:12](=[O:30])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]3[N:14]=[N:15][N:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[C:17]=3[CH3:18])[CH:10]=2)[C:5]1=[O:27])([CH3:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: Cc1c(-c2ccc3c(c2)CN(C(C)C)C3=O)nnn1-c1ccc(F)cc1F
Agent: BrBr
Agent: O=C(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc3c(c2)C(=O)N(C(C)C)C3=O)nnn1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 50.8 %

Procedure:
37 mg of the compound obtained in Example 119 was dissolved in 2.0 ml of acetic acid, then 41 mg of sodium acetate and 3 drops of bromine were added and the mixture was stirred at room temperature for 20 min. After adding saturated hydrogen carbonate water and ethyl acetate, organic layer was separated, and dried with anhydrous sodium sulfate. The residues obtained by distilling out the solvents under reduced pressure were purified by thin-layer silicagel chromatography (hexane:ethyl acetate=50:50) to obtain 19.5 mg of the above compound as a white solid.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16][CH:17]([C:22](OC)=[O:23])[C:18](OC)=[O:19].C[O-].[Na+].[Na]>CO>[OH:23][C:22]1[N:7]=[CH:5][NH:6][C:18](=[O:19])[C:17]=1[S:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][CH3:8]
Reactant: COC(=O)C(Sc1ccccc1OC)C(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccccc1Sc1c(O)nc[nH]c1=O
Temperature: 80 °C
Reaction time: 4 h
Yield: 21.6 %

Procedure:
0.86 g of formamidine acetate and 2 g of dimethyl (2-methoxy -phenylsulfanyl)-malonate (J. Org. Chem. 55, 33-38 [1990]) were added to a sodium methylate solution from 40 ml of MeOH and 0.54 g of sodium. The reaction mixture was stirred at 80° C. for 4 hours and concentrated. The residue was partitioned between toluene and water and the aqueous phase was adjusted to pH 3. The precipitate was filtered off under suction, washed with ether and dried. There was obtained 0.4 g of 6-hydroxy-5-(2-methoxy-phenylsulfanyl)-3,4-dihydro-pyrimidin-4-one. M.p. 291 ° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH2:18])[N:16]=[N:17][C:12]=2[CH:11]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([C:29]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[O:30])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:20]=[C:19]([CH3:21])[C:13]2[N:14]=[C:15]([NH:18][C:23]3[CH:24]=[CH:25][C:26]([C:29]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[O:30])=[CH:27][CH:28]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: CN1CCN(C(=O)c2ccc(Br)cc2)CC1
Reactant: COc1ccc(Cl)c(-c2cc(C)c3nc(N)nnc3c2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(C(=O)N5CCN(C)CC5)cc4)nnc3c2)c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 58.2 %

Procedure:
In a dry 25 mL round bottom flask, 7-(2-chloro-5-methoxy-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.282 g, 0.94 mmol, 1 equiv), (4-bromo-phenyl)-(4-methyl-piperazin-1-yl)-methanone (0.399 g, 1.41 mmol, 1.5 equiv), cesium carbonate (0.919 g, 2.82 mmol, 3 equiv), 4,5-bis(diphenylphosphino)-9,9-dimethyl xanthene (0.109 g, 0.188 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium (0.086 g, 0.094 mmol, 0.1 equiv) were combined. The reactants were flushed with argon, diluted with dioxane (12 mL) and outfitted with reflux condenser. The reaction was heated to reflux for 18 hours, then filtered hot and solvents were evaporated. The residue was diluted with toluene and water (approx. 2:1), and the mixture was heated to 70° C. and stirred for 20 min. The contents were then poured into 250 mL separatory funnel and shaken. The resulting precipitate was filtered off, washed with water and dried to yield a yellow powder (0.275 g, 58% yield). MS (ESI+): m/z=504.1, LC retention time: 1.75 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:15][CH3:16])=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[O:17]=[C:18]1[NH:27][C:26]2[N:25]=[C:24]([O:28][CH2:29][CH2:30][CH2:31][CH:32]=O)[CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19]1>>[Cl:2][C:3]1[C:4]([CH2:15][CH3:16])=[C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:24]3[N:25]=[C:26]4[C:21]([CH2:20][CH2:19][C:18](=[O:17])[NH:27]4)=[CH:22][CH:23]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CCc1c(Cl)cccc1N1CCNCC1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CC2
Agent: Cl
Product: CCc1c(Cl)cccc1N1CCN(CCCCOc2ccc3c(n2)NC(=O)CC3)CC1

