Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:49])[CH2:13][C:12]2[CH:11]=[C:10]3[N:5]([CH2:6][CH2:7][N:8]([C:15]4[C:20]([CH:21]=[O:22])=[C:19]([C:23]5[CH:28]=[C:27]([NH:29][C:30]6[CH:35]=[CH:34][C:33]([N:36]7[CH2:41][CH2:40][N:39]([CH:42]8[CH2:45][O:44][CH2:43]8)[CH2:38][C@H:37]7[CH3:46])=[CH:32][N:31]=6)[C:26](=[O:47])[N:25]([CH3:48])[CH:24]=5)[CH:18]=[CH:17][N:16]=4)[C:9]3=[O:14])[C:4]=2[CH2:3]1.[BH4-].[Na+]>CO>[OH:22][CH2:21][C:20]1[C:15]([N:8]2[CH2:7][CH2:6][N:5]3[C:4]4[CH2:3][C:2]([CH3:49])([CH3:1])[CH2:13][C:12]=4[CH:11]=[C:10]3[C:9]2=[O:14])=[N:16][CH:17]=[CH:18][C:19]=1[C:23]1[CH:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([N:36]3[CH2:41][CH2:40][N:39]([CH:42]4[CH2:45][O:44][CH2:43]4)[CH2:38][C@H:37]3[CH3:46])=[CH:32][N:31]=2)[C:26](=[O:47])[N:25]([CH3:48])[CH:24]=1
Reactant: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3ccnc(N4CCn5c(cc6c5CC(C)(C)C6)C4=O)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.6 %

Procedure:
A mixture of 153a (82 mg, 0.12 mmol), NaBH4 (22 mg, 0.60), and methanol (10 mL) was stirred at 25° C. for 1 h. It was then quenched with water (5 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×10 mL). The combined dichloromethane extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 153 (22 mg, 28%). MS-ESI: [M+H]+ 665. 1H NMR (500 MHz, CDCl3) δ 8.65 (d, J=2.0 Hz, 1H), 8.48 (d, J=5.0 Hz, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.83 (s, 1H), 7.36 (d, J=5.0 Hz, 1H), 7.32-7.26 (m, 1H), 6.84-6.80 (m, 2H), 5.30 (s, 1H), 4.71-4.32 (m, 7H), 4.15 (d, J=5.0 Hz, 2H), 3.85 (t, J=8.0 Hz, 1H), 3.71 (s, 3H), 3.57-3.43 (m, 2H), 3.08-3.06 (m, 2H), 2.57-2.48 (m, 7H), 2.22-2.20 (m, 1H), 1.27 (s, 6H), 0.98 (d, J=6.5 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:19])[CH:16]=2)[C:11]1=[O:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:20])[N:10]([CH:3]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:2][O:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:18]2
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc2c(c1)CN(C(CO)c1ccccc1)C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)CN(C(COS(C)(=O)=O)c1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(2-Hydroxy-1-phenyl-ethyl)-5-methyl-2,3-dihydro-isoindol-1-one (4.72 g, 17.66 mmol) and triethylamine (5.36 g, 53.97 mmol, 7.38 mL) were taken up in anhydrous DCM (50 mL), under argon and cooled to 0EC. Methanesulfonyl chloride (2.22 g, 19.43 mmol, 1.5 mL) was added to the reaction over 10 min. The reaction was stirred for 1 h at 0EC then allowed to slowly warm to room temp and stirred for 4 h. The reaction was slowly poured into saturated sodium bicarbonate and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with 1N HCl, water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. The product was used in the next step without further purification. Yield 5.61 g. 1H NMR (CDCl3, 300 MHz): δ 2.44 (s, 3H), 3.01 (s, 3H), 4.15 (d, J=16 Hz, 1H), 4.43 (d, J=17 Hz, 1H), 4.77 (dd, J=5, 11 Hz, 1H), 5.03 (dd, J=9, 11 Hz, 1H), 5.76 (dd, J=5, 9 Hz, 1H), 7.20-7.38 (, 7H), 7.76 (d, J=8, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH2:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[CH2:27]([N:29]=[C:30]=[O:31])[CH3:28]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:30]([NH:29][CH2:27][CH3:28])=[O:31])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCN=C=O
Reactant: CCC(N)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: CCNC(=O)NC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Yield: 37.6 %

