Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1.[C:20](=O)([O:24]CC)[O:21][CH2:22][CH3:23]>C(O)C>[CH3:2][C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:20]([O:21][CH2:22][CH3:23])=[O:24])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:10][CH:9]=1
Reactant: CCOC(=O)Cc1ccc(-c2sccc2C)cc1
Reactant: CCOC(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1ccc(-c2sccc2C)cc1
Reaction time: 0.5 h
Yield: 61.7 %

Procedure:
To a solution of 1.4 g (0.06 mole) of metallic sodium in 50 ml of ethanol was added 10 g (0.038 mole) of ethyl 4-(3-methyl-2-thienyl)phenylacetate [I.R. (liquid film): νC=O 1735 cm-1 ], followed by adding 14.3 g (0.121 mole) of diethyl carbonate. The mixture was stirred at 50° to 60° C. for 30 minutes and freed from the ethanol by distillation under reduced pressure. To the residue were added 15 ml of 1 N hydrochloric acid and 50 ml of benzene and the mixture was shaken thoroughly. The organic layer was dried over anhydrous magnesium sulfate and freed from the solvent by distillation under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: benzene/n-hexane=2/1) to obtain 7.8 g (58% yield) of oily diethyl [4-(3-methyl-2-thienyl)phenyl]malonate.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[NH:8][N:9]=[N:10][C:11]=1[C:12](=[O:29])[NH:13][C:14]1[CH:19]=[CH:18][N:17]2[CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:22]=[C:16]2[N:15]=1)=[O:6].Cl>CO.C1COCC1>[C:23]1([C:21]2[N:22]=[C:16]3[N:15]=[C:14]([NH:13][C:12]([C:11]4[N:10]=[N:9][NH:8][C:7]=4[C:5]([OH:6])=[O:4])=[O:29])[CH:19]=[CH:18][N:17]3[CH:20]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1[nH]nnc1C(=O)Nc1ccn2cc(-c3ccccc3)nc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccn2cc(-c3ccccc3)nc2n1)c1nn[nH]c1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
NaOH (3N, 1.47 ml) was added to a solution of 5-(2-phenyl-imidazo[1,2-a]pyrimidin-7-ylcarbamoyl)-3H-[1,2,3]triazole-4-carboxylic acid methyl ester (example 26, 800 mg, 2.2 mmol) in methanol/THF=1:1 (16 ml), and the mixture was stirred for 6 h at RT. The mixture was acidified (pH=3) with HCl (2N), the suspension was stirred for 15 min, and filtered. The precipitated title compound (590 mg, 77%) was dried under vacuum, and used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=O.[Na][Na].[NH2:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][C:25]([OH:27])=[O:26]>CN(C)C=O.CO.O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH:22][C@H:23]([C:28]([OH:30])=[O:29])[CH2:24][C:25]([OH:27])=[O:26])=[O:19]
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Na][Na]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: O=C(O)C[C@H](NC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl)C(=O)O