Procedure:
In a manner similar to that of other examples above, 1-(3-chloro-2-ethyl-phenyl)-piperazine hydrochloride was coupled by reductive amination to 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-butyraldehyde followed by typical workup and purification to give the title compound. MS: APCI: M+1: 443.2 (Exact Mass: 442.21).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[N:7][CH:8]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:11][C:2]([F:1])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[O:10])=[N:7][CH:8]=1
Reactant: OCc1ccc(C(F)(F)F)cn1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of Example 34B (3.89 g, 22.0 mmol) in CH2Cl2 (10 mL) was added to a deoxygenated solution of Dess-Martin periodinane (1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one, 10.3 g, 24.2 mmol) in CH2Cl2 (73 mL) in one portion. The reaction was stirred under nitrogen at ambient temperature for about 20 minutes after which a solid formed. The reaction was diluted with 50 mL CH2Cl2 and carefully quenched with approximately 30 mL of saturated NaHCO3 solution. The undissolved solid was filtered, and the filtrate was transferred to a separatory funnel. The aqueous phase was extracted with CH2Cl2, and the combined organic layer was washed with brine, dried over Na2SO4, filtered, and evaporated at reduced pressure to 50 mL. This solution was then loaded on silica gel (Analogix® 40×150 column) and eluted with 25% to 50% EtOAc/hexanes. The result was 2.86 g (74%) of the title compound as a clear oil, which solidified on standing. 1H NMR (300 MHz, CDCl3) δ 10.15 (s, 1H), 9.06 (m, 1H), 8.15 (m, 1H), 8.09 (d, J=8.1, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[N:11]=[N:10]1.[BH4-].[Na+]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([OH:24])[CH3:23])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[N:11]=[N:10]1
Reactant: CC(=O)c1ccc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1C(C)O
Temperature: 25 °C
Yield: 94.4 %

Procedure:
To a 0° C. solution of 1-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanone (314 mg, 0.751 mmol) in THF/MeOH (6 mL/1 mL) is added sodium borohydride (116 mg, 3.04 mmol). The reaction is warmed to room temperature overnight. The reaction is concentrated and the residue is partitioned between EtOAc (100 mL) and 1 N HCl (20 mL). The aqueous layer is extracted with EtOAc (100 mL) and the combined organic layers are washed with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. The residue is purified via chromatography (40 g SiO2, 20% to 40% EtOAC/Hexanes) to yield the title compound (298 mg, 94%). LC-ES/MS m/e 419.7 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:16][C:17]([C:19]1[N:20]=[C:21]([CH2:24]Br)[S:22][CH:23]=1)=[O:18])C>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([O:13][CH2:24][C:21]2[S:22][CH:23]=[C:19]([C:17]([OH:18])=[O:16])[N:20]=2)=[CH:11][CH:12]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)c1csc(CBr)n1
Product: O=C(O)c1csc(COc2ccc(-c3ccccc3)cc2)n1

Procedure:
2-(Biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure B from 4-phenylphenol (available from Aldrich, Milwaukee, Wis.) and 2-bromomethyl-thiazole-4-carboxylic acid ethyl ester (Intermediate 3). Yield: 56 mg. Mass spectrum (ES) MH+=312.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[N:15][C:16]([NH:19][C:20]3[N:21]=[CH:22][C:23]4[C:29]([CH3:30])=[C:28]([C:31]([O:33]CC)=[CH2:32])[C:27](=[O:36])[N:26]([CH:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[C:24]=4[N:25]=3)=[CH:17][CH:18]=2)[CH2:9]1)(C)(C)C.Cl>C(Cl)(Cl)Cl>[C:31]([C:28]1[C:27](=[O:36])[N:26]([CH:37]2[CH2:41][CH2:40][CH2:39][CH2:38]2)[C:24]2[N:25]=[C:20]([NH:19][C:16]3[CH:17]=[CH:18][C:13]([N:10]4[CH2:11][CH2:12][N:7]([CH3:6])[CH2:8][CH2:9]4)=[CH:14][N:15]=3)[N:21]=[CH:22][C:23]=2[C:29]=1[CH3:30])(=[O:33])[CH3:32]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCC(NC(=O)OC(C)(C)C)C4)cn3)nc2n(C2CCCC2)c1=O
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CCN(C)CC4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.5 %