Procedure:
To a solution of crude 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-amine (100 mg) in tetrahydrofuran (2.3 mL) was added ethyl isocyanate (0.0222 mL, 0.280 mmol) at 0° C. The resultant mixture, was stirred at room temperature for 30 min and concentrated in vacuo. The residue was washed with ethyl acetate to give the title compound as a colorless solid (44.1 mg, 0.0917 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:19][CH:20]([CH3:22])[CH3:21])=[C:4]([CH:17]=[O:18])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:13])([CH3:12])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15].[CH3:23][Mg]Cl>C1COCC1>[Cl:1][C:2]1[C:3]([O:19][CH:20]([CH3:22])[CH3:21])=[C:4]([CH:17]([OH:18])[CH3:23])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH3:12])([CH3:13])[CH:8]=[C:7]2[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)Oc1c(C=O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)Oc1c(C(C)O)cc2c(c1Cl)OC(C)(C)C=C2C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-chloro-7-isopropoxy-4-isopropyl-2,2-dimethyl-2H-chromene-6-carbaldehyde, (Compound 135, 0.97 g, 3.0 mmol) in THF (15 mL) at was added methylmagnesium chloride (3M in THF, 1.6 mL, 4.8 mmol). After stirring at 0° C. for 30 min, the reaction was quenched with 1N HCl. The resulting mixture was diluted with water, extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (MgSO4), filtered, and concentrated under reduced pressure to give the title compound as a yellow foam.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([C:19](=[O:31])[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]3[CH:25]3[CH2:27][CH2:26]3)=[C:17]([CH3:32])[C:16]=2[F:33])[CH2:10]1)=O)(C)(C)C.[ClH:34]>C(O)C>[ClH:34].[NH2:8][CH:9]1[CH:13]([CH3:14])[CH2:12][N:11]([C:15]2[CH:24]=[C:23]3[C:18]([C:19](=[O:31])[C:20]([C:28]([OH:30])=[O:29])=[CH:21][N:22]3[CH:25]3[CH2:27][CH2:26]3)=[C:17]([CH3:32])[C:16]=2[F:33])[CH2:10]1
Reactant: Cc1c(F)c(N2CC(C)C(NC(=O)OC(C)(C)C)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: CCO
Product: Cc1c(F)c(N2CC(C)C(N)C2)cc2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
A mixture comprising 7-(3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (trans form) (120 mg), ethanol (4 ml) and 10% hydrochloric acid (4 ml) is refluxed for 30 minutes. After concentrating, the obtained residue is recrystallized from methanol - ethyl acetate to give 7-(3-amino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride (trans form) (60 mg), as white powder, m.p. 272°-275° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13].[Cl:14][C:15]1[C:16]([O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])=[N:17][NH:18][C:19]=1[CH3:20].Cl>C(OCC)(=O)C>[Cl:8][CH2:9][CH2:10][NH:11][C:12]([N:18]1[C:19]([CH3:20])=[C:15]([Cl:14])[C:16]([O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][C:23]=2[Cl:33])=[N:17]1)=[O:13]
Reactant: Cc1[nH]nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)c1Cl
