Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])OC.[Mg+2].COC(=O)[O-].[CH3:12][C:13]([C:15]1[N:16]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:28][CH3:29])[CH:17]=[CH:18][CH:19]=1)=[O:14].[N:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:35]=1.Cl>CO.CN(C)C=O>[NH:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:35]1[CH2:12][C:13]([C:15]1[N:16]([C:20]2[C:25]([CH2:26][CH3:27])=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:28][CH3:29])[CH:17]=[CH:18][CH:19]=1)=[O:14]
Reactant: C1=NCCCC1
Reactant: CCc1cccc(CC)c1-n1cccc1C(C)=O
Agent: COC(=O)[O-]
Agent: Cl
Agent: [Mg+2]
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1-n1cccc1C(=O)CC1CCCCN1
Temperature: 120 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
A mixture of 186 g (0.5 mole) of magnesium methyl carbonate reagent (2.69 millimoles/g) and 300 ml of dry dimethylformamide are heated to 120°C. under an atmosphere of carbon dioxide. The compound 1-(2,6-diethylphenyl)pyrrol-2-yl methyl ketone, 36.1 g (0.15 mole), is added and the mixture stirred at 120°C. for a period of 4 hours under a stream of nitrogen to form the chelate, allowing the methyl alcohol that forms to escape. The mixture is cooled to room temperature under an atmosphere of carbon dioxide and 15.1 g (0.18 mole) of 2,3,4,5-tetrahydropyridine (as α-tripiperidein) is added and stirring continued at room temperature for a period of 40 hours under an atmosphere of carbon dioxide. The reaction mixture is poured into a solution of 2 N hydrochloride acid and extracted with ethyl ether. The combined extracts are washed with water, dried over sodium sulfate and the solvent removed. The remaining aqueous phase is made alkaline using a solution of 2 N sodium carbonate and extracted with ethyl ether. The ether extract is washed, dried over sodium sulfate and the solvent removed. The residue is converted to the hydrochloride salt, triturated with ether to solidify and the crude 1-(2,6-diethylphenyl)pyrrol-2-yl 2-piperidylmethyl ketone recrystallized from a methylene dichloride-ethyl ether mixture to yield 16.4 g (30% yield) of a product having a M.P. of 162-4°C.
Reaction SMILES: OS(O)(=O)=O.[CH:6]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([F:19])=[CH:16][C:17]=2[F:18])=[CH:10][C:9]([C:20]([OH:22])=[O:21])=[C:8]([OH:23])[CH:7]=1.[CH3:24]O>>[F:18][C:17]1[CH:16]=[C:15]([F:19])[CH:14]=[CH:13][C:12]=1[C:11]1[CH:6]=[CH:7][C:8]([OH:23])=[C:9]([C:20]([O:22][CH3:24])=[O:21])[CH:10]=1
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Yield: 85 %

Procedure:
H2SO4 (9.6 mL, 179.12 mmol) was added to a solution of diflunisal (15.0 g, 59.95 mmol) in MeOH (200 mL). The reaction mixture was refluxed for 12 h and it was allowed to reach r.t. Solids were collected by filtration and washed with cold MeOH (20 mL) to furnish 13.42 g of methyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 85%).
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH3:4].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.ClCCl>CCCCC.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]=[C:2]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)[CH2:3][CH3:4]
Reactant: C1COCCN1
Reactant: CCC(C)=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCCCC
Solvent: ClCCl
Product: C=C(CC)N1CCOCC1
Reaction time: 20 h
Yield: 52.3 %

Procedure:
To a solution of 2-butanone (6.2 ml, 69 mmol) and morpholine (18.1 ml, 208 mmol) in n-pentane (400 ml) was added dropwise 1 M titanium tetrachloride solution in dichloromethane (38.1 ml, 38.1 mmol) at 0-5° C. The cooling bath was removed and the mixture was stirred for 20 h. The precipitate was removed by filtration and washed with two 100-ml portions of diethyl ether. The filtrate was concentrated in vacuo. The residue was distilled over a vigreux column in a Kugelrohr oven (1 mbar, 40-70° C.) to give the title compound (5.1 g, 52%) as colorless oil.
Reaction SMILES: F[C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=[O:5].CCN(CC)CC.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl>CCO.O>[F:14][C:7]1[C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=1
Reactant: O=C(O)c1c(F)ccc([N+](=O)[O-])c1F
Reactant: Nc1ccccc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)c1c(F)ccc([N+](=O)[O-])c1Nc1ccccc1
Temperature: 70 °C
Yield: 88.3 %