Procedure:
A solution of 3.9 g of the N-hydroxysuccinimide ester of 2-[2-(2,6-dichlorophenylamino)phenyl]-acetic acid in dimethylformamide is added dropwise to 2.00 g of the disodium salt of L-aspartic acid in 10 ml of methanol/water (1:1). The solution is concentrated by evaporation in vacuo after one hour at room temperature, the residue is taken up in ethyl acetate and dilute hydrochloric acid and partitioned and the ethyl acetate phase is washed with water, dried with Na2SO4 and concentrated by evaporation. By trituration of the residue with diethyl ether, crystals of N-{[2-(2,6-dichlorophenylamino)-phenyl]-acetyl}-aspartic acid are obtained; m.p. 157°-160° (decomposition), Rf =0.17 (CHCl3 :MeOH=1:1).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].[O-]CC.[Na+].CN([CH:18]=[C:19]1[C:23](=O)[CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]1)C>C(O)C>[CH3:6][S:7][C:8]1[N:9]=[CH:18][C:19]2[CH2:20][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][C:23]=2[N:10]=1
Reactant: CSC(=N)N
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CC1=O
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: CSc1ncc2c(n1)CN(C(=O)OC(C)(C)C)C2
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-methyl-2-thiopseudourea sulfate (3.5 g, 25 mmol) in ethanol at 0° C. was added a solution of sodium ethoxide (9.6 mL, 21%). After stirring for 10 min, a solution of tert-butyl 3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (2.0 g, 8.32 mmol) in ethanol was added, and the mixture was heated at 80° C. for 1 h. Additional 2-methyl-2-thiopseudourea sulfate (3.5 g, 25 mmol) and sodium ethoxide (9.6 mL, 21%) was added and heated at 80° C. for 1 h. The ethanol was removed under reduced pressure, the residue was diluted with ethyl acetate (400 mL), washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, and concentrated. The residue was purified on a Biotage silica gel cartridge (gradient 10-35% ethyl acetate in hexanes) to yield tert-butyl 2-(methylthio)-5,7-dihydro-6H-pyrrolo[3,4-d]pyrimidine-6-carboxylate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].C([Li])CCC.[CH:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C1COCC1.CCCCCC>[OH:20][CH:13]([CH:3]1[O:4][CH2:5][CH2:6][NH:1][C:2]1=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1COCCN1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C1NCCOC1C(O)c1ccccc1
Temperature: -62 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
Under an atmosphere of nitrogen and in a anhydrous apparatus a mixture of 2.02 g of morpholin-3-one in 60 ml of anhydrous THF was stirred. Dropwise addition was made at room temperature of 26.7 ml of 15% butyl lithium in hexane over 45 minutes. After 2.5 hours of stirring at room temperature the whole was cooled to -62° C. and a solution of 2.02 ml of freshly distilled benzaldehyde in 10 ml of anhydrous THF was added, over 45 minutes. The mixture was kept at -62° C. for 3 hours, allowed to rise to room temperature and kept at this temperature for a further 16 hours. A little water was added and the whole was evaporated to dryness. The residue was taken up with a dilute solution of NaHCO3, extracted with ethyl acetate and washed with H2O. The solution was dried over Na2SO4, filtered and evaporated to dryness. The solid residue was ground with 40 ml of ethyl ether and filtered, to obtain 2.4 g of 2-(α-hydroxy-benzyl)-morpholin-3-one which was crystallized from ethyl acetate, melting point 130°-140° C. Yield 58.0%.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:14]([C:17]1[N:18]=[C:19]([CH2:22][C@H:23]2[C@H:29]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[O:28][CH2:27][CH2:26][N:25]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:24]2)[S:20][CH:21]=1)(=O)[NH2:15].N1C=CC=CC=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1COCC1>[C:14]([C:17]1[N:18]=[C:19]([CH2:22][C@H:23]2[C@H:29]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=3)[O:28][CH2:27][CH2:26][N:25]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:24]2)[S:20][CH:21]=1)#[N:15]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](Cc2nc(C(N)=O)cs2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](Cc2nc(C#N)cs2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.1 %

Procedure:
Trifluoroacetic anhydride (0.080 mL, 0.57 mmol) was added to a solution of tert-butyl (6R,7R)-6-[(4-carbamoyl-1,3-thiazol-2-yl)methyl]-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (126 mg, 0.26 mmol) and pyridine (0.084 mL, 1.04 mmol) in THF (4 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, triethylamine (0.144 mL, 1.04 mmol) and trifluoroacetic anhydride (0.080 mL, 0.57 mmol) were added, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (100 mg).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[H-].[Na+].[Br:9][C:10]1[C:11]([Cl:32])=[CH:12][C:13](F)=[C:14]([S:16]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH3:30])([CH3:29])[CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:15]=1.Cl>CN(C=O)C>[Br:9][C:10]1[C:11]([Cl:32])=[CH:12][C:13]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])=[C:14]([S:16]([N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([CH3:30])([CH3:29])[CH2:21][CH2:20]2)(=[O:18])=[O:17])[CH:15]=1
Reactant: OCCCCO
Reactant: CC1(C)CCN(S(=O)(=O)c2cc(Br)c(Cl)cc2F)c2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CCN(S(=O)(=O)c2cc(Br)c(Cl)cc2OCCCCO)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 171 %