Reactant: O=C=NCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1c(Cl)c(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)nn1C(=O)NCCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Triethylamine (0.10 g, 1.0 mmol) and 2-chloroethyl isocyanate (0.12 g, 1.1 mmol) were added to a solution of 4-chloro-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole (0.35 g, 1.0 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 8 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-(2-chloroethyl)-4-chloro-3-(2,6-dichloro-4-trifluoromethylphenyloxy)-5-methylpyrazole-1-carboxamide (0.44 g, yield: 97.6%). mp: 141-143° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.62 (s, 3H), 3.55-3.65 (m, 4H), 6.80-7.05 (m, 1H), 7.67 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:5])[CH3:2].[NH2:22][C:23]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:24]=1[C:25]([OH:27])=O>>[Cl:32][C:30]1[CH:31]=[C:23]2[C:24]([C:25](=[O:27])[N:19]([S:16]([C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:15][CH:14]=3)(=[O:17])=[O:18])[C:20](=[O:21])[NH:22]2)=[CH:28][CH:29]=1
Reactant: CCOC(=O)CCCOc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: CCOC(=O)CCCOc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1
Yield: 26.9 %

Procedure:
763 mg (2.44 mmol) of 4-(3-ethyloxycarbonylpropyloxy)benzenesulfonylisocyanate and 418 mg (2.44 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 306 mg of the above-identified compound (yield 27.0%). Properties: colorless crystal, Melting point: 167°-169° C., PMR (δppm, DMSO-d6):1.18 (3H,s), 1.98-2.03 (1H,m), 2.46 (2H,t), 4.04-4.14 (4H,m), 7.12 (1H,s), 7.16 (2H,d), 7.21 (1H,d), 7.85 (1H,d), 8.09 (2H,d), 11.58 (1H,s).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][CH:5]=[CH:6][N:7]=1)[CH3:2].[CH2:8]([O:10][CH2:11][CH2:12]Cl)[CH3:9].C(N(CC)CC)C>>[CH2:8]([O:10][CH2:11][CH2:12][N:4]1[CH:5]=[CH:6][N:7]=[C:3]1[CH2:1][CH3:2])[CH3:9]
Reactant: CCc1ncc[nH]1
Reactant: CCOCCCl
Solvent: CCN(CC)CC
Product: CCOCCn1ccnc1CC
Reaction time: 72 h

Procedure:
In an autoclave of 100 mL, 2-ethylimidazole (19.2 g, 200 mmol) was made reacted with 2-chloroethyl ethyl ether (26.0 g, 240 mmol) at 145 deg C. for 72 hours. Brown liquid that was obtained was washed with 120 mL of a compound liquid of ethanol and ether (volume ratio thereof is 1:5), and then made reacted with triethylamine (20.2 g, 200 mmol) in the autoclave of 100 mL at 130 deg C. for 24 hours. Solid salts that was formed was removed by filtration, and residue (filtrate) was subjected to reduced-pressure distillation by using a Vigreux column of 20 cm. The product was a transparent liquid which has a boiling point of 171-175 deg C. when a pressure is 10 Pa. 1H-NMR measurement of obtained amine was performed, and it was confirmed that chemical shifts, δ (ppm), are 6.91 (d, 1H), 6.87(d, 1H), 4.00-3.97(t, 2H), 3.63-3.60 (t, 2H), 3.44-3.39(4, 2H), 2.75-2.65(m, 2H), 1.33-1.29(t, 3H), and 1.15-1.12(t, 3H), and 1-(2-ethoxyethyl)-2-ethyl imidazole was synthesized.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:35])([CH3:34])[C@@H:11]([O:26][Si:27]([CH3:33])([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:12]([O:14][CH:15]([O:19][C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH:16]([CH3:18])[CH3:17])=[O:13])(=[O:7])=[O:6].[N-:36]=[N+:37]=[N-:38].[Na+]>CS(C)=O>[N:36]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:35])([CH3:34])[C@@H:11]([O:26][Si:27]([CH3:33])([CH3:32])[C:28]([CH3:31])([CH3:30])[CH3:29])[C:12]([O:14][CH:15]([O:19][C:20]([O:22][CH:23]([CH3:25])[CH3:24])=[O:21])[CH:16]([CH3:18])[CH3:17])=[O:13])(=[O:7])=[O:6])=[N+:37]=[N-:38]
Reactant: CC(C)OC(=O)OC(OC(=O)[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCCl)C(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)OC(=O)OC(OC(=O)[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-])C(C)C

Procedure:
