Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([C:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=1[N:28]([C:32](=[O:34])C)C(=O)C)(C(OCC)=O)C(OCC)=O)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].O>[O-]CC.[Na+].C(O)C>[CH2:5]([N:4]([CH2:1][CH2:2][CH3:3])[CH:8]1[CH2:19][C:20]2[C:21](=[C:22]([O:26][CH3:27])[CH:23]=[CH:24][CH:25]=2)[NH:28][C:32]1=[O:34])[CH2:6][CH3:7]
Reactant: CCCN(CCC)C(Cc1cccc(OC)c1N(C(C)=O)C(C)=O)(C(=O)OCC)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCN(CCC)C1Cc2cccc(OC)c2NC1=O
Reaction time: 0.33 h
Yield: 90.1 %

Procedure:
Diethyl (dipropylamino){(2-(diacetylamino)-3-methoxyphenyl)methyl}propanedioate (6.34 g) was dissolved in sodium ethoxide in ethanol (150 mL of 1.4 M). After 20 min, the solution was heated under reflux for 15 hours; water was added to the reaction after 1 hour (1 mL), 3 hours (2 mL), 4 hours (5 mL) and 5 hours (15 mL). The solution was filtered to remove precipitated inorganic material and the solvents were removed trader reduced pressure, and the residue was partitioned between ethyl acetate and water. The oil obtained after evaporation of the ethyl acetate was chromatographed on silica gel to give 3.3 g of 3-(dipropylamino)-3, 4-dihydro-8-methoxy-2(1H)quinolinone. The product was crystallized from pentane to give 2.0 g of product, mp 50°°-54° C. Anal Calcd for C16H24N2O2 : C, 69.53; H, 8.75; N, 10.14. Found: C, 69.56; H, 8.98; N, 10.24.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6](=[O:9])[CH2:5][CH:4]=1.Cl.[Cl:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[CH:33])[CH:27]=3)=[N:20][CH:21]=[N:22]2)=[CH:17][C:16]=1[O:34][CH2:35][CH2:36][O:37][CH3:38]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[ClH:11].[C:32]([C:28]1[CH:27]=[C:26]([NH:25][C:19]2[C:18]3[C:23](=[CH:24][C:15]([O:14][CH2:13][CH2:12][N:3]4[CH:4]=[CH:5][C:6](=[O:9])[CH:7]=[CH:8]4)=[C:16]([O:34][CH2:35][CH2:36][O:37][CH3:38])[CH:17]=3)[N:22]=[CH:21][N:20]=2)[CH:31]=[CH:30][CH:29]=1)#[CH:33]
Reactant: O=C1C=CN=CC1
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCCl)c(OCCOC)cc23)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCn4ccc(=O)cc4)c(OCCOC)cc23)c1
Temperature: 22 °C
Reaction time: 0.67 h
Yield: 47.1 %

Procedure:
NaH (30 mg of 60% in mineral oil, 0.77 mmol) was added to anhydrous DMF (2.0 mL) followed by pyrid-4-one (79 mg, 0.83 mmol). The mixture was stirred 40 minutes at 22° C. until all solids dissolved and the evolution of H2 ceased. The title product of Example 34 (120 mg, 0.28 mmol) and tetrabutylammonium iodide (15 mg) were added and the reaction mixture was stirred at 22° C. for 7 days under N2. Additional pyrid-4-one (79 mg) and NaH (30 mg of 60%) were dissolved in DMF (2 mL) and the solution was added to the reaction mixture. After another 4 days stirring the mixture was partitioned between CHCl3 and brine. The organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica utilizing 10% methanol/CH2Cl2 to afford 65 mg of the free base of the title product which was converted to the mono-hydrochloride salt according to the procedure described for Example 28 (66 mg; M.P. 240°-248° C. (dec); LC-MS: 457 (MH+); anal. RP-HPLC RT: 3.23 min)
Reaction SMILES: [C:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16]([CH3:19])([CH3:18])[CH2:15][CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:13]=2[CH:26]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>ClCCl>[C:1]([C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16]([CH3:19])([CH3:18])[CH2:15][CH:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N+:21]=3[O-:35])[C:13]=2[CH:26]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)CC(c2ccccn2)c2cc(C(=O)c3ccccc3)ccc2O1
Solvent: ClCCl
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C(=O)c3ccccc3)ccc2O1
Yield: 20.3 %

