Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N-]C(C)C)([CH3:3])[CH3:2].[Li+].[C:9]([O:13][C:14]([N:16]1[CH:20]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][CH:22]=2)[CH2:19][CH2:18][C:17]1=[O:29])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(I)C=C>C1COCC1>[C:9]([O:13][C:14]([N:16]1[C@@H:20]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[N:28])=[CH:25][CH:26]=2)[CH2:19][C@H:18]([CH2:3][CH:1]=[CH2:2])[C:17]1=[O:29])=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC1c1ccc(C#N)cc1
Reactant: CC(C)[N-]C(C)C
Agent: C=CCI
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@H](c2ccc(C#N)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
A solution of freshly prepared lithium diisopropylamide (2.80 mmol) in 10 mL of THF was added dropwise into a solution of N-tert-butyloxycarbonyl-5-(4-cyanophenyl)-2-pyrrolidinone (763 mg, 2.67 mmol) in 10 mL of THF at −78° C. After stirring for 1 hr at −78° C., allyl iodide (488 μL, 5.33 mmol) was added. The mixture was stirred at −78° C. for 1 hr, and then quenched with 5.0 mL of sat'd NH4Cl solution. The mixture was poured into a mixture of brine (20 mL) and CH2Cl2 (20 mL), and the aqueous layer was separated and extracted with CH2Cl2 (3×20 mL). Organic layers were combined, dried over MgSO4, and concentrated. Chromatography on a Biotage 40+M cartridge using 1:4 v/v EtOAc/hexanes as the eluant gave 745 mg (86%) of the title compound: 1H NMR δ 1.35 (s, 9H), 1.99-2.05 (m, 1H), 2.21-2.29 (m, 1H), 2.63-2.76 (m, 2H), 5.06-5.11 (m, 2H), 5.17-5.20 (m, 1H), 5.68-5.77 (m, 1H), 7.32 (d, J=8.2, 2H), 7.67 (d, J=8.4, 2H).
Reaction SMILES: [H-].[Na+].[CH:3](/[C:11]1[NH:12][CH:13]=[CH:14][CH:15]=1)=[CH:4]\[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Br[CH2:17][C:18]([O:20][CH3:21])=[O:19].O>CN(C)C=O>[CH:3]([C:11]1[N:12]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=1)=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COC(=O)CBr
Reactant: C(=C/c1ccc[nH]1)\c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cccc1C=Cc1ccccc1
Yield: 34.5 %

Procedure:
Sodium hydride (0.3 g, 0.0063 mol) was washed with petrol 60°-80° and suspended in dimethylformamide (DMF, 25 ml). The (E)-2-styrylpyrrole (1.0 g, 0.006 mol) in DMF (10 ml) was added dropwise at room temperature. After stirring for 11/2 hours, methyl bromoacetate (0.56 ml, 0.006 mol) in DMF (5 ml) was added dropwise. After 16 hours it was poured into water (200 ml) and extracted with ether (3×100 ml). The extracts were washed with brine dried and evaporated under reduced pressure to give a brown oil. Purification by column chromatography using silica gel with ethyl acetate: petrol 60°-80°, (1:1) as the eluent gave methyl (2-styrylpyrrol-1-yl)acetate (0.5 g, 30% yield) as a buff amorphous solid.