Procedure:
To a solution of 2,6-difluoro-3-nitrobenzoic acid (5 g, 24.6 mmol) in EtOH (25 mL) and water (25 mL) at 0° C. were added Et3N (6.2 mL, 44.3 mmol) and aniline (2.3 g, 24.6 mmol). The reaction mixture was heated at 70° C. for 4 h under a nitrogen atmosphere. After cooling to RT, the pH of the solution was adjusted to 1 by addition of 1N HCl. A precipitate formed and this solid was collected by filtration, washed with water to afford the title compound (6.0 g, 88%). 1H NMR (DMSO-d6, 400 MHz): δ 9.02 (1H, s), 8.18 (1H, dd, J=9.29, 5.78 Hz), 7.25-7.16 (2H, m), 7.05 (1H, t, J=9.07 Hz), 7.00-6.91 (3H, m)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9](COCC[Si](C)(C)C)[C:10]([C:19]3[CH:20]=[C:21]4[CH:27]=[CH:26][NH:25][C:22]4=[N:23][CH:24]=3)=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[N:12]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:43])C(=O)C1.Cl>C(#N)C>[Cl:43][C:27]1[C:21]2[C:22](=[N:23][CH:24]=[C:19]([C:10]3[NH:9][C:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=4)=[N:12][C:11]=3[C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH:20]=2)[NH:25][CH:26]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(F)cc2)nc(-c2ccncc2)c1-c1cnc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CC#N
Product: Fc1ccc(-c2nc(-c3ccncc3)c(-c3cnc4[nH]cc(Cl)c4c3)[nH]2)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 44.9 %

Procedure:
To a solution of 5-(2-(4-fluorophenyl)-4-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)-1H-pyrrolo[2,3-b]pyridine (18 mg, 0.04 mmol) in ACN (0.6 mL) was added NCS (5 mg, 0.04 mmol). After stirring for 18 h, the reaction mixture was partitioned between EtOAc (20 mL) and aqueous saturated NaHCO3 (10 mL). The layers were separated and the organic phase was washed with aqueous 0.1 M HCl solution (10 mL), brine (10 mL), and dried (Na2SO4). After concentrating in vacuo, the resulting crude product was dissolved in ethanol (1.5 mL) and conc. HCl (0.25 mL, 3 mmol) was added and the reaction was heated at 60° C. for 20 min and then concentrated in vacuo. The crude material was dissolved in DMSO (1.3 mL) and purified by reverse phase HPLC, which after lypholization, yielded 7 mg (38%) of the title compound as the TFA salt: —LC/MS (m/z): 390.1 (MH+), tR=0.67 min.
Reaction SMILES: [NH:1]([C:5]1[CH:14]=[C:13]([C:15]([NH:17][N:18]=[C:19]([C:21]2[C:25]([OH:26])=[C:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=3)[S:23][CH:22]=2)[CH3:20])=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8])[C:2]([CH3:4])=[O:3].[OH-].[Na+].Cl>C(O)(C)C>[NH:1]([C:5]1[CH:14]=[C:13]([C:15]([NH:17][N:18]=[C:19]([C:21]2[C:25]([OH:26])=[C:24]([C:27]3[CH:28]=[CH:29][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:31][CH:32]=3)[S:23][CH:22]=2)[CH3:20])=[O:16])[CH:12]=[CH:11][C:6]=1[C:7]([OH:9])=[O:8])[C:2]([CH3:4])=[O:3]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)cc1NC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(=O)Nc1cc(C(=O)NN=C(C)c2csc(-c3ccc(C(C)(C)C)cc3)c2O)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 35.5 %

Procedure:
To a suspension of methyl 2-acetamino-4-[(2-{1-[5-(4-t-butylphenyl)-4-hydroxy-3-thienyl]ethylidene}-hydrazino)carbonyl]benzoate (50.8 mg, 0.1 mmol) in isopropyl alcohol (1.0 mL), 0.2 M sodium hydroxide aqueous solution (1.1 mL, 0.22 mmol) was added, and the mixture was stirred at room temperature for 6 hours. After completion of the stirring, 1 M hydrochloric acid (220 μL) was added, and the precipitated solid was filtered and then washed with methanol to obtain 17.5 mg of the desired product as a pale yellow solid (yield 35%).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][CH2:14][CH2:15][C@@H:16]([NH2:20])[C:17]([OH:19])=[O:18])=[O:12])[C:8](=[O:9])[N:4]2[C@H:3]1[C:21]([OH:23])=[O:22].[Cl-].[K+]>OCC(CO)O>[CH3:1][C:2]1[CH2:24][S:6][C@@H:5]2[C@H:7]([NH:10][C:11]([CH2:13][CH2:14][CH2:15][C@@H:16]([NH2:20])[C:17]([OH:19])=[O:18])=[O:12])[C:8](=[O:9])[N:4]2[C:3]=1[C:21]([OH:23])=[O:22]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)CCC[C@@H](N)C(=O)O)C(=O)N2[C@H]1C(=O)O
Agent: [Cl-]
Agent: [K+]
Solvent: OCC(O)CO
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CCC[C@@H](N)C(=O)O)[C@H]2SC1

