Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[C:2]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)#[N:3].O.[NH2:11][NH2:12].[C:13]1([CH3:19])C=CC=CC=1>>[N:7]1[CH:8]=[CH:9][C:4]([C:2]2[N:11]=[N:12][CH:13]=[CH:19][N:3]=2)=[CH:5][CH:6]=1
Reactant: NN
Reactant: Cc1ccccc1
Reactant: N#Cc1ccncc1
Solvent: O
Product: c1cc(-c2nccnn2)ccn1
Temperature: 50 °C
Yield: 85.2 %

Procedure:
In a 2000-ml four-necked flask were charged 200 ml of water, 200.0 g (1.92 mole) of 4-cyanopyridine and 192.0 g (3.84 mole) of hydrazine monohydrate. The mixture was reacted for 4 hours under stirring at 50° C. After confirmation of the disappearance of the raw material by HPLC analysis, 400 ml of toluene was added and excessive hydrazine monohydrate was distilled off. This operation was conducted again. To the residue were successively added 800 ml of water and 278.4 g (1.92 mole) of a 40% aqueous glyoxal solution. The mixture was reacted for 2 hours at an external temperature of 100° C. After completion of the reaction, the reaction mixture was cooled to 5° C., whereby 222.4 g (yield: 85.2%) of the target compound was obtained as pale yellow crystals.
Reaction SMILES: C1(=O)[N:5]([C@@H:6]2[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[O:12][C@H:7]2[O:8][CH2:9][CH:10]=[CH2:11])[C:4](=[O:19])[C:3]2=CC=CC=C12.C(N)CCC>CO>[C:4]([NH:5][C@@H:6]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[O:12][C@H:7]1[O:8][CH2:9][CH:10]=[CH2:11])(=[O:19])[CH3:3]
Reactant: C=CCO[C@@H]1O[C@H](CO)[C@@H](O)C[C@H]1N1C(=O)c2ccccc2C1=O
Solvent: CCCCN
Solvent: CO
Product: C=CCO[C@@H]1O[C@H](CO)[C@@H](O)C[C@H]1NC(C)=O
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
A mixture of allyl 2,3-dideoxy-2-phthalimido-β-D-glucopyranoside, Compound 22, (100 mg, 0.30 mmol) and BuNH2 (4 mL) in MeOH (20 mL) was refluxed for 10 hours, then cooled and evaporated. Acetic anhydride (2 mL) was added to a solution of the residue in MeOH (10 mL) at 0-5° C., and the mixture was stirred for three hours at 0-5° C. The mixture was concentrated, and the residue was triturated in MeOH with Et2O to give Compound 1i (40 mg, 54 percent).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9](I)=[CH:8][C:6]=2[N:7]=1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][CH:26]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:28]=1)=[O:22])[CH3:19]>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.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>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[S:10][C:9]([C:27]3[CH:28]=[C:23]([C:21]([O:20][CH2:18][CH3:19])=[O:22])[CH:24]=[N:25][CH:26]=3)=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sc(I)cc2n1
Reactant: CCOC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1cncc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1
Yield: 75 %

Procedure:
2-Chloro-6-iodo-4-morpholinothieno[3,2-d]pyrimidine 19, 200 mg of 3-ethoxycarbonylpyridine-5-boronic acid pinacol ester (250 mg) and 23 mg of bis(triphenylphosphine)palladium(II) dichloride in 1.5 mL of 1M Na2CO3 aqueous solution and 1.5 mL of acetonitrile was heated to 100° C. in a sealed microwave reactor for 10 min. The reaction mixture was evaporated. The crude product was purified by flash chromatography eluting with 10-100% EtOAc/hexane to yield ethyl 5-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)pyridine-3-carboxylate (240 mg, 75%).
Reaction SMILES: II.O[PH2]=O.[CH3:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH:21]([C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)O)=[CH:19][N:20]=3)[N:17]=2)[CH:9]=[N:8]1>C(O)(=O)C.O>[CH3:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:16]([C:18]([CH2:21][C:23]4[CH:24]=[C:25]5[C:30](=[CH:31][CH:32]=4)[N:29]=[CH:28][CH:27]=[CH:26]5)=[CH:19][N:20]=3)[N:17]=2)[CH:9]=[N:8]1
Reactant: Cn1cc(-c2ccc3ncc(C(O)c4ccc5ncccc5c4)n3n2)cn1
Agent: II
Agent: O=[PH2]O
Solvent: CC(=O)O
Solvent: O
Product: Cn1cc(-c2ccc3ncc(Cc4ccc5ncccc5c4)n3n2)cn1
Reaction time: 0.5 h

