Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:6])[CH2:4][OH:5].[C:7]1(C)[CH:12]=CC(S(O)(=O)=O)=C[CH:8]=1>C(OC(C)=O)C.Cl.COC(OC)(C)C>[CH3:8][C:7]1([CH3:12])[O:6][CH:3]([CH2:2][NH2:1])[CH2:4][O:5]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: NCC(O)CO
Agent: Cl
Solvent: COC(C)(C)OC
Solvent: CCOC(C)=O
Product: CC1(C)OCC(CN)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 533.6 %

Procedure:
3-Aminopropane-1,2-diol (400 mg, 4.4 mmol) was dissolved in EtOAc—HCl (20 mL). And the reaction mixture was stirred at r.t. for 30 min. The reaction mixture was concentrated in vacuo to get to the white solid. The white solid was added in 2,2-dimethoxy-propane (10 mL) and toluene-4-sulfonic acid (86 mg, 0.5 mmol) was added into the mixture. The reaction mixture was stirred at 60° C. for 12 h. The reaction mixture was concentrated in vacuo, washed by acetone to give (2,2-dimethyl-1,3-dioxolan-4-yl)methanamine (350 mg, yield: 46%). 1HNMR (DMSO-d6, 400 MHz): δ8.08 (s, 2H), 4.32 (s, 1H), 4.05 (q, J=4.8 Hz, 1H), 3.73 (t, J=6.4 Hz, 1H), 3.00-2.78 (m, 2H), 1.37 (s, 3H), 1.28 (s, 3H)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[OH-].[Na+].Cl>CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH:11]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][O:18]2)[C:12]([OH:14])=[O:13])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: COC(=O)C(CC1CCCO1)c1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCO2)C(=O)O)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
To a solution of methyl 2-[4-(methylsulfonyl)phenyl]-3-(tetrahydrofuran-2-yl)propanoate (1.94 g) in methanol (25 mL) was added 2M aqueous sodium hydroxide solution (6.21 mL), and the mixture was stirred at 50° C. for 16 hr. The reaction mixture was acidified with 6M hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the title compound (1.69 g, 91%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[C:5]([CH:7](OC)[O:8]C)[N:6]=1.C(O)(=O)C(O)=O.O.Cl>C1COCC1>[Cl:1][C:2]1[O:3][C:4]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)=[C:5]([CH:7]=[O:8])[N:6]=1
Reactant: COC(OC)c1nc(Cl)oc1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1nc(Cl)oc1-c1ccc(C(F)(F)F)cc1
Yield: 83 %

Procedure:
A mixture of Example 52D (1.59 g, 4.94 mmol) and oxalic acid (0.71 g, 7.9 mmol) in THF (16 mL)/water (8 mL) was stirred at ambient temperature for 2 hr. Additional oxalic acid (0.71 g, 7.9 mmol) and THF (16 mL) were added and the reaction mixture was stirred for 2 additional hr. HCl (4 N in dioxane, 5 mL) was then added and the reaction mixture was stirred 16 hr at ambient temperature, and then quenched by addition of saturated aq Na2CO3 solution (10 mL). The mixture was partitioned between Et2O and H2O, and the separated aqueous phase was extracted with Et2O. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified on silica gel (Analogix® Intelliflash 280™; SF25-120 g column; 100% hexane 7 min, then 0% to 20% EtOAc/hexanes eluant, 23 min) which yielded 1.13 g (83%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.27-8.21 (m, 2H), 7.97 (dd, J=9.0, 0.6, 2H). MS (DCI+) m/z 293 (M+NH4).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([C:13]([O:15]C)=O)=[C:10](/[N:17]=[CH:18]/[N:19]([CH3:21])C)[CH:9]=2)=[CH:4][CH:3]=1.NC[C:24]1[CH:25]=[C:26]([N:30]2[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]2)[CH:27]=[CH:28][CH:29]=1>C1(O)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]3[C:13](=[O:15])[N:19]([CH2:21][C:28]4[CH:29]=[CH:24][CH:25]=[C:26]([N:30]5[CH2:34][CH2:33][C@@H:32]([OH:35])[CH2:31]5)[CH:27]=4)[CH:18]=[N:17][C:10]=3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1/N=C/N(C)C
Reactant: NCc1cccc(N2CC[C@@H](O)C2)c1
Solvent: Oc1ccccc1
Product: O=c1c2sc(-c3ccc(Cl)cc3)cc2ncn1Cc1cccc(N2CC[C@@H](O)C2)c1
Temperature: 150 °C
Yield: 579.6 %