Procedure:
The fractions containing 80% of the enzyme activity from the major peak were pooled. The pooled fractions were supplemented with 0.1 mM penicillin N and were loaded onto a second Mono Q column (0.5×5 cm) which had been equilibrated with the glycerol-free buffer, pH 7.0, (instead of pH 8.0 for UDG buffer), which was supplemented with 0.05 M KCl. The bound proteins were eluted with a linear gradient of KCl 0.05-0.2 M) in the equilibration buffer. The activity and protein elution patterns are shown in FIG. 4A. The three fractions with a synthase activity of at least 275 mU/ml were pooled.
Reaction SMILES: [CH2:1]([N:8](CC1C=CC=CC=1)[C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[S:29](=[O:38])(=[O:37])[CH2:28][CH2:27]3)[N:16]=2)[CH2:12]OC1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1N=C(Cl)C2[C:49](=[CH:50]C=C(C)C=2)N=1.S1C2C=CC=CC=2CNCC1>>[CH2:1]([NH:8][C:9]1([CH2:13][NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH3:25])[CH:23]=3)[N:18]=[C:17]([N:26]3[CH2:32][C:31]4[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=4[S:29](=[O:37])(=[O:38])[CH2:28][CH2:27]3)[N:16]=2)[CH2:50][CH2:49][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(NCC3(N(Cc4ccccc4)Cc4ccccc4)COC3)c2c1
Reactant: Cc1ccc2nc(Cl)nc(Cl)c2c1
Agent: c1ccc2c(c1)CNCCS2
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)nc(NCC3(NCc4ccccc4)CCC3)c2c1

Procedure:
The title compound was prepared in analogy to N-{[3-(dibenzylamino)oxetan-3-yl]methyl}-2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinazolin-4-amine in Example 61-1 in Scheme 24 by using 2,4-dichloro-6-methylquinazoline, 1-(aminomethyl)-N-dibenzylcyclobutanamine and 2,3,4,5-tetrahydro-1,4-benzothiazepine.
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:16])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.[Br:17]Br.O>C(O)(=O)C>[Br:17][C:4]1[C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=[C:2]([CH3:1])[C:3]=1[OH:16]
Reactant: Cc1cc2c(cc1O)C(C)(C)CCC2(C)C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(c(Br)c1O)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 92.2 %

Procedure:
In 500 mL roundbottom flask, 3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol (10.2 g, 46.72 mmol) was dissolved in 100 mL Acetic Acid. To this solution Bromine (8.2 g, 51.39 mmol) was added. The reaction was stirred at room temperature for 20 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The separated organic layer was washed with brine, dried over magnesium sulfate and concentrated. The crude product was purified by silica gel chromatography eluted with hexane to yield 1-Bromo-3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthalenol (12.8 g, 92% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[CH:11]=[CH2:12].[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N:19]=[C:20]=[O:21])[CH:14]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:20](=[O:21])[NH:19][C:15]2[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:3]=1[CH:11]=[CH2:12]
Reactant: O=C=Nc1cccnc1
Reactant: C=Cc1cc2c(cc1Cl)NCC2
Product: C=Cc1cc2c(cc1Cl)N(C(=O)Nc1cccnc1)CC2

