Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[CH:36][CH:35]=4)=[N:18][CH:19]=[C:20]([CH2:22][N:23]4[CH2:28][CH2:27][N:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH2:25][CH2:24]4)[CH:21]=3)[N:10]=2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O.C([O-])(O)=O.[Na+]>>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([NH:40][C:41](=[O:43])[CH3:42])=[CH:36][CH:35]=3)=[N:18][CH:19]=[C:20]([CH2:22][N:23]3[CH2:24][CH2:25][N:26]([S:29]([CH3:32])(=[O:30])=[O:31])[CH2:27][CH2:28]3)[CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(S(C)(=O)=O)CC4)cnc3Nc3ccc(NC(C)=O)cc3)n2)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1ccc(Nc2ncc(CN3CCN(S(C)(=O)=O)CC3)cc2-c2nc(C)nc(N)n2)cc1
Yield: 73.6 %

Procedure:
A solution of N-(4-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-2-ylamino)phenyl)acetamide (0.140 g, 0.186 mmol) in trifluoroacetic acid (Aldrich) (1.383 mL, 18.62 mmol) and trifluoromethane sulfonic acid (TCI) (0.494 mL, 5.59 mmol) was stirred at rt in a sealed tube for 1 h. The reaction mixture was first neutralized with sat. NaHCO3 then extracted with CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (120 g, 4% MeOH in DCM) to give the product as a yellow solid (0.070 g). m/z (ESI, +ve ion) 512.0 (M+H)+. 1H NMR (300 MHz, CDCl3) δ 11.85 (s, 1H); 8.72 (s, 1H); 8.28 (d, J=0.73 Hz, 1H); 7.68 (s, 2H); 7.48 (d, J=8.48 Hz, 2H); 7.12 (br. s., 1H); 5.43 (br. s., 2H); 3.53 (s, 2H); 3.26 (br. s., 4H); 2.78 (s, 3H); 2.59 (s, 7H); 2.19 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[NH2:27].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:27][NH:26][C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: NNc1ccncc1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNc1ccncc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
A 50-mL, 3-necked, round-bottomed flask was charged with (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g) and EtOAc (10.0 mL). 4-Hydrazinylpyridine hydrochloride (0.16 g, 1.2 eq.) was added at −40° C. followed by the simultaneous addition of T3P (50% in EtOAc, 0.85 mL, 2.0 eq.) and DIPEA (0.49 mL, 4.0 eq.). The reaction mixture was stirred for 30 min at −40° C. before being concentrated under reduced pressure (35° C., 20 mmHg) to afford 0.35 g of crude material. Purification by column chromatography using MeOH:CH2Cl2 as a mobile phase (compound was eluted with 4% MeOH in CH2Cl2) afforded 80 mg (yield: 29.85%) (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N′-(pyridin-4-yl)acrylohydrazide. 1H NMR (400 MHz, DMSO-d6) δ, 10.53 (br s, NH exchangeable, 1H), 9.58 (s, 1H), 8.88 (br s, NH exchangeable, 1H), 8.84 (s, 2H), 8.29 (s, 1H), 8.09-8.11 (d, 2H), 7.52-7.54 (d, J=10.4 Hz, 1H), 6.66-6.69 (m, 2H), 6.06-6.10 (d, J=14.4 Hz, H); LCMS for C18H13F6N6O [M+H]+ 443.33; found 443.24 (RT 2.241 min, purity: 90.17%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.Br[CH2:17][C:18]([C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)=[O:19]>>[NH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:9][CH:8]=2)[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:17]=1[C:18]([C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)=[O:19]
Reactant: O=C(CBr)c1cncnc1
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2cncnc2)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 5-bromoacetylpyrimidine (step 1). 1H-NMR (CDCl3) δ: 9.29 (1 H, s), 9.03 (2 H, s), 8.02 (1 H, d, J=1.6 Hz), 7.57 (1 H, d, J=8.4 Hz), 7.35 (1 H, dd, J=1.6, 8.4 Hz), 6.13 (2 H, br s), 4.01 (2 H, q, J=7.1 Hz), 1.02 (3 H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([C:23]2[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3Cl)[CH:24]=2)=[O:22])=[CH:14][CH:13]=1>>[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]([C:23]2[S:31][C:30]3[C:25](=[N:26][CH:27]=[CH:28][C:29]=3[NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2]([CH3:1])=[CH:10]4)[CH:24]=2)=[O:22])=[CH:14][CH:13]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: O=C(NCCc1ccncc1)c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(C(=O)NCCc5ccncc5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-1H-indol-5-ylamine and 7-chloro-thieno[3,2-b]pyridine-2-carboxylic acid (2-pyridin-4-yl-ethyl)-amide by a procedure analogous to Example 1C. MS: 428 (MH+); HPLC Rf: 4.09 min.; HPLC purity 99%.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25](=O)[C:26]#[CH:27])[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1.Cl.[OH:32][C:33]([CH3:38])([CH3:37])[C:34]([NH2:36])=[NH:35].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:30])[N:4]([C:19]2[CH:24]=[C:23]([C:25]3[CH:26]=[CH:27][N:36]=[C:34]([C:33]([OH:32])([CH3:38])[CH3:37])[N:35]=3)[CH:22]=[CH:21][C:20]=2[CH3:29])[C:5]([CH3:18])=[N:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1
Reactant: CC(C)(O)C(=N)N
Reactant: C#CC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(OC)cc3)c(Cl)c2=O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(COc2nc(C)n(-c3cc(-c4ccnc(C(C)(C)O)n4)ccc3C)c(=O)c2Cl)cc1
Temperature: 75 °C
Yield: 42.5 %