Reaction SMILES: N[C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([Cl:8])[N:7]=1.C(ON=O)CC(C)C.[ClH:22]>C(#N)C.O>[CH3:13][O:12][C:10]([C:3]1[C:2]([Cl:22])=[N:7][C:6]([Cl:8])=[C:5]([Cl:9])[N:4]=1)=[O:11]
Reactant: COC(=O)c1nc(Cl)c(Cl)nc1N
Reactant: Cl
Agent: CC(C)CCON=O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(Cl)c(Cl)nc1Cl
Temperature: 65 °C
Yield: 42 %

Procedure:
Methyl 3-amino-5,6-dichloro-2-pyrazinecarboxylate (2.6 g, 11.8 mmol), CuCl2 (2.37 g, 17.6 mmol) and iso-amylnitrite (2.07 g, 17.7 mmol) were combined in 100 mL of acetonitrile and heated at 65° C. for 18 h. The solution was cooled, acidified with 2N HCl (50 mL), diluted with water (100 mL), and extracted with DCM (3×30 mL). The combined extracts were dried, concentrated and the residue was purified by flash chromatography (eluent: 10 to 50% EtOAc+0.1% triethylamine in hexane) to afford 56a (1.21 g, 42% yield).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[C:7]([C:10](OC)=[O:11])[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH:1]1[C:9]2[CH:8]=[C:7]([CH2:10][OH:11])[N:6]=[CH:5][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)c1cc2[nH]cnc2cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2[nH]cnc2cn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
17.7 g of methyl 1H-imidazo[4,5-c]pyridine-6-carboxylate (example D2) were added in portions to a suspension of 19.0 g lithiumaluminium hydride in 0.6 I anhydrous tetrahydrofuran under nitrogen atmosphere at 0° C. After the addition was completed, the ice/water bath was removed and the mixture was stirred at room temperature for 12 h. 30 ml ethyl acetate followed by 100 ml methanol are slowly added at 0° C. (until gas evolution has stopped). Water (50 ml) was slowly added and the resulting precipitate was filtered. The precipitate was suspended in 11 methanol and filtered through a plug of CELITE® (diatomaceous earth). The combined filtrates are evaporated under vacuum to give crude 1H-imidazo[4,5-c]pyridin-6-ylmethanol as a brown solid that was used for the next step without further purification. To a N,N-dimethylformamide solution (140 ml) of 1H-imidazo[4,5-c]pyridin-6-ylmethanol were added 28.0 g tert-butyldimethylsilyl chloride and 19.4 g imidazole. The mixture was stirred at room temperature for 12 h and then poured into ice water (2.5 I). The resulting solid was filtered, washed with 100 ml water and dissolved in 0.5 I ethyl acetate. The organic layer was dried with MgSO4 and then concentrated under vacuum to a volume of about 100 ml. 50 ml n-hexane were added and the precipitating solid was filtered and washed with 50 ml n-hexane. The filtrate was concentrated and the resulting precipitate was washed with n-hexane. Both batches of solid were combined and dried under vacuum to yield the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=1[O:30][C:29]([CH3:32])=[CH:28][C:27]3=[O:33])[C:7]([C:15]([O:17]CCC#N)=[O:16])=[C:8]([CH3:14])[NH:9]2)[CH3:2].[OH-].[Na+].C(OCC)C>COCCOC.O>[CH2:1]([O:3][C:4]1[N:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]3[C:31]=1[O:30][C:29]([CH3:32])=[CH:28][C:27]3=[O:33])[C:7]([C:15]([OH:17])=[O:16])=[C:8]([CH3:14])[NH:9]2)[CH3:2]
Reactant: CCOc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(=O)OCCC#N)=C(C)N2
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Solvent: CCOCC
Product: CCOc1nccc2c1C(c1cccc3c(=O)cc(C)oc13)C(C(=O)O)=C(C)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
270 mg (0.61 mmol) of the compound from Example 32A are dissolved in 15 ml of 1,2-dimethoxyethane/water (2:1 v/v), 1.21 ml (1.21 mmol) of 1 N sodium hydroxide solution are added, and the mixture is stirred at room temperature for 1 h. 30 ml of diethyl ether are then added to the reaction mixture. The aqueous phase is separated off and acidified with 1 N hydrochloric acid. The resulting precipitate is filtered off and washed with water and a little diethyl ether. Drying in vacuo at 40° C. results in 167 mg (70% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-])=O)=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[C:23]#[N:24])=[CH:18][CH:17]=1>CO.C1COCC1.[Ni]>[NH2:12][C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:25])([CH3:26])[C:23]#[N:24])=[CH:20][CH:21]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2
Reactant: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)cc1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C#N)c1ccc(Nc2c(N)cnc3ccc(Br)cc23)cc1

Procedure:
24 g (58.4 mmol) of 2-[4-(6-bromo-3-nitro-quinolin-4-ylamino)-phenyl]-2-methyl-propionitrile (Example 1e) is shacked in 300 ml of MeOH-THF (1:1) under 1.1 bar of H2 in the presence of 8.35 g of Raney-Ni for 1 h. After completion of the reaction, the catalyst is filtered off and the filtrate is evaporated to dryness to give the title compound as a yellow foam. ES-MS: 381, 383 (M+H)+, Br pattern; analytical HPLC: tret=3.21 min (Grad 1).
