Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[C:13]=1[O:22][CH3:23])[OH:11])[CH3:5])[CH3:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:3][CH:4]([O:6][CH2:7][C:8]#[C:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[C:13]=1[O:22][CH3:23])=[O:11])[CH3:5])[CH3:2]
Reactant: CCOC(C)OCC#CC(O)c1ccc(OC)c(OC)c1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(C)OCC#CC(=O)c1ccc(OC)c(OC)c1OC
Reaction time: 0.25 h

Procedure:
A solution of 12 g (37 mmol) of 4-(1-ethoxyethoxy)-1-(2,3,4-trimethoxyphenyl)-2-butyn-1-ol in 50 ml of methylene chloride was added dropwise at 0° to a suspension of 95.3 g (1.1 mol) of manganese dioxide in 150 ml of methylene chloride. The reaction mixture was stirred at 0° for 15 minutes, filtered over magnesium sulphate and concentrated. Chromatography of the residue over 300 g of silica gel (elution agent ether/hexane 1:1) yielded 4-(1-ethoxyethoxy)-1-(2,3,4-trimethoxyphenyl)-2-butyn-1-one as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.CC(N=NC(C#N)(C)C)(C#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][Br:11])[C:5]#[N:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(CBr)c(Br)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 56.5 %

Procedure:
A solution of 3-bromo-4-methylbenzonitrile (1 g, 5.10 mmol) in chloroform (20 mL) was heated to 40-50° C. and N-bromosuccinimide (0.953 g, 5.36 mmol) was added in one portion followed by AIBN (8.38 mg, 0.051 mmol). After 1.5 hr. additional AIBN (20 mg) was added and the reaction was allowed to stir at 50° C. overnight. Additional AIBN (20 mg) and N-bromosuccinimide (1.1 g) were added, a reflux condenser was attached and the solution was heated to reflux. After several hours, additional AIBN (20 mg) was added and the reaction was allowed to stir at reflux overnight. The reaction was quenched by the addition of water and sat. aq. sodium bicarbonate. The organic phase was separated, concentrated in vacuo and purified by flash column chromatography (120 g silica, eluting with 0%-20% Ethyl Acetate in hexanes) to afford 3-bromo-4-(bromomethyl)benzonitrile as a pale yellow solid (800 mg, 2.88 mmol). 1H NMR (500 MHz, MeOD) δ ppm 4.70 (s, 2H), 7.71 (d, J=8.0 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 8.04 (s, 1H).
Reaction SMILES: [CH2:1]([C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([CH3:20])[C:14]=1[S:21]([NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[N:7]=1)(=[O:23])=[O:22]
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: CCCCCc1csc(N)n1
Product: CCCCCc1csc(NS(=O)(=O)c2c(C)cc(Cl)cc2Cl)n1

Procedure:
The title compound was prepared from 4-pentyl-1,3-thiazol-2-ylamine (METHOD I) and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (28.6 mg) with purity >90%. MS (pos) m/z 393.1, 395.1.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:4](=[O:19])[C:3]=1[CH2:20][CH2:21]O.O.C([O-])(O)=O.[Na+]>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][N:7]=3)[C:2](=[O:1])[C:3]3[CH2:20][CH2:21][O:19][C:4]2=3)=[CH:17][CH:16]=1
Reactant: Cc1ccc(-n2c(=O)c(CCO)c(O)c3cccnc32)cc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Cc1ccc(-n2c3c(c(=O)c4cccnc42)CCO3)cc1
Temperature: 70 °C