Procedure:
To a solution of 5-chloro-6-(4-methoxy-benzyloxy)-2-methyl-3-(2-methyl-5-propynoyl-phenyl)-3H-pyrimidin-4-one from Step H (660 mg, 1.56 mmol) in acetonitrile (3 mL) was added 2-hydroxy-2-methylpropionamidine HCl (324 mg, 2.34 mmol) and potassium carbonate (645 mg, 4.68 mmol) and heated at 75° C. for eighteen hours. The reaction was returned to ambient temperature and filtered to remove excess salts. The filtrate was concentrated to provide a dark red oil. Normal phase chromatography (ethyl acetate/heptanes) provided the pyrimidine as a yellow oil (336 mg, 42%). MS (M+H): 507
Reaction SMILES: [C:1]([N:5]1[C:26](=[O:27])[N:8]2[CH:9]=[C:10]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)[N:11]=[C:12]([NH:13][CH:14]([CH3:16])[CH3:15])[C:7]2=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH2:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>CCOC(C)=O>[C:1]([N:5]1[C:26](=[O:27])[N:8]2[CH:9]=[C:10]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([NH:36][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:22])[N:11]=[C:12]([NH:13][CH:14]([CH3:16])[CH3:15])[C:7]2=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCc1ccccc1
Reactant: CC(C)Nc1nc(-c2cccc(C(=O)O)c2)cn2c(=O)n(C(C)(C)C)nc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)Nc1nc(-c2cccc(C(=O)NCCc3ccccc3)c2)cn2c(=O)n(C(C)(C)C)nc12

Procedure:
A solution of 50 mg of the product of Step A, 33 mg of phenethylamine, 68 mg of triethylamine and 258 mg of 1-propanephosphonic acid cyclic anhydride in EtOAc (3.0 mL) was warmed to 80° C. The organic layer was washed with sat. sodium chloride solution, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography to afford 3-(2-tert-butyl-8-isopropylamino-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-a]pyrazin-6-yl)-N-phenethyl-benzamide as a white solid. MS (M+H+)=473.4.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[NH:21]1[CH:25]=[N:24][N:23]=[N:22]1>>[N:21]1([CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][CH:5]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Reactant: c1nnn[nH]1
Product: CN(C(=O)Oc1ccc(CCn2cnnn2)cc1)c1ccccc1
Yield: 10 %

Procedure:
The title compound was prepared in 10% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and tetrazole. NMR (400 MHz; CDCl3): δ 3.19 (t, 2H), 3.40 (br s, 3H), 3.47 (s, 1H), 4.61 (t, 2H), 6.98-7.07 (m, 4H), 7.25-7.42 (m, 5H), 8.26 (s, 1H); HPLC-MS: m/z=324.1 (M+1); Rt=3.36 min.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]OS(C)(=O)=O)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[Cl-:35].[K+].CS(C)=O>O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Cl:35])[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[CH3:23])=[O:14])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [Cl-]
Reactant: CCCCc1ccc(CN(CCCCCCOS(C)(=O)=O)C(=O)Nc2ccc(Cl)cc2C)cc1
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1ccc(CN(CCCCCCCl)C(=O)Nc2ccc(Cl)cc2C)cc1
Yield: 85 %