Procedure:
The title compound was synthesized like described in Tetrahedron Letters, 2001, 42, 831-833): iodine (207 mg, 0.82 mmol) and H3PO2 (0.44 mL of a 50% aqueous solution, 4.07 mmol) were added to a solution of (rac)-[6-(1-methyl-1H-pyrazol-4-yl)-imidazo[1,2-b]pyridazin-3-yl]-quinolin-6-yl-methanol (Example 1, 145 mg, 0.41 mmol) in acetic acid (1 mL). The RM was subjected to MW-irradiation at 150° C. for 30 min. The RM was diluted with water and extracted with EtOAc. The organic layer was separated and washed carefully with sat. K2CO3-sol then dried filtered and concentrated. Purification by HPLC and then liberation of the free base afforded the title compound as a white solid (tR 1.055 min (conditions 1), MH+=341.2, 1H-NMR in DMSO-d6: 8.9 (d, 1H), 8.5 (s, 1H), 8.4 (d, 1H), 8.2 (d, 1H), 8.1 (s, 1H), 8.05 (s, 1H), 8.0 (d, 1H), 7.9 (d, 1H), 7.8 (s, 1H), 7.7 (d, 1H), 7.6 (dd, 1H), 4.6 (s, 2H), 4.0 (s, 3H)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:17][CH2:16]2)=[C:11]([CH:18]=[C:19]2[C:23]([CH3:25])([CH3:24])[O:22][C:21]([CH3:27])([CH3:26])[C:20]2=[O:28])[CH:10]=1.[OH-:29].[Li+]>CO.OO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:17][CH2:16]2)=[C:11]([CH:18]2[C:19]3([C:20](=[O:28])[C:21]([CH3:27])([CH3:26])[O:22][C:23]3([CH3:24])[CH3:25])[O:29]2)[CH:10]=1
Reactant: [OH-]
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3Cl)ccc2C2CC2)C1=O
Agent: OO
Agent: [Li+]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(-c3ccc(Cl)cc3Cl)ccc2C2CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 429.9 %