Procedure:
A solution of 4-hydroxy-3-(2-hydroxyethyl)-1-(4-methylphenyl)-1,8-naphthyridin-2(lH)-one (2.2 g.) in Eaton's Reagent (10% P205 in methane sulfonic acid; 40 ml.) was stirred in an atmosphere of nitrogen and heated to 70° C. for 2 hr. After cooling, the product was poured into water, adjusted to pH 4 with NaHCO3, filtered, washed with water, air dried and was recrystallized from isopropanol with decolorization to yield the product, m.p. 246°-248.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]=[C:6](S)[C:5]=3[CH:13]=[CH:14][CH:15]=2.[N:16]1([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH:20]=[CH:19][N:18]=[CH:17]1>CN(C)C=O>[Cl:1][C:2]1[C:3]2[C:4]3[C:8](=[C:9]([Cl:11])[CH:10]=1)[N:7]=[C:6]([NH:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][N:16]1[CH:20]=[CH:19][N:18]=[CH:17]1)[C:5]=3[CH:13]=[CH:14][CH:15]=2
Reactant: SC1=Nc2c(Cl)cc(Cl)c3cccc1c23
Reactant: NCCCCCn1ccnc1
Solvent: CN(C)C=O
Product: Clc1cc(Cl)c2cccc3c2c1N=C3NCCCCCn1ccnc1
Yield: 24.5 %

Procedure:
A mixture of 5.0 g of 6,8-dichloro-benz[cd]indole-2-thiol, 3.1 g of 5-(1H-imidazol-1-yl)pentanamine, 100 ml of dry dimethylformamide and 6.3 g of mercuric acetate was reacted as described in Example 1, giving 1.8 g of the desired product, mp 191°-192.5° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12]O)=[CH:6][CH:5]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C([Br:30])C=C>CC#N>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][Br:30])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CCCO)cc1
Reactant: C=CCBr
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: COC(=O)c1ccc(CCCBr)cc1
Temperature: 25 °C

Procedure:
A solution of 4-(3-hydroxy-propyl)-benzoic acid methyl ester (11.98 g) and 1,1′-carbonyldiimidazole (9.0 g, 55.50 mmol) in CH3CN (200 mL) was stirred at room temperature for 1.5 h. Allyl bromide (20 mL) was added and the reaction mixture was heated under reflux for 20 h. The reaction mixture was cooled to room temperature and saturated aqueous NaHCO3was added. The aqueous solution was washed with EtOAc (3×) and the organic solutions were combined, dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (9:1 hexanes:EtOAc) provided the title compound of Preparation 4.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:13])[CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1.O=[C:15]1[CH2:20][CH2:19][N:18]([C:21]2[CH:34]=[CH:33][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:23][CH:22]=2)[CH2:17][CH2:16]1>>[OH:13][C@H:3]([CH2:4][O:5][C:6]1[CH:7]=[N:8][C:9]([CH3:12])=[CH:10][CH:11]=1)[CH2:2][NH:1][CH:15]1[CH2:16][CH2:17][N:18]([C:21]2[CH:34]=[CH:33][C:24]([CH2:25][CH:26]3[S:30][C:29](=[O:31])[NH:28][C:27]3=[O:32])=[CH:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc(OC[C@@H](O)CN)cn1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Product: Cc1ccc(OC[C@@H](O)CNC2CCN(c3ccc(CC4SC(=O)NC4=O)cc3)CC2)cn1

Procedure:
The title compound was prepared from (2S)-1-amino-3-[(6-methyl-3-pyridinyl)oxy]-2-propanol (which was obtained in Example 127) and 5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (which was obtained in Example 38) in substantially the same manner, as described in Example 125. The product was obtained as a yellow solid; mp 87° C. (decomposed); 1H NMR (400 MHz, DMSO-d6) δ 1.44–1.49 (m, 2 H), 1.93–1.97 (m, 2 H), 2.38 (s, 3 H), 2.64–2.70 (m, 2 H), 2.77–2.95 (m, 4 H), 3.23–3.27 (m, 1H), 3.35 (brs, 2 H), 3.64–3.67 (m, 2H), 3.93–4.02 (m, 3 H), 4.58–4.62 (m, 1 H), 6.84–6.86 (m, 2 H), 7.03–7.05 (m, 2 H), 7.15–7.17 (m, 1 H), 7.27–7.30 (m, 1 H), 8.14–8.15 (m, 1 H); MS (ES) m/z: 469 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH:22]=O)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27].[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH3:1][C:2]1([CH3:29])[CH2:7][CH:6]([C:8]2[C:16]3[C:11](=[C:12]([C:24]([NH2:26])=[O:25])[CH:13]=[C:14]([C:17]4[CH:21]=[C:20]([CH2:22][N:30]5[CH2:34][CH2:33][CH2:32][CH2:31]5)[S:19][CH:18]=4)[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][S:3]1(=[O:28])=[O:27]
Reactant: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CCS1(=O)=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CC1(C)CC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5)c4)cc23)CCS1(=O)=O
Yield: 17.6 %