Procedure:
A mixture of 2.0 g of 1-[(4-butylphenyl)methyl]-3-(4-chloro-2-methylphenyl)-1-[6-[(methylsulfonyl)oxy]-hexyl]urea, 0.74 g of potassium chloride, and 3.0 ml of dimethyl sulfoxide was heated at an oil bath temperature of 60°-80° C. for 16 hours. The mixture was diluted with water and extracted with dichloromethane. The organic layer was washed with three 40 ml portions of brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated in vacuo to yield 1.5 g of a brown oil. The oil was purified by chromatography to yield 1.5 g of the desired product as a light yellow oil in 86% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>CO.CCOCC>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(O)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: COc1cc(O)ccc1C(=O)O
Temperature: 40 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
To a solution of the methyl 2-methoxy-4-hydroxybenzoate (27 g, 147 mmol) from Step 3 above in MeOH (250 mL) was added 2N sodium hydroxide (147 mL, 2 eq) and the reaction was stirred for 5 hours at 40° C. The reaction was brought to pH 4 with the addition of 6N HCl and the solvent was reduced to one-third volume under reduced pressure. The aqueous mixture was extracted with methylene chloride (5×300 mL) and the combined organic phases were washed with water, brine, and dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure to give a solid which was suspended in ether and filtered. 2-Methoxy-4-hydroxybenzoic acid was obtained in 80% yield.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:9])[CH:6]([CH3:8])[CH3:7]>O.C(O)(=O)C>[N:1](=[C:10]([C:5](=[O:9])[CH:6]([CH3:8])[CH3:7])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[OH:3]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)C(C)C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
A solution of sodium nitrite (43.8 g.) in water (92 ml.) was added dropwise, with stirring, to a solution of ethyl isobutyrylacetate (100.3 g.) in acetic acid (80 ml.) at 0°. After stirring at 0° for 30 minutes then at room temperature for 3 hours, water (100 ml.) was added and the mixture extracted with ether. The extracts were washed with water, saturated sodium bicarbonate solution and water. After drying (CaSO4), the solution was evaporated to give ethyl 2-oximino-4-methyl-3-oxopentanoate (112 g.) as a crude oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[F:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[NH:42][CH2:41][C:40]3[CH:39]=[N:38][N:37]([CH3:43])[C:36]=3[NH:35][C:34]=2[CH:44]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:42]2[CH2:41][C:40]3[CH:39]=[N:38][N:37]([CH3:43])[C:36]=3[NH:35][C:34]3[CH:44]=[C:30]([Cl:29])[CH:31]=[CH:32][C:33]2=3)=[O:16])=[CH:12][C:11]=1[F:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1NC2
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1F
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(F)c1)C2
Reaction time: 3 h
Yield: 54.5 %

Procedure:
A solution of 4-(tert-butoxycarbonylamino-methyl)-3-fluoro-benzoic acid from Example E3 (568 mg, 2.1 mmol) in dichloromethane (25 ml) at room temperature was treated with DMAP (256 mg, 2.1 mmol), DIEA (1.1 ml, 6.3 mmol) then WSCD (520 mg, 2.7 mmol). The mixture was stirred for 3 h then 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E1 (450 mg, 1.9 mmol) was added. The mixture was stirred for 4 days then washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (503 mg, 54%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([OH:14])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:32][CH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[N:38]([CH:44]1[CH2:49][CH2:48][C:47](=[O:50])[NH:46][C:45]1=[O:51])[CH2:37]2.O>CN(C=O)C>[O:51]=[C:45]1[CH:44]([N:38]2[CH2:37][C:36]3[C:40](=[CH:41][CH:42]=[C:34]([CH2:33][NH:32][C:12](=[O:14])[CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)[CH:35]=3)[C:39]2=[O:43])[CH2:49][CH2:48][C:47](=[O:50])[NH:46]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)Cc1ccc2ncccc2c1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1ccc2ncccc2c1)NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of quinolin-6-yl-acetic acid (0.19 g, 1.02 mmol) in dry DMF (5 mL) was added CDI (0.16 g, 1.02 mmol). After 1 h of stirring at rt, 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.30 g, 0.81 mmol) was added. After 18 h, water (20 mL) was added. The solids were collected by filtration, washed with water and dried in vacuo for 18 h to give N-((2-(2,6-dioxopiperidin-3-yl)-1-oxoisoindolin-5-yl)methyl)-2-(quinolin-6-yl)acetamide as a white solid (355 mg, 99%). HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 ml/min, 240 nm, 10/90, CH3CN/0.1% H3PO4, 4.54 min (95.6%); mp: 205-207° C.; 1H NMR (DMSO-d6) δ 1.89-2.10 (m, 1H), 2.37 (qd, J=4.3, 13.2 Hz, 1H), 2.63 (br. s., 1H), 2.80-3.02 (m, 1H), 3.73 (s, 2H), 4.12-4.30 (m, 1H), 4.30-4.48 (m, 3H), 5.10 (dd, J=5.1, 13.2 Hz, 1H), 7.29-7.47 (m, 2H), 7.52 (dd, J=4.2, 8.3 Hz, 1H), 7.60-7.76 (m, 2H), 7.84 (s, 1H), 7.97 (d, J=8.7 Hz, 1H), 8.32 (d, J=7.7 Hz, 1H), 8.75 (t, J=5.9 Hz, 1H), 8.87 (dd, J=1.7, 4.2 Hz, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.48, 31.18, 42.16, 42.31, 47.03, 51.55, 121.53, 122.02, 122.91, 127.07, 127.52, 127.72, 128.72, 130.36, 131.21, 134.66, 135.61, 142.32, 143.73, 146.73, 150.07, 167.87, 169.99, 170.98, 172.86. LCMS: MH=443; Anal Calcd for C25H22N4O4+1.6H2O: C, 63.71%; H, 5.39%; N, 11.89%. Found: C, 63.71%; H, 5.25%; N, 11.99%.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:15][CH2:16][C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][CH:18]=1.[NH4+].[Cl-]>CC(O)C>[N:8]1([C:5]2[N:6]=[N:7][C:2]([NH:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:25][CH:26]=3)=[CH:3][CH:4]=2)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Clc1ccc(N2CCOCC2)nn1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Product: COC(=O)c1ccc(CNc2ccc(N3CCOCC3)nn2)cc1
Temperature: 150 °C
Yield: 8.2 %