Procedure:
Methyl 5-(4-chlorophenyl)-3-{[(1E)-(dimethylamino)methylene]amino}thiophene-2-carboxylate (0.131 g, 0.41 mmol) and (3R)-1-[3-(aminomethyl)phenyl]pyrrolidin-3-ol (0.062 g, 0.26 mmol, purity 80%) in phenol (0.5 g) were subjected to microwave heating at 150° C. for 1 h. The product was precipitated with ether and decanted. The solid residue was washed with MeOH and CH2Cl2 to give 0.66 g (57%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 7.90 (s, 1H), 7.88 (d, 2H, J=8.7 Hz), 7.56 (d, 2H, J=8.7 Hz), 7.11 (t, 1H, J=7.9 Hz), 6.56-6.52 (m, 2H), 6.43 (d, 1H, J=7.5 Hz), 5.15 (s, 2H), 4.92 (d, 1H, J=7.5 Hz), 3.40-3.18 (m, 3H), 3.03 (bd, 1H, J=9-7 Hz), 2.07-1.95 (m, 1H), 1.91-1.82 (m, 1H). 13C NMR (100 MHz, DMSO-d6) δ 157.6, 156.1, 149.8, 149.6, 147.8, 137.4, 134.3, 131.3, 129.4, 127.9, 121.8, 121.7, 114.1, 110.9, 110.7, 69.2, 55.9, 48.9, 45.4, 33.6. MS (ESI+) 438.1 (M+1H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([CH2:11][C:12]([O:14]C)=[O:13])[N:4]=1.[OH-].[Na+]>O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH2:11][C:12]([OH:14])=[O:13])[N:6]=1
Reactant: COC(=O)Cc1nc(OC)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)nc(CC(=O)O)n1
Temperature: 25 °C

Procedure:
20 g of methyl (4,6-dimethoxypyrimidin-2-yl)acetate are stirred for 2 hours at 50° C. with 3.9 g of sodium hydroxide in 300 ml of water. The mixture is cooled to room temperature and extracted three times using diethyl ether, and the aqueous phase is acidified to pH 2 using 2N hydrochloric acid and extracted four times using 150 ml portions of ethyl acetate. The organic phase is dried over sodium sulfate, the solvent is distilled off, and the residue is dried in vacuo. This gives 13.1 g of (4,6-dimethoxypyrimidin-2-yl)acetic acid of melting point 175°-177° C.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].[H-].[Na+].Br[C:12]1[S:13][C:14]([Br:17])=[CH:15][N:16]=1>CN(C)C=O.O1CCCC1.[Cl-].[Na+].O>[Br:17][C:14]1[S:13][C:12]2=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:1]=[CH:2][N:16]2[CH:15]=1
Reactant: Brc1cnc(Br)s1
Reactant: [C-]#[N+]CC(=O)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1ncn2cc(Br)sc12
Reaction time: 2 h

