Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=O)[CH:13]([CH2:16][C:17]([OH:19])=O)[C:12]3=[N:20][N:21]=[C:22]([CH3:23])[N:11]3[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)=[CH:4][CH:3]=1.[CH2:28]([NH2:30])[CH3:29].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>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH:13]([CH2:16][C:17]([NH:30][CH2:28][CH3:29])=[O:19])[C:12]3=[N:20][N:21]=[C:22]([CH3:23])[N:11]3[C:10]3[CH:24]=[CH:25][CH:26]=[CH:27][C:9]2=3)=[CH:6][CH:7]=1
Reactant: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)C(=O)C2CC(=O)O
Reactant: CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)CC1CN(c2ccc(Cl)cc2)c2ccccc2-n2c(C)nnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
A mixture of 2-(6-(4-chlorophenyl)-1-methyl-5-oxo-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-4-yl)acetic acid (15 mg, 0.04 mmol), ethanamine (4 mg, 1.12 mmol), HATU (19 mg, 0.05 mmol), DIEA (8 mg, 0.06 mmol) in DCM (5 mL) was stirred overnight at room temperature. The mixture was concentrated and purified by prep-HPLC to give 2-(6-(4-chlorophenyl)-1-methyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepin-4-yl)-N-ethylacetamide as a white solid (4 mg).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][CH2:5][CH2:6][CH2:7][C:8](Cl)=[O:9]>O1CCCC1>[Cl:4][CH2:5][CH2:6][CH2:7][C:8]([N:2]([CH3:3])[CH3:1])=[O:9]
Reactant: O=C(Cl)CCCCl
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)CCCCl
Yield: 99 %

Procedure:
A solution of 50.0 g (1.11 mole) of dimethylamine in 100 ml of tetrahydrofuran was added dropwise to a solution of 28.2 (0.20 mole) of 4-chlorobutyryl chloride in 50 ml of tetrahydrofuran. The reaction mixture was stirred mechanically while the temperature was maintained between 5° C. and 15° C. throughout the addition. After the final addition, the solution was filtered to remove solid precipitates, and the filtrate concentrated under reduced pressure to yield 29.6 g (99%) of a yellow liquid. An analytical sample was prepared by filtering the liquid through a small bed of silica gel and eluting with ethyl acetate-hexane (1:1). The fractions containing the desired product were combined and concentrated under reduced pressure to give the title compound as a light-yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[NH:17][C:16]2=O)=[C:4]([F:27])[CH:3]=1.P(Cl)(Cl)([Cl:30])=O.C(N(CC)CC)C.C1(C)C=CC=CC=1>[Cl-].[Na+].O>[Cl:30][C:16]1[N:15]([C:5]2[CH:6]=[C:7]([O:8][C:9]3[N:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[C:2]([Cl:1])=[CH:3][C:4]=2[F:27])[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ncccn2)c(Cl)cc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: O=c1cc(C(F)(F)F)nc(Cl)n1-c1cc(Oc2ncccn2)c(Cl)cc1F
Yield: 49.9 %

Procedure:
A mixture of 3-[4-chloro-2-fluoro-5-(2-pyrimidinyloxy)phenyl]-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione(2.01 g, 0.005 mol), phosphorus oxychloride (3.83 g, 0.025 mol), triethylamine (2.02 g, 0.02 mol and toluene (7 ml) was heated under reflux for 2 hours. The reaction mixture was poured into brine, and extracted with ethyl acetate. The organic phase was separated, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography on silica gel(40% ethyl acetate/hexane) to give compound III-2 (1.05 g, yield 49.9%) as a white solid, m.p.132-134.5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CCN(C(C)C)C(C)C.[CH2:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36](O)=O)=[CH:31][CH:30]=1)[CH3:27].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:14]1([CH2:13][N:12]2[C:3]3=[N:4][CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=[C:2]3[N:1]=[C:36]2[CH2:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:26][CH3:27])=[CH:30][CH:31]=2)[CH2:16][CH2:15]1
Reactant: CCOc1ccc(CC(=O)O)cc1
Reactant: COC(=O)c1cnc(NCC2CC2)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2nc3cc(C(=O)OC)cnc3n2CC2CC2)cc1
Yield: 33.7 %