Procedure:
To a solution of (1-{6-[8-cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (394 mg, 0.68 mmol) in chloroform (5 ml) was added hydrogen chloride (2 M ethereal solution, 2.0 ml, 4.0 mmol). The reaction mixture was stirred at RT for 12 h. The solvents were evaporated and the residue was dissolved in ethanol. The ethanol was evaporated to give 6-acetyl-8-cyclopentyl-5-methyl-2-[5-(4-methyl-piperazin-1-yl)-pyridin-2-ylamino]-8H-pyrido[2,3-d]pyrimidin-7-one (239 mg, 0.52 mmol). MS (APCI+) 487, 391, 279 (100); 1H NMR δ (400 MHz, DMSOd6) 8.98 (s, 1H), 8.34 (br, 2H), 7.78–7.73 (m, 2H), 7.51 (br, 1H), 5.89–5.80 (m, 1H), 3.98 (br, 2H), 3.62–3.51 (m, 4H), 2.40–3.23 (m, 2H), 2.44 (s, 3H), 2.25–2.20 (m, 2H), 2.16–2.13 (m, 1H), 1.93 (br, 2H), 1.80–1.78 (m, 2H), 1.61–1.58 (m, 2H); Anal. Calc'd for C24H29N7O2, 2.10 HCl, 2.85 H2O, 0.45 C2H5OH: C, 50.16; H, 6.68; N, 16.45; Cl−, 12.49. Found: C, 50.37; H, 6.90; N, 16.45; Cl−, 12.61.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH2:16][OH:17])[CH2:15][CH2:14][CH2:13][CH2:12]1.ClC1C=CC(Cl)=CC=1C1(C[O:32][S:33]([CH3:36])(=O)=[O:34])CCCC1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH2:16][O:17][S:33]([CH3:36])(=[O:34])=[O:32])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CS(=O)(=O)OCC1(c2cc(Cl)ccc2Cl)CCCC1
Reactant: OCC1(c2ccc3ccccc3c2)CCCC1
Product: CS(=O)(=O)OCC1(c2ccc3ccccc3c2)CCCC1
Yield: 54 %

Procedure:
Methanesulfonic acid 1-naphthalen-2-yl-cyclopentylmethyl ester (214) (16.0 g, 54.0%) was synthesized as a white solid from (1-naphthalen-2-yl-cyclopentyl)-methanol (213) (22.0 g, 97.34 mmol) following the procedure described for methanesulfonic acid 1-(2,5-dichlorophenyl)-cyclopentylmethyl ester (201).
Reaction SMILES: Cl[CH:2]([CH3:33])[CH2:3][CH2:4][C:5]([NH:7][C@@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15](=[O:32])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[N:18][C:17]=2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30][CH3:31])[CH:25]=2)[CH2:10][CH2:9]1)=[O:6].[H-].[Na+]>CN1CCCC1>[F:22][C:20]1[CH:19]=[N:18][C:17]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([S:30][CH3:31])[CH:25]=2)=[C:16]([CH:21]=1)[C:15]([NH:14][C@H:11]1[CH2:12][CH2:13][C@@H:8]([N:7]2[CH2:33][CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH2:9][CH2:10]1)=[O:32]
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](NC(=O)CCC(C)Cl)CC2)c1
Agent: CN1CCCC1
Agent: [H-]
Agent: [Na+]
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@@H](N3CCCCC3=O)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
cis-N-[4-(4-Chloro-pentoylamino)-cyclohexyl]-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide (259 mg, 0.486 mmol) was dissolved in N-methylpyrrolidine (5 ml) under nitrogen at room temperature and sodium hydride (60% dispersion in mineral oil, 49 mg, 1.21 mmol) was added. The reaction was stirred at room temperature for 18 h and quenched with water (10 ml) then extracted with ethyl acetate (5×10 ml). The combined organic extracts were washed with water (3×5 ml), brine (5 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with dichloromethane:methanol (97:3, by volume) and the product was triturated with diethylether (2 ml) to give 5-Fluoro-2-(3-methylsulfanyl-phenoxy)-N-[cis-4-(2-oxo-piperidin-1-yl)-cyclohexyl]-nicotinamide (69 mg) as a white solid.
Reaction SMILES: [Cl:1][GeH:2]([Cl:4])[Cl:3].[C:5]([O:15][CH2:16][CH3:17])(=[O:14])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Cl:1][Ge:2]([Cl:4])([Cl:3])[CH:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][C:5]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Cl[GeH](Cl)Cl
Reactant: CCOC(=O)C=Cc1ccccc1
Product: CCOC(=O)CC(c1ccccc1)[Ge](Cl)(Cl)Cl
Reaction time: 2 h
Yield: 78.7 %