Procedure:
94 mg of 6-benzoyl-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran and 52 mg of m-chloroperbenzoic acid were stirred in 15 ml of dichloromethane at room temperature until thin-layer chromatography indicated that the reaction was complete. The mixture was washed in succession with sodium bisulphite solution and sodium bicarbonate solution, then dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using 10% (v/v) methanol/ethyl acetate for the elution. After trituration with diethyl ether there were obtained 20 mg of 2-(6-benzoyl-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 134°-136° C.
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(O)C.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>[C:1]([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
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: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(-c3ccccc3)ccc12
Temperature: 120 °C
Yield: 183.5 %

Procedure:
In a sealed tube, a solution of 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (150 mg, 0.35 mmol) phenylboronic acid (60 mg, 0.49 mmol) a 2M aqueous solution of sodium carbonate (350 μl, 0.70 mmol) in toluene (2.4 ml) and ethanol (0.5 ml) was degassed with argon for 10 min and then tetrakis(triphenylphosphine)palladium (20 mg, 0.018 mmol) was added. The tube was sealed and the mixture was heated under argon at 120° C. for 4 hours. After cooling, the reaction mixture was poured onto a saturated solution of ammonium chloride and extracted with ethyl acetate. The extracts were washed with brine, dried over sodium sulfate and absorbed over silica gel for purification by flash chromatography (gradient cyclohexane/dichloromethane: 0-80%) to yield 2-Isoquinolin-3-yl-7-phenyl-chromen-4-one O-tert-butyl oxime (135 mg, 91%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[CH:26]>CN(C)C=O.C(NCC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[C:26][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: C#CC(C)(C)C
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(C)(C)C#Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Yield: 65.2 %

Procedure:
A mixture of 382 mg (1 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 91 mg (1.1 mmole) 3,3-dimethyl-1-butyne, 38 mg copper(I)-iodide and 35 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 1 hour in 5 ml dimethylformamide and 5 ml diethylamine. The solvents are removed and the residue is diluted with dichloromethane. The dichloromethane solution is washed twice with water, dried over magnesiumsulfate and concentrated in vacuo. Recrystallisation of the residue from ethanol yields 250 mg (65%) pure 4-[2-(3,3-dimethyl-but-1-ynyl)-6-pyrrolidine-1-yl-pyridine-4-sulfonyl]-phenylamine als a light brown solid mp.: 242-244° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][CH:13]1[CH2:15][CH2:14]1>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][CH2:12][CH:13]1[CH2:15][CH2:14]1
Reactant: BrCC1CC1
Reactant: Cc1cc(Br)c(O)cc1F
Product: Cc1cc(Br)c(OCC2CC2)cc1F

Procedure:
Starting from 2-bromo-5-fluoro-4-methyl-phenol (example B.a3) and commercially available bromomethyl-cyclopropane the title compound is obtained as colorless oil after distillation at 5×10−3 mbar.
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[C:15](=[O:21])[C@H:14]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:12])=O)(C)(C)C.[ClH:39]>O1CCOCC1>[ClH:39].[NH2:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[C:15](=[O:21])[C@H:14]1[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:12]
Reactant: CN1CCCN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)[C@H](Cc2ccccc2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCCN(C(=O)C[C@H](N)Cc2cc(F)c(F)cc2F)[C@H](Cc2ccccc2)C1=O

Procedure:
The title compound from Step C was dissolved in 4M hydrogen chloride in dioxane and evaporated after 2.5 h to yield the desired product.
Reaction SMILES: I[C:2]1[CH:26]=[CH:25][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH:21]4[CH2:24][CH2:23][CH2:22]4)[CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][CH2:30]C[C:28]1=[O:33].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.[Cu]>[CH:21]1([N:18]2[CH2:19][CH2:20][N:15]([C:13]([C@H:10]3[CH2:11][CH2:12][C@H:7]([O:6][C:5]4[CH:25]=[CH:26][C:2]([N:27]5[CH2:32][CH2:31][CH2:30][C:28]5=[O:33])=[CH:3][CH:4]=4)[CH2:8][CH2:9]3)=[O:14])[CH2:16][CH2:17]2)[CH2:24][CH2:23][CH2:22]1
Reactant: O=C1CCCCN1
Reactant: O=C(C1CCC(Oc2ccc(I)cc2)CC1)N1CCN(C2CCC2)CC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=C1CCCN1c1ccc(O[C@H]2CC[C@H](C(=O)N3CCN(C4CCC4)CC3)CC2)cc1

