Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:9]=[N:10][N:11]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=3)[C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]=1[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])=[O:35].C(ON=O)CC(C)C>C1COCC1>[F:33][C:30]([F:31])([F:32])[C:22]1[CH:21]=[C:20]([CH:25]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:23]=1)[CH2:19][N:11]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:8]([C:4]2[C:3]([C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])=[O:35])=[CH:2][CH:7]=[CH:6][N:5]=2)[N:9]=[N:10]1
Reactant: Nc1ccnc(-c2nnn(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c2-c2ccccc2)c1C(=O)c1ccccc1Cl
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)c1cccnc1-c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Temperature: 72 °C
Yield: 61 %

Procedure:
Dissolve {4-amino-2-[1-(3,5-bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazol-4-yl]-pyridin-3-yl}-(2-chloro-phenyl)-methanone (40.0 mg, 0.067 mmol) in THF (2 mL), add isoamylnitrite (12.0 mg, 13.8 μL, 0.101 mmol) and heat 72° C. for 0.5 h, then cool to RT. Pour the mixture through a plug of Celite® 1 cm and silica gel 2 cm. Concentrate the clear liquid to 1.5 mL and apply to a 2 mm chromatotron plate with CH2Cl2 and EtOAc and elute with a EtOAc/hexane gradient to provide 24 mg of the title compound. Exact Mass 586.1: MS (IS): m/z=586.9 (M+1); 1H NMR (300 MHz, CDCl3) 8.53 (bs, 1H), 7.87 (d, J=7.4 Hz, 1H), 7.72 (s, 1H), 7.45-7.00 (m, 9H), 5.37 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:24]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: OC1CCN(c2nncc3cc(Br)ccc23)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCC(O)C3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(6-bromophthalazin-1-yl)pyrrolidin-3-ol (0.11 g, 0.37 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.11 g, 0.37 mmol), tetrakis(triphenylphosphine)palladium (22 mg, 0.019 mmol) and 2M potassium carbonate (0.6 mL, 1.2 mmol) in 5 mL DME/EtOH (4:1) was stirred at 90° C. for 2 h. The mixture was directly purified via flash chromatography (silica gel) eluting with 2% 2M ammonia in MeOH/DCM (0.13 g) to afford the title compound as a yellow solid. Found MS (ES+): 389(M+H)+.
Reaction SMILES: C(C1OC2C=CC(Br)=CC=2C=1)C1C=CC=CC=1.C(Cl)(=O)C1C=CC(OC)=CC=1.[CH2:29]([C:36]1[O:37][C:38]2[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][C:39]=2[C:40]=1[C:41](=[O:50])[C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[C:56]([N:60]1[CH2:63][CH:62](CCl)[CH2:61]1)([CH3:59])([CH3:58])[CH3:57]>>[CH2:29]([C:36]1[O:37][C:38]2[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][C:39]=2[C:40]=1[C:41](=[O:50])[C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:61]2[C-:62]=[CH:63][N+:60]=2[C:56]([CH3:59])([CH3:58])[CH3:57])=[CH:44][CH:43]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)N1CC(CCl)C1
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)oc3ccc(Br)cc23)cc1
Agent: Brc1ccc2oc(Cc3ccccc3)cc2c1
Agent: COc1ccc(C(=O)Cl)cc1
Product: CC(C)(C)[N+]1=C(COc2ccc(C(=O)c3c(Cc4ccccc4)oc4ccc(Br)cc34)cc2)[C-]=C1

Procedure:
2-Benzyl-5-bromobenzofuran is acylated with p-anisoyl chloride as described above, the resulting 2-benzyl-5-bromo-3-(4-methoxybenzoyl)benzofuran is dimethylated and the product thus formed is reacted with N-t-butyl-3-chloromethylazetidine as described in Example 3 to give the title compound.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.[SH:21][CH:22]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1.C(N(CC)C(C)C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][N:6]1[C:5]2[CH:19]=[CH:20][C:2]([S:21][CH:22]3[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25]3)=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(S)C1
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(Br)ccc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(SC3CN(C(=O)OC(C)(C)C)C3)ccc21
Temperature: 160 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of 2-(5-bromo-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (STEP A, 338 mg, 1.00 mmol), tert-butyl 3-mercaptoazetidine-1-carboxylate (STEP D, 246 mg, 1.30 mmol), Xantphos (28.9 mg, 0.0500 mmol), tris(dibenzylideneacetone)dipalladium (22.3 mg, 0.0250 mmol) and N,N-diisopropylethylamine (262 microL, 1.50 mmol) in 1,4-dioxane (4 mL) was stirred at 160° C. for 1 h under microwave. The mixture was concentrated in vacuo and the residue was purified by amine gel column chromatography (hexane-ethyl acetate, gradient) to give the title compound (442 mg, 99%) as a yellow oil.
