Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20])(=[O:13])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O:20][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:12])=[O:13]
Reactant: CS(=O)(=O)c1ccccc1O
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccccc1Oc1ccc(C=O)cc1
Temperature: 100 °C
Yield: 53.3 %

Procedure:
4-Fluorobenzaldehyde (0.690 mL, 6.4 mmol) and 2-(methylsulfonyl)phenol (1.2 g, 7.0 mmol) were dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (0.85 g, 6.1 mmol) was added. The mixture was heated at 100° C. for 4 days. The reaction was diluted with ethyl acetate and extracted with water three times. The combined aqueous layers were extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate, filtered, and evaporated on the rotovap. The residue was chromatographed on silica gel using a 20–40% ethyl acetate in hexanes. The major component was collected to give a solid (0.942 g, 53%). 1H NMR (400 MHz, CDCl3): δ 9.97 (s, 1H), 8.12 (dd, J=8.0 Hz, J′=1.6 Hz, 1H), 7.92 (dd, J=6.6 Hz, J′=2.1 Hz, 2H), 7.64 (m, 1H), 7.38 (td, J=7.9 Hz, J′=1.0 Hz, 1H), 7.18 (dd, J=6.7 Hz, J′=1.9 Hz, 2H), 7.07 (dd, J=8.8.2 Hz, J′=1.0 Hz, 1H), 3.28 (s, 3H); LCMS found for C14H13O4S (M+H)+: m/z=277.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([NH2:23])[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2.[CH3:37][S:38](Cl)(=[O:40])=[O:39].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[C:10]2[C:15]([N:16]=1)=[C:14]([N:17]1[CH2:22][CH2:21][C:20]([NH:23][S:38]([CH3:37])(=[O:40])=[O:39])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:19][CH2:18]1)[N:13]=[CH:12][N:11]=2
Reactant: NC1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NC1(c2ccccc2)CCN(c2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Reaction time: 16 h
Yield: 82 %

Procedure:
To a solution of 1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-amine (8.4 mg, 0.016 mmol, 1 eq.) in 2 mL of THF was added methanesulfonyl chloride (0.01 mL) and triethylamine (0.02 mL). The mixture was stirred for 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 8 mg (82%) of N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]-4-phenylpiperidin-4-yl}methanesulfonamide. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.22 (s, 3 H) 2.30-2.44 (m, 2H) 2.47-2.66 (m, 2H) 4.20 (br. s., 2 H) 4.75 (s, 2 H) 7.08-7.64 (m, 13 H) 8.38 (s, 1 H), [M+H]+ 593.3.
Reaction SMILES: Br[CH:2]([CH2:8]Br)[C:3]([O:5]CC)=[O:4].C(=O)([O-])[O-].[K+].[K+].[SH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]>CC(C)=O.C(Cl)Cl>[O:23]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[S:16][CH2:8][CH:2]1[C:3]([OH:5])=[O:4]
Reactant: Oc1ccccc1S
Reactant: CCOC(=O)C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C(O)C1CSc2ccccc2O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred mixture of 41.6 g of ethyl 2,3-dibromopropionate, 400 ml of dry acetone and 11.1 g of potassium carbonate, there was added dropwise at 27° C. a solution of 19.5 g of o-mercaptophenol in 75 ml of acetone. After the addition was complete, the reaction mixture was stirred at room temperature for 10 minutes and an additional 50.9 g of potassium carbonate was added. The reaction mixture then was refluxed for 2 hours, and allowed to stand overnight at room temperature. The mixture was filtered and the solid was washed with acetone, the washings being added to the filtrate. The acetone was stripped to leave a liquid, which was taken up in methylene chloride. The resulting solution was washed with water and dried (MgSO4), and the solvent was stripped. The resulting liquid was dry column chromatographed through silica gel, using a 4:16:80 by volume mixture of tetrahydrofuran, ethyl acetate and hexane (Solvent No. 2) as eluent, to give the ethyl ester of 2,3-dihydro-1,4-benzoxathiin-2-carboxylic acid (1A), as a light yellow liquid, boiling point not determined.
Reaction SMILES: O[C:2]([C:12]1[C:13]([NH:18][C:19](=[O:24])[C:20](C)(C)C)=[N:14][CH:15]=[CH:16][CH:17]=1)([CH3:11])CC(OC(C)(C)C)=O>Cl>[CH3:11][C:2]1[C:12]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[NH:18][C:19](=[O:24])[CH:20]=1
Reactant: CC(C)(C)OC(=O)CC(C)(O)c1cccnc1NC(=O)C(C)(C)C
Agent: Cl
Product: Cc1cc(=O)[nH]c2ncccc12
Yield: 70.4 %