Procedure:
To a solution of 64 (2.0 g, 10.0 mmol) and methyl 4-(aminomethyl)benzoate hydrochloride (2.2 g, 11.0 mmol) in i-PrOH (200 mL) was added NH4Cl (2.14 g, 40.0 mmol). The reaction mixture was heated at 150° C. for 72 h and concentrated. The residue was dissolved in water and the aqueous phase was extracted with. \the aqueous phase was separated, treated with 1N NaOH (pH 8) and extracted with EtOAc. The extract was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (MeOH/CH2Cl2: 2/98 to 5/95) to afford the title compound 65 (270 mg, 0.82 mmol, 8% yield). 1H NMR: (400 MHz, CDCl3) δ (ppm): 7.97 (d, J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 6.90 (d, J=9.2 Hz, 1H), 6.69 (d, J=9.2 Hz, 1H), 5.16-5.06 (bs, 1H), 4.67 (s, 2H), 3.90 (s, 3H), 3.82 (t, J=4.8 Hz, 4H), 3.41 (t, J=4.8 Hz, 4H).
Reaction SMILES: [CH2:1]([CH:4]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]2[C:6]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:7][C:8]3[C:13]2=[CH:12][CH:11]=[C:10]([O:19][CH2:20][O:21][CH3:22])[CH:9]=3)[CH2:5]1)C=C.[O:27]1[CH2:32][CH2:31][O:30]CC1>O>[CH2:23]([C:6]12[CH2:5][CH:4]([CH2:1][C:31](=[O:30])[CH2:32][OH:27])[C:16](=[O:17])[C:15]([CH3:18])=[C:14]1[C:13]1[C:8](=[CH:9][C:10]([O:19][CH2:20][O:21][CH3:22])=[CH:11][CH:12]=1)[CH2:7]2)[CH2:24][CH2:25][CH3:26]
Reactant: C1COCCO1
Reactant: C=CCC1CC2(CCCC)Cc3cc(OCOC)ccc3C2=C(C)C1=O
Solvent: O
Product: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(CC(=O)CO)C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of (2SR,9aSR)-2-allyl-9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (170 mg, 0.48 mmol) in dioxane (9 mL) was diluted with water (3 mL) and treated with a single crystal of OSO4 followed by NaIO4 (125 mg, 0.58 mmol). The mixture was stirred at room temperature for 15 minutes, treated with more NaIO4 (132 mg, 0.62 mmol), and stirred an additional 30 minutes at room temperature. Workup provided a gum which was purified by PLC on two 0.1×20×20 cm silica gel GF plates, developing twice with 4:1 hexanes-EtOAc. The minor UV visible band provided (2RS,9aSR)-9a-butyl-2-(3-hydroxy-2-oxopropyl)-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (26 mg) as an oil. The major UV visible band afforded (2RS,9aSR)-9a-butyl-7-methoxymethoxy-4-methyl-2-(2-oxoethyl)-1,2,9,9a-tetrahydro-3H-fluoren-3-one (85 mg) as an oil.
Reaction SMILES: [Li]CCCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[N:8]1.[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCCCCC.C1COCC1>[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]([CH:24]([C:11]2[N:7]([CH3:6])[N:8]=[N:9][CH:10]=2)[OH:25])=[CH:26][CH:27]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: Cn1ccnn1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1nncc1C(O)c1ccc(OCc2ccccc2)cc1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
A solution of n-BuLi (11.6 mL, 1.6 M, 18.6 mmol) in hexane was added dropwise to a solution of 73.1 (1.29 g, 15.5 mmol) in THF (75 mL) at −40° C. After stirring at −40° C. for 2 hours, 4-(benzyloxy)benzaldehyde was added at −40° C., and the reaction was warmed to room temperature. The reaction was quenched saturated NH4Cl (aq) after 3 hours of stirring and then extracted with EtOAc. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue 73.2 was used in the next reaction without further purification. MS ESI (pos.) m/e 296.2 (M+H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[ClH:21].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][Cl:26]>CN(C=O)C>[ClH:26].[ClH:21].[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][N:12]1[C:13]2=[N:14][CH:15]=[CH:16][CH:17]=[C:18]2[C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])=[CH:11]1
Reactant: CN(C)CCCl
Reactant: O=S(=O)(c1ccccc1)c1c[nH]c2ncccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(S(=O)(=O)c2ccccc2)c2cccnc21
Temperature: 20 °C
Reaction time: 3 h