Procedure:
To a solution of 1,4-butanediol (0.44 mL, 5 mmole) in DMF (5 mL) at 0° C. was added sodium hydride (60%, 48 mg, 1.2 mmole) and the mixture stirred for 10 minutes. A solution of 1-(5-bromo-4-chloro-2-fluoro-benzenesulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (0.41 g, 1 mmole) in DMF (5 mL) was added. The mixture warmed to rt and was stirred for 1 hour. 1N hydrochloric acid solution (1 mL) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and was dried over anhydrous MgSO4. Concentration of the filtrate provided a residue that was purified by silica gel chromatography [eluent: 40% ethyl acetate in hexane] to afford 4-[4-bromo-5-chloro-2-(4,4-dimethyl-3,4-dihydro-2H-quinoline-1-sulfonyl)-phenoxy]-butan-1-ol as a light yellow foam (0.86 g). MS: 503.9 (M+H)+; tR=2.66 min (method 1).
Reaction SMILES: C([N:8]1[CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[C:10]([CH3:16])=[C:9]1[C:17]([O:19][CH2:20][CH3:21])=[O:18])C1C=CC=CC=1.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>C(O)(=O)C>[CH2:20]([O:19][C:17]([C:9]1[NH:8][CH:13]=[C:12]([CH3:14])[C:11](=[O:15])[C:10]=1[CH3:16])=[O:18])[CH3:21]
Reactant: CCOC(=O)c1c(C)c(=O)c(C)cn1Cc1ccccc1
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]cc(C)c(=O)c1C
Yield: 94.5 %

Procedure:
To a solution of pyridone 5 (5.1 g, 17.89 mmol) in acetic acid (100 ml) was added 10% Pd--C (0.2 g), and the reaction mixture was hydrogenated (55 Psi) at room temperature overnight. The mixture was then filtered through Celite and the filtrate was evaporated. The residue was thoroughly washed with 10% potassium carbonate, water and dried in vacuo to give compound 6 as a white powder (3.3 g, 95% yield) m.p. 124°-126° C. 1H-NMR (DMSO-d6) δ 7.52 (brs, 1H), 4.45 (q, J=7.2 Hz, 2H), 2.40 (s, 3H), 2.07 (s, 3H), 1.42(t, J=7.2 Hz, 3H). Ms(13eV)m/z(%): 195.0(M+, 100), 165.9(40), 148.9(50), 122.9(80), 121.0(100). Anal. Calcd for C10H13NO3 : C, 61.53; H, 6.71; N, 7.18. Found: C, 61.48; H, 6.63; N, 7.09.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]([N:12]2[C:16](=O)[CH2:15][CH2:14][C:13]2=O)[CH:9]=[CH:10][CH:11]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[N:12]1([C:8]2[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=2)[CH2:4][OH:3])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cccc(N2C(=O)CCC2=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCc1cccc(N2CCCC2)c1
Temperature: 25 °C
Yield: 46.9 %

Procedure:
0.25 g of N-(3-ethoxycarbonylphenyl)succinimide [synthesized by heat condensing ethyl m-aminobenzoate with succinic anhydride in acetic acid] was dissolved in 5 ml of anhydrous tetrahydrofuran, and with stirring under ice cooling, 0.17 g of lithium aluminium hydride was added. The mixture was maintained at room temperature for 30 minutes, and then heated under reflux for 4 hours. After the reaction, ethyl acetate and water were added. The organic layer was separated, and then worked up in a customary manner and purified by medium-pressure liquid chromatography [Lobar column, size B, Lichroprep Si 60 (E. Merck & Co.); eluting solvent: hexane/ethyl acetate=10/1) to give 84 mg (yield 47%) of the captioned compound as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5](=O)[CH:6]=[CH:7][NH:8]2.P(Br)(Br)[Br:15].O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:15][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[N:8]=[CH:7][CH:6]=1
Reactant: COc1cccc2[nH]ccc(=O)c12
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2nccc(Br)c12
Yield: 85 %