Procedure:
To a mixture of 0.87 g (3.27 mmol) of cis-(4-cyclobutyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone, 0.80 g (3.64 mmol) of 4-iodephenol, 1.05 g (4.00 mmol) of triphenylphisphine in 20 ml THF, 0.92 g (4.00 mmol) of di-tert-butyl azodicarboxylate was added at 0° C., and stirred for 12 h at room temperature. After evaporation, the residue was purified by column chromatography on silica gel eluting with cyclohexane and ethyl acetate=from 100:0 to 2:1. The combined product fractions were evaporated to dryness to yield 0.54 g (21% yields, about 65% purity) of [4-(4-iodo-phenoxy)-cyclohexyl]-(4-cyclobutyl-piperazin-1-yl)-methanone. A mixture 100 mg of [4-(4-iodo-phenoxy)-cyclohexyl]-(4-cyclobutyl-piperazin-1-yl)-methanone, 142 mg (1.67 mmol) of 2-piperidone, 77 mg (0.56 mmol) of potassium carbonate and 37 mg (1.12 mmol) of copper was stirred at 175 degree for 6 hr. The mixture was diluted with AcOEt, filtered through celite. The filtrate was evaporated. The mixture was purified with preparative HPLC (CH3CN: 0.05% HCOOH-water, Zorbax Comb Ht 20*50 mm, 5 micron). The combined product fractions were evaporated. The residue was solved with saturated NaHCO3, extracted with AcOEt, washed with brine, dried over MgSO4, and evaporated to dryness to yield 31 mg (52%) of the title compound. MS (m/e): 426.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.[CH3:26][O:27]C(Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.Cl>ClCCl>[Cl:1][C:2]1[C:7]2[C:8]([CH:26]=[O:27])=[C:9]([CH3:11])[O:10][C:6]=2[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1
Reactant: Cc1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Reactant: COC(Cl)Cl
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1oc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Cl)c2c1C=O
Reaction time: 2 h
Yield: 90.9 %

Procedure:
2.0 g (53 mmol) of 3-(4-chloro-6-fluoro-2-methylbenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil and 36.5 g (0.32 mol) of dichloromethyl methyl ether were dissolved in 100 ml of dichloromethane, and 200 ml (0.20 mol) of tin tetrachloride (1M dichloromethane solution) was dropwise added thereto at 0° C. After completion of the dropwise addition, stirring was carried out at room temperature for 2 hours. After completion of the reaction, the reaction solution was poured into a mixture of dilute hydrochloric acid and ice and extracted with dichloromethane. The organic layer was washed with water and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 19.5 g (yield: 90.7%) of the desired product as white crystals. Melting point: 148-150° C.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[Na].O.[CH2:17]([O:19][C:20](=[O:32])[CH:21](Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:18]>C(O)C>[CH2:17]([O:19][C:20](=[O:32])[CH:21]([O:14][C:11]1[CH:10]=[CH:9][C:8]([C:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[CH:13][CH:12]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH3:18]
Reactant: Oc1ccc(C2=CCCCCC2)cc1
Reactant: CCCCCCCCCC(Br)C(=O)OCC
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCCCCCCCCC(Oc1ccc(C2=CCCCCC2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
10 g of p-(1-cycloheptenyl)-phenol in a little absolute ethanol are first added to a solution of 1.6 g of sodium in 100 ml of absolute ethanol, which is stirred at room temperature whilst excluding water; 25.2 g of α-bromo-undecanoic acid ethyl ester are then added dropwise, the mixture is left at 50°C for 24 hours, the ethanol is removed in vacuo and the residue is partitioned between ether and ice-cold 1 N sodium hydroxide solution. The organic phase is washed until neutral, dried over sodium sulphate and concentrated by evaporation in vacuo. Crude α-[p-(1-cycloheptenyl)-phenoxy]-undecanoic acid ethyl ester boiling at 160° C/0.06 mm Hg is obtained in the evaporation residue.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:7][C:6]23[CH2:17][CH:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[CH:5]2[CH2:4]1)[C:9]1[CH:18]=[CH:19][CH:20]=[CH:21][C:8]3=1.[N+:22]([O-])([O-:24])=[O:23].[K+]>F>[ClH:1].[N+:22]([CH:4]1[CH:5]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH:10]3[CH2:17][C:6]2([C:8]2[CH:21]=[CH:20][CH:19]=[CH:18][C:9]3=2)[CH2:7][N:3]1[CH3:2])([O-:24])=[O:23]
Reactant: O=[N+]([O-])[O-]
Reactant: CN1CC2c3ccccc3C3CC2(C1)c1ccccc13
Agent: Cl
Agent: F
Agent: [K+]
Product: CN1CC23CC(c4ccccc4C2C1[N+](=O)[O-])c1ccccc13
Temperature: 25 °C
Yield: 57.6 %