Procedure:
A solution of 1.3 g of tert-butyl 3-hydroxy-3-(2-pivalamidopyridin-3-yl)butanoate (3.9 mmol) in 2 mL 3N HCl was microwaved at 160° C. for 5 minutes. The resulting mixture was washed with Et2O (2×10 mL). The aqueous layer was basified using saturated K2CO3. The precipitate formed was filtered and washed with water to give 440 mg (71%) of the desired title compound. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.40 (d, J=1.17 Hz, 3 H) 6.43 (s, 1 H) 7.24 (dd, J=7.91, 4.69 Hz, 1 H) 8.12 (dd, J=7.91, 1.76 Hz, 1 H) 8.49 (dd, J=4.69, 1.76 Hz, 1 H) 11.92 (br. s., 1 H).
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][N:2]1[C:14]1[CH:22]=[CH:21][C:17]([C:18]([O-:20])=O)=[CH:16][N:15]=1.[NH2:23][OH:24].[OH-].[Na+]>O1CCOCC1>[OH:24][NH:23][C:18](=[O:20])[C:17]1[CH:21]=[CH:22][C:14]([N:2]2[CH2:3][CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[N:15][CH:16]=1
Reactant: O=C([O-])c1ccc(N2CCc3c([nH]c4ccccc34)C2)nc1
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(NO)c1ccc(N2CCc3c([nH]c4ccccc34)C2)nc1
Reaction time: 0.25 h

Procedure:
A solution of 6-(1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)nicotinate (12 mg) in dioxane (1.5 mL) was treated with 50% aqueous hydroxylamine (0.2 mL). After 15 minutes, 1N sodium hydroxide (0.06 mL) was added and the reaction was stirred for 72 hours. The reaction was quenched with 1N hydrochloric acid (0.06 mL) and the solvent evaporated. The residue was purified by preparative hplc and the pure samples freeze dried to give N-hydroxy-6-(1,3,4,9-tetrahydro-2H-b-carbolin-2-yl)nicotinamide as a yellow solid (4 mg), m/e=308 (M+1). 1H NMR (DMSOd6) ppm: 2.8 (2H, m), 4.05 (2H, m), 4.85 (2H, s), 6.9-7.08 (3H, m), 7.29 (1H, d), 7.39 (1H, d), 7.87-7.91 (1H, m), 8.5 (1H m), 10.9 (1H, s), 11.05 (1H, bs).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[N:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:30]1([CH2:40][CH2:41][S:42]([NH2:45])(=[O:44])=[O:43])[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1>CS(C)=O>[Cl:17][C:6]1[N:5]=[C:4]([C:18]2[N:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:3]=[C:2]([NH:45][S:42]([CH2:41][CH2:40][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32][CH:31]=2)(=[O:43])=[O:44])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: NS(=O)(=O)CCc1cccc2ccccc12
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2cccnn2)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2cccnn2)nc1NS(=O)(=O)CCc1cccc2ccccc12
Temperature: 90 °C
Reaction time: 72 h
Yield: 89.2 %