Following the general procedure for the preparation of azides of Description 16, a mixture of 2-methyl-1-(methylethoxycarbonyloxy)propyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(1,1,2,2-tetramethyl-1-silapropoxy)butanoate (47a) (0.6 g max.) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 69 mg (1.1 mmol) of sodium azide (NaN3). After work-up, the crude title compound (47b) was used in the next step without further purification. MS (ESI) m/z 590.22 (M+Na)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.[Li]CCCC.CCOCC.Br[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[O:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:24][N:23]=1>C1COCC1.[Cl-].[Zn+2].[Cl-]>[O:29]1[CH2:30][CH2:31][CH2:32][O:33][CH:28]1[C:25]1[CH:26]=[CH:27][C:22]([C:9]2[S:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:8]=2)=[N:23][CH:24]=1
Reactant: Clc1ccnc2ccsc12
Reactant: Brc1ccc(C2OCCCO2)cn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Product: Clc1ccnc2cc(-c3ccc(C4OCCCO4)cn3)sc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.7 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine (6) (13.33 g, 79 mmol) in THF (204 mL) at −5° C./−10° C. was added n-BuLi (2.5 M in hexanes, 31.6 mL, 79 mmol) over 50 min. After 30 min, a solution of zinc chloride in ether (1M, 79 mL, 79 mmol) was added at −5° C./−10° C. over 50 min and the reaction mixture was allowed to warm-up to r.t. After 45 min, 2-bromo-5-(1,3-dioxan-2-yl)pyridine (28) (15.98 g, 65.5 mmol) and palladium tetrakistriphenylphosphine (2.27 g, 1.964 mmol) in THF (28 mL) were added and the mixture was heated to reflux for 2 h, cooled down to r.t., and concentrated. The residue was diluted with DCM (600 mL), H2O (500 mL) and NH4OH (100 mL), stirred at r.t. for 1 h and the phases were separated. The aqueous phase was extracted with DCM (2×100 mL); the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated. The residue was triturated with MTBE (150 mL), to afford intermediate 29 (12.796 g, 59% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.66-8.65 (m, 2H), 8.43 (d, J=0.8 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.4 Hz, 1H), 7.59 (dd, J=5.0, 0.6 Hz, 1H), 5.68 (s, 1H), 4.19 (dd, J=11.6, 4.8 Hz, 2H), 3.99 (t, J=11.4 Hz, 2H), 2.07-2.01 (m, 1H), 1.49 (d, J=13.2 Hz, 1H). MS (m/z): 333.1 (M+H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:54][C:55]1[CH:60]=[CH:59][CH:58]=[C:57]([N:61]=[C:62]=[O:63])[CH:56]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:62]([NH:61][C:57]2[CH:58]=[CH:59][CH:60]=[C:55]([F:54])[CH:56]=2)=[O:63])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: O=C=Nc1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(F)c1)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 60 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 1-fluoro-3-isocyanatobenzene as the starting materials in 60% yield. LCMS for C31H32ClFN7O2 (M+H)+: m/z=588.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[C:10](Br)[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:25])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>COCCOC>[CH2:21]([O:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([C:10]2[CH:9]=[C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])[CH:13]=[CH:12][C:11]=2[O:14][C:15]([F:18])([F:17])[F:16])=[CH:28][CH:27]=1)=[O:25])[CH3:22]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(Br)c1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)OC(C)(C)C)ccc2OC(F)(F)F)cc1
Yield: 72.8 %

Procedure:
A mixture of (3-bromo-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (250 mg), 4-ethoxycarbonyl-phenyl boronic acid (136 mg), cesium carbonate (228 mg) and tetrakis(triphenylphosphine)palladium0 (catalytic quantity), in 1:2 aqueous DME (15 ml) was heated to reflux for 18 h. The mixture was then cooled and partitioned between water and ethyl acetate. The dried extracts were evaporated and the residue purified on silica gel. Elution with 5-40% ethyl acetate:petrol gave a pale yellow solid (217 mg)
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:22][CH2:21][C:16]3(OCC[O:17]3)[CH2:15][CH2:14]2)=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[OH-].[Na+]>Cl.O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][C:16](=[O:17])[CH2:21][CH2:22]2)=[CH:7][C:6]=1[N+:23]([O-:25])=[O:24]
Reactant: CC(=O)Nc1ccc(CCN2CCC3(CC2)OCCO3)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(CCN2CCC(=O)CC2)cc1[N+](=O)[O-]
Yield: 100 %

Procedure:
A suspension of 5.24 g (15.0 mmol) of 1-(8-[2-(4-acetamido-3-nitrophenyl)ethyl]-1,4-dioxa-8-azaspiro[4.5]decane in 30 mL 2N hydrochloric acid was heated at reflux for 1.5 hours. The cooled mixture was basified (pH 9-10) with saturated sodium carbonate solution and 10N sodium hydroxide, diluted with 100 ml water, and extracted with methylene chloride (3×150 ml). The extract was washed with 50 ml water and brine, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to give 3.95 g (100%) of 1-[2-(4-amino-3-nitrophenyl)ethyl]-4-piperidone as an oil.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][N:10](C3CCCCO3)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[F:29][C:30]([F:34])([F:33])[S:31]Cl.O>C1COCC1.CCOCC.CCCCCC>[C:1]1([C:7]2[N:8]=[C:9]([S:31][C:30]([F:34])([F:33])[F:29])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)SCl
Reactant: c1ccc(-c2ncn(C3CCCCO3)c2-c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: FC(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Temperature: -78 °C
Yield: 46.8 %

Procedure:
Under nitrogen and in glassware dried with a heat gun, a solution of 0.9 g (3 mmole) of 4,5-diphenyl-1-(2-tetrahydropyranyl)imidazole in 15 ml THF and 15 ml ether was chilled to -78° C. To the cold solution was added dropwise a solution of 2.5 ml (4 mmole) of 1.6 M n-butyl lithium in hexane in 10 ml ether. The solution was stirred at -78° C., then 0.55 g (4 mmole) of trifluoromethanesulfenyl chloride (TOXIC) was added as a gas. The mixture was stirred at -78° C. for 2 hours, then at RT overnight. The mixture was poured into water and extracted with ether (pH of aqueous layer ~4). The aqueous layer was neutralized with bicarbonate then extracted with more ether. The combined ether extracts were dried and concentrated. The crude residue was chromatographed on 50 g SilicAR CC-7, eluting with 98% toluene/2% ethyl acetate, to give 0.45 g (47%) of product. Recrystallization from toluene gave 0.3 g (31%) of white solid, mp 254°-6°. ; Anal. Calc'd. for C16H11F3N2S: C, 59.99; H, 3.46; N, 8.75. Found: C, 60.20; H, 3,57; N, 8.52.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:27]([O-])=O)[CH:5]=[C:6]([CH3:26])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]CC2C=CC=CC=2)=[C:11]([CH:23]([CH3:25])[CH3:24])[CH:10]=1.[H][H]>C(O)C.O1CCCC1.C(OCC)(=O)C.CCCCCCC.[Pd]>[CH3:26][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH:23]([CH3:24])[CH3:25])[CH:10]=1)[NH2:27]
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(OCc2ccccc2)c(C(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1cc(N)cc(C)c1Oc1ccc(O)c(C(C)C)c1
Reaction time: 18 h

Procedure:
3,5-Dimethyl-4-(3'-isopropyl-4'-benzyloxyphenoxy)-nitrobenzene, (2.86 kg, 7.31 mol) is dissolved in a mixture of ethanol/tetrahydrofuran (10:1, 114L) and cooled to 10°. This is admixed with 10% Pd/C (800g) and the system is pressurized to 15 psi with hydrogen gas. The hydrogenation is continued for 18 hours. The mixture is then filtered through Celite and the Celite is washed with tetrahydrofuran (30 L). The filtrate is then evaporated in vacuo to dryness (50°, 3 Torr). The solid residue is triturated with heptane (3L) and filtered. The filter cake is washed with heptane (2×500 mL) to obtain crude product which is then dissolved in hot ethyl acetate (14 L) and diluted with heptane (30 L). The product slowly precipitates and the mixture is cooled at 10°for 1 hour, collected by filtration and washed with ethyl acetate/hexane 1:2 (2×500 mL). The filter cake is then dried (60°, 3 Torr) for 24 hours to yield 3,5-dimethyl4-(3'-isopropyl-4'-hydroxyphenoxy)-aniline, m.p. 180°-181°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([O:20]CC)=[O:19])=[CH:16][N:17]=2)[CH:14]=1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([OH:20])=[O:19])=[CH:16][N:17]=2)[CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cnc2ccc(CCC(=O)OC(C)(C)C)cn12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)CCc1ccc2ncc(C(=O)O)n2c1
Temperature: 60 °C

Procedure:
A stirring mixture of ethyl 6-(3-tert-butoxy-3-oxopropyl)imidazo[1,2-a]pyridine-3-carboxylate (71) (400 mg, 1.26 mmol) and 2N LiOH (1 mL) in THF:MeOH (4:1, 4 mL) was heated at 60° C. for 30 minutes. The reaction was cooled to room temperature and the pH was adjusted between 3-5 with 10% citric acid. The solvent was partially reduced. The resulting solid was collected by vacuum filtration and washed with excess water. Crude 6-(3-(tertbutoxy)-3-oxopropyl)imidazo[1,2-a]pyridine-3-carboxylic acid (72) was dried and used in the next step without further purification. 1H NMR (400 MHz, d6-DMSO) δ 9.11 (s, 1H), 8.20 (s, 1H), 7.72 (dd, J=0.8, 9.2 Hz, 1H), 7.50 (dd, J=1.6, 9.2 Hz, 1H), 2.91 (t, J=6.8 Hz, 2H), 2.60 (t, J=7.2, 2 H), 1.33 (s, 9H). MS m/z 291.13 (M+1)+.
Reaction SMILES: I[CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].[CH2:8]([OH:12])[CH2:9][CH:10]=[CH2:11].C(B(CC)CC)C.CCO.C([O-])(O)=O.[Na+].[PH2](O)=O.N(C(C)(C)C#N)=NC(C)(C)C#N.Cl>O>[OH:12][CH2:8][CH2:9][CH2:10][CH2:11][CH:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7]
Reactant: C=CCCO
Reactant: O=C1OCCC1I
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCB(CC)CC
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C1OCCC1CCCCO
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a mixture of 3-iodo-dihydrofuran-2(3H)-one (15.0 g, 70.8 mmol) and but-3-en-1-ol (12.2 mL, 142 mmol) in water (680 mL) under an argon atmosphere was added a 1 M solution of triethylborane in EtOH (7.1 mL, 7.1 mmol). The flask was then charged with air and the reaction was stirred at room temperature for 2 hours. Solid NaHCO3 (35.7 g, 425 mmol) was added, followed by the careful addition of 50% hypophosphorous acid (39 mL, 360 mmol). After stirring at room temperature for 15 minutes, 2,2′-azobisisobutyronitrile (1.2 g, 7.1 mmol) was added and the reaction was heated to reflux for 1 hour. The reaction was cooled to room temperature, adjusted to pH=1 via the addition of 3% HCl, and then extracted three times with EtOAc. The organic layers were combined, dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed (2:1 EtOAc/hexanes) to provide the product as a colorless oil (3.7 g, 33%).