Reaction SMILES: [H-].[Na+].C([N-]C(C)C)(C)C.[Li+].C([O:13][C:14]([C:16]1[C:20]([C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[CH:22]=2)=[CH:19][S:18][C:17]=1[NH:29][C:30](=[O:34])[CH2:31][C:32]#[N:33])=O)C>C1COCC1>[CH3:27][C:25]1[CH:26]=[C:21]([C:20]2[C:16]3[C:14]([OH:13])=[C:31]([C:32]#[N:33])[C:30](=[O:34])[NH:29][C:17]=3[S:18][CH:19]=2)[CH:22]=[C:23]([CH3:28])[CH:24]=1
Reactant: CCOC(=O)c1c(-c2cc(C)cc(C)c2)csc1NC(=O)CC#N
Agent: CC(C)[N-]C(C)C
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)c1
Temperature: 25 °C

Procedure:
To a suspension of either NaH (60% suspension in mineral oil, pre washed with hexanes, 0.25 g, 6.2 mmol) held at room temperature or Lithium diisopropylamide (LDA, 2M solution in THF, 11.3 mmol, 5.6 mL) held at −78° C. in THF (30 mL) was added a solution of 2-(2-cyano-acetylamino)-4-(3,5-dimethyl-phenyl)-thiophene-3-carboxylic acid ethyl ester (0.968 g, 2.83 mmol) in THF (15 mL) dropwise via syringe over 10 minutes. The mixture was stirred at room temperature for 5 hours (or in the case of LDA, allowed to warm to room temperature over 16 hours), cooled to 0° C. and then quenched by dropwise addition of MeOH (5 mL) followed by 1N HCl to adjust the pH <3. The resultant slurry was filtered and the solid was washed with water (4×4 mL), ether (3×4 mL) and (Na2SO4), filtered and concentrated under reduced pressure to provide the target compound. The filtrate was concentrated and purified on a RP-HPLC system to provide additional compound. MS (ESI) m/e 295 (M−H)+; 1H NMR (300 MHz, MeOH-d4): δ ppm 12.53 (br s, 1H), 7.04 (s, 2H), 6.99 (s, 1H), 6.90 (s, 1H), 2.32 (s, 6H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1[NH2:17])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1[NH2:17]
Reactant: [N-]=[N+]=NCCOc1cc(Cl)cc([N+](=O)[O-])c1N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NCCOc1cc(Cl)cc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-(2-azido-ethoxy)-4-chloro-6-nitro-phenylamine (1.9 g, 7.36 mmol) and triphenylphosphine (2.27 g, 8.65 mmol) in tetrahydrofuran (80 ml) and water (2 ml) was allowed to stir for 24 hours at room temperature. The solvent was removed under vacuum and the solid washed with methylene chloride (30 ml) to afford an orange solid: mp 156-157° C.