Procedure:
To a solution of 4-[1-(2′,4′-dichloro-4-cyclopropylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (20.0 g, 0.048 mol) in methanol (800 ml) at 35° C. is added 50% aqueous hydrogen peroxide (4.80 ml, 0.072 mmol), followed immediately by 2M lithium hydroxide (4.80 ml, 9.60 mmol) solution. The mixture is stirred at this temperature for a further 2 hours, then allowed to cool to room temperature. Then reaction mixture is quenched with 10% sodium metabisulfite (negative KI-starch indicator test) then diluted with diethyl ether. Most of the methanol is removed under vacuum, and the crude mixture is partitioned between distilled water and diethyl ether. The aqueous phase is further extracted with diethyl ether (×2), then all organics are combined and washed with saturated sodium bicarbonate (×2) then brine. After drying over magnesium sulfate the suspension is filtered and the filtrate concentrated in vacuo to afford 2-(2′,4′-dichloro-4-cyclopropylbiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxa-spiro[2.4]heptan-7-one (17.80 g) as an orange foam. This material is of sufficient purity to use directly in the next step without further purification.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13](#[N:15])[CH3:14].[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH:19]=[O:20].[Cl-].[NH4+]>O1CCCC1>[F:16][C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:18]=1[CH:19]([OH:20])[CH2:14][C:13]#[N:15]
Reactant: O=Cc1ccc(F)cc1F
Reactant: CC#N
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#CCC(O)c1ccc(F)cc1F
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
To a stirring solution of diisopropylamine (0.97 mL, 6.89 mmol) in tetrahydrofuran (15 mL) at −70° C. under nitrogen was added a solution of n-butyllithium (2.88 mL, 7.20 mmol, 2.5 M in hexane). After the addition was complete, the mixture was stirred at −70° C. for 10 minutes and removed cooling bath for 5 minutes. The mixture was cooled back to −70° C., acetonitrile (0.33 mL, 6.26 mmol) was added and the reaction mixture was then stirred at −70° C. for 30 minutes. 2,4-difluoro-benzaldehyde (1.09 g, 7.52 mmol) was added and the resulting solution was allowed to warm to ambient temperature. After 4 hours at ambient temperature, saturated aqueous ammonium chloride (5 mL) was added to the reaction mixture and it was concentrated at reduced pressure. The resulting crude product was diluted with ethyl acetate (25 mL), washed with water (10 mL) followed by saturated aqueous sodium chloride (10 mL). The organic layer was concentrated and purified by column chromatography (40 g silica gel cartridge) eluting with ethyl acetate/hexane (0%-10%) to give the product as light yellow oil (960 mg, 70%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:14])=[C:5]([C:10]([F:13])=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:14][C:4]1[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:10]([F:13])[CH:11]=[CH:12][C:3]=1[CH2:2][N:18]1[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COC(=O)c1c(F)ccc(CBr)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(F)ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)c1F
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To a room temperature solution of methyl 3-(bromomethyl)-2,6-difluorobenzoate (14.24 g, nominally 51.2 mmol, 1.0 equiv) and tert-butyl piperazine-1-carboxylate (9.1 g, 50.24 mmol, 1.0 equiv) in DMF (50 mL) was added K2CO3 (27.8 g, 201 mmol, 4.0 equiv) as a solid. The resulting mixture was allowed to stir overnight. The reaction mixture was diluted with EtOAc and washed repeatedly with H2O. The combined aqueous layers were washed once with EtOAc, and the combined organic layers were washed once with brine, dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel chromatography (10%-60% EtOAc/hexanes) provided tert-butyl 4-(2,4-difluoro-3-(methoxycarbonyl) benzyl)piperazine-1-carboxylate (7.70 g, 41.4% over two steps). LCMS m/z (APCI)=371.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][C:3]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:12][C:13]([F:33])([F:32])[O:14][C:15]1[CH:31]=[CH:30][C:18]2[NH:19][C:20]([S:22][C:23]3[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=3)=[N:21][C:17]=2[CH:16]=1.[C:34]1(=O)[CH2:39][CH2:38][CH2:37][C:36](=[O:40])[CH2:35]1>C(O)CCC>[CH2:10]([O:9][C:7]([C:3]1[NH:4][CH:5]=[C:6]2[CH:28]([C:26]3[O:27][C:23]([S:22][C:20]4[NH:19][C:18]5[CH:30]=[CH:31][C:15]([O:14][C:13]([F:32])([F:33])[F:12])=[CH:16][C:17]=5[N:21]=4)=[CH:24][CH:25]=3)[C:35]3[C:36](=[O:40])[CH2:37][CH2:38][CH2:39][C:34]=3[NH:1][C:2]=12)=[O:8])[CH3:11]
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)c1[nH]ccc1N
Reactant: O=Cc1ccc(Sc2nc3cc(OC(F)(F)F)ccc3[nH]2)o1
Solvent: CCCCO
Product: CCOC(=O)c1[nH]cc2c1NC1=C(C(=O)CCC1)C2c1ccc(Sc2nc3cc(OC(F)(F)F)ccc3[nH]2)o1
Yield: 36.5 %

