Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1>O>[C:6]([C@@H:4]([C@H:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([O-:8])=[O:7].[CH3:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][NH2+:14][CH2:13]1.[CH3:1][C@@H:2]1[CH2:4][CH2:6][CH2:15][NH2+:14][CH2:13]1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: CC1CCCNC1
Solvent: O
Product: C[C@@H]1CCC[NH2+]C1
Product: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Reaction time: 2 h
Yield: 30.7 %

Procedure:
To a solution of L-(+)-tartaric acid (37.9 g, 0.253 mol) in H2O (40 mL), racemic 3-methyl-piperidine (25 g, 0.252 mol) was added slowly. The mixture was kept at room temperature for 2 h. The desired isomer was crystallized from water and collected by filtration. The solid obtained was recrystallized three times from MeOH/EtOH/H2O=50/25/2 (154 mL) to give the desired product (13.5 g) as a white solid (99.6% ee). [Enantiomeric excess (% ee) was determined by HPLC after derivatization with Cbz-Val].
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=1)=[O:5])C.O.[OH-].[Na+].Cl>O1CCOCC1>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[CH2:17][CH2:16][O:15][C:13]1[C:9]2[O:10][CH2:11][O:12][C:8]=2[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:14]=1
Reactant: CCOC(=O)c1cc(OCCc2ccc(Cl)cc2Cl)c2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(OCCc2ccc(Cl)cc2Cl)c2c(c1)OCO2
Temperature: 60 °C
Reaction time: 16 h

Procedure:
0.41 g (1.07 mmol) of 7-[2-(2,4-Dichloro-phenyl)-ethoxy]-benzo[1,3]dioxole-5-carboxylic acid ethyl ester was dissolved in 15 ml of dioxan. 5 ml of water and 2N aqueous NaOH was added to the solution to give a pH of 13. The reaction solution was heated at 60° C. for 4 h and stirred at room temperature for 16 h. The reaction solution was cooled to 0° C. and concentrated hydrochloric acid was added to give a pH of 1–2, whereupon the product precipitated from solution. The suspension was stirred for 30 min, then the product was filtered off and dried under reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([OH:19])=O)[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.CCN(C(C)C)C(C)C.[CH:29]1[N:33]=[CH:32][N:31]([C:34](N2C=NC=C2)=O)[CH:30]=1.CN(C)CCN>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([C:17]([NH:33][CH2:29][CH2:30][N:31]([CH3:34])[CH3:32])=[O:19])[CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=C(O)c1ccc2c(=O)[nH]c3nccc(Cl)c3c2c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CCNC(=O)c1ccc2c(=O)[nH]c3nccc(Cl)c3c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.2 %

Procedure:
295 (60 mg, 0.22 mol), DIEA (0.08 mL, 0.44 mmol), and CDI (71 mg, 0.44 mmol) were suspended in DMF (2 mL) and stirred for 4 h at room temperature. N1,N1-Dimethylethane-1,2-diamine (77 mg, 0.87 mmol) was added, and the reaction mixture was stirred for another 3 h. The reaction mixture was quenched with water. The resulting precipitate was filtered, washed with MeOH and H2O, and dried under vacuum to produce provide 296 (61 mg, 81% yield) as a solid. LC-MS (M+H=345, obsd.=345).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][C@@H:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15](OC(=O)C)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+:30].[CH3:31][NH:32][N:33]1[C:37]([SH:38])=[N:36][N:35]=[N:34]1.[C:39](=O)([O-])O.[Na+]>P([O-])([O-])([O-])=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][C@@H:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([O-:24])=[O:23])=[C:15]([CH2:39][S:38][C:37]4[N:33]([NH:32][CH3:31])[N:34]=[N:35][N:36]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+:30]
Reactant: CNn1nnnc1S
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(OC(C)=O)CS[C@H]12)c1csc(N)n1
Reactant: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Product: CNn1nnnc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Yield: 44.4 %