Procedure:
Following general procedure 13B: Combined methyl 5-amino-6-[(cyclopropylmethyl)amino]nicotinate (950 mg, 4.3 mmol), DIPEA (1.1 ml), 4-ethoxyphenylacetic acid (850 mg, 4.72 mmol) and HATU (1.80, 4.74 mmol) in DMF (15 mL). The crude product was purified by flash chromatography on silica gel (EtOAc) to produce the desired product (530 mg, 34%).
Reaction SMILES: [CH:1]([C:3]1[C:12]([CH3:13])=[C:11]([CH3:14])[C:10]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=3)=[CH:18][CH:17]=2)=[CH:9][C:4]=1[C:5](OC)=[O:6])=O.Cl.[NH2:29][C@H:30]1[CH2:34][CH2:33][CH2:32][C@@H:31]1[OH:35].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[OH:35][C@H:31]1[CH2:32][CH2:33][CH2:34][C@@H:30]1[N:29]1[CH2:1][C:3]2[C:4](=[CH:9][C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:26]=[CH:25][N:24]([CH3:27])[N:23]=4)=[CH:18][CH:17]=3)=[C:11]([CH3:14])[C:12]=2[CH3:13])[C:5]1=[O:6]
Reactant: N[C@H]1CCC[C@@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(-c3ccn(C)n3)cc2)c(C)c(C)c1C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-c3ccn(C)n3)cc2)cc2c(c1C)CN([C@H]1CCC[C@@H]1O)C2=O
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 44.2 %

Procedure:
A solution of methyl 2-formyl-3,4-dimethyl-5-(4-(1-methyl-1H-pyrazol-3-yl)benzyl)benzoate (0.09 g), (1S,2S)-2-aminocyclopentanol hydrochloride (0.03 g), triethylamine (0.03 mL) and anhydrous magnesium sulfate (0.06 g) in THF (1.80 mL) was stirred at room temperature for 46 hr under nitrogen atmosphere. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (1.80 mL) and THF (1.80 mL), sodium triacetoxyborohydride (0.10 g) was added thereto, and the mixture was stirred at room temperature for 7.5 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.04 g).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[N:6][C:5]=1[CH3:20].CC(C[AlH]CC(C)C)C>C1COCC1>[CH3:20][C:5]1[C:4]([CH2:3][OH:2])=[CH:9][CH:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:18])([F:17])[F:19])[CH:11]=2)[N:6]=1
Reactant: COC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1CO

Procedure:
1.96 g (6.62 mmol) of the above synthesized 2-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid methyl ester in 14 ml of abs. THF was cooled down to 0° C. and reacted with 13.8 ml of DIBAL-H-solution (1.2 M in toluene, 2.5 eq.) for 1 h. Careful quenching with ice/NH4Cl, twofold extraction with AcOEt, washing with brine, drying over sodium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2, hexane/AcOEt=55/45) to deliver finally 1.66 g of the title compound as white crystals of mp. 75-77° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([O:29][CH2:30][CH2:31][O:32][CH3:33])[C:11]3[CH2:17][N:16]([C:18]([C:20]4[CH:21]=[N:22][N:23]5[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=45)=[O:19])[CH2:15][CH2:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH3:34][Sn](C)(C)C>CN(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>[CH3:33][O:32][CH2:31][CH2:30][O:29][C:10]1[C:11]2[CH2:17][N:16]([C:18]([C:20]3[CH:21]=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)=[O:19])[CH2:15][CH2:14][C:12]=2[N:13]=[C:8]([C:5]2[CH:6]=[N:7][C:2]([CH3:34])=[CH:3][CH:4]=2)[N:9]=1
Reactant: COCCOc1nc(-c2ccc(Cl)nc2)nc2c1CN(C(=O)c1cnn3ccccc13)CC2
Reactant: C[Sn](C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COCCOc1nc(-c2ccc(C)nc2)nc2c1CN(C(=O)c1cnn3ccccc13)CC2
Temperature: 150 °C
Yield: 48.5 %

Procedure:
To a solution of 30 mg (0.065 mmol) O-2 in 1 mL DMF in a microwave vial was added approximately 20 uL (˜0.15 mmol) tetramethyltin and 8 mg (˜10 mol %) tetrakistriphenylphosphinepalladium(0). The reaction was heated by microwave irradiation for 20 minutes at 150° C. After cooling, the reaction was purified by reverse phase HPLC (CH3CN/H2O with TFA as modifier), and the fractions containing the product were partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to provide R-1 as a white solid (14 mg, 49% yield). HRMS m/z (M+H) 445.1977 found, 445.1983 required.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=O)[CH:13]=1>C1(C)C=CC=CC=1>[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]=[CH:9][C:10]#[N:11])[CH:13]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1cccnc1
Solvent: Cc1ccccc1
Product: N#CC=Cc1cccnc1
Yield: 69.2 %

