Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH3:11])[NH:8][C:6]=2[N:7]=1.[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][CH:19]=1.C[Si](Cl)(C)C>C(O)CCC>[CH:13]1([NH:12][C:4]2[C:5]3[CH:10]=[C:9]([CH3:11])[NH:8][C:6]=3[N:7]=[C:2]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)[N:3]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Cc1cc2c(NC3CCC3)nc(Cl)nc2[nH]1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Cc1cc2c(NC3CCC3)nc(Nc3ccc4cn[nH]c4c3)nc2[nH]1
Temperature: 116 °C
Yield: 7.8 %

Procedure:
A mixture of 2-chloro-N-cyclobutyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (55 mg, 0.23 mmol), 6-aminoindazole (62 mg, 0.46 mmol) and trimethylsilyl chloride (0.040 mL, 0.31 mmol) in nBuOH (2 mL) was heated at 116° C. overnight. It was then purified by HPLC to give the titled compound (6 mg). MS 334.4 (M+H); UV 239.1, 316.2 nm
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH3:15])=[N:13][N:14]=[C:6]3[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:10]([CH2:29][C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[C:9]2[C:8](=[O:11])[N:7]3[C:12]([CH3:15])=[N:13][N:14]=[C:6]3[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(C)nnc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCn1c2nc(Br)n(Cc3ccc(OC)cc3)c2c(=O)n2c(C)nnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
The mixture of 7-bromo-3-methyl-9-pentyl-6,9-dihydro-5h-[1,2,4]triazolo[4,3-a]purin-5-one (200 mg, 0.59 mmol), 4-methoxyphenyl methylbromide (0.094 mL, 0.65 mmol), potassium carbonate (244 mg, 1.77 mmol) in DMF (10 ml) was stirred at room temperature for 2 hours. The reaction was quenched with water and the solid formed was filtered and dried over to yield the desired product (270 mg, 99.7%). LCMS calculated for C20H24BrN6O2: 459.1; found 460.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][CH2:29][C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:6]1.[CH3:34][O:35][CH2:36][C:37]#[CH:38]>CCN(CC)CC.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>[CH3:34][O:35][CH2:36][C:37]#[C:38][C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][CH2:29][C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([N:10]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:11]([O:13][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:12])=[N:6]1
Reactant: C#CCOC
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OCC21COC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COCC#Cc1ccc2c(c1)C1(COC(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=N1)C1(COC1)CO2
Yield: 23.6 %

Procedure:
A mixture of di-tert-butyl (6′-bromodispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)imidodicarbonate (150 mg, 0.286 mmol) and 3-methoxyprop-1-yne (0.072 mL, 0.86 mmol) in Et3N (1.5 mL) was purged with argon. To the mixture was added Pd(PPh3)4 (13 mg, 0.011 mmol) and CuBr (4.9 mg, 0.034 mmol), and the mixture was refluxed for 3 hours under an argon atmosphere. The mixture was partitioned between CHCl3 and brine, and filtered through celite. The organic layer of the filtrate was dried over MgSO4, filtered off, and the filtrate was evaporated. Silicagel column chromatography (EtOAc-hexane, a linear gradient of EtOAc from 0 to 25%) afforded di-tert-butyl [6′-(3-methoxyprop-1-yn-1-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate (34.7 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:50][N:51]1[C:59]2[C:54](=[C:55]([F:60])[CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52]1>CN(C=O)C>[F:60][C:55]1[CH:56]=[CH:57][CH:58]=[C:59]2[C:54]=1[CH:53]=[CH:52][N:51]2[NH:50][C:14]([C:10]1[C:11]([CH3:13])=[N:12][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[N:8][CH:9]=1)=[O:16]
Reactant: Cc1nc(-c2ccccn2)ncc1C(=O)O
Reactant: Nn1ccc2c(F)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccccn2)ncc1C(=O)Nn1ccc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
A solution of 2-(pyridine-2-yl)-4-methylpyrimidine-5-carboxylic acid (0.11 g) and HATU (0.19 g) in dry DMF (7 mL) is treated with DIPEA (0.09 mL) and stirred at rt under N2 for 30 min. 1-Amino-4-fluoroindole (0.112 g) is added and the mixture is stirred at rt for 24 h. The mixture is concentrated in vacuo. The residue is dissolved in EtOAc, washed with water and brine and dried (MgSO4), filtered, and concentration in vacuo. The residue is purified by silica gel chromatography eluting with 75% EtOAc to afford 2-(pyridin-2-yl)-4-methylpyrimidine-5-carboxylic acid-(4-fluoroindol-1-yl)amide (0.085 gms, 50%). MS: 348 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.82 (s, 3H), 6.65 (d, 1H), 6.93-6.97 (q, 1H), 7.19-7.26 (m, 1H), 7.35-7.38 (d, 1H), 7.62 (d, 1H), 7.74-7.78 (m, 1H), 8.20-8.25 (t, 1H), 8.58-8.61 (d, 1H), 8.85-8.86 (d, 1H), 9.33 (s, 1H), 12.15 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[C:4]([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:3]=1.[N+:21]([O-])([OH:23])=[O:22].CO>C(O)(C(F)(F)F)=O.O>[Br:1][C:2]1[CH:3]=[C:4]([C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)[C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:12])([CH3:13])[CH3:11])=[C:6]([N+:21]([O-:23])=[O:22])[CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(Br)cc1-c1ncccn1
Reactant: O=[N+]([O-])O
Solvent: CO
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)Nc1c(-c2ncccn2)cc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 5400.6 %