Procedure:
A mixture of 3-amino-2-ethoxycarbonyl-pyrrole (0.235 g, 1.52 mmol), 5-(5-trifluoromethoxy-1H-benzoimidazol-2-ylsulfanyl)-furan-2-carbaldehyde (0.50 g, 1.52 mmol) and 1,3-cyclohexanedione (0.171 g, 1.52 mmol) in 5 ml of 1-butanol is heated at reflux temperature for 4 hours. The reaction mixture is then concentrated under reduced pressure. The residue is then purified on a silica gel column (40 g) eluted successively with cyclohexane/ethyl acetate (7/3, v/v) and cyclohexane/ethyl acetate (1/1, v/v). The fractions containing the expected product are concentrated under reduced pressure. The obtained solid is washed with acetonitrile (100 ml), pentane (50 ml) and dried under vacuum to yield 310 mg of 8-oxo-9-[5-(5-trifluoromethoxy-1H-benzimidazol-2-ylsulfanyl)-furan-2-yl]-4,5,6,7,8,9-hexahydro-2H-pyrrolo[3,4-b]quinoline-3-carboxylic acid ethyl ester as a white powder. Yield=36%. Analytical LC/MS (method C): m/z=559 (positive ion mode [M+H]+), m/z=557 (negative ion mode [M−H]−).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:25][CH:26]1[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]1)[C:11]1[CH:12]=[C:13]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH:14]=[CH:15][C:16]=1[F:17].C([O-])(=O)C([O-])=O.[OH:39][C:40]1[CH:53]=[CH:52][CH:51]=[CH:50][C:41]=1[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=O>C(O)C.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:25][CH:26]1[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]1)[C:11]1[CH:12]=[C:13]([C:18]#[C:19][CH2:20][CH2:21][CH2:22][CH2:23][N:24]=[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:41]2[CH:50]=[CH:51][CH:52]=[CH:53][C:40]=2[OH:39])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: O=C(c1ccccc1)c1ccccc1O
Reactant: CN1CCC(OC(c2nc3ccccc3[nH]2)c2cc(C#CCCCCN)ccc2F)CC1
Agent: O=C([O-])C(=O)[O-]
Solvent: O
Solvent: CCO
Product: CN1CCC(OC(c2nc3ccccc3[nH]2)c2cc(C#CCCCCN=C(c3ccccc3)c3ccccc3O)ccc2F)CC1

Procedure:
A mixture of 6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylamine, oxalate (example 557, 70 mg), 2-hydroxybenzophenone (30 mg) in ethanol (4 mL) is refluxed for 4 h. The mixture is then cooled, diluted with water and extracted with ethyl acetate. Pooled extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol/ammonia from 100/0/0 to 90/10/0.5) to afford 2-[(6-{3-[(1H-benzimidazol-2-yl)(1-methylpiperidin-4-yloxy)methyl]-4-fluorophenyl}hex-5-ynylimino)phenylmethyl]phenol. TLC (Eluent: CH2Cl2/MeOH/NH4OH 95/5/0.5) Rf=0.15.
Reaction SMILES: [OH:1][C@@H:2]([CH2:26][OH:27])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1.[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C.C(#N)C>[OH:1][C@@H:2]([CH2:26][OH:27])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[C:12]([F:29])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1
Reactant: F[B-](F)(F)F
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc21
Yield: 33 %

Procedure:
To a solution of (R)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 6) (1 g, 2.06 mmol, 1 eq) in DMF (19 mL) was added dropwise a mixture of Selectfluor (801 mg, 2.26 mmol, 1.1 eq) in acetonitrile (9 mL) and DMF (5 mL) at ambient temperature while stirring under nitrogen. The reaction mixture was stirred for 10 minutes at ambient temperature and filtered. The filtrate was purified by preparatory LC/MS (30-55% CH3CN in H2O) to give (R)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 18) as an off-white solid. The recovered starting material was subjected to the same reaction conditions to produce a second crop of product. The total yield of product was 347 mg (33% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.36-3.40 (m, 1H) 3.43-3.50 (m, 1H) 3.58 (s, 3H) 3.61-3.72 (m, 1H) 3.72-3.82 (m, 1H) 4.27-4.37 (m, 1H) 4.78-4.87 (m, 1H) 5.14 (d, J=5.81 Hz, 1H) 6.93-7.03 (m, 1H) 7.53 (d, J=8.84 Hz, 1H) 7.65-7.74 (m, 1H) 8.52 (s, 1H) 10.25 (d, J=1.01 Hz, 1H). [M+H] calc'd for C17H15F21N4O4, 505. found, 505.
Reaction SMILES: C([O:4][C:5]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])C=C.O.C(OCC)(=O)C.CN(C)[C:23]1[CH:28]=CC=C[CH:24]=1>>[CH2:28]([C:12]1[C:5]([OH:4])=[C:6]([CH:9]=[CH:10][C:11]=1[OH:13])[CH:7]=[O:8])[CH:23]=[CH2:24]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cc(O)ccc1C=O
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCc1c(O)ccc(C=O)c1O