Procedure:
To a solution of 1.5 g (5.06 mmoles) of 2-methyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole hydrochloride in 25 ml of anhydrous hydrofluoric acid cooled at -78° was added 562 mg (5.06 mmoles) of potassium nitrate. The reaction mixture was allowed to warm to room temperature and the hydrofluoric acid was evaporated under a stream of nitrogen. The residue was dissolved in methylene chloride, and the solution washed with 1N aqueous sodium hydroxide, with water, and dried over potassium carbonate. The solvent was removed under vacuum, the residue was dissolved in ether and insolubles were removed by filtration. The ethereal filtrate was treated with dry hydrogen chloride to give 1.0 g of nitro-2-methyl-2,3,8,12b-tetrahydro-1H-3a,8-methanodibenzo[3,4:6,7]cyclohepta[1,2-c]pyrrole hydrochloride as a colorless solid, m.p. 202°-207° (slight decomp.).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)(=O)C.[OH-].[Na+]>CO>[OH:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2
Reactant: CC(=O)OCc1cccc2cccnc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1cccc2cccnc12
Yield: 96.5 %

Procedure:
To a solution of 8-acetoxymethylquinoline (12.07 g) in methanol (80 ml) was added an 30% aqueous solution of sodium hydroxide, and the mixture was heated and refluxed for 1.5 hours. After distilling off the methanol, the resulting residue was extracted with chloroform. After drying over anhydrous magnesium sulfate, the solvent was distilled off. The residue was recrystallized from ethyl acetate-n-hexane to give 8-hydroxymethylquinoline (9.21 g).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.[OH:36][CH2:37][CH2:38][N:39]1[CH:44]=[CH:43][C:42](I)=[CH:41][C:40]1=[O:46].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:42]3[CH:43]=[CH:44][N:39]([CH2:38][CH2:37][OH:36])[C:40](=[O:46])[CH:41]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: O=c1cc(I)ccn1CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C[C@@H](c1ccc(-c2ccn(CCO)c(=O)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 26.8 %