Procedure:
Ethyl isocyanoacetate (0.9 ml, 8.2 mmol) was gradually added dropwise to a suspension of sodium hydride (60% in mineral oil, 378 mg, 9.4 mmol) in N,N-dimethylformamide (5 ml) in an argon atmosphere under ice cooling. The mixture was stirred at the same temperature for 2 hr. This solution was added dropwise to a solution of 2,5-dibromothiazole (1.0 g, 4.1 mmol) in tetrahydrofuran (13 ml) cooled to −20° C. (brine/ice water) through a cannula over a period of 20 min, and, while allowing the temperature to rise to around 0° C., the mixture was stirred for 2 hr. After the completion of the reaction, saturated brine was added thereto, and the mixture was extracted with ethyl acetate (20 ml×5). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ethyl acetate to give ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate. The solvent was removed from the ethyl acetate washing liquor by distillation, and the residue was purified by chromatography on silica gel (hexane:ethyl acetate=1:2). The resultant purification product was combined with the crystal prepared above to give ethyl 2-bromoimidazo[5,1-b]thiazole-7-carboxylate (1.1 g, 90%) as a white solid.
Reaction SMILES: C[Al](C)C.[NH3:5].O1CCOCC1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][N:24]=1)[C:16]([O-])=[O:17]>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:21]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][N:24]=1)[C:16]([NH2:5])=[O:17]
Reactant: O=C([O-])c1ccc(Nc2nccc(-c3ccccc3)n2)c(Cl)c1
Reactant: N
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)c1ccc(Nc2nccc(-c3ccccc3)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Trimethylaluminum (0.8 mL, 2.0 mmol, 2.5M in hexanes) was slowly added to a solution of ammonia in dioxane (4 mL, 0.5 mmol) under argon at room temperature. After stirring for 15 min at room temperature, 3-chloro-4-(4-phenylpyrimidin-2-ylamino)benzoate (0.67 g, 2.0 mmol) in CH2Cl2 was added slowly. The mixture was stirred at room temperature until the ester had been consumed as judged by analytical HPLC analysis. The reaction was quenched with 1 N HCl and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×), and the combined organics were dried (MgSO4) and concentrated to afford (3-chloro-4-(4 phenylpyrimidin-2-ylamino)benzamide. MS (ESI) 325 (M+H).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH3:5][Mg]Br.[CH:8](=[C:15]1/[CH2:16][C:17]2([CH2:41][CH3:42])[C:23]3=[CH:24][C:25]4[CH:26]=[N:27][N:28]([C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[C:29]=4[CH:30]=[C:22]3[CH2:21][CH2:20][CH2:19][CH:18]2[CH2:38][C:39]/1=[O:40])/[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[CH:8](=[C:15]1/[CH2:16][C:17]2([CH2:41][CH3:42])[C:23]3=[CH:24][C:25]4[CH:26]=[N:27][N:28]([C:31]5[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=5)[C:29]=4[CH:30]=[C:22]3[CH2:21][CH2:20][CH2:19][CH:18]2[CH2:38][C:39]/1([CH3:5])[OH:40])/[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[Mg]Br
Reactant: CCC12C/C(=C\c3ccccc3)C(=O)CC1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC12C/C(=C\c3ccccc3)C(C)(O)CC1CCCc1cc3c(cnn3-c3ccc(F)cc3)cc12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 55 %

Procedure:
THF (2 mL) was added to cerium(III) chloride (0.130 g, 0.527 mmol). The suspension was warmed to about 50° C. for about 30 min then cooled to about −78° C. A solution of methylmagnesium bromide (3.0 M solution in Et2O, 0.165 mL, 0.495 mmol) and THF (2 mL) was added dropwise and the reaction mixture was stirred for about 15 min. A solution of rac-(4aS,12bR,E)-2-benzylidene-12b-ethyl-9-(4-fluorophenyl)-1,4,4a,5,6,7,9,12b-octahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3 (2H)-one (53, R1=4-Fluorophenyl, R2=Ethyl) (0.100 g, 0.215 mmol) and THF (2 mL) was added dropwise via syringe and the reaction was stirred at about −78° C. for about 1 h. Methylmagnesium bromide (3.0 M solution in Et2O, 0.16 mL, 0.48 mmol) was added. After about 1 h, methylmagnesium bromide (3.0 M solution in Et2O, 0.1 mL, 0.3 mmol) was added. After about 1 h, the reaction was quenched with MeOH (1 mL) maintaining an internal temperature of less than about −60° C. Sat. aq. NH4Cl (2 mL), water (2 mL), and EtOAc (20 mL) were added and the mixture was allowed to warm to rt. EtOAc (50 mL) and water (20 mL) were added. The layers were separated and the aqueous layer was extracted with EtOAc (20 mL). The combined organics were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (25 g) using a gradient of 0-10% EtOAc in heptane. The product fractions were combined and concentrated under reduced pressure to give rac-(3R,4aS,12bR,E)-2-benzylidene-12b-ethyl-9-(4-fluorophenyl)-3-methyl-1,2,3,4,4a,5,6,7,9,12b-decahydrobenzo[6,7]cyclohepta[1,2-f]indazol-3-ol (54, R1=4-Fluorophenyl, R2=Ethyl, R3=Methyl) (0.057 g. 55% yield); LC/MS, method 3, Rt=3.16 min.; MS m/z: 481 (M+H)+. 1H NMR (400 MHz, DMSO) δ 7.76-7.70 (m, 2H), 7.64 (s, 1H), 7.62-7.55 (m, 2H), 7.46 (s, 1H), 7.43-7.35 (m, 5H), 6.86 (s, 1H), 6.80 (s, 1H), 4.57 (s, 1H), 3.63-3.53 (m, 1H), 3.06-2.86 (m, 2H), 2.36-1.99 (m, 4H), 1.81-1.61 (m, 2H), 1.61-1.42 (m, 3H), 1.39 (s, 3H), 1.30-1.22 (m, 1H), 0.51 (t, J=7.3 Hz, 3H).
Reaction SMILES: Br.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl.CS(O[CH2:28][CH2:29][CH2:30][N:31]1[CH2:36][CH2:35][CH2:34][C@H:33]([CH3:37])[CH2:32]1)(=O)=O>CN(C)C=O>[CH3:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][CH2:34][C@H:33]([CH3:37])[CH2:32]3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1
Reactant: C[C@H]1CCCN(CCCOS(C)(=O)=O)C1
Reactant: Cc1cc(-c2ccc(O)cc2)ccn1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(OCCCN3CCC[C@H](C)C3)cc2)ccn1