Procedure:
3-(2,2-Dimethyl-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (30 mg, 0.070 mmol) was dissolved in dimethyl sulfoxide (1.5 mL) and put in a microwave vial. The mixture was stirred and 1-2 drops of acetic acid, and pyrrolidine (0.058 mL, 0.697 mmol) was added. Stirred for 30 minutes at 23° C., before adding sodium triacetoxyborohydride polymer bound (299 mg, 0.697 mmol). The vial was sealed using a silicon septum, and the mixture left stirring overnight at 23° C. The mixture was quenched with water, extracted with DCM, the DCM solution was evaporated to dryness, and the resulting mixture was rerun through the same process: 1.5 mL of DMSO, 1 drop of glacial acetic acid, and 0.577 mL of pyrrolidine. Left stirring 30 min and then 299 mg of polymer bound sodium triacetoxyborohydride was added and the mixture was left stirring 16 h. The sodium triacetoxyborohydride polymer bound was removed by filtration. The mixture was dissolved in 1 mL of DMSO, and the product was purified by preparative HPLC(NH4OH buffer). The desired fractions were concentrated, giving 6 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)Cl>[CH3:1][C:2]1([CH3:13])[CH:11]2[O:22][CH:10]2[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)C=Cc2ccccc2C1=O
Solvent: ClCCl
Product: CC1(C)C(=O)c2ccccc2C2OC21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3 g (17.4 mmol) of 2,2-dimethyl-1-oxo-1,2-dihydronaphthalene (L. H. Klemm, J. Shabtai, D. R. Taylor, J. Org. Chem., 1968, 33, 1480) in 30 ml of CH2Cl2, were added 6.00 g (19.1 mmol) of m-chloroperbenzoic acid dissolved in 90 ml CH2Cl2 and the resulting mixture was stirred overnight at room temperature. The resulting solution was washed successively with Na2S2O5 and NaHCO3 solutions and dried over MgSO4. The solvent was removed to yield 3.27 g of a crude that was chromatographed on silica gel eluting with hexane-CH2Cl2 mixtures of increasing polarity. 2.09 of the title compound of this preparation were obtained as a colorless oil (yield: 64%).
Reaction SMILES: ClCCCO.[F-].[K+].[F:8][CH2:9][CH2:10][CH2:11][OH:12].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>C(O)CO.N1C=CC=CC=1.[Na+].[I-]>[CH3:20][C:19]1[CH:21]=[CH:22][C:16]([S:13]([O:12][CH2:11][CH2:10][CH2:9][F:8])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: OCCCF
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OCCCCl
Agent: [F-]
Agent: [I-]
Solvent: OCCO
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCF)cc1
Temperature: 130 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
A mixture of 3-chloropropanol (2.5 mL, 30 mmol), KF (3.5 g, 60 mmol) and NaI (50 mg, 0.33 mmol) in ethylene glycol (10 mL) was placed in a round-bottom flask attached to a short-path distillation condenser. The mixture was heated at 130° C. and the resulting 3-fluoropropanol was collected as a colorless liquid. To a 0° C. solution of 3-fluoropropanol (600 mg, 7.68 mmol) in pyridine (8 mL) was added tosyl chloride (3.2 g, 16.78 mmol) over 30 min. The reaction mixture was stirred at 0° C. for 4 h and quenched by adding ice-cold water and EtOAc. The product fluorotosylate was purified as described in Method 14 above to afford compound 21 (1.2 g, 67%) as a slightly yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.83 (d, J=10.0 Hz, 1H), 7.38 (d, J=10.0 Hz, 2H), 4.59 (dt, J=50.0 & 5.0 Hz, 2H), 4.28 (dt, J=30.0 & 5.0 Hz, 2H), 2.47 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([CH3:36])([CH3:35])[C@H:9]2[C@:22]([CH3:25])([CH2:23][CH:24]=1)[C@@H:21]1[C@:12]([CH3:34])([C@@:13]3([CH3:33])[C@H:18]([CH2:19][CH2:20]1)[C@H:17]1[C@H:26]([C:29]([CH3:31])=[CH2:30])[CH2:27][CH2:28][C@:16]1([NH2:32])[CH2:15][CH2:14]3)[CH2:11][CH2:10]2)(=O)=O.P(=O)(O)(O)O.[K].CC1(C)C(C)(C)OB([C:53]2[CH2:58][CH2:57][CH:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55][CH:54]=2)O1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:32][C@:16]12[CH2:28][CH2:27][C@@H:26]([C:29]([CH3:31])=[CH2:30])[C@@H:17]1[C@@H:18]1[C@@:13]([CH3:33])([CH2:14][CH2:15]2)[C@@:12]2([CH3:34])[C@@H:21]([C@:22]3([CH3:25])[C@@H:9]([CH2:10][CH2:11]2)[C:8]([CH3:35])([CH3:36])[C:7]([C:53]2[CH2:58][CH2:57][CH:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55][CH:54]=2)=[CH:24][CH2:23]3)[CH2:20][CH2:19]1
Reactant: CCOC(=O)C1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: C1COCCO1
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 75 °C
Yield: 65.6 %