Reaction SMILES: [OH-].[Li+].[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[S:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[C:21]([CH2:32][C:33]([O:35]C)=[O:34])([CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:20][CH2:19]4)=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1>C(O)C.O>[Cl:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[S:12][C:13]([C:16]3[CH:17]=[C:18]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[C:21]([CH2:32][C:33]([OH:35])=[O:34])([CH2:27][C:28]([F:31])([F:30])[F:29])[CH2:20][CH2:19]4)=[CH:14][N:15]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CC1(CC(F)(F)F)CCc2cc(-c3cnc(Nc4cccc(Cl)c4)s3)ccc2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CC1(CC(F)(F)F)CCc2cc(-c3cnc(Nc4cccc(Cl)c4)s3)ccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
Lithium hydroxide (0.05 g, 1.18 mmol) was added to a solution of 26D2 (0.12 g, 0.236 mmol) in 8 mL of ethanol-water (3:1) mixture, and the reaction mixture was stirred at room temperature for 1 h. After the solvent was removed in vacuo, the residue was dissolved in water. The aqueous layer was acidified by addition of saturated citric acid solution until pH 2 was attained. The resulting solution was cooled to 0° C. and solids obtained were filtered off and dried under vacuum to afford the title compound (0.07 g, 59%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 10.9 (s, 1H), 7.95 (m, 2H), 7.88 (d, J=8.4 Hz, 1H), 7.56 (d, J=8.1 Hz, 1H), 7.5 (m, 2H), 7.35 (t, J=8.1 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 3.14-2.80 (m, 4H), 2.69 (d, J=18.4 Hz, 1H), 2.46-2.31 (m, 2H), 2.12 (m, 1H). ESI-MS m/z: 495 (M+H)+; HPLC purity: 99%
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[CH3:10][O:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17](F)[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=1[N+:24]([O-:26])=[O:25].CC#N>O1CCCC1>[CH3:10][O:11][C:12](=[O:27])[C:13]1[CH:18]=[C:17]([N:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]2=[O:3])[C:16]([C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=1[N+:24]([O-:26])=[O:25]
Reactant: Oc1ccccn1
Reactant: COC(=O)c1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Product: COC(=O)c1cc(-n2ccccc2=O)c(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.7 %

Procedure:
To a suspension of NaH (315 mg, 1.4 eq) in 50 ml of tetrahydrofuran, a solution of 2-hydroxypyridine (801 mg, 1.5 eq) in 5 ml of tetrahydrofuran is added drop-wise. The mixture is stirred at room temperature for 30 min before addition of 5-fluoro-2-nitro-4-trifluoromethyl-benzoic acid methyl ester (1.5 g, 5.61 mmol) in 10 ml of tetrahydrofuran. The resulting mixture is stirred at room temperature for 16 hours. The solvent is removed in vacuo and the crude oil is solubilised in ethyl acetate. The organic phase is washed with sat NaHCO3 solution, dried over sodium sulfate and concentrated in vacuo to afford a crude yellow oil. The crude product is purified by flash-chromatography (ethyl acetate/hexane (0:100 to 100:0)) to obtain 2-nitro-5-(2-oxo-2H-pyridin-1-yl)-4-trifluoromethyl-benzoic acid methyl ester as a yellow solid (1.3 g, 68% yield) (ES-MS: m/z 328 [M+H+CH3CN]+, Rt 4.67 min.).