Procedure:
A solution of sodium 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-acetoxy-3-cephem-4-carboxylate (1.43 g, 3 mmol), 1-methylamino-5-mercapto-1H-tetrazole (0.590, 4.5 mmol) and sodium hydrogen carbonate (0.378 g, 4.5 mmol) in phosphate buffer (pH 6.4, 45 ml) was stirred at 60° C. for 8 hours. Then the solution was treated in a manner similar to that described in Example 7 to give pale yellow powder of sodium 7β-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-methylamino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylate (0.73 g, 44%).
Reaction SMILES: CN([CH:4]=[C:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)C.O.C(=O)([O-])[OH:24].[Na+]>Cl.CS(C)=O>[OH:24][CH:4]=[C:5]1[C:17]2[N:16]3[CH:18]=[CH:19][N:20]=[C:15]3[C:14](=[O:21])[NH:13][C:12]=2[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2
Reactant: CN(C)C=c1c2ccccc2c2[nH]c(=O)c3nccn3c12
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=c1[nH]c2c3ccccc3c(=CO)c2n2ccnc12

Procedure:
10-Hydroxymethylene-5H,10H-imidazo[1,2-a]-indeno[1,2-e]pyrazin-4-one may be obtained in the following way: a solution of 1.4 g of 10-dimethylaminomethylene-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one in 35 ml of 5N hydrochloric acid is stirred for 30 minutes at a temperature in the region of 25° C. After addition of 60 ml of water and neutralization with 120 ml of saturated aqueous sodium hydrogen carbonate, the solid formed is isolated by filtration, washed twice with 60 ml in total of water and air-dried. The product obtained (1.1 g) is dissolved in 120 ml of dimethyl sulphoxide and, after addition of 120 ml of water, the solid formed is isolated by filtration, washed twice with 10 ml in total of distilled water and twice with 10 ml in total of acetone and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 1 g of 10-hydroxymethylene-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained as a 60/40 mixture of the Z and E forms, decomposing without melting at 290° C. [NMR spectrum: (200 MHz; DMSO-d6 ; δ in ppm): a 60/40 mixture of isomers is observed: from 7.20 to 7.40 (mt, 2H: --H7 and --H8); 7.56 and 7.64-8.29 and 8.79 (4 broad s, twice 1H: --H of the imidazole); from 7.80 to 8.15 (mt, 2H: --H6 and --H9); 8.21 and 8.24 (2s, 1H in total: =CH--O--); 12.43 (mult., 1H: --NH--)].
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]1[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10](SC)[N:9]=1.[S:19]([O-:24])(O[O-])(=O)=[O:20].[K+].[K+].[CH3:27]C(C)=O>O>[OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]1[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]([S:19]([CH3:27])(=[O:24])=[O:20])[N:9]=1
Reactant: CC(C)=O
Reactant: CSc1ncc(C(N)=O)c(N[C@H]2CCC[C@@H]2O)n1
Reactant: O=S(=O)([O-])O[O-]
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ncc(C(N)=O)c(N[C@H]2CCC[C@@H]2O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
To a mixture of 4-((1S,2S)-2-hydroxycyclopentylamino)-2-(methylthio)pyrimidine-5-carboxamide (800 mg, 2.98 mmol) in acetone (10 mL) was added a solution of potassium peroxymonosulfate (4.66 g, 7.45 mmol) in water (10 mL), and the resulting mixture was stirred at room temperature for 2 h. When the starting material was consumed, the reaction mixture was partitioned between ethyl acetate (20 mL) and water (15 mL). The aqueous layer was extracted with ethyl acetate (20 mL×3). The combined organic layers were washed with brine, dried over sodium sulfate and filtered. The filtrate was evaporated in vacuo to give 4-((1S,2S)-2-hydroxycyclopentylamino)-2-(methylsulfonyl)pyrimidine-5-carboxamide (700 mg, 2.3 mmol, yield 78%) as a solid. MS (ESI): m/z 301.2 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:14])([F:13])[F:12])=[N:8][NH:9][CH:10]=1)=[O:5])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[CH2:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1)=[O:24].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:11]([F:13])([F:14])[F:12])=[N:8][N:9]([CH2:22][C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:29][CH2:30]2)=[O:24])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC(=O)N2CCN(c3ccc(F)cc3)CC2)nc1C(F)(F)F