Procedure:
A solution of quinolone (c) (3.2 g, 18 mmol) in DMF (22 ml) was treated with phosphorous tribromide (2.2 ml). After 2 hours the mixture was added to water and neutralised with saturated aqueous sodium bicarbonate solution. Filtration and drying afforded a yellow solid (3.6 g, 85%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5](=[O:13])[C:4]1=[O:14])[CH3:2].[CH3:15][O:16][C:17]1[C:18]([CH3:23])=[N:19][CH:20]=[CH:21][CH:22]=1.FC(F)(F)C(O)=O>O1CCOCC1>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[C:5]([OH:13])([CH2:23][C:18]2[C:17]([O:16][CH3:15])=[CH:22][CH:21]=[CH:20][N:19]=2)[C:4]1=[O:14])[CH3:2]
Reactant: COc1cccnc1C
Reactant: CCN1C(=O)C(=O)c2cc(C)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCN1C(=O)C(O)(Cc2ncccc2OC)c2cc(C)ccc21
Temperature: 110 °C

Procedure:
To a flame dried sealed tube cooled under argon was added the 1-ethyl-5-methylindoline-2,3-dione (0.03 grams, 0.15 mmol) and 3-methoxy-2-methyl-pyridine (0.072 grams, 0.59 mmol, purchased from Fisher Scientific) and 0.5 mL of 1,4 dioxane. After the addition of trifluoro acetic acid (2 μL) the vessel was sealed and heated to 110° C. for 48 hours. The reaction was then concentrated. 1H-NMR δ 8.21 (s, 1H), 7.35 (bs, OH), 7.26 (m, 1H), 7.20 (d, 1H), 7.09 (d, 1H), 6.90 (s, 1H), 6.75 (d, 1H), 3.78 (s, 3H), 3.77 (m, 2H), 3.34 (d, 1H), 3.18 (d, 1H), 2.27 (s, 3H), 1.28 (t, 3H). Calculated mass for C18H20N2O3, 312.15. Observed 313.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:16]=[N:17][NH:18][N:19]=3)=[N:8][C:4]=2[CH:3]=1.IC.[C:28]([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]([C:20]([CH3:22])([CH3:21])[CH3:23])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:16]=[N:17][N:18]([CH3:28])[N:19]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)n1c(-c2ccccc2-c2nn[nH]n2)nc2cc(Br)ccc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: Cn1nnc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a vial is added 5-bromo-1-tert-butyl-2-[2-(2H-tetrazol-5-yl)-phenyl]-1H-benzimidazole (158 mg, 0.4 mmol) in DMF (5 mL), followed by the addition of iodomethane (114 mg, 0.8 mmol) and K2CO3 (110 mg, 0.8 mmol). The reaction mixture is stirred at room temperature for 0.5 hour. The reaction mixture is diluted with EtOAc, washed with water then, brine, dried with Na2SO4, filtered and concentrated. The residue is loaded to a silica gel column. The column is eluted with 0-3% MeOH/CH2Cl2. The product fractions are collected and is concentrated to afford 5-bromo-1-tert-butyl-2-[2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-1H-benzimidazole (62 mg, 38%). LCMS (ESMS): m/z 411.59, 413.47 (M++1)
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[CH:4]=1)#[CH:2].Br[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[OH:23]>C(N(CC)CC)C.C(NCC)C.[Cu]I.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>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]2[O:23][C:1]([C:3]3[CH:12]=[CH:11][C:10]4[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=4)[CH:4]=3)=[CH:2][C:16]=2[CH:21]=1
Reactant: Oc1ccc(Cl)cc1Br
Reactant: C#Cc1ccc2cc(OC)ccc2c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CCN(CC)CC
Product: COc1ccc2cc(-c3cc4cc(Cl)ccc4o3)ccc2c1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
A mixture of 2-ethynyl-6-methoxynaphthalene (1.82 g, 10 mmol), 2-bromo-4-chlorophenol (2.01 g, 10 mmol), copper (I) iodide (0.1 g, 0.52 mmol), tetrakis(triphenylphosphine)palladium (0.58 g, 0.5 mmol) in triethylamine (10 mL) and diethylamine (10 mL) was heated at reflux for 1 hour under an atmosphere of nitrogen then cooled to room temperature. The solid was collected by filtration, washed with ether and dried to give the title compound as a solid (2.0 g). 1HNMR (300 MHz, DMSO-d6): δ8.4 (s, 1H), 8.0-7.9 (m, 3H), 7.75 (d, 1H, J=1.8 Hz), 7.69 (d, 1H, J=9.2 Hz), 7.46 (s, 1H), 7.38-7.32 (m, 2H), 7.24 (dd, 1H, J=9.2, 1.8 Hz), and 3.9 ppm (s, 3H).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].Br[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17]>C1COCC1>[C:5]([CH:4]([CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[C:3]([O:9][CH2:10][CH3:11])=[O:8])(=[O:6])[CH3:7]
Reactant: CC(C)=CCCBr
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC=C(C)C)C(C)=O
Reaction time: 0.5 h
Yield: 21.2 %