Procedure:
To a solution of 3-[4,6-dichloro-5-(2-methoxyphenoxy)-2-pyrimidinyl] pyridazine, (0.06 g, 0.7 mmol) in dimethylsulfoxide (4 ml) was added potassium carbonate (0.13 g, 0.94 mmol) immediately followed by 2-(1-naphthyl) ethanesulfonamide (0.044 g, 0.18 mmol). The mixture was stirred vigorously for 72 hours at 90° C. and then quenched with hydrochloric acid solution (2 M, 4 ml). Ice-cold water (5 ml) was added and a white precipitate was observed. The resultant mixture was partitioned between water (10 ml) and dichloromethane (3×10 ml). The combined organic extracts were washed with water (3×10 ml), dried (magnesium sulfate) and concentrated under vacuum, yielding a yellow oil. Trituration with 1 ml of ice cold water, followed by filtration gave the title compound as a white solid (0.088 g), m.p. 191.5° C.
Reaction SMILES: [C@@H:1]12[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([CH:5]=[CH:6]1)[C:3]([C:15]([O:17][CH3:18])=[O:16])=[C:2]2[C:19]([O:21][CH3:22])=[O:20]>CO.O=[Pt]=O>[C@@H:4]12[N:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:1]([CH2:6][CH2:5]1)[CH:2]([C:19]([O:21][CH3:22])=[O:20])[CH:3]2[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1=C(C(=O)OC)[C@@H]2C=C[C@H]1N2C(=O)OC(C)(C)C
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)C1C(C(=O)OC)[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
(1R,4S)-7-tert-butyl 2,3-dimethyl 7-azabicyclo[2.2.1]hepta-2,5-diene-2,3,7-tricarboxylate (XLVII) (3.41 g, 11.04 mmol) was dissolved in MeOH (50 mL) under an argon atmosphere. Adams' catalyst was added and the reaction was flushed with hydrogen. The mixture was stirred under hydrogen overnight at room temperature. The catalyst was filtered off and the solvent was removed in vacuo to give a yellow oil. The oily residue was crystallized from hot heptane to give (1R,4S)-7-tert-butyl 2,3-dimethyl 7-azabicyclo[2.2.1]heptane-2,3,7-tricarboxylate (XLVIII) as a white solid (3.28 g, 10.49 mmol, 95% yield). 1H NMR (CDCl3) (two isomers in a 3/1 ratio) δ ppm [1.40 (s, 2nd isomer), 1.44 (s, 2nd isomer), 9H], 1.60-2.00 (m, 4H), [3.66 (s, 1st isomer), 3.71 (s, 2nd isomer), 6H], [4.37 (brs, 1st isomer), 4.51 (brs, 2nd isomer), 2H]; ESIMS found for C15H23NO6 m/z 336 (M+Na).
Reaction SMILES: Br[C:2]1[C:3]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH:10]2[C:15]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=3)[CH2:20][CH2:19]2)=[O:16])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.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.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(O)(C)(C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:5]1[N:6]=[CH:7][C:2]2[N:17]([CH:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH3:28])[CH:25]=4)[CH2:20][CH2:19]3)[C:15](=[O:16])[CH:10]3[CH2:11][O:12][CH2:13][CH2:14][N:9]3[C:3]=2[N:4]=1
Reactant: COc1ccc2c(c1)C(NC(=O)C1COCCN1c1nc(Cl)ncc1Br)CC2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(N1C(=O)C3COCCN3c3nc(Cl)ncc31)CC2

Procedure:
The title compound was prepared in a manner similar to PREPARATION x35 using 4-(5-bromo-2-chloropyrimidin-4-yl)-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)morpholine-3-carboxamide (PREPARATION x42, 472 mg, 1.009 mmol), Xantphos (43.8 mg, 0.076 mmol), potassium phosphate (214 mg, 1.009 mmol) and palladium(II) acetate (11.33 mg, 0.050 mmol) in dioxane (5 mL) and tert-butanol (1 mL). ESI-MS m/z [M+H]+ calc'd for C19H19ClN4O3, 387.11; found 387.4.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:14])([CH3:3])=[CH2:2].[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([CH2:25]O)[CH:24]=1)[N:21]([CH3:27])[C:20]([CH3:28])=[C:19]2[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[Cl:15][C:16]1[CH:17]=[C:18]2[C:22](=[C:23]([CH2:25][N:6]3[C:7]4[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=4[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]3=[O:14])[CH:24]=1)[N:21]([CH3:27])[C:20]([CH3:28])=[C:19]2[CH3:29]
Reactant: Cc1c(C)n(C)c2c(CO)cc(Cl)cc12
Reactant: C=C(C)n1c(=O)[nH]c2ccc(C)cc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=C(C)n1c(=O)n(Cc2cc(Cl)cc3c(C)c(C)n(C)c23)c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a solution of 1-Isopropenyl-6-methyl-1,3-dihydro-benzimidazol-2-one (50 mg, 0.27 mmol) and (5-Chloro-1,2,3-trimethyl-1H-indol-7-yl)-methanol (60 mg, 0.27 mmol), triphenylphosphine (84 mg, 0.32 mmol) in THF (2 mL) was added dropwise DIAD (0.06 mL, 0.32 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with ethyl acetate and washed with water (×2). The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 4:1 Hexanes:ethyl acetate as an eluent to afford 60 mg of the desired product as a brownish oil. LCMS (ESMS): m/z 394.28 (M+H+).
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([Cl:10])=[O:9])[N:3]=[CH:4][CH:5]=1.[NH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][C:17]1([NH:22]C(=O)OC(C)(C)C)[CH3:21].CCN(C(C)C)C(C)C.Cl.O1CCOCC1>C(Cl)Cl>[ClH:10].[NH2:22][C:17]1([CH3:21])[CH2:18][CH2:19][CH2:20][CH:16]1[NH:15][C:8](=[O:9])[C:7]1[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=1[N:2]1[N:3]=[CH:4][CH:5]=[N:1]1
Reactant: CC(C)(C)OC(=O)NC1(C)CCCC1N
Reactant: O=C(Cl)c1ccccc1-n1nccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(N)CCCC1NC(=O)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 2-(2H-1,2,3-triazol-2-yl)benzoyl chloride (213 mg, 1.03 mmol) (which was prepared from 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 0.194 g, 1.03 mmol) and thionyl chloride (0.112 ml, 1.541 mmol)) in dry DCM (3.1 ml) was added tert-butyl N-(2-amino-1-methylcyclopentyl)carbamate (Intermediate 24; 200 mg, 0.93 mmol) and DIPEA (489 μl, 2.80 mmol). The reaction was stirred at room temperature for 17 hours and was then partitioned between a saturated solution of sodium bicarbonate and DCM, filtered through a hydrophobic frit and concentrated in vacuo. This was then purified by column chromatography (silica, 0-100% ethyl acetate/petrol). The resulting product was then dissolved in 1,4-dioxane (5 ml) and to this was then added HCl in 1,4-dioxane (4 M, 2.3 ml, 9.33 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated in vacuo, azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([C:30](=[O:32])[CH3:31])[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[CH:34][C:35](Br)=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[C:38](=O)([O-])[O-:39].[Cs+].[Cs+].CO>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>[C:30]([N:14]([CH2:15][C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][N:7]([C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:6])[C:8]2[CH:36]=[C:35]([O:39][CH3:38])[CH:34]=[CH:33][C:9]1=2)(=[O:32])[CH3:31]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Br)ccc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc2c(c1)N(C(=O)OC(C)C)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)=O
Yield: 30.5 %