Procedure:
Protocol T was followed using 3-Trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/1) afforded the title compound as colorless oil. 1H NMR (400 MHz, CDCl3); 8.15 (s, 1H), 6.98–7.04 (m, 2H), 6.86–6.92 (m, 2H), 5.1 (s, 2H), 4.28–4.38 (q, 2H), 3.78–3.84 (m, 2H), 3.62–3.74 (m, 2H), 3.04–3.2 (m, 4H), 1.3–1.4 (t, 3H). 13C NMR (400 MHz, CDCl3): 163.4, 160.5, 159.2, 156.2, 147, 137.2, 119, 118.8, 116, 115.8, 61, 54, 50.8, 50.0, 45.0, 42.2, 14.2.
Reaction SMILES: [C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Ni:9].C([Br:13])C=C.[CH:14]([C-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1)([CH3:16])[CH3:15].[Na+:22]>C1COCC1>[CH:14]([C-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1)([CH3:16])[CH3:15].[Na+:22].[CH2:15]([Ni:9][Br:13])[CH:14]=[CH2:17]
Reactant: [Ni]
Reactant: C=CCBr
Agent: CC(C)[c-]1cccc1
Agent: [C-]#[O+]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[Ni]Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium isopropylcyclopentadienide is prepared in THF as described in Preparation A. Then dimeric allyl nickel bromide is prepared by reacting 70 g of nickel carbonyl and 50 ml of allyl bromide in 200 ml of THF. The final solution is added dropwise onto the solution of sodium isopropylcyclopentadienide and allowed to stir at room temperature for two hours. The mixture becomes violet immediately and NaBr precipitates. The solution containing isopropylcyclopentadienyl nickel allyl is transferred to another flask and solvent is removed by pumping at or below room temperature. The product is removed by vacuum distillation at 10-2 torr in the range of 30°-40° C.
Reaction SMILES: [CH2:1]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:2][CH2:3][C:4]#[CH:5].CN(C)CCN(C)C.C([Li])CCC.[CH2:26]1[O:28][CH2:27]1>O1CCCC1.O>[O:8]1[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]1[O:6][CH2:1][CH2:2][CH2:3][C:4]#[C:5][CH2:26][CH2:27][OH:28]
Reactant: C1CO1
Reactant: C#CCCCOC1CCCCO1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OCCC#CCCCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
To a cooled solution (-20° C.) of tetrahydro- 2-(4-pentynyloxy)-2H-pyran (1) (16.8 g. 0.10 mole) and tetramethylethylene diamine (45.2 mL, 0.30 mole, distilled from CaH2 under nitrogen) in anhydrous tetrahydrofuran (100 mL. distilled from sodium/benzophenone under nitrogen) was added via syringe a solution of n-butyllithium (41.0 mL, 0.101 mole, 2.44 N in hexane). The mixture was allowed to warm to 0° C. over 30 minutes and stirred at 0° C. for 1 h followed by the addition, via cannula, of ethylene oxide (8 8 g, 0.20 mole, freshly condensed into an argon filled graduated cylinder). The solution was stirred at 0° C. for 1 h and then stored in a refrigerator (5° C.) for 3 days. The reaction mixture was poured into water (200 mL) and extracted with ether (1×200 mL, 2×50 mL). The organic layers were combined and washed with water (5×50 mL), saturated sodium chloride (50 mL), dried (MgSO4), and concentrated to provide 22.80 g of a crude amber oil which was chromatographed (ethyl acetate/hexane 1:1) to provide 12.09 g (59%) of the title compound: Rf =0.32 (ethyl acetate/hexane:1/1) 1H PMR (CDCl3); δ 4.60 (t, J=3 Hz, 1H), 3.85 (m, 2H), 3.67 (t, J=6 Hz, 2H), 3.50 (m, 2H), 2.71 (bs, 1H), 2.40 (m, 4H), 2.29 (m, 2H), 1.78 (m, 4H), 1.52 (m, 4H); 13C NMR (CDCl3): 98.9, 81.5, 77.1, 65.9, 62.2, 61.3, 30.7, 29.0, 25.5, 23.1, 19.5, 15.7 ppm; IR (CHCl3): 3600, 3460 cm-1 ; Analysis calculated for C13H20O3 : C, 67.89; H, 9.50; Found: C, 67.96; H, 9 79.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[S:15][CH:16]=[CH:17][N:18]=1.[CH3:19][C@H:20]1[CH2:25][C:24](=[O:26])[CH2:23][CH2:22][O:21]1.[Cl-].[NH4+]>C1COCC1>[Cl:13][C:14]1[S:15][C:16]([C@@:24]2([OH:26])[CH2:23][CH2:22][O:21][C@@H:20]([CH3:19])[CH2:25]2)=[CH:17][N:18]=1
Reactant: C[C@H]1CC(=O)CCO1
Reactant: Clc1nccs1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C[C@H]1C[C@@](O)(c2cnc(Cl)s2)CCO1
Temperature: -78 °C
Reaction time: 1 h
Yield: 111.3 %