Reaction SMILES: [CH3:1][CH2:2][C:3]([O:5][CH:6]1[CH:23]([O:24][CH3:25])[CH:22]([O:26][CH:27]2[O:32][CH:31]([CH3:33])[CH:30]([O:34][CH:35]3[O:40][CH:39]([CH3:41])[CH:38]([O:42][C:43]([CH2:45][CH3:46])=[O:44])[C:37]([OH:48])([CH3:47])[CH2:36]3)[CH:29]([N:49]([CH3:51])[CH3:50])[CH:28]2[OH:52])[CH:21]([CH2:53][CH:54]=[O:55])[CH2:20][CH:19]([CH3:56])[CH:18]([OH:57])[CH:17]=[CH:16][CH:14]2[O:15][CH:13]2[CH2:12][CH:11]([CH3:58])[O:10][C:8](=[O:9])[CH2:7]1)=[O:4].[CH2:59](O)[C:60](N)(CO)[CH2:61][OH:62].C([O-])(=O)/C=C\C([O-])=O.C(OC(=O)CC)(=O)CC>C(C(C)=O)C(C)C>[CH3:1][CH2:2][C:3]([O:5][CH:6]1[CH:23]([O:24][CH3:25])[CH:22]([O:26][CH:27]2[O:32][CH:31]([CH3:33])[CH:30]([O:34][CH:35]3[O:40][CH:39]([CH3:41])[CH:38]([O:42][C:43]([CH2:45][CH3:46])=[O:44])[C:37]([OH:48])([CH3:47])[CH2:36]3)[CH:29]([N:49]([CH3:50])[CH3:51])[CH:28]2[OH:52])[CH:21]([CH2:53][CH:54]=[O:55])[CH2:20][CH:19]([CH3:56])[CH:18]([O:57][C:61]([CH2:60][CH3:59])=[O:62])[CH:17]=[CH:16][CH:14]2[O:15][CH:13]2[CH2:12][CH:11]([CH3:58])[O:10][C:8](=[O:9])[CH2:7]1)=[O:4]
Reactant: CCC(=O)OC1CC(=O)OC(C)CC2OC2C=CC(O)C(C)CC(CC=O)C(OC2OC(C)C(OC3CC(C)(O)C(OC(=O)CC)C(C)O3)C(N(C)C)C2O)C1OC
Reactant: NC(CO)(CO)CO
Agent: CCC(=O)OC(=O)CC
Agent: CCC(=O)OC1/C=C/C2OC2CC(C)OC(=O)CC(OC(=O)CC)C(OC)C(OC2OC(C)C(OC3CC(C)(O)C(OC(=O)CC)C(C)O3)C(N(C)C)C2O)C(CC=O)CC1C
Agent: CCC(=O)OC1CC(=O)OC(C)CC2OC2/C=C/C(O)C(C)CC(CC=O)C(OC2OC(C)C(OC3CC(C)(O)C(OC(=O)CC)C(C)O3)C(N(C)C)C2O)C1OC
Solvent: CC(=O)CC(C)C
Product: CCC(=O)OC1C=CC2OC2CC(C)OC(=O)CC(OC(=O)CC)C(OC)C(OC2OC(C)C(OC3CC(C)(O)C(OC(=O)CC)C(C)O3)C(N(C)C)C2O)C(CC=O)CC1C
Temperature: 28 °C
Reaction time: 1 h

Procedure:
A 10 l-capacity galss-linked reaction vessel (with stirrer) was charged with 2 l of methyl isobutyl ketone warmed at 28° C. in advance, in which was dissolved 10 g of maridomycin III. To the solution was then added 2 l of a tris(hydroxymethyl)aminomethane-maleate buffer solution (0.2M. pH 7.0) dissolving 500 mg of carboxyl esterase obtained in Reference Example 1. To the solvent layer was added 20 ml of propionic anhydride, and the reaction was allowed to proceed for one hour under stirring. The reaction solution was shifted to a 10 l capacity separating funnel, and thus the aqueous phase was removed. To the remainder was added 500 ml of an aqueous solution of sodium bicarbonate (2%) (w/v). The mixture was sufficiently stirred, followed by removing the aqueous portion. Washing with an aqueous solution of sodium bicarbonate was repeated once more, followed by washing with 2 l of distilled water twice in the separating funnel. The organic phase was shifted to a 3 l-capacity conical flask, to which was added 100 g of anhydrous sodium sulfate, and the mixture was left standing for two hours. The anhydrous sodium sulfate was filtered off by using filter paper, and the reaction solution was concentrated to dryness to obtain 10 g of 9-propionyl maridomycin III as crude crystals.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26](O)=[O:27])=[C:17]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.[CH3:35][S:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])=[O:37]>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][CH2:25][C:26]([N:42]3[CH2:43][CH2:44][N:39]([S:36]([CH3:35])(=[O:38])=[O:37])[CH2:40][CH2:41]3)=[O:27])=[C:17]([N:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)[N:16]=2)=[CH:13][N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CCC(=O)O)c3n2)cn1
Reactant: CS(=O)(=O)N1CCNCC1
Product: CS(=O)(=O)N1CCN(C(=O)CCn2cnc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)CC1

Procedure:
3-(2-(2-(Tert-butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)propanoic acid (50 mg) was reacted with 1-(methylsulfonyl)piperazine via General Procedure F followed by Boc deprotection via General Procedure E to give 33.8 mg 112 as white solid following reverse phase purification. MS (Q1) 517.2 (M)+
Reaction SMILES: Br[C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][S:12]([O-:14])=[O:13].[Na+]>CN1C(=O)CCC1.CCOC(C)=O.[Cu]I>[OH:10][C:5]1[CH:4]=[CH:3][C:2]([S:12]([CH3:11])(=[O:14])=[O:13])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: CS(=O)[O-]
Reactant: O=Cc1cc(Br)ccc1O
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(O)c(C=O)c1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
5-Bromosalicylaldehyde (0.402 g, 2.0 mmol), sodium methanesulfinate (0.918 g, 9.0 mmol), and copper(I) iodide (1.71 g, 9.0 mmol) were combined in NMP (16 mL) and stirred under N2 at 140° C. overnight. The mixture was diluted with 1:1 EtOAc:hexanes (150 mL) and filtered through a pad of Celite. The filtrate was washed three times with H2O, and then dried, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C:29]([OH:32])([CH3:31])[CH3:30])(=[O:27])=[O:26])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19]>>[Cl:15][C:16]1[CH:24]=[C:23]([S:25]([CH2:28][C:29]([OH:32])([CH3:30])[CH3:31])(=[O:26])=[O:27])[CH:22]=[CH:21][C:17]=1[C:18]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:4]=1)=[O:19]
Reactant: CC(C)(O)CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CC(C)(O)CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
8 g of methyl 4-amino-2-chlorobenzoate was dissolved in 16 mL of MeOH, 8 mL of H2O and 8 mL of concentrated hydrochloric acid and was then cooled to 0 C. A solution of 3.9 g of sodium nitrite in 15 mL of H2O was added dropwise over 30 min. The reaction was stirred at 0° C. for an additional 1 h. The cold diazonating mixture was added to a solution of 13.8 g of potassium ethyl xanthate in 10 mL of H2O at 50˜60° C. The reaction was heated to 65° C. for 2 h and monitored by TLC until complete. The mixture was cooled to 25° C. and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), and concentrated. Purified by silica gel chromatography (0-10% ethyl acetate/hexane) to afford methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate. A solution of 2.6 g of sodium hydroxide in 20 mL of H2O was added to 5.9 g of methyl 2-chloro-4-(ethoxycarbonothioylthio)benzoate in 40 mL of EtOH The reaction mixture was heated to 70° C. for 1 h. Upon completion, the mixture was cooled to 25° C., and then acidified to pH 3 by the addition of 10 N HCl. The solid was filtered and washed with H2O to give 2-chloro-4-mercaptobenzonic acid. 3.8 g of 2-chloro-4-mercaptobenzonic acid in 40 mL of 5% sulfuric acid-methanol was refluxed under nitrogen atmosphere for 3 h. After concentration of the reaction mixture, 10 mL of H2O was added and the resulting mixture was made alkaline with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated to yield methyl 2-chloro-4-mercaptobenzoate. 80 mg of isobutylene oxide was reacted with methyl 2-chloro-4-mercaptobenzoate via Procedure S to afford methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate. 190 mg of methyl 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoate was hydrolyzed via Procedure M to give 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid. 160 mg of 2-chloro-4-(2-hydroxy-2-methylpropylthio)benzoic acid was reacted via procedure R to give 2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid. 60 mg of 4-chloro-3-(pyridine-2-yl)aniline was coupled to 2-chloro-4-(2-hydroxy-2-methylpropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(2-hydroxy-2-methylpropylsulfonyl)benzamide. MS (Q1) 479.1 (M)+.