Procedure:
Combine isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-bromo-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (0.100 g, 0.168 mmol), palladium acetate (0.001 g, 0.0033 mmol), 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (0.002 g, 0.0041 mmol), cesium carbonate (0.082 g, 0.252 mmol), and methanol (0.03 mL, 0.67 mmol) in toluene (1 mL) in a 10 mL microwave vessel and irradiate the mixture at 110° C. for 30 min (45 W). Dilute the mixture with ethyl acetate (20 mL), filter through Celite® and remove the solvent under reduced pressure. Purify the residue using chromatography on silica gel, eluting with hexanes/ethyl acetate (60:40), to provide the title compound as a white solid (0.028 g, 30%): ESI MS 547 (M+H)
Reaction SMILES: CO[CH2:3][C:4](=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)[CH3:5].[BrH:21]>C(O)(=O)C.O>[CH3:5][C:4](=[C:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)[CH2:3][Br:21]
Reactant: Br
Reactant: COCC(C)=C1c2ccccc2CCc2ccccc21
Solvent: O
Solvent: CC(=O)O
Product: CC(CBr)=C1c2ccccc2CCc2ccccc21

Procedure:
The above ether (3.6 g, 13.6 mmol) was dissolved in acetic acid (40 ml) and 48% hydrobromic acid (20 ml) was added. After 7 days the mixture was diluted with water (200 ml) and extracted with benzene (100 ml). The organic phase was dried (MgSO4), filtered and the solvent was evaporated in vacuo to give 3.8 g of crude 5-(1-methyl-2-bromoethylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:12][C:11]2([CH2:17][CH2:16][N:15]([C:18](=[O:24])[CH:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH2:14][CH2:13]2)[NH:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:31])(C)C>CC(CC)=O>[ClH:31].[CH2:1]([C@@H:8]1[NH:12][C:11]2([CH2:17][CH2:16][N:15]([C:18](=[O:24])[CH:19]([CH2:20][CH3:21])[CH2:22][CH3:23])[CH2:14][CH2:13]2)[NH:10][C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: CCC(CC)C(=O)N1CCC2(CC1)NC(=O)[C@H](Cc1ccccc1)N2
Solvent: O
Solvent: CCC(C)=O
Product: Cl
Reaction time: 8 h