Procedure:
To a flask containing (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl trifluoromethanesulfonate (1.22 g, 2.187 mmol) was added phosphoric acid, potassium salt (1.393 g, 6.56 mmol), ethyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-enecarboxylate (0.613 g, 2.187 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (S-phos) (0.067 g, 0.164 mmol), and palladium(II)acetate (0.025 g, 0.109 mmol). The mixture was diluted with 1,4-dioxane (10 mL) and water (1 mL), was flushed with nitrogen, then was sealed and heated to 75° C. After 15 h of heating, the mixture was cooled to rt and was concentrated under reduced pressure. The residue was diluted with water (40 mL) and was extracted with ethyl acetate (3×50 mL). The organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography using a 10-70% EtOAc in hexanes gradient and an 80 g silica gel column. The fractions containing the expected product were combined and concentrated under reduced pressure to give ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (806 mg, 1.434 mmol, 65.6% yield) as an off-white solid. LCMS: m/e 562.7 (M+H)+, 2.17 min (method 1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=1>>[Cl:51][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][CH:48]=1)[O:44][CH2:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Reactant: Clc1cccc(OCCCCBr)c1
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4cccc(Cl)c4)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.065 g of 1-(4-bromobutoxy)-3-chlorobenzene are used to prepare the title compound. Rf=029 (2:1 EtOAc-heptane); Rt=6.16.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[N+]=[N-]>[Pd].C(O)C>[Si:14]([O:13][C:7]1([CH2:6][CH2:5][CH2:4][NH2:1])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OC1(CCCN=[N+]=[N-])CCCCC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC1(CCCN)CCCCC1
Reaction time: 4 h
Yield: 102.1 %