Procedure:
To a 5° C. suspension of N-(4-bromo-2-pyrimidin-2-yl-phenyl)-2,2-dimethyl-propionamide (32.6 grams, 97.5 mmoles) in TFA (400 mL) was added 90% nitric acid (70 mL, 1.46 mmoles) over a 30 minute period. The mixture was then allowed to warm to room temperature and stir for a total of 2 hours. The crude reaction (now homogenous) was poured into ice producing a pasty mass. The mixture was diluted to 2 L total volume with water, treated with 500 mL of methanol, and vigorously stirred for 12 hours. The resulting solids were filtered, washed with copious amounts of water, then vacuum dried at 50° C. to afford the title compound (29.9 grams, 81% yield) as a tan powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][N:32](C)[C:33](=O)OC(C)(C)C)=[CH:27][C:26]=3[CH3:41])=[N:22][N:21]=2)=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:17]([S:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[N:4]=[C:3]([C:20]3[O:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([CH2:31][NH:32][CH3:33])=[CH:27][C:26]=4[CH3:41])=[N:22][N:21]=3)[C:2]([NH2:1])=[N:7][CH:6]=2)=[CH:13][CH:12]=1)(=[O:15])=[O:16])([CH3:19])[CH3:18]
Reactant: Cc1cc(CN(C)C(=O)OC(C)(C)C)ccc1-c1nnc(-c2nc(-c3ccc(S(=O)(=O)C(C)C)cc3)cnc2N)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4)cnc3N)o2)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.4 %

Procedure:
To a solution of tert-butyl N-[[4-[5-[3-amino-6-(4-isopropylsulfonylphenyl)pyrazin-2-yl]-1,3,4-oxadiazol-2-yl]-3-methyl-phenyl]methyl]-N-methyl-carbamate (120 mg, 0.2074 mmol) in CH2Cl2 (10 mL) was added TFA (709.5 mg, 479.4 μL, 6.222 mmol) and the resulting solution stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo and redissolved in CH2Cl2 (20 ml) and concentrated. The residue was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. Product fractions were combined and lypholised to give the product as a yellow solid (48.0 mg, 39%); 1H NMR (400 MHz, DMSO) d 1.2 (d, 6H), 2.6 (s, 3H), 2.75 (s, 3H), 3.4-3.5 (m, 1H), 4.25 (s, 2H), 7.7 (d, 1H), 7.72 (s, 1H), 8.0-8.1 (m, 3H), 8.2 (d, 1H), 8.4 (d, 2H), 8.8 (br s, 2H) and 9.2 (s, 1H) ppm; MS (ES+) 479.4
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[N:18]=3)[N:13]=[CH:12][CH:11]=2)[C:6](=[O:22])[CH2:5]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[O:30]=[C:31]1[CH2:36][S:35][C:34]2[CH:37]=[CH:38][C:39]([CH:41]=O)=[N:40][C:33]=2[NH:32]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[CH3:21][O:20][C:17]1[N:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[C:10]2[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:1][CH2:41][C:39]2[CH:38]=[CH:37][C:34]3[S:35][CH2:36][C:31](=[O:30])[NH:32][C:33]=3[N:40]=2)[CH2:5][C:6]1=[O:22]
Reactant: COc1ccc2nccc(N3CCN(CCN)CC3=O)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2nccc(N3CCN(CCNCc4ccc5c(n4)NC(=O)CS5)CC3=O)c2n1
Reaction time: 12 h
Yield: 37.4 %