Procedure:
A Following the procedure described in example 56A, but starting from 2-methyl-4-(4-hydroxyphenyl)pyridine hydrobromide (130 m g), potassium carbonate (415 g), (3S)-1-(3-methanesulfonyloxypropyl)-3-methylpiperidine hydrochloride (170 mg) and N,N-dimethylformamide (5 mL) gives 82 mg of 2-methyl-4-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyridine, dioxalate as a pale yellow powder melting at 97° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:12][C:11]([O:22][CH3:23])=[C:10]([O:24][CH3:25])[CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].IC.[C:30]1(S)C=CC=CC=1>C(OCC)(=O)C.CN(C)C=O.O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[S:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:12][C:11]([O:22][CH3:23])=[C:10]([O:24][CH3:25])[CH:9]=2)=[O:5])[CH3:2].[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:30])[C:8]2[C:13]([C:14]=1[S:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:12][C:11]([O:22][CH3:23])=[C:10]([O:24][CH3:25])[CH:9]=2)=[O:5])[CH3:2]
Reactant: Sc1ccccc1
Agent: CCOC(=O)c1[nH]c2cc(OC)c(OC)cc2c1Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Sc2ccccc2)c2cc(OC)c(OC)cc2n1C
Temperature: 25 °C

Procedure:
To a 0° C. tetrahydrofuran solution of 5,6-dimethoxy-3-phenylsulfanyl-1H-indole-2-carboxylic acid ethyl ester (0.500 g, 1.40 mmol) was added sodium hydride (95%, 0.037 g, 1.54 mmol) followed by iodomethane (0.096 mL, 1.54 mmol). 5,6-dimethoxy-3-phenylsulfanyl-1H-indole-2-carboxylic acid ethyl ester was synthesized in a manner analogous to Intermediate 1, using benzene thiol instead of 2-methyl benzenethiol. N,N-Dimethylformamide was added to homogenize the reaction. The reaction was allowed to warm to room temperature and stir overnight. The reaction was diluted with ethyl acetate (100 mL). The organic layers were washed with 1N hydrochloric acid (25 mL) and brine (25 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the title product, which was used without further purification.
Reaction SMILES: C([O:3][P:4]([CH:9]([NH:18][CH:19]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=[CH:20]1)[P:10](=[O:17])([O:14]CC)[O:11]CC)(=[O:8])[O:5]CC)C.CO.O>C(Cl)(Cl)(Cl)Cl>[CH2:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:19]1[NH:18][CH:9]([P:10](=[O:11])([OH:14])[OH:17])[P:4](=[O:3])([OH:5])[OH:8]
Reactant: CCOP(=O)(OCC)C(NC1C=CCCCC1)P(=O)(OCC)OCC
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CO
Product: O=P(O)(O)C(NC1CCCCCC1)P(=O)(O)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 34.8 %