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[CH:10]=[CH:9][C:8]1=[O:19].FC(F)(F)C(O)=O>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][C:8](=[O:19])[N:7]2[CH2:6][CH:2]=[O:1])=[CH:12][CH:13]=1
Reactant: COc1ccc2ccc(=O)n(CC3OCCO3)c2c1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2ccc(=O)n(CC=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 0.56 g of 1-(1,3-dioxolan-2-ylmethyl)-7-methoxyquinolin-2(1H)-one, 5.6 mL of a 90% aqueous trifluoroacetic acid solution was added, the mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure, water and chloroform was added thereto, and the reaction mixture was adjusted to pH 7.0 with an aqueous saturated sodium hydrogen carbonate solution and stirred for 2 hours. The organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and the extract were combined, the resultant solution was washed sequentially with water and an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain 0.36 g of a yellow oily substance, (7-methoxy-2-oxoquinolin-1(2H)-yl)acetaldehyde.
Reaction SMILES: C(Cl)(Cl)Cl.CCCCCC.C[O:12][C:13](=[O:34])[CH2:14][C:15]1[CH:33]=[CH:32][C:18]2[C:19]3(OCC[O:28]3)[C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[CH:22]=[CH:23][C:17]=2[CH:16]=1>CC(C)=O.CCCCCC>[CH:16]1[C:17]2[CH:23]=[CH:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[C:19](=[O:28])[C:18]=2[CH:32]=[CH:33][C:15]=1[CH2:14][C:13]([OH:34])=[O:12]
Reactant: COC(=O)Cc1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
2.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionic acid methyl ester is stirred in 25 ml. of 1:1 concentrated sulfuric acid:water for 12 hours. The mixture is poured into water and extracted with ethyl acetate and the extract is washed, dried and evaporated to afford a 70% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139° C.; m.p. (acetone-hexane) 113°-115° C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid methyl ester gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5° C.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:16][C:17]([CH2:19]Cl)=[CH2:18]>CN(C=O)C>[CH2:16]=[C:17]1[CH2:19][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:1]=2[O:2][CH2:18]1
Reactant: Oc1ccccc1O
Reactant: C=C(CCl)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=C1COc2ccccc2OC1

Procedure:
A solution of catechol (4.4 g, 40 mmol), Cs2CO3 (27.7 g, 85 mmol) and 3-chloro-2 chloromethyl-prop-1-ene(5 g, 40 mmol) in DMF (80 mL) was striired overnight at rt. The reaction was partitioned between ether and water and the organic extract was washed with brine, dried (MgSO4), filtered and concentrated to 5.46 g (84%) of a yellow oil. MS 163 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10](O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:15][C@H:10]1[CH2:11][CH2:12][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9]1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Br)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To a stirred solution of N-Boc-(R)-3-hydroxypyrrolidine (0.936 g, 5 mmol) in THF (25 mL) was added carbon tetrabromide (2.487 g, 7.50 mmol) followed by triphenylphosphine (1.967 g, 7.50 mmol). The resulting suspension was allowed to stir at 60° C. for 1 h. Insoluble material was filtered, and concentrated. The residue was purified by silica gel column chromatography with a gradient of EtOAc (5-30%) in hexanes to afford 72 (1.12 g, 90%) as a colorless oil. LRMS (ESI): calc. 249.0; found 271.9 (MNa)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1.[CH:19]([C:21]1[NH:22][C:23]2[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=2[C:29]=1[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=O>N1CCCCC1.C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[C:16]2[C:12]([C:13](=[CH:19][C:21]3[NH:22][C:23]4[CH2:24][CH2:25][CH2:26][CH2:27][C:28]=4[C:29]=3[CH2:30][CH2:31][C:32]([OH:34])=[O:33])[C:14](=[O:18])[NH:15]2)=[CH:11][CH:10]=1
Reactant: COc1ccccc1-c1ccc2c(c1)NC(=O)C2
Reactant: O=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccccc1-c1ccc2c(c1)NC(=O)C2=Cc1[nH]c2c(c1CCC(=O)O)CCCC2
Reaction time: 4 h
Yield: 35.3 %

Procedure:
A mixture of 103 mg of 6-(2-methoxyphenyl)-2-oxindole, 95 mg of 3-(2-formyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propionic acid and piperidine (3 drops) in ethanol (2 mL) was held in a sealed tube at 90° C. for 4 hrs. The reaction mixture was concentrated and acidified with 6 N hydrochloric acid. The precipitate was collected by filtration and washed with water and hexane to give 67 mg of 3-{2-[6-(2-methoxyphenyl)-2-oxo-1,2-dihydroindol-3-ylidenemethyl]-4,5,6,7-tetrahydro-1H-indol-3-yl}-propionic acid as a brown solid (35% yield).