Procedure:
To a solution of 4-(2-aminoethyl)-1-[6-(methyloxy)-1,5-naphthyridin-4-yl]-2-piperazinone (168 mg, 0.558 mmol) in DCM-EtOH (6 mL, 5:1) at 25° C. were added Na2SO4 (158 mg, 1.11 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (108 mg, 0.558 mmol). After 12 h, Na(OAc)3BH (177 mg, 0.837 mmol) was added and following an additional 2 h, the solution was partitioned between DCM-H2O. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) affording the title compound (100 mg, 37%) as a yellow solid: LCMS (ES) m/e 480 (M+H)+; 1H NMR (CD3OD, 400 MHz) δ 8.81 (d, J=4.7 Hz, 1H), 8.28 (d, J=9.1 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.71 (d, J=4.7 Hz, 1H), 7.28 (d, J=9.1 Hz, 1H), 7.06 (d, J=8.1 Hz, 1H), 4.04 (s, 3H), 3.92-3.94 (m, 2H), 3.88 (s, 2H), 3.51 (s, 2H), 3.34 (2H), 3.00-3.03 (m, 2H), 2.82-2.84 (m, 2H), 2.77-2.79 (m, 2H).
Reaction SMILES: [OH-:1].[Li+].OO.C([C@@H]1COC(=O)N1[C:18](=[O:38])[C@@H:19]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[CH2:20][N:21]([CH:29]([CH3:31])[CH3:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])C1C=CC=CC=1>O.C1COCC1>[C:24]([O:23][C:22]([N:21]([CH:29]([CH3:30])[CH3:31])[CH2:20][C@H:19]([C:32]1[S:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[C:18]([OH:38])=[O:1])=[O:28])([CH3:25])([CH3:26])[CH3:27]
Reactant: [OH-]
Reactant: CC(C)N(C[C@@H](C(=O)N1C(=O)OC[C@H]1Cc1ccccc1)c1ccc(Cl)s1)C(=O)OC(C)(C)C
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)s1)C(=O)OC(C)(C)C
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
A mixture solution of lithium hydroxide (374 mg, 15.6 mmol) in H2O (60 mL) and 30% hydrogen peroxide (1.60 mL, 15.6 mmol) was added dropwise to a solution of tert-butyl (S)-3-((R)-4-benzyl-2-oxooxazolidin-3-yl)-2-(5-chlorothiophen-2-yl)-3-oxopropyl(isopropyl)carbamate (7.54 g, 14.9 mmol) in THF (150 mL) at −5° C. The mixture was stirred at −5° C. After 10 minutes, the reaction was quenched with 10% Na2SO3 (16 mL) at −5° C. and stirred at room temperature for 30 minutes. The THF was removed in vacuo. The aqueous layer was acidified with 1M NaH2PO4 and extracted with DCM (3×100 mL). The combined organics were dried (Na2SO4), filtered and concentrated to give (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(5-chlorothiophen-2-yl)propanoic acid which was used in the next step without purification. MS (APCI+) [M+H]+ 348.2.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:5]=1[NH2:6].C1COCC1.Br[C:18]1[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[N:21]=[C:22]([Cl:24])[CH:23]=1>CN(C=O)C>[Cl:24][C:22]1[CH:23]=[C:18]([NH:6][C:5]2[C:4]([F:3])=[CH:10][CH:9]=[CH:8][C:7]=2[F:11])[C:19]2[N:20]([CH:25]=[CH:26][N:27]=2)[N:21]=1
Reactant: Nc1c(F)cccc1F
Reactant: Clc1cc(Br)c2nccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Fc1cccc(F)c1Nc1cc(Cl)nn2ccnc12
Temperature: 50 °C