Procedure:
Sodium hydride was added portionwise to a stirred solution of ethyl acetoacetate (0.1 mole , 13.0 g) in 300 ml THF. The solution was stirred for 30 minutes. 5-Bromo-2-methyl-2-pentene (0.11 moles, 17.9 g) was added dropwise over 30 minutes. The solution stirred at room temperature for 40 hours. The solution was concentrated in vacuo. Ethyl acetate and water were added. The organic phase was dried over sodium sulfate and concentrated. The product was purified by HPLC over silica gel eluted with a gradient of 0-40% ethyl acetate in hexane to yield 4.5 g of ethyl 2-acetyl-6-methyl-5-heptenoate.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][C@@H:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][N:20]=2)[C:15]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:14][CH2:13][C@H:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[F:34])=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.CO>[C:3]([O:7][C:8]([NH:10][C@@H:11]1[C:21]2[C:16](=[N:17][CH:18]=[CH:19][N:20]=2)[C:15]([CH2:22][C:23]([OH:25])=[O:24])=[CH:14][CH2:13][C@H:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[F:34])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CC1=CC[C@@H](c2cccc(F)c2F)[C@H](NC(=O)OC(C)(C)C)c2nccnc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1c2nccnc2C(CC(=O)O)=CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a 50 mL round-bottomed flask was dissolved methyl 2-((5S,6S)-5-(tert-butoxycarbonylamino)-6-(2,3-difluorophenyl)-6,7-dihydro-5H-cyclohepta[b]pyrazin-9-yl)acetate (5) in 4:1 tetrahydrofuran/methanol (2.5 mL). Lithium hydroxide (0.588 mL, 0.588 mmol) was added and the mixture was stirred at rt for 16 h. LCMS indicated complete conversion. The mixture was concentrated and further dried under a high vacuum to remove water to give a slightly orange solid, which was directly carried on to the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4=[C:14]([CH2:17][CH2:18][CH2:19][C:20](=[O:29])/[C:21]/4=[CH:22]/[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[OH-].[OH-].[Pd+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH:21]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)[C:20](=[O:29])[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCCc2cc3c(cnn3-c3ccc(F)cc3)cc2/C1=C\c1ccccn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: O=C1CCCc2cc3c(cnn3-c3ccc(F)cc3)cc2C1Cc1ccccn1
Yield: 99.6 %