Reaction SMILES: [NH2:1][S:2]([C:5]1[N:9]([CH3:10])[C:8]([C:11]([OH:13])=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:14]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO>[NH2:1][S:2]([C:5]1[N:9]([CH3:10])[C:8]([C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: Cc1ccccc1
Reactant: Cn1c(C(=O)O)ccc1S(N)(=O)=O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)c1ccc(S(N)(=O)=O)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
5-(Aminosulfonyl)-1-methyl-1H-pyrrole-2-carboxylic acid (1310 mg; 6.42 mmol; 1 eq.), commercially available (ASDI), is dissolved in MeOH (24 ml), then toluene (8 ml) is added followed by the dropwise addition of (trimethylsilyl)diazomethane (9.62 ml; 2M; 19.25 mmol; 3 eq). The solution is stirred at r.t. for 2 hr and another equivalent of (trimethylsilyl)diazomethane (3.21 ml; 2 M; 6.42 mmol; 1 eq) is added to reaction mixture. After 1 hr stirring, the solvent is concentrated to dryness and the resulting off white solid is recrystallized in MeOH to afford 851.1 mg (61%) of the title compound. 1H NMR (DMSO-d6) δ 7.58 (d, J=1.5 Hz, 1H), 7.13 (s, 2H), 7.06 (d, J=1.9 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H). HPLC (max plot) 100%; Rt 1.19 min. LC/MS: (ES−) 217.1.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C.CCOC(C)=O.O>[N:23]([CH2:6][C@@H:7]([NH:15][C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[N+:24]=[N-:25]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)CC1CCCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CN=[N+]=[N-])CC1CCCCC1
Temperature: 80 °C
Yield: 68.8 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3-cyclohexylpropyl methanesulfonate (23.3 g, 0.070 mol) in anhydrous DMF (300 mL) was added solid NaN3 (13.5 g, 0.21 mol). The reaction mixture was heated at 80° C. overnight. After cooling to rt, the reaction solution was diluted with EtOAc (1200 mL) and water (400 mL). The organic phase was separated and washed with brine (3×300 mL), dried over Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel to give (S)-tert-butyl 1-azido-3-cyclohexylpropan-2-ylcarbamate as a clear oil (13.6 g, 69%). 1H NMR (400 MHz, CDCl3): 4.45 (d, J=8.0 Hz, 1H), 3.84 (m, 1H), 3.45 (m, 1H), 3.31 (m, 1H), 1.81-1.60 (m, 5H), 1.45 (s, 9H), 1.40-0.78 (m, 8H). MS (E/Z): 383 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[CH:17].[Li]CCCC.Cl[C:24]([O:26][CH3:27])=[O:25]>C1COCC1>[CH3:27][O:26][C:24](=[O:25])[C:17]#[C:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: COC(=O)Cl
Reactant: C#CCCCCCCCCOC1CCCCO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C#CCCCCCCCCOC1CCCCO1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