Procedure:
To 60% NaH (22.5 mg, 0.563 mmol) in DMF (400 μl) was added 2,6-difluoroaniline (24 mg, 0.186 mmol). After stirring at RT for 5 minutes THF (1000 μl) was added followed by 8-bromo-6-chloroimidazo[1,2-b]pyridazine (50 mg, 0.186 mmol, prepared as described in Example 1, step (1b). The reaction was heated at 50° C. for 3 hours. The reaction was quenched with a few drops of water and methanol. The solution was then concentrated in vacuo to give crude 6-chloro-N-(2,6-difluorophenyl)imidazo[1,2-b]pyridazin-8-amine.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([CH2:12][CH2:13][CH3:14])[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)Cl.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH2:12]([C:3]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:5][CH2:6][CH:2]1[O:1][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH3:18])=[CH:20][CH:21]=1)[CH2:13][CH3:14]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CCCC1(C(=O)OCC)CCCC1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCC1(C(=O)OCC)CCCC1OC(=O)c1ccc(C)cc1
Reaction time: 12 h

Procedure:
Ethyl 2-hydroxy-1-n-propyl-cyclopentane carboxylate (6.00 g) was diluted using 60 ml of methylene chloride. At room temperature and with magnetic stirring, pyridine (3.66 ml) was slowly added, then 4-methyl-benzoyl chloride (6.12 ml) was dropwise added. Upon the completion of the addition, the reaction was continued for 12 hours. Then solvent was removed, and the residue was extracted using ethyl acetate and water. Organic layer was washed, in turn, using 10% hydrochloric acid aqueous solution to pH of about 2, using saline solution to neutrality, using 10% aqueous solution of sodium carbonate for three times, and then using saline solution to neutrality. The organic layer was dried, and removing solvent gave 10.41 g of yellow liquid. MS: m/e 319(M+′+1), 318(M+′), 317(M+′−1), 259, 230, 199, 182, 153, 105(base), 77.
Reaction SMILES: C([O:3][C:4](=[O:7])[CH2:5][SH:6])C.CC([O-])(C)C.[K+].Cl[CH:15]=[C:16]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:17](=O)[CH:18]([CH3:20])[CH3:19]>C(O)C.C1COCC1.CCOCC>[CH2:22]([C:16]1[C:17]([CH:18]([CH3:20])[CH3:19])=[C:5]([C:4]([OH:3])=[O:7])[S:6][CH:15]=1)[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)CC(=CCl)C(=O)C(C)C
Reactant: CCOC(=O)CS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCO
Product: CC(C)Cc1csc(C(=O)O)c1C(C)C
Temperature: 12.5 °C
Reaction time: 15 h
Yield: 1 %

Procedure:
Mercapto-acetic acid ethyl ester (9.86 g, 82.1 mmol) is slowly added to a solution of KOtBu (9.50 g, 84.7 mmol) in ethanol (50 mL) cooled to 10-15° C. The mixture is diluted with THF (100 mL) before a solution of the crude 1-chloro-2-isobutyl-4-methyl-pent-1-en-3-one (corresponds to 8.1 g, 43 mmol) in THF (50 mL) is added. The reaction mixture is stirred at 40° C. for 15 h, then at reflux for further 20 h, and at 35° C. for 48 h. The mixture is diluted with ether (300 mL) and washed with 1N aq. NaOH (3×100 mL), 1 M aq. KHSO4 (100 mL) and brine (100 mL). The organic phase is dried (Na2SO4), filtered and evaporated. The resulting residue is dissolved in ethanol (30 mL), 2 N aq. LiOH (30 mL) is added, and the mixture is stirred at reflux for 48 h. The mixture is extracted with diethyl ether, then the aq. phase is acidified with 25% aq. HCl and extracted with DCM. The organic extracts are dried (MgSO4), filtered and evaporated. The brown oil is diluted in acetonitrile (5 mL) and allowed to crystallize at 4° C. The crystalline material is collected, washed with acetonitrile and dried to afford pure 4-isobutyl-3-isopropyl-thiophene-2-carboxylic acid (98 mg) as pale yellow crystals; 1H NMR (CD3OD): δ 7.16 (s, 1H), 3.68 (hept, J=7.0 Hz, 1H), 2.48 (d, J=7.6 Hz, 2H), 1.84 (hept, J=7.0 Hz, 1H), 1.34 (d, J=7.0 Hz, 6H), 0.92 (d, J=6.4 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:42]=[C:41]([Cl:43])[CH:40]=[CH:39][C:35]=1[CH2:36][CH2:37][NH2:38].C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:18])[NH:38][CH2:37][CH2:36][C:35]3[CH:39]=[CH:40][C:41]([Cl:43])=[CH:42][C:34]=3[Cl:33])=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NCCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4Cl)cc3)c(Cl)cc21
Temperature: 5 °C
Reaction time: 20 h