Procedure:
95 ml (0.60 mol) of cyanomethylphosphonic acid diethyl ester and 50 ml (0.55 mol) of pyridine-3-carbaldehyde are dissolved in 1 L of toluene and mixed with 55 g (0.55 mol) of KHCO3. The mixture is heated for 1 hour in a preheated oil bath. The cooled mixture is mixed with additional toluene and washed with 1M NaHCO3, twice with water and with saturated common salt solution. The organic phase is dried and concentrated by evaporation in a vacuum. The residue is recrystallized from ethyl acetate/hexane, and 49.5 g (69%) of product is obtained. Melting point 99.5-101° C.
Reaction SMILES: N1C(C)=CC(C)=CC=1C.Cl[C:11]([O:13][CH3:14])=[O:12].[CH3:15][S:16][C:17](=[NH:43])[CH:18]([C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:33]=1[F:42])[NH:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[CH:22][CH:21]=1.Cl>C1(C)C=CC=CC=1>[CH3:14][O:13][C:11](=[O:12])[N:43]=[C:17]([S:16][CH3:15])[C:18]([C:32]1[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[CH:34][C:33]=1[F:42])=[N:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[CH:24][CH:25]=1
Reactant: COc1cc(F)c(C(Nc2ccc(-c3noc(C)n3)cc2)C(=N)SC)cc1OC
Reactant: COC(=O)Cl
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Solvent: Cc1ccccc1
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(OC)c(OC)cc1F
Temperature: 80 °C
Reaction time: 18 h

Procedure:
After adding 9.85 ml of collidine and 4.94 ml of methyl chloroformate to a solution of 8.89 g of 2-(2-fluoro-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylamino]thioacetimidic acid methyl ester in 300 ml of toluene, the mixture was stirred at 80° C. for 18 hours under a nitrogen atmosphere. After cooling the reaction mixture, dilute hydrochloric acid was added and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The desiccating agent was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (4.12 g, isomeric mixture) as a light yellow solid.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:10]([NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:26]([NH2:28])=[O:27])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[ClH:36]>C(O)(=O)C>[NH2:1][C@@H:2]([C:10]([NH:12][C@H:13]([C:18]([NH:20][C@H:21]([C:26]([NH2:28])=[O:27])[CH2:22][CH2:23][CH2:24][CH3:25])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[ClH:36]
Reactant: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(N)=O
Agent: Cl
Solvent: CC(=O)O
Product: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1ccccc1)C(N)=O
Yield: 79 %

Procedure:
Condensation of BocDPheOH (2.65 g.) and HLeuOBz hydrobromide salt (3.02 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocDPhe-LeuOBz in 54% yield. Debenzylation of BocDPhe-LeuOBz (2.25 g.) by hydrogenation with palladium catalyst gave BocDPhe-LeuOH in 87% yield. Condensation of BocDPhe-LeuOH (1.50 g.) and HNleNH2 hydrochloride salt (0.667 g.) using dicyclohexylcarbodiimide and N-hydroxysuccinimide gave BocDPhe-Leu-NleNH2 in 60% yield. De-t-butoxycarbonylation of BocDPhe-Leu-NleNH2 (1.00 g.) using hydrogen chloride in acetic acid gave HDPhe-Leu-NleNH2 hydrochloride salt in 79% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([NH:19]C(=O)C)(C(OCC)=O)[C:9]([O:11][CH2:12]C)=[O:10])[CH:2]=1.[ClH:23]>>[ClH:23].[ClH:23].[CH3:12][O:11][C:9](=[O:10])[C@H:8]([CH2:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[NH2:19]
Reactant: CCOC(=O)C(Cc1cccnc1)(NC(C)=O)C(=O)OCC
Agent: Cl
Product: COC(=O)[C@@H](N)Cc1cccnc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100 %