Procedure:
A mixture of 36 g (0.2 mol) of trichlorogermane and 35.2 g (0.2 mol) of ethyl cinnamate was stirred for 2 hours, and then the reaction product was distilled under vacuum to afford 56 g of a fraction, b.p. 169°-170° C./4 mmHg. Yield 78.7%.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]2[CH2:19][CH2:18]2)[N:12]=1)([CH3:10])[CH3:9])(C)(C)C>Cl.CCOCC.CO>[CH:17]1([C:13]2[N:12]=[C:11]([C:8]([NH2:7])([CH3:9])[CH3:10])[CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1cccc(C2CC2)n1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: CC(C)(N)c1cccc(C2CC2)n1
Yield: 73.6 %

Procedure:
Dissolve [1-(6-cyclopropyl-pyridin-2-yl)-1-methyl-ethyl]-carbamic acid tert-butyl ester (1.3 g, 4.7 mmol) in 2 N HCl/Et2O (excess) with a small amount of methanol to effect solution. Stir until the starting material is consumed, monitoring by LC-MS. Evaporate and partition the residue between dichloromethane and aqueous sodium bicarbonate. Extract with dichloromethane, filter and evaporate to give 1-(6-cyclopropyl-pyridin-2-yl)-1-methyl-ethylamine as an orange oil (610 mg, 75%). LC-MS ESI m/z: 177.2 (M+H)+, Tr=1.80 min, method 1.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([OH:17])[CH2:15][CH2:14][N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@@H:10]1[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>>[CH2:1]([O:8][C@@H:9]1[C@@H:10]([CH2:11][OH:12])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:14][CH2:15][C@H:16]1[OH:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C[C@@H]1[C@@H](OCc2ccccc2)[C@H](O)CCN1C(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(OCc1ccccc1)N1CC[C@@H](O)[C@H](OCc2ccccc2)[C@H]1CO

Procedure:
reducing the lactol (24) with sodium borohydride to give a diol (25) from which the protecting groups are removed by hydrogenolysis to give the desired fagomine (3) ##STR17## wherein Bn=CH2Ph and Z=COOCH2Ph.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][N:19]=[CH:20]2)=O)(C)(C)C.[ClH:25].CO>>[ClH:25].[CH:20]1[C:21]2[C:16](=[C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH2:8])[CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:18][N:19]=1
Reactant: CC(C)(C)OC(=O)NCCCCCNc1cccc2cnccc12
Agent: Cl
Solvent: CO
Product: NCCCCCNc1cccc2cnccc12

Procedure:
According to the method of the above Example, deprotection was performed (room temperature, 31 hours) by using Intermediate 31 (327 mg) and 10% hydrogen chloride/methanol solution (5 ml). The solvent was evaporated under reduced pressure, and the residue was added with methanol (1 ml) and diethyl ether (3 ml). The deposited precipitates were collected by filtration and washed with diethyl ether to obtain the title compound (262 mg) as light yellow powdery solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59]>C(Cl)Cl>[CH2:61]([O:60][P:56]([CH2:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][NH:47][C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:13])([O:57][CH2:58][CH3:59])=[O:63])[CH3:62]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOP(=O)(CCOCCOCCN)OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CCOCCOCCNC(=O)[C@H](C)NC(=O)OC(C)(C)C)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (3.5 eq), followed by diethyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)phosphonate (1.2 eq, from example 5, step 3). The reaction was stirred at room temperature for 2 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give the title product as a colorless viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][NH:8][C:9]2[C:14]3[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)=[CH:16][NH:17][C:13]=3[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[C:28]([NH:35][CH2:36][CH2:37][CH2:38][CH2:39]Br)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9]2[C:14]3[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=4)=[CH:16][N:17]([CH2:39][CH2:38][CH2:37][CH2:36][NH:35][C:28](=[O:29])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:13]=3[CH:12]=[CH:11][N:10]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(CNc2nccc3[nH]cc(-c4cccc(OC)c4)c23)cc1
Reactant: CC(C)(C)OC(=O)NCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nccc3c2c(-c2cccc(OC)c2)cn3CCCCNC(=O)OC(C)(C)C)cc1
Yield: 102.8 %