Procedure:
6-Chloro-5-vinylindoline (D62) (0.13 g, crude) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The crude product was recrystallised from ethanol/diethyl ether to give the title compound (22 mg) as a yellow crystalline solid m.p. 195°-200° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5](OS(C(F)(F)F)(=O)=O)[CH2:6][N:7]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)=[CH:14][CH:13]=1)[S:8]([CH3:11])(=[O:10])=[O:9])=[O:4].[CH3:37][NH:38][CH2:39][CH2:40][CH2:41][Cl:42]>C(Cl)Cl>[Cl:42][CH2:41][CH2:40][CH2:39][N:38]([C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][N:7]([C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)[S:8]([CH3:11])(=[O:9])=[O:10])[CH3:37]
Reactant: COC(=O)[C@@H](CN(c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)S(C)(=O)=O)OS(=O)(=O)C(F)(F)F
Reactant: CNCCCCl
Solvent: ClCCl
Product: COC(=O)[C@H](CN(c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)S(C)(=O)=O)N(C)CCCCl
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a solution of N-[(2R)-2-methoxycarbonyl-2-trifluoromethanesulfonyloxyethyl]-N-[4-(4-trifluoromethylphenoxy)phenyl]methanesulfonamide (565 mg, 1.0 mmol) from Step C in dried CH2Cl2 (2 mL) at 0° C. under N2 was added N-methyl-3-chloropropyl-amine (ca. 1.0 M in CH2Cl2, 4.0 mL, 4.0 mmol) dropwise. The mixture was allowed to warm to room temperature and was stirred for 1 h. The mixture was directly concentrated to give a crude mixture, which was purified by silica gel chromatography using EtOAc/hexane (1/4 to 1/1) as the eluent to give 455 mg of the product (81%) as a sticky oil. 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J=9.0 Hz, 2H), 7.35 (d, J=9.0 Hz, 2H), 7.12-7.04 (m, 4H), 3.96-3.90 (m, 2H), 3.69 (s, 3H), 3.59-3.54 (m, 2H), 3.47 (t, J=7.5 Hz, 1H), 2.94 (s, 3H), 2.75-2.55 (m 2H), 2.27 (s, 3H), 1.90-1.83 (m, 2H); MS (EI) 522 (M++1, 100).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]([OH:9])=O)([CH3:4])([CH3:3])[CH3:2].P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1[Br:36])[C:32](=[O:37])[CH2:31][CH2:30]2>CO.O.ClCCl>[C:1]([O:5][CH2:6][C:7]([NH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1[Br:36])[C:32](=[O:37])[CH2:31][CH2:30]2)=[O:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OCC(=O)O
Reactant: Nc1cc2c(cc1Br)C(=O)CC2
Agent: CCOP(=O)(Cl)OCC
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OCC(=O)Nc1cc2c(cc1Br)C(=O)CC2
Temperature: 27.5 °C
Reaction time: 20 h
Yield: 88.9 %

Procedure:
A flame-dried 10 L, 4 necked round bottom flask was equipped with a mechanical stirrer, a reflux condenser, a thermo-socket and a nitrogen inlet. The flask was charged with tert-butoxyacetic acid (250 g, 1.89 mol, 1 eq) and dry dichloromethane (6.25 L). The flask was cooled in an ice-salt mixture to −5-0° C. To the solution was added diethyl chlorophosphate slowly over a period of 15 min (816 g, 4.72 mol, 2.5 eq) followed by the dropwise addition of triethylamine (478 g, 4.73 mol, 2.5 eq) over a period of 30 minutes with the temperature of the reaction not exceeding 25° C. during the addition. The stirred reaction mixture was gradually allowed to warm to 25-30° C. for one hour and then 5-amino-6-bromo-1-indanone (282.5 g, 1.25 mol, 0.66 eq) and triethylamine (478 g, 4.73 mol, 2.5 eq) were added. The reaction was refluxed for 24 hours and an aliquot was removed and analyzed by HPLC. The reaction was found to be complete (Starting material <0.5%). The solvent was removed on the rotary evaporator in vacuo affording a brown viscous residue. To the residue was added 4.7 L of a 20% methanol/water mixture. The sticky mixture was stirred with a mechanical stirrer for 20 hours. A free flowing solid formed which was filtered off and washed with 500 ml of water and dried at 55° C. in vacuo for 8 hours. 378 g (89%) of the desired tert-butoxyacetanilide was obtained as a tan powder after drying.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH2:9])[CH:3]=1.[C:10](=O)([O-])[O-:11].[Na+].[Na+]>C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][NH:9][CH:10]=[O:11])[CH:3]=1
Reactant: NCc1cc(Br)ccn1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=CO
Product: O=CNCc1cc(Br)ccn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a 500-mL round-bottom flask, was placed (4-bromopyridin-2-yl)methanamine (compound 39.1, 8.0 g, crude) and formic acid (200 mL). The solution was stirred for 2 h at 100° C., then cooled and the pH was adjusted to 7 by careful and slow addition of aqueous sodium carbonate (sat.). The aqueous phase was extracted with ethyl acetate (3×200 mL) and the combined organic layers were washed with brine (3×30 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate as the eluent to yield the title compound as a yellow oil (8.0 g, 90% pure, 65% yield over 2 steps).
Reaction SMILES: C([Li])CCC.[C:6]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:7][C:8]([OH:10])=O.[C:15]([CH2:17][CH:18]1[CH2:21][CH:20](C(Cl)=O)[CH2:19]1)#[N:16]>CCCCCC.O1CCCC1.Cl>[C:15]([CH2:17][CH:18]1[CH2:21][CH:20]([C:8](=[O:10])[CH2:7][C:6]([O:12][CH2:13][CH3:14])=[O:11])[CH2:19]1)#[N:16]
Reactant: CCOC(=O)CC(=O)O
Reactant: N#CCC1CC(C(=O)Cl)C1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(=O)C1CC(CC#N)C1
Temperature: -60 °C
Reaction time: 0.17 h