Procedure:
A solution of (E)-1-(4-fluorophenyl)-5-(pyridin-2-ylmethylene)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (0.519 g, 1.354 mmol) in toluene (25 mL) containing 20% Pd(OH)2 (0.090 g, 0.128 mmol) was evacuated and placed under hydrogen. The mixture was stirred under an atmosphere of hydrogen provided via a balloon at rt for about 11 h then the catalyst was removed by filtration through Celite®. The filtrate was concentrated under reduced pressure to yield 1-(4-fluorophenyl)-5-(pyridin-2-ylmethyl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (7, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.52 g, 100%); LC/MS, method 3, Rt=2.06 min, MS m/z 386 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.48-8.46 (m, 1H), 8.27 (d, J=0.8 Hz, 1H), 7.84-7.75 (m, 2H), 7.72-7.63 (m, 3H), 7.47-7.38 (m, 2H), 7.36 (d, J=7.8 Hz, 1H), 7.21-7.17 (m, 1H), 4.95-4.92 (m, 1H), 3.88-3.81 (m, 1H), 3.44-3.36 (m, 1H), 3.34-3.27 (m, 1H), 3.12-3.06 (m, 1H), 2.98-2.90 (m, 1H), 2.47-2.40 (m, 1H), 2.27-2.17 (m, 1H), 1.60-1.57 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:47]([O:48][CH2:49][CH2:50][CH2:51][O:52][C:53]2[C:54]([O:90][CH3:91])=[CH:55][C:56]3[C:62](=[O:63])[N:61]4[CH:64]=[C:65]([C:67]5[CH:72]=[CH:71][C:70]([N:73]6[CH2:78][CH2:77][N:76]([CH3:79])[CH2:75][CH2:74]6)=[CH:69][CH:68]=5)[CH2:66][C@H:60]4[C:59](=O)[N:58](COCC[Si](C)(C)C)[C:57]=3[CH:89]=2)=[CH:46][C:6]2[N:7](COCC[Si](C)(C)C)[C:8](=O)[C@@H:9]3[CH2:15][C:14](/[CH:16]=[CH:17]/[CH2:18][NH:19][C:20](=[O:36])[O:21][CH2:22][CH:23]4[C:35]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:29]5[C:24]4=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:13][N:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1.[Li+].[B-](CC)(CC)CC>C1COCC1>[CH3:1][O:2][C:3]1[C:47]([O:48][CH2:49][CH2:50][CH2:51][O:52][C:53]2[C:54]([O:90][CH3:91])=[CH:55][C:56]3[C:62](=[O:63])[N:61]4[CH:64]=[C:65]([C:67]5[CH:68]=[CH:69][C:70]([N:73]6[CH2:74][CH2:75][N:76]([CH3:79])[CH2:77][CH2:78]6)=[CH:71][CH:72]=5)[CH2:66][C@H:60]4[CH:59]=[N:58][C:57]=3[CH:89]=2)=[CH:46][C:6]2[N:7]=[CH:8][C@@H:9]3[CH2:15][C:14](/[CH:16]=[CH:17]/[CH2:18][NH:19][C:20](=[O:36])[O:21][CH2:22][CH:23]4[C:35]5[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=5[C:29]5[C:24]4=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:13][N:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@H]1C(=O)N3COCC[Si](C)(C)C)N(COCC[Si](C)(C)C)C(=O)[C@@H]1CC(/C=C/CNC(=O)OCC3c4ccccc4-c4ccccc43)=CN1C2=O
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(cc1OCCCOc1cc3c(cc1OC)C(=O)N1C=C(c4ccc(N5CCN(C)CC5)cc4)C[C@H]1C=N3)N=C[C@@H]1CC(/C=C/CNC(=O)OCC3c4ccccc4-c4ccccc43)=CN1C2=O
Temperature: -78 °C
Yield: 46.8 %

Procedure:
SEM dilactam 14e (0.250 g, 0.196 mmol, 1.0 eq.) was solubilised in THF (13 mL) and cooled to −78° C. under a nitrogen atmosphere. Super hydride solution (0.40 mL, 0.401 mmol, 2.04 eq.) was added dropwise over 5 min. After 20 min an aliquot was washed with water for LCMS and TLC analysis. After 30 mins water (30 mL) was added and the cold bath removed. The organic layer was extracted with EtOAc (2×40 mL) and the combined organic extracts washed with brine (40 mL), dried with MgSO4, filtered and removed under reduced pressure. The crude product was dissolved in MeOH (13 mL), DCM (7 mL) and water (1.7 mL) and enough silica gel to form a thick stirring suspension. After 5 days the suspension was filtered through a sintered funnel and washed with DCM/MeOH 9:1 (˜200 mL) until complete elution of product. The organic layer was washed with brine (2×70 mL), dried with MgSO4, filtered and the solvent removed under reduced pressure. Purification by flash chromatography (silica gel, CHCl3 100 to 96:4 v/v CHCl3/MeOH) afforded the product as a pale yellow solid (0.090 g, 47%). LC/MS (2.112 min (ES+)), m/z: 981.0 [M+H]+.