A flame-dried round-bottomed flask was charged with 9-decyn-1-ol tetrahydropyranyl ether (1 equiv, 31.7 mmol, 7.55 g) and THF (40 mL), and cooled to −78° C. n-BuLi (1.1 equiv, 34.9 mmol, 21.8 mL of a nominally 1.6 M solution in hexanes) were added dropwise over 5 min. The reaction was stirred for 30 min at −78° C. and then added to a solution of methyl chloroformate (1.5 eq, 47.6 mmol, 4.50 g, 3.7 mL) in THF (20 mL) dropwise via cannula. The reaction was stirred for 30 min at −78° C., then warmed to rt over 1 h and quenched dropwise with H2O (40 mL). The layers were separated and the aqueous layer was extracted with Et2O (2×25 mL). The combined organic layers were dried with Na2SO4, evaporated in vacuo, and purified by flash column chromatography (step gradient, 5% EtOAc/Hex to 10% EtOAc/Hex) to afford Methyl-11-[(tetrahydro-2H-pyran-2-yl)oxy]-undecynoate (8.50 g, 28.7 mmol, 90%). TLC Rf=0.33 (10% EtOAc/Hex) 1HNMR (600 MHz): δ 4.55-4.61 (1H), 3.84-3.91 (m, 1H), 3.70-3.78 (m plus ovlp. s, 4H), 3.47-3.54 (m, 1H), 3.39 (dt, 1H, J1=9.6 Hz, J2=6.7 Hz), 2.33 (t, 2H, J=7.1 Hz), 1.80-1.89 (1H), 1.68-1.76 (1H), 1.50-1.63 (8H), 1.28-1.44 (8H); 13CNMR (150 MHz): δ 154.3, 98.9, 89.9, 72.9, 67.6, 62.3, 52.5, 30.8, 29.7, 29.2, 28.9, 28.7, 27.5, 26.2, 25.5, 19.7, 18.6; FTIR: 2932, 2856, 2236, 1714, 1434, 1249, 1075, 1023, 752 cm−1; HRMS-ESI: calc. for C17H28NaO4 (M+Na)+: 319.1885. found: 319.1887.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[C:6]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH2:20])=[S:19])=[CH:13][CH:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3]1.Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)=O>C(O)C>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]2[N:20]=[C:18]([NH:17][C:14]3[CH:13]=[CH:12][C:11]([C:6]4[CH:7]=[CH:8][CH:9]=[C:10]5[C:5]=4[CH2:4][NH:3][C:2]5=[O:1])=[CH:16][CH:15]=3)[S:19][CH:22]=2)=[CH:26][CH:27]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: NC(=S)Nc1ccc(-c2cccc3c2CNC3=O)cc1
Solvent: CCO
Product: COc1ccc(-c2csc(Nc3ccc(-c4cccc5c4CNC5=O)cc3)n2)cc1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A suspension of Example 125A (90 mg, 0.32 mmol) and 2-bromo-1-(4-methoxy-phenyl)ethanone (73 mg, 0.32 mmol) in ethanol (3 mL) was stirred at reflux for 2 hours, cooled to room temperature, and filtered. The filter cake was washed with ethanol and dichloromethane and dried to give 118 mg (90% yield) of the desired product as the hydrobromide salt. 1H NMR (300 MHz, DMSO-d6) δ 3.80 (s, 3H); 4.55 (s, 2H); 7.01 (d, J=8.81 Hz, 2H); 7.21 (s, 1H); 7.58–7.64 (m, 3H); 7.66–7.69 (m, 2H); 7.86 (dd, J=8.81, 7.12 Hz, 4H); 8.67 (s, 1H); 10.43 (s, 1H); MS (ESI(+)) m/e 414 (M+H)+.