Procedure:
2.5 ml of trimethylsililiodide was added dropwise to an ice-cold solution of 1.55 g of tetraethyl(2-cycloheptenyl)aminomethylenebis(phosphonate) in 25 ml of carbon tetrachloride. Then, the mixture was stirred at room temperature for 2.5 hours. 2 ml of methanol and 1 ml of purified water were added to the ice-cold reaction solution and it was concentrated under reduced pressure. To the obtained residue were added methanol and acetone to give a white solid. The residue was recrystallized from water-methanol to give 0.39 g of (2-cycloheptyl)aminomethylenebis(phosphonic acid) as colorless crystals in the form of needles.
Reaction SMILES: [OH:1][CH:2]([C@H:4]1[CH2:8][CH2:7][N:6]([C:9](OC(C)(C)C)=O)[CH2:5]1)[CH3:3].Cl.CCN(C(C)C)C(C)C.ClC1[C:36]2[C:31](=[N:32][CH:33]=[CH:34][N:35]=2)[CH:30]=[C:29]([Cl:37])[N:28]=1>C1COCC1>[Cl:37][C:29]1[N:28]=[C:9]([N:6]2[CH2:7][CH2:8][CH:4]([C@@H:2]([OH:1])[CH3:3])[CH2:5]2)[C:36]2[C:31](=[N:32][CH:33]=[CH:34][N:35]=2)[CH:30]=1
Reactant: CC(O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Clc1cc2nccnc2c(Cl)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](O)C1CCN(c2nc(Cl)cc3nccnc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-butyl 3-(1-hydroxyethyl)pyrrolidine-1-carboxylate was treated with HCl solution (in EtOAc, 5 mL) at room temperature for 2 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in anhydrous THF (10 mL). To the resulted THF solution, DIPEA (570 mg, 4.4 mmol) and 5,7-dichloropyrido[4,3-b]pyrazine (400 mg, 2.0 mmol) were added, and the reaction was stirred at room temperature overnight. The volatiles were removed under reduced pressure, and the residue was dissolved in ethyl acetate, washed with brine and dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography to afford the title compound. MS (m/z): 279 (M+H)+.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[C:30]([Br:31])=[CH:29][CH:28]=[CH:27][C:26]=2[Br:32])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([O:43][Si](C(C)(C)C)(C)C)[CH2:37]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:33])[CH:21]([O:24][C:25]2[C:26]([Br:32])=[CH:27][CH:28]=[CH:29][C:30]=2[Br:31])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:51])[C@@H:15]2[CH2:34][CH2:35][C@H:36]2[O:41][C:40](=[O:42])[CH2:39][C@H:38]([OH:43])[CH2:37]2)=[CH:10]1
Reactant: CCC(Oc1c(Br)cccc1Br)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1c(Br)cccc1Br)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 36.9 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.36 g of ([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2,6-dibromophenoxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 43, above] and 37.5 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.37 g of the title compound as white crystals, melting at between 114° and 116° C.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C([O:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:34]3[C:29](=[CH:30][C:31]([C:35](O)=[O:36])=[CH:32][CH:33]=3)[C:28]([CH3:38])=[C:27]2[CH3:39])=[CH:21][CH:20]=1)=[O:12])(C)(C)C>>[CH:1]1([NH:5][C:35]([C:31]2[CH:30]=[C:29]3[C:34](=[CH:33][CH:32]=2)[N:26]([CH2:25][C:22]2[CH:21]=[CH:20][C:19]([C:14]4[C:13]([C:11]([OH:12])=[O:10])=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:24][CH:23]=2)[C:27]([CH3:39])=[C:28]3[CH3:38])=[O:36])[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NC1CCC1
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NC3CCC3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using cyclobutylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.[CH:14]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)=[CH2:15].C(C1C=CC=CN=1)=C.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[CH2:14][CH2:15][N:2]1[CH2:3][CH2:4][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[CH2:1]1
Reactant: C=Cc1ccc2ccccc2n1
Reactant: c1ccc2c3c([nH]c2c1)CCNC3
Agent: C=Cc1ccccn1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: c1ccc2nc(CCN3CCc4[nH]c5ccccc5c4C3)ccc2c1