Reaction SMILES: FC(F)(F)[C:3]([N:5]([CH:23]([CH3:25])[CH3:24])[C:6]1[CH:19]=[C:18]2[O:20][CH2:21][O:22][C:17]2=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)=[O:4].[NH3:28]>O1CCCC1>[CH:23]([N:5]1[C:6]2[C:7](=[CH:16][C:17]3[O:22][CH2:21][O:20][C:18]=3[CH:19]=2)[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:28][C:3]1=[O:4])([CH3:25])[CH3:24]
Reactant: N
Reactant: CC(C)N(C(=O)C(F)(F)F)c1cc2c(cc1C(=O)c1ccccc1)OCO2
Solvent: C1CCOC1
Product: CC(C)n1c(=O)nc(-c2ccccc2)c2cc3c(cc21)OCO3

Procedure:
A mixture of 1.0 g. of 2-(N-trifluoroacetylisopropylamino)-4,5-methylenedioxybenzophenone (prepared as in Example C) and 50 ml. of tetrahydrofuran saturated with anhydrous ammonia is stirred at room temperature for 48 hours. The solvent is removed in vacuo and the residue recrystallized from isopropanol to give 1-isopropyl-4-phenyl-6,7-methylenedioxy-2(1H)-quinazolinone, m.p. 189°-190°C.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN1C(=O)N(C)CCC1.CCOCC>[CH:1]([N:14]1[CH2:17][CH:16]([NH:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: NCc1ccccc1
Solvent: CN1CCCN(C)C1=O
Solvent: CCOCC
Product: c1ccc(CNC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a solution of methanesulfonic acid 1-benzhydrylazetidin-3-yl ester (0.32 g, 1 mmol) in N,N′-dimethylpropyleneurea (0.5 ml) was added benzylamine (0.5 ml, 5 mmol), and the mixture was stirred at 70° C. for 18 h. It was then cooled to room temperature and diluted with ether (30 ml). The resulting suspension was filtered and the ether solution was evaporated. The residue was partitioned between hexanes and water, and hexanes solution was washed with saturated sodium bicarbonate solution and dried over anhydrous sodium sulfate. It was then filtered through a pad of silica gel, and the filter pad was eluted with a 1:1 mixture of ether-hexanes. Evaporation of solvents followed by trituration with isooctane gave 0.22 g of a white solid; m.p. 73-75° C.; MS (ES) m/z 329.0 (MH+); HRMS (El) Calcd. for C23H24N2 (M+): 328.1940, Found: 328.1936.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]([CH2:37][C:38](O)=[O:39])=[N:29]1>>[O:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[C:30]([CH2:37][C:38]([NH:27][C@H:24]2[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]3[CH2:17][CH2:18][N:13]([C:9]4[N:10]=[CH:11][CH:12]=[C:7]5[CH2:6][CH2:5][O:4][C:8]=45)[CH2:14][CH2:15]3)[CH2:22][CH2:23]2)=[O:39])=[N:29]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Reactant: O=C(O)Cc1noc2ccccc12
Agent: Cl
Product: O=C(Cc1noc2ccccc12)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (122 mg, 100%), MS (ISP) m/z=490.4 [(M+H)+], mp 211° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 2-benzo[d]isoxazol-3-yl-acetic acid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[Cl:11].S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][CH3:18])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Br)c(Cl)c1

Procedure:
To a suspension of 4-bromo-3-chlorobenzoic acid (5.00 g, 21.2 mmol) in ethanol (50 mL) was added sulphuric acid (5 mL) and the resultant mixture heated to reflux for 60 h. The reaction was partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was extracted with further ethyl acetate and the combined organic fractions dried (phase separator) and concentrated in vacuo to give the title compound as a brown oil/solid (5.09 g, 19.3 mmol). δH (d6-DMSO, 400 MHz): 8.06 (1H, d), 7.96 (1H, d), 7.80 (1H, dd), 4.33 (2H, q), 1.33 (3H, t). MS (ES): no mass ion observed.