Procedure:
n-Butyl-lithium (2.5M in hexane, 57.5 ml) was dropwise added during 30 minutes to a solution of di-isopropylamine (19.3 ml) in THF (180 ml) which had been cooled to -78° C. The mixture was stirred at -78° C. for 1 hour. The reaction vessel was shielded from light and 2-chlorothiazole (15.0 g) was added dropwise during 20 minutes, whilst keeping the temperature of the reaction mixture below -70° C. The mixture was stirred at -78° C. for 1.5 hours. (2S)-2-Methyltetrahydropyran-4-one (12.9 g) was added during 20 minutes. The mixture was stirred and allowed to warm briefly to -25° C. to obtain a homogeneous solution. The mixture was recooled to -70° C. and stirred at that temperature for 1 hour. A 5% aqueous solution of ammonium chloride was added and the mixture was extracted with diethyl ether. The organic solution was washed with brine, dried (MgSO4) and evaporated. There was thus obtained a mixture (29.4 g) of (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran and the corresponding (2S,4S)-isomer in a ratio of 1:4. The mixture so obtained was dissolved in diethyl ether (250 ml) and the solution was cooled to 0° C. A concentrated (25% v/v) aqueous solution of sulphuric acid was added and the mixture was stirred and allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 16 hours. The mixture was diluted with ethyl acetate (750 ml) and neutralised to pH3 by the addition of sodium bicarbonate. The organic solution was washed with brine, dried (MgSO4) and evaporated to give a mixture (26 g) of (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran and the corresponding (2S,4S)-isomer in a ratio of 9:1. The material was purified by column chromatography using a 1:1 mixture of petroleum ether (b.p. 40°-60° C.) and ethyl acetate as eluent. There was thus obtained (2S,4R)-4-(2-chlorothiazol-5-yl)-4-hydroxy-2-methyltetrahydropyran (21 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13]4[C:14](=[CH:19][CH:20]=[CH:21][C:12]=4[C:11]2=S)[CH:15]=[CH:16][CH:17]=3)[CH:6]=[CH:7][CH:8]=1.[N:23]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][N:25]=[CH:24]1>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:18]3[C:13]4[C:14](=[CH:19][CH:20]=[CH:21][C:12]=4[C:11]2=[N:31][CH2:30][CH2:29][CH2:28][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)[CH:15]=[CH:16][CH:17]=3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CN2C(=S)c3cccc4cccc2c34)c1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: COc1cccc(CN2C(=NCCCn3ccnc3)c3cccc4cccc2c34)c1
Yield: 80.1 %