Procedure:
Diethyl 2-(3-pyridylmethyl)-2-acetamidomalonate was dissolved in 6N HCl (30 mL) and heated to reflux for 19 hours whereupon it was cooled to room temperature and the HCl solution was removed by evaporation in vacuo. The intermediate amino acid dihydrochloride salt was taken up into MeOH (30 mL) saturated with HCl gas and stirred for 3.5 hours. The MeOH/HCl was removed by evaporation in vacuo to give 3-(3-pyridyl)alanine methyl ester dihydrochloride (2.235 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1.[CH3:15][Si]([N-][Si](C)(C)C)(C)C.[Na+].C([O-])(O)=O.[Na+].O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[CH:4]([CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1
Reactant: COC(=O)CCc1cccc(C#N)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
To a solution of 3-(3-cyano-phenyl)-propionic acid methyl ester of Step A (220 mg, 1.16 mmol) in THF (5 mL) at −78° C. was added sodium bis(trimethylsilyl)amide (1 M in THF, 1.2 mL, 1.2 mmol). The reaction was stirred for 0.5 h and Mel (0.08 mL, 1.28 mmol) was added. After 1 h, a solution of saturated NaHCO3:water (1:1) was added and the reaction was warmed to room temperature. The aqueous solution was washed with CH2Cl2 (3×) and the combined organic solutions were dried (MgSO4), filtered, and concentrated. Medium pressure chromatography (6:1 hexanes:EtOAc) provided the title compound of Step B as a colorless oil (62 mg). 1H NMR (400 MHz, CDCl3) δ 7.50-7.34 (m, 4H), 3.62 (s, 3H), 3.01 (m, 1H), 2.71 (m, 2H), 1.16 (d, 3H).
Reaction SMILES: [I:1]C1NC=CC=1.[CH2:7]([C:9]1[C:13]([CH3:14])=[CH:12][NH:11][C:10]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:8].C(C1NC(C(OCC)=O)=C(CC)C=1C)(O)=O.C([O-])(O)=O.[Na+].II.[Na+].[I-]>O.ClCCCl>[CH2:7]([C:9]1[C:13]([CH3:14])=[C:12]([I:1])[NH:11][C:10]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:8]
Reactant: CCOC(=O)c1[nH]cc(C)c1CC
Reactant: Ic1ccc[nH]1
Agent: CCOC(=O)c1[nH]c(C(=O)O)c(C)c1CC
Agent: II
Agent: O=C([O-])O
Solvent: ClCCCl
Solvent: O
Product: CCOC(=O)c1[nH]c(I)c(C)c1CC
Temperature: 25 °C

Procedure:
This procedure is an adaptation of a general iodopyrrole formation procedure (Collman, J. P.; Chong, A. O.; Jameson, G. B.; Oakley R. T.; Rose, E.; Schmittou, E. R.; Ibers, J. A. J. Am. Chem. Soc. 1981, 103, 516-533) where pyrrole (13) has been substituted for ethyl 5-carboxy-3-ethyl-4-methylpyrrole-2-carboxyate. A solution of NaHCO3 (15.7 g, 0.19 mol) in 60 ml H2O was heated to 50° C. in a 1 L round bottom flask. To this was added 700 ml of 1,2-dichloroethane followed by ethyl 3-ethyl-4-methylpyrrole-2-carboxylate (13) (Barton, D. H. R.; Zard, S. Z. J. Chem. Soc. Chem. Comm. 1985, 1098-1100. Sessler, J. L.; Johnson, M. R.; Creager, S.; Fettinger, J.; Ibers J. A. to be submitted to J. Am. Chem. Soc.) (10 g, 55 mmol). A solution of I2 (15.7 g, 62 mmol) and NaI (19.8 g, 0.13 mol) in 60 ml H2O was then added portionwise to the mixture over a 5 minute period. Undissolved I2 was washed into the mixture with H2O and the resulting mixture was heated at reflux for one hour. The mixture was then cooled to room temperature and crystalline Na2S2O3 (4 g) added to discharge excess iodine. The mixture was then transferred to a separatory funnel, the organic layer separated, and the aqueous phase washed with CHCl3 (3×50 ml). The combined organic layers were washed with a 5% solution of Na2S2O3 (3×50 ml), a 5% solution of NaHCO3 (3×50 ml), a saturated brine solution (3×50 ml), and dried over Na2SO4 before the solvent was removed on the rotorary evaporator to leave an off-white solid which was recrystallized from CH hexanes giving a first crop of 11.8 g (70%) with m.p. 122°-124° C. (lit. Collman, J. P.; Chong, A. O.; Jameson, G. B.; Oakley R. T.; Rose, E.; Schmittou, E. R.; Ibers, J. A. J. Am. Chem. Soc. 1981, 103, 516-533 m.p. 120°-121° C.).
Reaction SMILES: [NH2:1][C:2](=[C:10]([C:15](=O)[CH:16]([CH3:18])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1.CN(C)C(=O)C.[C:26]([N:28]([CH3:33])[S:29]([CH3:32])(=[O:31])=[O:30])#[N:27].[H-].[Na+]>O>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]2[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH:16]([CH3:18])[CH3:17])[N:27]=[C:26]([N:28]([S:29]([CH3:32])(=[O:31])=[O:30])[CH3:33])[N:1]=2)=[CH:4][CH:5]=1
Reactant: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Reactant: CN(C#N)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Reaction time: 6 h
Yield: 29.1 %