Procedure:
Sodium azide (1.78 g, 27.4 mmol) was added to a solution of 3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propyl methanesulfonate (prepared as described in Part D, 24.9 mmol) in dimethylformamide (100 mL). The reaction mixture was stirred for 2.5 d and additional sodium azide (160 mg) was added. The mixture was stirred an additional 1d, then was diluted with diethyl ether (250 mL) and washed with water (3×75 mL). The combined aqueous layers were back-extracted with diethyl ether (50 mL). The combined organic layers were washed with brine (100 mL), dried over MgSO4, filtered, and concentrated to afford {[1-(3-azidopropyl)cyclohexyl]oxy}(tert-butyl)dimethylsilane (7.05 g, 95% over two steps) as a pale yellow oil. A mixture of the {[1-(3-azidopropyl)cyclohexyl]oxy}(tert-butyl)dimethylsilane (7.05 g, 23.7 mmol) and 5% palladium on carbon (0.71 g) in ethanol (100 mL) was hydrogenated at 30 psi (2.1×105 Pa) for 4 h on a Parr apparatus. The reaction mixture was filtered through CELITE filter agent, which was rinsed afterwards with dichloromethane, and the filtrate was concentrated to give 3-(1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)propan-1-amine as a pale yellow oil (6.57 g, 102%) that contained a trace amount of solvent.
Reaction SMILES: [C:1](=[O:8])([O:3][C:4](C)([CH3:6])[CH3:5])[NH2:2].C(=O)(O[C:12]([CH3:15])([CH3:14])[CH3:13])N.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:25]=CC(N)=C[CH:20]=1>O1CCCC1>[C:1](=[O:8])([O:3][C:4]1[CH:6]=[CH:20][C:19]([C:18]([F:17])([F:26])[F:27])=[CH:25][C:5]=1[C:12]([CH3:15])([CH3:14])[CH3:13])[NH2:2]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(N)=O
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(F)(F)F)ccc1OC(N)=O

Procedure:
First, di-tert-butyl dicarbamate (30 mL) was added to a tetrahydrofuran (50 mL) solution of 4-trifluoromethylaniline (10 mL). The reaction mixture was then refluxed for 10 hours. The solvent was distilled off under reduced pressure. Water was added to the residue to solidify the resulting product. The product was then washed with hexane. The title compound (18.7 g) was obtained as colorless crystals.
Reaction SMILES: P([O-])([O-])([O-])=O.[Na].[F:7][C:8]1[C:13]([F:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:11]=[CH:10][C:9]=1[C:19]1[N:20]=[C:21]([NH:24][C:25](=[O:41])[CH2:26][C:27]2[C:35]3[C:34](=[O:36])[N:33]([CH3:37])[C:32](=[O:38])[N:31]([CH3:39])[C:30]=3[O:29][C:28]=2[CH3:40])[S:22][CH:23]=1.[P:42]([O:54][CH2:55]Cl)([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].[I-].[Na+]>CC(C)=O>[P:42]([O:54][CH2:55][N:20]1[C:19]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:18])[F:17])=[C:13]([F:14])[C:8]=2[F:7])=[CH:23][S:22][C:21]1=[N:24][C:25](=[O:41])[CH2:26][C:27]1[C:35]2[C:34](=[O:36])[N:33]([CH3:37])[C:32](=[O:38])[N:31]([CH3:39])[C:30]=2[O:29][C:28]=1[CH3:40])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])([O:49][C:50]([CH3:51])([CH3:52])[CH3:53])=[O:43]
Reactant: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C
Reactant: Cc1oc2c(c1CC(=O)Nc1nc(-c3ccc(C(F)(F)F)c(F)c3F)cs1)c(=O)n(C)c(=O)n2C
Agent: O=P([O-])([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1oc2c(c1CC(=O)N=c1scc(-c3ccc(C(F)(F)F)c(F)c3F)n1COP(=O)(OC(C)(C)C)OC(C)(C)C)c(=O)n(C)c(=O)n2C

Procedure:
The title compound was prepared according to the general procedure as described in method C for the preparation of phosphate derivatives by coupling reaction of sodium salt of N1-[4-(2,3-Difluoro-4-trifluoromethylphenyl)-1,3-thiazol-2-yl]-2-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydrofuro[2,3-d]pyrimidin-5-yl)acetamide (2.0 g, 3.73 mmol) with di-tert-butyl chloromethyl phosphate (Intermediate 1) (2.41 g, 9.328 mmol) in presence of sodium iodide (559 mg, 3.731 mmol) in dry acetone (50 ml) to obtain 3.0 g of a product as a pale yellow solid; ESI-MS (m/z): 736.70 (M+H)+.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[OH-:9].[Na+]>>[C:1]([OH:8])(=[O:7])[C@H:2]([CH2:3][C:4]([OH:6])=[O:5])[OH:9]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: [OH-]
Agent: [Na+]
Product: O=C(O)C[C@H](O)C(=O)O