Procedure:
A mixture of 2.5 g of 1-[(3-methoxyphenyl)methyl]benz[cd]indole-2(1H)-thione (Ck), 1.1 g of 1H-imidazole-1-propanamine, 200 ml ethyl alcohol, and 2.6 g of mercuric acetate is reacted as described in Example 3, giving 2.6 g of the desired product, mp. 95°-96° C.
Reaction SMILES: [CH:1]1([N:7]2[CH2:15][C:14]3[C:13](=[O:16])[N:12]4[N:17]=[C:18]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH:19]=[C:11]4[NH:10][C:9]=3[C:8]2=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>O>[CH2:34]([O:33][C:31]([CH2:30][CH2:29][CH2:28][N:10]1[C:9]2[C:8](=[O:26])[N:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:15][C:14]=2[C:13](=[O:16])[N:12]2[N:17]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:19]=[C:11]12)=[O:32])[CH3:35]
Reactant: CCOC(=O)CCCBr
Reactant: O=C1c2[nH]c3cc(-c4ccccc4)nn3c(=O)c2CN1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CCCn1c2c(c(=O)n3nc(-c4ccccc4)cc13)CN(C1CCCCC1)C2=O
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of 100 g (2.87) mmole) of 6-cyclohexyl-4,7-dihydro-2-phenyl-5H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8-dione (see preparation 1), 0.82 ml. (5.7 mmoles), of ethyl 4-bromobutyrate and 0.41 g., 3.0 mmole of potassium carbonate in 11 ml. of -dimethyl-sulfoxide (DMSO) was stirred at 50° C. for 16.5 hours. Then 35 ml. of water was added and the mixture was suction filtered. The collected solid was washed with more water and air dried. The crude solid was recrystallized from 95% ethanol (100 ml), reflux cooled to room temperature, affording 1.11 g (84% yield) of the titled compound as very fine white needles, m.p. 195°-196° C. 1H NMR (CDCl3, δ) 8.06 (d, 2H, phenyl-H (ortho), 7.45 (m, 3H, phenyl-H), 6.70 (s, 1H, pyrazole-H, 4.74 (t, 2H, J=Hz, 4-NCH 2), 4.37 (s, 2H, lactam CH2), 4.16 (q, 2H, J=7 Hz, OCH2), 4.15 (m, 1H, 6-NCH), 2.49 (t, 2H, CH2CO2C2H5), 2.23 (m, 2H, CH2), 1.15-1.95 (m, 10H, cyclohexyl CH2), 1.26 (t, 3H, J"7 Hz, CH3.
Reaction SMILES: [CH:1]([C:3]1[C:4]([O:19][CH3:20])=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10])=O.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH3:20][O:19][C:4]1[C:3]([CH2:1][NH:24][CH3:23])=[CH:18][CH:17]=[CH:16][C:5]=1[O:6][C:7]1[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: COc1c(C=O)cccc1Oc1nc(C)ccc1C#N
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CNCc1cccc(Oc2nc(C)ccc2C#N)c1OC
Yield: 41 %

Procedure:
2-(3-Formyl-2-methoxy-phenoxy)-6-methyl-nicotinonitrile (0.30 g, 1.1 mmol), methylamine (2M in methanol, 3.0 mL, 6.0 mmol) and sodium cyanoborohydride (90 mg, 1.4 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (50 ML) for 20 h. The solvent was removed in vacuo. The residue was treated with 10% sodium carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was separated and fumaric acid (0.13 g, 1.1 mmol) was added. After the solvent was removed in vacuo, the residue was triturated with ethyl acetate overnight, collected by filtration, and dried to give 2-(2-methoxy-3-methylaminomethyl-phenoxy)-6-methyl-nicotinonitrile fumarate (180 mg, 40%) as an off-white solid.
Reaction SMILES: [H-].[Na+].Cl.Cl[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][NH:20][C:21]2=[O:24])=[CH:16][CH:15]=1.O>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][N:20]([CH2:5][C:6]3[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=3)[C:21]2=[O:24])=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)C(=O)NCC2
Reactant: ClCc1cccnc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)C(=O)N(Cc1cccnc1)CC2
Reaction time: 0.25 h
Yield: 72.7 %