Procedure:
3-(S)-Benzyl-8-(2-ethylbutyryl)-1,4,8-triazaspiro[4,5]decan-2-one (610 mg, 1.8 mmol) was dissolved in ethyl methyl ketone (5 ml), treated with water (18 μL) and TMSCl (247 μL) and stirred overnight. The solid precipitated in this process was filtered off, washed with ether and dried in vacuo. The product 3-(S)-benzyl-8-(2-ethylbutyryl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 590 mg (87%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH3:11][Mg]I.C(OCC)C.C(OCC)C.Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])([CH3:11])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]I
Reactant: CC(=O)c1cccc(Br)c1
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)(O)c1cccc(Br)c1
Reaction time: 0.33 h

Procedure:
In a nitrogen atmosphere with cooling with ice, 5.29 mL of 3′-bromoacetophenone was added to 25 mL of 2 M methylmagnesium iodide/diethyl ether solution and 100 mL of diethyl ether, and stirred for 20 minutes. Water and 2 N hydrochloric acid were added to the reaction liquid, extracted with ethyl acetate, washed with aqueous saturated sodium hydrogencarbonate solution and saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain crude 2-(3-bromophenyl)propan-2-ol.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[CH3:31][Sn](C)(C)C.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([CH3:31])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 63 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (105 mg, 0.23 mmol), tetramethyltin (0.2 mL, 1.13 mmol) and PdCl2(PPh3)2 (32 mg, 0.045 mmol) in 5 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc (50 mL) and brine (10 mL) were added. 1M HCl was added with stirring until pH was about 2. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was chromatographed (0-40% EtOAc/hexanes+2% AcOH) to give 58 mg of the title compound. MS: (+) m/z 401.12 (M+1).
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][OH:21])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[CH3:28][O:29][CH2:30][CH:31]1[CH2:33][O:32]1>>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][O:21][CH2:33][CH:31]([OH:32])[CH2:30][O:29][CH3:28])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: COCC1CO1
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Agent: [Na]
Product: CCOC(=O)c1c2ccc(CC(=O)NOCC(O)COC)ccc-2c(C(=O)OCC)c1N
Yield: 15 %

Procedure:
In an analogous manner to that described in Example 1, from diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and 2-methoxymethyl-oxirane the title compound is obtained in 15% yield as a wax.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[N:6]1.[NH2:19][C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.S([O-])([O-])(=O)=O.[Mg+2].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.O>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[NH:19][CH2:2][CH2:3][CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][CH:12]=2)[CH:7]=[N:6]1
Reactant: Nc1ncccn1
Reactant: CCOC(=O)c1ccc2c(cnn2CCC=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc2c(cnn2CCCNc2ncccn2)c1
Reaction time: 6 h

Procedure:
Ethyl 1-(3-oxopropyl)-1H-indazole-5-carboxylate (1.0 g, 4.06 mmol, prepared as described in Jadhav et al, U.S. Pat. No. 5,760,028) was dissolved in toluene (15 mL) and 2-aminopyrimidine (463 mg, 4.9 mmol) added, along with anhydrous magnesium sulfate (2.44 g, 20 mmol) under nitrogen. The mixture was vigorously stirred for six hours, filtered under nitrogen, the solids washed (10 mL toluene), and the filtrate treated with sodium triacetoxyborohydride (8.6 g, 40 mmol). The reaction was stirred under nitrogen for 18 hours, diluted with toluene (25 mL), and poured into water (100 mL). Saturated sodium bicarbonate solution (80 mL) was added to adjust pH>8. The layers were separated and the aqueous layer extracted with three portions of ethyl acetate. The combined organics were washed with saturated bicarbonate solution, water, and brine, dried over sodium sulfate, filtered, and concentrated under vacuum to afford a golden oil (1.3 g). This purified by preparative HPLC (Vydac C18, 21.2 mm×25 cm, 90% acetonitrile/water/0.1% TFA; 10-70% B over 30 minutes). The product fractions were frozen and lyophilized to afford the desired product as a white powder (520 mg, 40%). LRMS (ES): 326.2 ([M+H]+. HRMS: Calculated for C17H20N5O2: 326.1617. Found: 326.1605. 1HNMR (600.1343 MHz, CDCl3): 9.68 (bs, 1H), 8.58 (m, 1H), 8.49 (s, 1H), 8.12 (s, 1H), 8.08 (m, 1H), 8.03, (t, 1H), 7.50 (d, 1H), 6.73 (t, 1H), 4.55 (m, 2H), 4.39 (q, 2H), 3.36 (m, 2H), 2.35 (m, 2H), 1.41 (t, 3H).