Procedure:
A mixture of compounds (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (72 mg 0.150 mmol), 1-(2-hydroxyethyl)-4-iodopyridin-2(1H)-one (48 mg 0.181 mmol), Pd(PPh3)2Cl2 (14 mg, 0.020 mmol), and Cs2CO3 (2 mL) in 1,4-dioxane (8 mL) was stirred at reflux for 2 h. After the reaction was finished, the mixture was washed with water, and extracted with EtOAC. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to get the crude product, which was purified by TLC to provide compound (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-(2-hydroxyethyl)-2-oxo-1,2-dihydropyridin-4-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (19.7 mg, 28%). LC-MS Method 2 tR=1.065 min, m/z=491.2; 1HNMR (CDCl3): 51.10 (d, 6H), 1.50 (d, 3H), 2.20 (m, 5H), 2.35 (m, 1H), 3.50 (m, 1H), 3.90 (m, 2H), 4.10 (m, 2H), 5.60 (m, 1H), 6.40 (m, 1H), 6.70 (s, 1H), 6.95 (d, 2H), 7.35 (m, 8H).
Reaction SMILES: [Na].Cl.[NH2:3][C:4]([NH2:6])=[NH:5].[C:7]([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:22]2[CH:23]=[C:24]([C:29](OC)=[O:30])[C:25](Cl)=[N:26][CH:27]=2)=[CH:16][CH:15]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>C(O)(C)(C)C.C(O)C>[NH2:5][C:4]1[N:6]=[C:29]([OH:30])[C:24]2[CH:23]=[C:22]([C:21]#[C:20][C:17]3[CH:18]=[CH:19][C:14]([C:12]([O:11][C:7]([CH3:9])([CH3:8])[CH3:10])=[O:13])=[CH:15][CH:16]=3)[CH:27]=[N:26][C:25]=2[N:3]=1
Reactant: COC(=O)c1cc(C#Cc2ccc(C(=O)OC(C)(C)C)cc2)cnc1Cl
Reactant: N=C(N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)(C)O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(C#Cc2cnc3nc(N)nc(O)c3c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
To a solution containing 0.11 g of sodium in 30 ml of anhydrous tert.-butanol is added 0.45 g of guanidine hydrochloride. After stirring the mixture at room temperature for 15 minutes, 0.35 g of methyl 5-(4-tert.-butoxycarbonylphenyl)ethynyl-2-chloro-3-pyridinecarboxylate is added in one portion. The mixture is heated under reflux under nitrogen for 4 hours, cooled, diluted with ethanol, and the solvent removed under reduced pressure. The residue is dissolved in water and filtered to remove a small amount of insoluble material. The filtrate is acidified with a 3N hydrochloric acid solution and the precipitate that forms is collected by filtration, washed with water, and dried under reduced pressure to give 0.15 g (44%) of 2-amino-4-hydroxy-6-(4-tert.-butoxycarbonylphenylethynyl)pyrido[2,3-d]pyrimidine as a pale yellowish solid: m.p. >260° C.; NMR (DMSO-d6, 80 MHz) delta 1.55 (s, 9H), 7.71 (d, 2H, J=8.6 Hz), 7.96 (d, 2H, J= 8.6 Hz), 8.36 (d, 1H, J=2.5 Hz), 8.73 (d, 1H, J=2.5 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1.Cl>CN(C)C(=O)C.O>[CH:31]([C:30]1[CH:33]=[CH:34][C:27]([O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8](=[CH:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=2)=[CH:28][CH:29]=1)=[O:32]
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccc(C=C(C(=O)O)c2ccc(O)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C=C(C(=O)O)c2ccc(Oc3ccc(C=O)cc3)cc2)cc1
Temperature: 190 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of 38 (7.27 g, 28.6 mmol) and potassium carbonate (8.68 g, 62.9 mmol) in 200 mL N,N-dimethylacetamide was added 4-fluorobenzaldehyde (3.9 mL, 36.4 mmol). The reaction mixture was heated to 190° C. for 1.5 h under argon then cooled to room temperature. The addition of 5% HCl in water to pH 1 resulted in the product separating out as oil. Approximately 50 mL ethyl acetate was added to the mixture which is allowed to stir 16 h. The solid was collected and recrystallized out of toluene, rinsed with hexane and dried under vacuum to yield a white powder (8.1 g, 79.0%). 1H NMR (400 MHz, DMSO-d6) δ 12.71 (s, 1H), 9.94 (s, 1H), 7.97(d, J=8.8 Hz, 2H), 7.76 (s, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.18 (d, J=6.8 Hz, 2H), 7.16 (d, J=6.4 Hz, 2H), 7.07 (d, J=8.0 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 2.25 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][S:7](Cl)(=[O:9])=[O:8].[CH2:16]([O:18][C:19](=[O:23])[CH2:20][NH:21][CH3:22])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][N:21]([CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:23])[S:7]([CH2:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)Cc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CNC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)CN(C)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
In this example, 22 g of 3-trifluoromethylbenzylsulfonyl chloride was added cautiously to a solution containing 27 g of the hydrochloride salt of sarcosine ethyl ester and 12 g of potassium carbonate in 90 ml of water at room temperature. The reaction mixture was heated to about 70° C. and maintained at this temperature for about four hours. The mixture was allowed to cool and then extracted with ethyl ether. The ethyl ether extract was dried over magnesium sulfate, filtered, and evaporated to dryness yielding 9.5 g of the title compound as an off-white solid.