Procedure:
3.10 g of 2-allyloxy-4-hydroxybenzaldehyde was dissolved in 6 ml of N,N-dimethylaniline, and the reaction solution was heated to reflux under nitrogen atmosphere. Approximately 2.5 hours later, the reaction solution was stood to cool. Thereafter, water and ethyl acetate were added to the reaction solution, so as to separate an organic layer. The obtained organic layer was washed with 5 N hydrochloric acid, water, and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure. The residue was then purified by silica gel column chromatography (hexane/ethyl acetate), so as to obtain 0.88 g of the subject compound.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH:18]=O)[CH2:14][CH2:13]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][NH:10][C@@H:8]2[CH2:9][C@H:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:14][CH2:13]1
Reactant: CN1CCC(C=O)CC1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.1 %

Procedure:
A mixture of [trans-2-phenylcyclopropyl]amine (540 mg, 4.05 mmol), 1-methyl-4-piperidinecarbaldehyde (506 mg, 3.98 mmol) and AcOH (1 mL, 0.017 mmol) in chloroform (15 mL) was stirred at room temperature for 18 hours. Sodium triacetoxyborohydride (947 mg, 4.47 mmol) was added and stirring continued for 18 hours. Upon completion, saturated NaHCO3 was added to the reaction mixture and the mixture was extracted with THF—CHCl3 (2×50 mL). The organics were combined, dried over Na2SO4 and concentrated. The residue was adsorbed onto silica and purified via column chromatography on the ISCO Companion (gradient 0-100% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 40 g column) to obtain pure final compound (166 mg, 13% yield) as an off white solid: LC-MS (ES) m/z=245 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.17-7.27 (m, 2H), 7.06-7.15 (m, 1H), 6.97-7.06 (m, 2H), 2.64-2.77 (m, 2H), 2.41-2.49 (m, 2H), 2.27 (br. s., 1H), 2.18 (ddd, J=3.28, 4.23, 7.14 Hz, 1H), 2.08-2.15 (m, 3H), 1.70-1.83 (m, 2H), 1.57-1.70 (m, 2H), 1.30 (ddd, J=4.29, 7.26, 10.93 Hz, 1H), 1.01-1.16 (m, 2H), 0.86-0.98 (m, 2H).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:8]([O:16][CH:17]([F:19])[F:18])=[C:9]([N+:13]([O-])=O)[CH:10]=[CH:11][CH:12]=1>[Fe].O>[Br:6][C:7]1[C:8]([O:16][CH:17]([F:18])[F:19])=[C:9]([CH:10]=[CH:11][CH:12]=1)[NH2:13]
Reactant: O=[N+]([O-])c1cccc(Br)c1OC(F)F
Agent: [Fe]
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1cccc(Br)c1OC(F)F
Yield: 65.8 %

Procedure:
Into a 100-ml four-necked flask provided with a reflux condenser, a stirrer and a thermometer were fed 0.95 g (17.0 mmol) of an iron powder, 0.11 g (1.0 mmol) of 98% sulfuric acid, 15 ml of water and 1.62 g (6.0 mmol) of 3-bromo-2-difluoromethoxynitrobenzene. The mixture was heated on an oil bath and refluxed for 2 hours. After the completion of a reaction, azeotropic distillation was conducted while 220 ml of water was added gradually. The distillate was subjected to extraction two times each using 100 ml of ether. The ether layer was dried over anhydrous sodium sulfate and then subjected to distillation. The residue was distilled under vacuum to obtain 0.94 g of 3-bromo-2-difluoromethoxyaniline (yield: 65.4%, purity: 98.5%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][N:6]=1)=O.[OH-].[NH4+:13]>CO>[Cl:11][C:9]1[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH2:13])=[O:2])[CH:10]=1
Reactant: COC(=O)c1cc(Cl)ccn1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cc(Cl)ccn1
Reaction time: 0.17 h
Yield: 85 %