Procedure:
To a suspension of 3.70 g of sodium hydride (about 60%) in 80 ml of dimethylformamide was added portionwise 5.30 g of 3-chloromethylpyridine hydrochloride under ice cooling. The mixture was stirred under ice cooling for 15 minutes, and a solution of 4.09 g of 3,4-dihydro-7-methoxy-1 (2H)-isoquinolinone in 30 ml of dimethylformamide was added dropwise in 15 minutes thereto. The mixture was stirred at 10° C. for 1 hour, mixed with water and shaken with toluene. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The resultant residue was chromatographed on a column of silica gel, eluting with ethyl acetate to give 4.50 g of the titled compound.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH:26]=1)[CH:24]=O)([CH3:18])([CH3:17])[CH3:16].[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.C(O)C.[ClH:46]>O1CCCC1>[ClH:46].[C:15]([C:19]1[CH:20]=[C:21]([C:28]2[CH:29]=[N:30][C:31]([C:34]([F:35])([F:37])[F:36])=[CH:32][CH:33]=2)[C:22]([OH:27])=[C:23]([CH2:24][N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[CH:26]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1cc(C=O)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CN2CCCC2)c(O)c(-c2ccc(C(F)(F)F)nc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
Sodium triacetoxyborohydride (0.30 g, 1.4 mmol) was added to a solution of 5-(tert-butyl)-2-hydroxy-3-(6-(trifluoromethyl)pyridin-3-yl)benzaldehyde (0.35 g, 1.1 mmol) and pyrrolidine (0.11 mL, 1.3 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature under nitrogen for 16 hours. Additional pyrrolidine (011 mL, 1.3 mmol) and sodium triacetoxyborohydride (0.30 g, 1.4 mmol) were added and the reaction was stirred under nitrogen for 6 hours. The reaction was partitioned between ethyl acetate (25 mL) and saturated aqueous sodium bicarbonate solution (25 mL). The organic phase was dried with sodium sulfate, filtered and concentrated under reduced pressure to give a yellow syrup. The product was purified using flash chromatography on silica eluting with a solvent gradient of 0 to 100% ethyl acetate in hexanes to give a yellow syrup which was dissolved in 1.25 M hydrochloric acid in ethanol (10 mL, 12.5 mmol). The mixture stood for 20 minutes and was concentrated under reduced pressure to give a white solid which was triturated with diethyl ether (10 mL) and solid was filtered off to afford 4-(tert-butyl)-2-(pyrrolidin-1-ylmethyl)-6-(6-(trifluoromethyl)pyridin-3-yl)phenol hydrochloride (0.18 g, 42% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][NH2:13])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].C(O[CH:17]=[C:18]([C:21]#[N:22])[C:19]#[N:20])C.C(OCC)(=O)C>C(O)C>[NH2:22][C:21]1[N:12]([C:3]2[C:2]([Cl:1])=[C:6]([C:7]([F:10])([F:8])[F:9])[N:5]([CH3:11])[N:4]=2)[N:13]=[CH:17][C:18]=1[C:19]#[N:20]
Reactant: CCOC=C(C#N)C#N
Reactant: Cn1nc(NN)c(Cl)c1C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cn1nc(-n2ncc(C#N)c2N)c(Cl)c1C(F)(F)F

Procedure:
1.4 g (6.5 mmole) 4-Chloro-3-hydrazino-1-methyl-5-trifluoromethylpyrazole and 0.81 g (6.5 mmole) ethoxymethylenemalononitrile in 20 ml ethanol were stirred for 10 hours at room temperature and for 2 hours at 50° C. After addition of 100 ml ethyl acetate, the mixture was washed with saturated sodium hydrogen carbonate, dried over sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (methylene chloride).
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][C:4]([CH:6]1[C:11](=[O:12])OC(C)(C)OC1=O)=[O:5].[C:17]12([CH2:27][NH2:28])[CH2:26][CH:21]3[CH2:22][CH:23]([CH2:25][CH:19]([CH2:20]3)[CH2:18]1)[CH2:24]2>O1CCOCC1>[C:17]12([CH2:27][NH:28][C:11](=[O:12])[CH2:6][C:4](=[O:5])[CH2:3][CH:2]([CH3:1])[CH3:16])[CH2:24][CH:23]3[CH2:22][CH:21]([CH2:20][CH:19]([CH2:25]3)[CH2:18]1)[CH2:26]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: CC(C)CC(=O)C1C(=O)OC(C)(C)OC1=O
Solvent: C1COCCO1
Product: CC(C)CC(=O)CC(=O)NCC12CC3CC(CC(C3)C1)C2
Yield: 54.3 %

Procedure:
A solution of 5-(3-methylbutanoyl)-2,2-dimethyl-1,3-dioxane-4,6-dione (2.76 g, 12 mmol) and (1-adamantylmethyl)amine (2 g, 12 mmol) in anhydrous 1,4-dioxane (10 mL) was heated under reflux for 2 h. Solvent was removed in vacuo. The residue was diluted with EtOAc (50 mL), washed with water, aq K2CO3 and brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by chromatography on a silica gel column eluted with 20:1 PE/EtOAc to give the N-(1-adamantylmethyl)-5-methyl-3-oxohexanamide (1.90 g, 54.4%). 1H NMR: (400 MHz, CDCl3): δ=0.92 (s, 3H), 0.96 (s, 3H), 1.54 (s, 7H), 1.62-1.73 (m, 9H), 1.98 (s, 4H), 2.12(m, 1H), 2.45(d, 2H), 2.95(d, 2H), 3.65(s, 2H).