Procedure:
The title compound was prepared following the procedure of Example 2 with the exception that 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole was used instead of 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole and 2-vinylquinoline replaced 2-vinylpyridine. The product was converted to the dihydrochloride; mp 195°-197° C.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1.[NH2:20][OH:21].[OH-].[K+].CO>C1COCC1>[OH:21][NH:20][C:3](=[O:2])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=1
Reactant: COC(=O)C=CC=CCSc1ccc(N(C)C)cc1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1ccc(SCC=CC=CC(=O)NO)cc1
Temperature: 0 °C
Yield: 43.1 %

Procedure:
To a solution of 6-(4-dimethylamino-phenylsulfanyl)-hexa-2,4-dienoic acid methyl ester (0.556 g, 2.0 mmol) in distilled THF (10 mL) containing aqueous hydroxylamine (50%, 1.21 mL, 18.4 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 2.8 mL, 2.8 mmol) over a period of 30 minutes. After stirring the mixture at 0° C. for an additional hour, distilled water (10 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The solution was then extracted with ethyl acetate (2×50 mL), and the combined extracts were dried over anhydrous MgSO4, and evaporated to dryness. The solid residue was recrystallised from ethyl acetate to give the title compound (0.24 g, 43%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:14]=3[N:15]=2)[C:7](F)=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:21]([NH2:24])[CH2:22][CH3:23]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[O:12][C:13]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:14]=3[N:15]=2)[C:7]([NH:24][CH2:21][CH2:22][CH3:23])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc3cc(Cl)ccc3o2)c1
Reactant: CCCN
Product: CCCNc1ccc([N+](=O)[O-])cc1-c1nc2cc(Cl)ccc2o1

Procedure:
Prepared by the method of Example 54a), from 2-(3-nitro-6-fluorophenyl)-5-chlorobenzoxazole (263 mg, 0.9 mmol) and propylamine (400 μL, 5.0 mmol) the subtitle compound was obtained (296 mg, 99%). 1H NMR (DMSO) δ 9.33(t, 1H), 9.02(s, 1H), 8.44(dd, 1H), 8.16–8.11(m, 2H), 7.75(dd, 1H), 7.29(d, 1H), 3.67(q, 2H), 1.97(m, 2H), 1.28(t, 3H).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[Li]CCCC.[CH3:21][N:22]1[CH:26]=[CH:25][C:24]([CH3:27])=[N:23]1.CN1C(C)=CC=N1.[CH2:35]([Sn:39](Cl)([CH2:44][CH2:45][CH2:46][CH3:47])[CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH3:38]>C1COCC1.O>[CH3:21][N:22]1[C:26]([Sn:39]([CH2:40][CH2:41][CH2:42][CH3:43])([CH2:44][CH2:45][CH2:46][CH3:47])[CH2:35][CH2:36][CH2:37][CH3:38])=[CH:25][C:24]([CH3:27])=[N:23]1
Reactant: Cc1ccn(C)n1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccnn1C
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cc(C)nn1C
Temperature: -78 °C
Reaction time: 2 h
Yield: 36 %

Procedure:
To a solution of LDA (prepared from diisopropylamine (3.6 mL, 1.1 equiv) and n-BuLi (1.6M in hexanes, 14.3 mL, 1.1 equiv) in THF (80 mL) at −78° C. was added dropwise a solution containing a 1:1 mixture of 1,3-dimethyl-1H-pyrazole and 1,5-dimethyl-1H-pyrazole (2 g, 1 equiv) in THF (5 mL) with keeping the temperature below −70° C. At the end of the addition, the mixture was stirred for 30 min at −78° C. before addition of tributyltin chloride (6.16 mL, 1.1 equiv) with keeping the temperature below −70° C. The mixture was then stirred at −78° C. for 30 min and at r.t. for 2 h. The mixture was poured into water and then extracted with AcOEt (3 times). The organic phases were combined, dried (Na2SO4) and concentrated in vacuo to give a yellow paste. The crude product was purified by flash chromatography (hexanes to EtOAc/hexanes (40:60)) to yield 1,3-dimethyl-5-tributylstannanyl-1H-pyrazole (2.88 g, 36%) as a colorless syrup. (TLC rf 0.46 in EtOAc/hexanes 20:80).