Procedure:
For the purpose of examination as to fumarase activity, the bacterial cells were suspended in 100 ml of a 1.0 M aqueous solution of fumaric acid having a pH adjusted to 7.0 by NaOH and were reacted at 45° C. for 2 hours and the L-malic acid thereby formed was reacted with 2,7-naphthalenediol in the presence of sulfuric acid. The amount of the L-malic acid was determined by the color which it had developed. The amount of the succinic acid which had been formed was determined by high pressure liquid chromatography.
Reaction SMILES: [CH3:1][C:2]([CH3:52])([CH3:51])[C@@H:3]([C:12]1[NH:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]4[NH:37][C:36]([C@@H:38]([NH:43]C(=O)OC(C)(C)C)[C:39]([CH3:42])([CH3:41])[CH3:40])=[N:35][CH:34]=4)=[CH:29][CH:28]=2)[CH:21]=[CH:20]3)=[CH:15][N:16]=1)[NH:4]C(OC(C)(C)C)=O.[ClH:53].O1CCOCC1>C(Cl)Cl>[ClH:53].[NH2:4][C@H:3]([C:12]1[NH:13][C:14]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]4[NH:37][C:36]([C@@H:38]([NH2:43])[C:39]([CH3:42])([CH3:41])[CH3:40])=[N:35][CH:34]=4)=[CH:29][CH:28]=2)[CH:21]=[CH:20]3)=[CH:15][N:16]=1)[C:2]([CH3:51])([CH3:52])[CH3:1]
Reactant: CC(C)(C)OC(=O)N[C@H](c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)[C@H](N)c1ncc(-c2ccc(-c3ccc4cc(-c5cnc([C@@H](N)C(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a reaction mixture of tert-butyl (S)-1-(5-(4-(6-(2-((S)-2,2-dimethyl-1-(tert-butoxycarbonylamino)propyl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropylcarbamate (0.2 g, 0.283 mmol) in DCM was added 4M hydrogen chloride in dioxane (2 mL, 8 mmol). The reaction mixture was stirred at rt for 4 h and then concentrated to dryness to yield an HCl salt of (S)-1-(5-(4-(6-(2-((S)-1-amino-2,2-dimethylpropyl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-2,2-dimethylpropan-1-amine as a yellow solid. LC-MS (Cond. 1): [M+H]+ 507.43, Rt=3.241 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:12]([CH2:13][OH:14])=[N:11][NH:10][C:7]2=[N:8][CH:9]=1)([O-])=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:12]([CH2:13][OH:14])=[N:11][NH:10][C:7]2=[N:8][CH:9]=1
Reactant: O=[N+]([O-])c1cnc2[nH]nc(CO)c2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cnc2[nH]nc(CO)c2c1
Temperature: 110 °C

Procedure:
A sealed microwave vial was charged with (5-nitro-1H-pyrazolo[3,4-b]pyridin-3-yl)methanol (0.10 g, 0.515 mmol), iron (0.345 g, 6.18 mmol), ammonium chloride (0.110 g, 2.06 mmol) and ethanol:water (2.25 mL, 4:1). The mixture was heated in a microwave reactor at 110° C. for 20 minutes. The reaction mixture was filtered through a pad of celite. The filtrate was diluted with ethyl acetate and washed with saturated aqueous NaHCO3. The aqueous layer was extracted with ethyl acetate (2×). The combined organic layers were dried with sodium sulfate, filtered and concentrated in vacuo to afford crude (5-amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methanol that was used into the next step without further purification.