Procedure:
A solution of n-butyllithium in hexane (2.5M, 146 ml) was added dropwise to a mechanically stirred solution of ethyl hydrogen malonate (24.3 g, 0.18 ml) in dry tetrahydrofuran (210 ml) cooled to -60° C. under nitrogen atmosphere. After addition, the reaction mixture was stirred at -10° C. for 10 minutes then cooled to -60° C. and a solution of 3-cyanomethylcyclobutanecarbonyl chloride (17.0 g, 0.11 ml) in dry tetrahydrofuran (230 ml) added dropwise at such a rate to maintain temperature below -10° C. The reaction mixture was stirred overnight at room temperature, diluted with aqueous hydrochloric acid (2M, 180 ml) and extracted with diethyl ether (2×200 ml). The combined extracts were washed with a saturated solution of sodium bicarbonate (100 ml), water (100 ml) and brine solution (100 ml), dried, filtered and evaporated to a yellow oil (20.5 g). The crude product was purified by chromatography eluting with diethyl ether-hexane (1:1 and then 3:2) to give the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:12](#[N:15])[CH:13]=[CH2:14].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[O:11][CH:13]([CH3:14])[C:12]#[N:15]
Reactant: C=CC#N
Reactant: COc1ccc(O)cc1OC
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: COc1ccc(OC(C)C#N)cc1OC
Yield: 65.5 %

Procedure:
Thus 5 gm of 3,4-dimethoxyphenol; 6.88 g acrylonitrile and 0.5 ml. of Triton B, trade name of N-Benzyltrimethylammonium hydroxide, (40% soln.), were combined and refluxed for 18 hours. After cooling the reaction mixture was extracted with chloroform and washed with 5% sodium hydroxide, and with saturated salt solution. The organic layer after drying over anhydrous sodium sulfate gave 4.4 gm of 3,4-dimethoxy phenoxy propionitrile on removal of the solvent. The amount of 2.2 g of the nitrile was combined with 40 ml. of water and 80 ml. of concentrated hydrochloric acid and refluxed for 2 hours. The reaction mixture on cooling was extracted with ether and washed with water and 5% sodium hydroxide. The basic wash was acidified with 6N hydrochloric acid and extracted twice with ether. The ethereal extract was washed twice with water and with saturated salt solution. Drying over anhydrous sodium sulfate and removal of the solvent in vacuo gave 1.25 g of the crude 3,4-dimethoxy phenoxy propionic acid. The crude product was combined with 5 gm of polyphosphoric acid and heated at 75°-85° C. for 1 hour. The reaction mixture was extracted with ether and washed with 10% sodium carbonate solution and saturated salt solution. Drying over anhydrous sodium carbonate and removal of the solvent gave 0.35 gm of pure 6,7-dimethoxy chromanone. The chromanone was dissolved in 50 ml. dry ether and refluxed 1 hour with an excess of lithium aluminum hydride. On cooling, the reaction was stopped by addition of 10 ml. of water and then stirred for 15 minutes with 10 ml. of 2N hydrochloric acid. The reaction mixture was extracted with ether and washed with water and saturated salt solution to give on drying and removal of the solvent 0.31 gm of pure 6,7-dimethoxy chromene.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11](=[O:13])[CH3:12])=[C:5]([F:14])[C:4]=1[O:15][CH3:16].[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:21]([O:20][C:18](=[O:19])[C:17](=[O:23])[CH2:12][C:11](=[O:13])/[CH:10]=[CH:9]/[C:6]1[CH:7]=[CH:8][C:3]([Cl:2])=[C:4]([O:15][CH3:16])[C:5]=1[F:14])[CH3:22]
Reactant: CCOC(=O)C(=O)OCC
Reactant: COc1c(Cl)ccc(/C=C/C(C)=O)c1F
Agent: [Na]
Product: CCOC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)c(OC)c1F
Yield: 92.9 %