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid was dissolved in 700 mL of dichloromethane containing 8 drops of DMF and cooled to 5° C. Oxalyl chloride (31 mL, 355 mmol) was added as a solution in 10 mL of dichloromethane dropwise over 20 minutes keeping the reaction temperature between 8 and 11° C. After stirring at ambient temperature for 20 hours, the solution was cooled to 0° C. and 2,4-dichlorophenethyl amine (55 mL, 365 mmol) was added as a solution in 20 mL of dichloromethane dropwise over 20 minutes keeping the reaction temperature below 10° C. To the resulting thick, cream-colored slurry was added diisopropyl ethyl amine (70 mL, 402 mmol) dropwise over 20 minutes keeping the reaction temperature below 10° C. After 3 hours at ambient temperature, the reaction mixture was diluted with 2 L of dichloromethane and washed sequentially with three 500 mL portions of 1 N HCl, two 500 mL portions of water and two 500 mL portions of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give 178 g of crude ethyl 6-chloro-7-(4-(2,4-dichlorophenethylcarbamoyl)phenoxy)chroman-4-carboxylate. The crude material was slurried in hot ethyl acetate, cooled to ambient temperature and the solids were collected, washing with 20% ethyl acetate in hexanes. The white solids were dried under high vacuum to give ethyl 6-chloro-7-(4-(2,4-dichlorophenethyl-carbamoyl)phenoxy)chroman-4-carboxylate (145 g, 80% yield). 1H NMR (400 MHz, CDCl3) δ 7.68 (d, J=8.4 Hz, 2H), 7.40 (s, 1H), 7.36 (s, 1H), 7.20 (s, 2H), 6.96 (d, J=8.6 Hz, 2H), 6.53 (s, 1H), 6.12 (t, J=5.3 Hz, 1H), 4.21-4.29 (m, 4H), 3.67-3.75 (m, 3H), 3.05 (t, J=6.7 Hz, 2H), 2.30-2.35 (m, 1H), 2.05-2.14 (m, 1H), 1.31 (t, J=7.0 Hz, 3H).
Reaction SMILES: [C:1](=[O:3])=[O:2].[CH:4]([CH:6]=[C:7]=[O:8])=[O:5].[CH3:9][C:10]([CH3:12])=[O:11]>>[CH3:9][C:10]1([CH3:12])[O:3][C:1](=[O:2])[C:6](=[CH:7][OH:8])[C:4](=[O:5])[O:11]1
Reactant: O=C=O
Reactant: O=C=CC=O
Reactant: CC(C)=O
Product: CC1(C)OC(=O)C(=CO)C(=O)O1