Procedure:
450 mg (1.1 mmol) of (4-methoxybenzyl)-[3-(3-methoxyphenyl)-1H-pyrrolo-[3,2-c]pyridin-4-yl]amine from Example B3, 428 mg (1.7 mmol) of 4-(BOC-amino)butyl bromide and 0.9 g (2.8 mmol) of caesium carbonate in 60 ml of DMF are warmed to 60° C. over the course of 12 h. Aqueous work-up at RT and chromatographic purification gives 600 mg (82%) of a colourless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH2:28]([C@@H:30]1[CH2:34][CH2:33][S:32](=[O:36])(=[O:35])[NH:31]1)[CH3:29]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:31]4[C@H:30]([CH2:28][CH3:29])[CH2:34][CH2:33][S:32]4(=[O:36])=[O:35])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: CC[C@@H]1CCS(=O)(=O)N1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: CC[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)c(S(C)(=O)=O)c1
Yield: 25.4 %

Procedure:
Using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (664 mg) described in Preparation Example 112 and (R)-3-ethylisothiazolidine 1,1-dioxide (238 mg) described in Preparation Example 3 and by the reaction and treatment in the same manner as in Example 1, the title compound (194 mg) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([NH2:13])=[C:11]([CH3:14])[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH2:1]([N:8]1[C:12]([NH:13][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)=[C:11]([CH3:14])[CH:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cnn(Cc2ccccc2)c1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cnn(Cc2ccccc2)c1NC1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.2 %

Procedure:
To a solution (50 mL) of 1-benzyl-4-methyl-1H-pyrazol-5-amine (5 g) and tetrahydro-4H-pyran-4-one (3.2 g) in acetic acid was added sodium cyanoborohydride (6.8 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained extract was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.9 g, 38%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][C:24]=2[NH2:29])[CH:3]=1.[NH2:30][C:31]1[C:32]([C:38](O)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN1C(=O)CCC1>[NH2:30][C:31]1[C:32]([C:38]([NH:29][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][C:23]=2[C:4]2[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH:5]=2)=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1
Reactant: Nc1ccc(Br)nc1C(=O)O
Reactant: Cc1cc(-c2ccncc2N)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: On1nnc2cccnc21
Solvent: CN1CCCC1=O
Solvent: ClCCCl
Product: Cc1cc(-c2ccncc2NC(=O)c2nc(Br)ccc2N)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 35 %

Procedure:
Method 27 was followed using 6-methyl-N2,N2-di-BOC-4,4′-bipyridine-2,3′-diamine (1.0 equiv.), 3-amino-6-bromopicolinic acid (1.0 equiv.), EDC (1.0 equiv.), HOAt (1.0 equiv.) in NMP (0.48M) to yield 3-amino-6-bromo-N-(2′-(di-BOC-amino)-6′-methyl-4,4′-bipyridin-3-yl)picolinamide (35%). LCMS (m/z): 599.1/601.1 (MH+); LC Rt=3.69 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([CH3:23])[NH:8][C:7]=1[NH2:24])=[O:5])[CH3:2].[CH3:25]C[O-].[Na+].CI>C(O)C>[CH2:1]([O:3][C:4]([C:6]1([CH3:25])[CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([CH3:23])[N:8]=[C:7]1[NH2:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1ccccc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CI
Solvent: CCO
Product: CCOC(=O)C1=C(C)N=C(N)C(C)(C(=O)OCC)C1c1ccccc1
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A solution of 33.0 g of 2-amino-6-methyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester and 6.8 g of sodium ethylate in 500 ml of ethanol is brought to the boil and treated with 15 g of methyl iodide. After boiling for a further 60 minutes under reflux, the mixture is concentrated by distillation and the residue is taken up in 300 ml of chloroform and extracted by shaking twice with 100 ml of water. Concentration of the organic phase and recrystallization from ethanol gives 18.6 g (54% of theory) of 2-amino-3,6-dimethyl-4-phenyl-3,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 139° C.