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].C([Sn](CCCC)(CCCC)[C:36]1[CH:37]=[CH:38][C:39]([C:42]([F:45])([F:44])[F:43])=[N:40][CH:41]=1)CCC.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]([C:36]3[CH:41]=[N:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)[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: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C(F)(F)F)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(-c2ccc(C(F)(F)F)nc2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 84 %

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 (70 mg, 0.15 mmol), 5-tributylstannanyl-2-trifluoromethyl-pyridine (98 mg, 0.23 mmol) and PdCl2(PPh3)2 (21 mg, 0.030 mmol) in 4 mL of DMF was heated at 120° C. for 3 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. 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 (2-30% EtOAc/hexanes+1% AcOH) to give 67 mg of the title compound. MS: (+) m/z 532.30 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[H-].[Na+].[CH2:12]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[N:30]=[C:29]([N:31]3[CH2:40][CH2:39][C:34]4([O:38][CH2:37][CH2:36][O:35]4)[CH2:33][CH2:32]3)[CH:28]=[C:27](Cl)[N:26]=2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1>[CH2:12]([N:19]1[CH2:20][CH2:21][N:22]([C:25]2[N:26]=[C:27]([NH:5][C:4]3[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=3)[CH:28]=[C:29]([N:31]3[CH2:32][CH2:33][C:34]4([O:35][CH2:36][CH2:37][O:38]4)[CH2:39][CH2:40]3)[N:30]=2)[CH2:23][CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: Clc1cc(N2CCC3(CC2)OCCO3)nc(N2CCN(Cc3ccccc3)CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1ccc(Nc2cc(N3CCC4(CC3)OCCO4)nc(N3CCN(Cc4ccccc4)CC3)n2)cc1Cl
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 43.7 %

Procedure:
A mixture of 3,4-dichloroaniline (1.7 g, 10.5 mmol) and NaH (0.50 g, 20.9 mmol) in tetrahydrofuran (20 mL) was heated at reflux for 30 minutes and then cooled to room temperature. A solution of 8-[2-(4-benzyl-1-piperazinyl)-6-chloro-4-pyrimidinyl]-1,4-dioxa-8-azaspiro[4.5]decane (3.0 g, 7.0 mmol) in tetrahydrofuran (30 mL) was added to this mixture and the resulting solution was stirred for 22.5 hours. The reaction mixture was quenched with saturated NH4Cl, concentrated under reduced pressure, and redissolved in EtOAc. The organic layer was separated and washed with aqueous citric acid (2×300 mL), water (2×300 mL), and brine (2×300 mL). The crude product was purified by column chromatography [eluent: EtOAc/hexane (1:4)], giving the desired product (1.7 g, 44%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]=[CH:7][C:8](=[O:17])[N:9]3[CH2:13][C:12]([OH:16])([CH2:14][OH:15])[C:11]=1[C:10]=23.FC1C=NC2C=CC(=O)N3CC(=C)C=1C=23.C(N(CC)CC)C.[C:40]1([CH3:50])[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[CH:42][CH:41]=1.C([Sn](=O)CCCC)CCC>ClCCl.O1CCCC1.CN(C)C=O.O>[CH3:50][C:40]1[CH:45]=[CH:44][C:43]([S:46]([O:15][CH2:14][C:12]2([OH:16])[C:11]3=[C:2]([F:1])[CH:3]=[N:4][C:5]4[CH:6]=[CH:7][C:8](=[O:17])[N:9]([C:10]=43)[CH2:13]2)(=[O:48])=[O:47])=[CH:42][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=c1ccc2ncc(F)c3c2n1CC3(O)CO
Agent: C=C1Cn2c(=O)ccc3ncc(F)c1c32
Agent: CCCC[Sn](=O)CCCC
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2(O)Cn3c(=O)ccc4ncc(F)c2c43)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (4R/S)-3-fluoro-4-hydroxy-4-(hydroxymethyl)-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one (553 mg, 2.3 mmol) (racemic material, prepared from 3-fluoro-4-methylidene-4,5-dihydro-7H-pyrrolo[3,2,1-de]-1,5-naphthyridin-7-one using AD mix alpha/beta in a similar manner to Example 1(e) Method A) in dichloromethane/tetrahydrofuran/N,N-dimethylformamide (19 ml19 ml/2 ml) was treated with triethylamine (0.5 ml, 3.5 mmol), para-toluenesulphonyl chloride (446 mg, 2.3 mmol) and dibutyltin oxide (29 mg, 0.1 mmol) and stirred at room temperature overnight. Water was then added, the organic phase was separated and washed with saturated aqueous sodium bicarbonate, separated, dried over magnesium sulphate and evaporated under vacuum. The residue was chromatographed on silica eluting with 0-100% ethyl acetate in dichloromethane then 0-10% methanol in ethyl acetate affording a white solid (321 mg, 35%).