Procedure:
4-Chloro-pyridine-2-carboxylic acid methyl ester (2) (500 mg, 3 mmol) was dissolved in MeOH (5 ml) and concentrated ammonium hydroxide (5 ml) was added. After 10 minutes, the reaction mixture was partitioned between ethyl acetate and brine. The ethyl acetate was washed with brine one additional time, and the solvents were removed under vacuum to yield the title product 3 (400 mg (85%), 2.5 mmol) as a white solid. 1H NMR (DMSO-d6): δ 8.64 (d, J=5.3 Hz, 1H), 8.22 (bs, 1H), 8.03 (d, J=1.9 Hz, 1H), 7.83 (bs, 1H), 7.68 (dd, J=5.3 Hz, 1.9 Hz, 1H). MS (ESI-POS): [M+H]+=157.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[C:8]([O:11][CH:12]=[CH:13][CH:14]=[CH2:15])(=[O:10])[CH3:9].COC>>[C:8]([O:11][CH:12]=[CH:13][CH:14]1[NH:5][C:6](=[O:7])[CH2:15]1)(=[O:10])[CH3:9].[C:8]([O:11][CH2:12][CH2:13][CH:14]1[NH:5][C:6](=[O:7])[CH2:15]1)(=[O:10])[CH3:9]
Reactant: C=CC=COC(C)=O
Reactant: O=C=NS(=O)(=O)Cl
Agent: COC
Product: CC(=O)OC=CC1CC(=O)N1
Product: CC(=O)OCCC1CC(=O)N1

Procedure:
In words relative to the above diagram for the preparation of 1, the 4-(2-acetoxyvinyl)azetidine-2-one (3) is prepared by reacting chloro sulphonyl isocyanate and an acyloxybutadiene such as 1-acetoxybutadiene in a solvent such as anhydrous dimethyl ether at a temperature of from about -30° C. to 0° C. under a nitrogen atmosphere. The reaction intermediate 2 is converted to 3 by hydrolysis. The reduction of 3 to provide the 4-(2-acetoxyethyl)-2-azetidinone (4) is conducted by any convenient means such as hydrogenation in the presence of a catalyst such as platinum, palladium or oxides thereof under a hydrogen pressure of from 1 to 20 atmospheres in a solvent such as ethanol, ethylacetate, or the like at a temperature of from 0° to 25° C., for from 5 minutes to 1 hour. The 4-(2-hydroxyethyl)-2-azetidinone species, 5, is obtained from 4 by hydrolysis. The 8-oxo- 2,2-dimethyl-3-oxa-1-azabicyclo[4.2.0]octane species, 6, is obtained on treatment of 5 with 2,2-dimethoxypropane in the presence of a catalyst such as boron trifluoride etherate in a solvent such as methylene chloride at a temperature of from 0° to 40° C. for from 1 to 40 minutes. The azide intermediate 7 is prepared by treating 6 in a solvent such as tetrahydrofuran (THF), dimethoxyethane, dioxane, DMF or the like with a base such as lithium diisopropylamide, butyl lithium, phenyl lithium or the like at a temperature of from -25° to -78° C. for from one to three hours; whereupon an azide reagent such as tosylazide is introduced; after 1 to 3 hours at -35° to -50° C. the mixture is treated with a disproportionating agent such as trimethylchlorosilane to provide the azide 7 which may be isolated. The amino intermediate 8 is prepared by reducing 7 in a solvent such as ethylacetate, ethanol, dioxane, methanol or the like in the presence of a hydrogenation catalyst such as Pd on carbon, PtO2, Pd/CaCO3, or the like and hydrogen (4 to 50 atmospheres) for from 12 to 48 hours at a temperature of from 20° to 30° C. The N-acyl intermediate 8a is obtained from 8 on treatment in a solvent such as CH2Cl2, ether, chloroform or the like with the acid chloride of choice calculated to provide the acyl radical R1 at a temperature of from -25° to 0° C. for from 2 to 15 hours. Species 9 is obtained from 8a by acid hydrolysis.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]([C:14]#[N:15])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH3:2].[C:17]1([CH3:25])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Mg]Cl.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:14]#[N:15])[CH:6]([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH3:25])[CH3:2]
Reactant: CCOC(=O)C(C#N)=Cc1ccc(Br)cc1
Reactant: Cc1ccccc1[Mg]Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)C(c1ccc(Br)cc1)c1ccccc1C
Temperature: 85 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of 3-(4-bromo-phenyl)-2-cyano-acrylic acid ethyl ester (6.65 g) in toluene (50 mL) was added to a solution of o-tolylmagnesium chloride in THF (1M, 30.9) at 0° C. After the addition was complete, the solution was heated to 85° C. for 1.5 hours, and stirring was continued at rt overnight. The mixture was heated for additional 2 hours to 85° C., cooled and poured onto ice. 1M HCl was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (Et2O/n-heptane 1:3) to yield the title compound (6.45 g, 73%) as a light yellow oil, MS (ESI−): m/z=370.0444 ([M−H]−, 1Br).