Procedure:
Although the reaction mechanism is unknown, a process may be considered that at an intermediate step of the reaction, carbon dioxide, acetone and formyl ketene as intermediates are formed from formyl Meldrum's acid, and the formyl ketene reacts with the carbonyl compound to give the objective 1,3-dioxin-4-one derivative. In such a process, since the intermediate formyl ketene is extremely reactive, it is considered that resin formation is promoted in the case of high concentration reaction.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([CH:30]([OH:33])[CH2:31][CH3:32])[N:25]=[C:24]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)=[O:9])(C)(C)[CH3:4].[CH2:38](O)[CH3:39]>>[CH2:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([CH:30]([OH:33])[CH2:31][CH3:32])[N:25]=[C:24]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:20][CH:21]=1)=[O:9])[CH2:4][CH2:38][CH3:39]
Reactant: CCO
Reactant: [OH-]
Reactant: CCCCc1nc(C(O)CC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Product: CCCCOC(=O)c1ccccc1-c1ccc(Cn2c(CCCC)nc(C(O)CC)c2C(N)=O)cc1

Procedure:
0 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 368 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxypropyl)imidazole-5-carbonitrile [prepared as described in step (b) above] dissolved in 20 ml of ethanol, and the resulting mixture was heated under reflux for 6 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c), to afford 316 mg of the title compound as an amorphous solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[C:8]([O:14]C)(=O)[CH2:9][C:10]([CH3:12])=O.[C:16](O)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>>[C:16]([NH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:14])[CH2:9][C:10]([CH3:12])=[N:7][CH2:6][CH2:5]1)(=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCC(=O)O
Reactant: NCCNCCN
Reactant: COC(=O)CC(C)=O
Product: CCCCCCCCCCCC(=O)NCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 103.1 g (1 mole) of diethylenetriamine and 116.1 g (1 mole) of methyl acetoacetate. At 140° to 150° C., 18 g of water and 32 g of methanol were distilled off. Then, with the addition of 200.3 g (1 mole) of lauric acid, the amide formation was effected at 200° to 210° C. and 18 g of water was distilled off, leaving behind 4-lauramidoethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: C1(C)C=CC=CC=1.[SH:8][CH2:9][C:10]([OH:12])=[O:11].O.[C:14]([OH:18])(=[O:17])[CH:15]=O.O>C1COCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:18]1[C:14](=[O:17])[CH2:15][S:8][CH:9]1[C:10]([OH:12])=[O:11]
Reactant: O=C(O)CS
Reactant: O=CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1CSC(C(=O)O)O1
Yield: 74.6 %

Procedure:
Toluene (700 mL), mercaptoacetic acid (38 mL, 50.03 g, 0.543 mol), and p-toluenesulfonic acid (1.0 g) were added to a solution of glyoxylic acid monohydrate (50.0 g, 0.543 mol) in 200 mL of THF in a 2 L round bottom flask equipped with a Dean-Stark trap and condenser. The resultant reaction mixture was refluxed for 3 hours until 24.0 mL of H2O was azeotropically removed. The reaction mixture was cooled, followed by removal of solvent under reduced pressure to yield an off-white solid. This material was purified by recrystallization (hexanes-EtOAc) to give 60.0 g of the product as a crystalline white solid: m.p. 140°-143° C.; 1H NMR (DMSO) δ 3.84 (q, 2H, JAB=16.7 Hz), 6.00 (s, 1H).
Reaction SMILES: O=[C:2]([C:8]1[CH:20]=[CH:19][C:11]2[O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:10]=2[CH:9]=1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH2:21].O.O.C([O-])(=O)C.[Na+].Cl.[NH2:30]O>CO.O>[CH:9]1[C:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][C:11]=2[CH:19]=[CH:20][C:8]=1[C:2](=[N:30][OH:21])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: O=C(O)CCC(=O)c1ccc2oc3ccccc3c2c1
Reactant: O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)CCC(=NO)c1ccc2oc3ccccc3c2c1
Yield: 66.5 %

Procedure:
A solution of γ-oxo-2-dibenzofuranbutanoic acid (Example 1) (75.5 g) and sodium acetate trihydrate (114.9 g) in methanol (2.5 L) is treated with a solution of hydroxylamine hydrochloride (38.9 g) in water (150 mL of solution). The solution is heated to reflux for 3.5 hours then concentrated, cooled, and filtered. This solid was washed with water then dried in vacuo to give the crude title compound (71.32 g, 89.6% of theory). This solid was recrystallized from ethyl acetate, washed with hexane, and dried in vacuo to give 53.04 g (68% yield) of the title compound; mp 167-168° C. (d).