Procedure:
Using the procedure of Example 2, sodium pellets (5.52 g, 0.24 mol), (E)-4-(4-chloro-2-fluoro-3-methoxyphenyl)-but-3-en-2-one (2; 45.73 g, 0.20 mol) and diethyl oxalate (36.54 g, 0.25 mol) were reacted to give (E)-6-(4-chloro-2-fluoro-3-methoxyphenyl-2,4-dioxo-hex-5-enoic acid ethyl ester (5; 61.1 g, 93%) as yellow crystals: mp 67.5-69° C.; 1H NMR (400 MHz, CDCl3) δ 14.71 (s, 1H), 7.78 (d, J=16.1 Hz, 1H), 7.27-7.18 (m, 2H), 6.73 (d, J=16.1 Hz, 1H), 6.54 (s, 1H), 4.38 (q, J=7.1 Hz, 2H), 3.99 (d, J=1.2 Hz, 3H), 1.41 (t, J=7.1 Hz, 3H); HRMS-ESI (m/z): calcd for C15H14ClFNO5, 328.051. found, 328.051.
Reaction SMILES: CC(OC([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[CH:11](Br)[CH2:10][CH2:9]1)=O)(C)C.CC(OC(N1CCCC(=O)C(Br)C1)=O)(C)C.[C:33]([NH2:43])(=O)/[CH:34]=[CH:35]/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:36]1(/[CH:35]=[CH:34]/[C:33]2[O:15][C:12]3[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=3[N:43]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NC(=O)/C=C/c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)CC1
Agent: CC(C)(C)OC(=O)N1CCCC(=O)C(Br)C1
Product: C(=C/c1nc2c(o1)CCNCC2)\c1ccccc1
Temperature: 120 °C
Reaction time: 72 h
Yield: 15 %

Procedure:
A mixture of 4-bromohexahydro-5-oxo-1H-azepine-1-carboxylic acid 1,1-dimethylethyl ester and 3-bromohexahydro-4-oxo-1H-azepine-1-carboxylic acid 1,1-dimethylethyl ester (0.22 g, 0.50 mmol) and trans-cinnamamide (0.06 g, 0.38 mmol) was supported in silica gel (1 g) and mechanically stirred at 120° C. for 3 days. The product was eluted from the silica gel with a 7M solution of ammonia in MeOH and the filtrate evaporated in vacuo. The crude product was basified with a saturated solution of NaHCO3 and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvent evaporated in vacuo to yield 5,6,7,8-tetrahydro-2-[(E)-2-phenylethenyl]-4H-oxazolo[4,5-d]azepine (0.045 g, 15% yield, 32% pure) as a brown solid that was used in the next step without further purification. C15H16N2O LCMS: Rt 1.60, m/z 241 [M+H]+ (method 5). The compound 3-bromohexahydro-4-oxo-1H-azepine-1-carboxylic acid 1,1-dimethylethyl ester was not observed in the crude of the reaction.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][C:16]1([CH3:35])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:23]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[CH:26]=[CH:27][CH:28]=2)[O:17]1.C=O>C(Cl)Cl>[CH3:1][N:32]1[CH2:31][CH2:30][N:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([B:18]3[O:17][C:16]([CH3:35])([CH3:15])[C:20]([CH3:21])([CH3:22])[O:19]3)[CH:24]=2)[CH2:34][CH2:33]1
Reactant: CC1(C)OB(c2cccc(N3CCNCC3)c2)OC1(C)C
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CCN(c2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium triacetoxyborohydride (0.066 g, 0.31 mmol) was added to a solution of 1-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (60.0 mg, 0.208 mmol, from Boron Molecular) and 11.0 M aqueous formaldehyde (0.057 mL, 0.62 mmol) in methylene chloride (0.8 mL, 10 mmol) and then the reaction was stirred at r.t. for 1 hour. The mixture was diluted with methylene chloride, washed with saturated NaHCO3, water, brine, then dried over Na2SO4, filtered and concentrated to provide the product which was used in the next step. LCMS calculated for C17H28BN2O2 (M+H)+: m/z=303.2. Found 303.2.