Procedure:
A solution of 3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (400 mg, 1.55 mmol) in dry DMF is chilled to 0° C., treated with sodium hydride (60% in oil, 97 mg, 2.43 mmol), stirred for 3 h at 20° C., cooled to −20° C., treated with 2-(dimethylamino)-ethyl chloride hydrochloride (336 mg, 2.33 mmol), stirred at 60° C. for 16 h, cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over MgSO4 and concentrated in vacuo to afford the free amine of the title compound as a yellowish gum. The gum is dissolved in ethanol, treated with 1 N aqueous HCl and concentrated in vacuo. Crystallization of the resultant residue from ethanol/ether affords the title compound as a light tan solid, 111 mg, mp 214-217° C., characterized by mass spectral and HNMR analyses.
Reaction SMILES: [C:1]([S:5][CH:6]1[N:9]([CH:10]([C:24](=[O:30])[C:25]([CH3:29])([CH3:28])[CH2:26]Cl)[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:31])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][N:33]1[C:37]([SH:38])=[N:36][N:35]=[N:34]1>CN(C)C=O>[C:1]([S:5][CH:6]1[N:9]([CH:10]([C:24](=[O:30])[C:25]([CH3:29])([CH3:28])[CH2:26][S:38][C:37]2[N:33]([CH3:32])[N:34]=[N:35][N:36]=2)[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:31])[CH2:7]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)CCl
Reactant: Cn1nnnc1S
Solvent: CN(C)C=O
Product: Cn1nnnc1SCC(C)(C)C(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1SC(C)(C)C

Procedure:
A mixture of 118 mg (0.25 mmol) of p-nitrobenzyl 2-(4-tert-butylthio-2-oxo-1-azetidinyl)-5-chloro-4,4-dimethyl-3-oxopentanoate and 82 mg (0.59 mmol) of the Na salt of 1-methyl-5-mercapto-1,2,3,4-tetrazole are stirred for 20 hours at room temperature in 0.2 ml of dimethylformamide. The reaction mixture is chromatographed directly on a chromatography column containing 6 g of silica gel using toluene:ethyl acetate (19:1), to give 60 mg of pure title compound as a non-crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[NH:11])[NH:9][OH:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[C:14](OC)(=O)[CH3:15].O>O1CCCC1>[CH3:14][C:15]1[O:10][N:9]=[C:8]([C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH2:1])[N:11]=1
Reactant: COC(C)=O
Reactant: N=C(NO)c1cccc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc(N)c2)no1
Temperature: 65 °C

Procedure:
To a stirred solution of Intermediate 18 (5.3 g) in dry tetrahydrofuran (50 ml) was added 4 Å molecular sieves, followed by sodium hydride (60% dispersion in mineral oil; 1.5 g) and the mixture heated at 65° C. for 30 min. After cooling to room temperature methyl acetate (2.8 ml) was added and the mixture heated under reflux for 16 h. After cooling to 20° C. the mixture was added to water (100 ml) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulphate and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with dichloromethane to give the title compound as a white solid (4.0 g).