Procedure:
2.66 g (10.0 mmol) of methyl 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate were introduced into 12 g of N,N-dimethylacetamide together with 2.70 g (20.0 mmol) of N-cyano-N-methylmethanesulphonamide. 440 mg (11.0 mmol) of sodium hydride (60% in oil) were added to this solution at room temperature over the course of 2 h. An orange-red clear solution was obtained. After 6 h at room temperature, the reaction solution was poured onto 25 ml of water. The suspension was stirred in an ice bath for 30 minutes, and the precipitate was filtered off and washed with water (2×10 ml). After drying in a high vacuum, 1.11 g (29.1%) of methyl 4-(4-fluorophenyl)-6-isopropyl-2-(N-methanesulphonyl-N-methylamino)pyrimidine-5-carboxylate were obtained in the form of a pale beige solid. The product still contained traces of methyl 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate.
Reaction SMILES: [C:1]([O:5][P:6]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])([O:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:35])[C@@H:23]([CH3:34])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:33])([CH3:32])[C:28](=O)[CH2:29][CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl.[NH2:48][OH:49]>C(O)C>[C:37]([O:36][P:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])([O:8][C:9]1[C:10]2[CH2:22][C@:21]3([CH3:35])[C@@H:23]([CH3:34])[CH2:24][CH2:25][C@H:26]4[C:27]([CH3:33])([CH3:32])[C:28](=[N:48][OH:49])[CH2:29][CH2:30][C@@:20]34[O:19][C:11]=2[C:12]2[CH2:13][NH:14][C:15](=[O:18])[C:16]=2[CH:17]=1)=[O:7])([CH3:39])([CH3:40])[CH3:38]
Reactant: C[C@H]1CC[C@H]2C(C)(C)C(=O)CC[C@]23Oc2c(c(OP(=O)(OC(C)(C)C)OC(C)(C)C)cc4c2CNC4=O)C[C@]13C
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: C[C@H]1CC[C@H]2C(C)(C)C(=NO)CC[C@]23Oc2c(c(OP(=O)(OC(C)(C)C)OC(C)(C)C)cc4c2CNC4=O)C[C@]13C
Temperature: 25 °C
Reaction time: 7 h
Yield: 94.2 %

Procedure:
To a solution of Compound (62) (375 mg, 0.67 mmol) in 10 ml of ethanol was added 1.08 ml (13.4 mmol) of pyridine and 70 mg (1.00 mmol) of hydroxylamine hydrochloride, and the mixture stirred for 7 hours at room temperature. The reaction mixture was concentrated under reduced pressure to a half volume, and ethyl acetate and water were added thereto. After neutralizing with 0.2N HCl, the mixture was extracted with ethyl acetate. The extract was washed with an aqueous saturated sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (silica gel 18 g; chloroform:methanol=19: 1) to give 373 mg (97%) of Compound (63).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:25]4[CH:26]=[CH:27][CH:28]=[C:29]([CH3:30])[C:24]=4[CH3:23])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: Cc1cccc(B(O)O)c1C
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(C)c4C)c3O2)cc1
Yield: 62.8 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.305 mmol) with (2,3-dimethyl-phenyl)boronic acid (0.294 g, 1.96 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.041 g, 0.052 mmol), and potassium carbonate (0.41 g, 3.25 mmol) generally according to the procedure described for Intermediate 37 provided 0.335 g (62%) of (±)-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate. Treatment of (±)-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate with sodium azide (0.134 g, 2.06 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-7 amine. To a solution of (±)-2-(azidomethyl)-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-7 amine (0.135 g, 1.483 mmol) in tetrahydrofuran (5 mL) was added polymer supported triphenyl phosphine (0.152 g, 0.58 mmol) and the reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was filtered (celite) and the solvent removed in vacuo to provide a colorless oil. The oil was re-dissolved in isopropanol (3 mL) and hydrogen chloride (1.0 N in diethyl ether, 10.0 mL) was added. The resulting precipitate was filtered, washed (diethyl ether), and dried to afford 0.075 g (54%) of (±)-1-[7-(2,3-dimethylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine as a white solid, hydrochloride salt. mp >225° C.:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.CO[CH:15]1[CH2:19][CH2:18][CH:17](OC)O1>CC(O)=O>[Cl:1][C:2]1[C:3]([N:12]2[CH:15]=[CH:19][CH:18]=[CH:17]2)=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1cc([N+](=O)[O-])c(N)cc1Cl
Solvent: CC(=O)O
Product: Nc1cc(Cl)c(-n2cccc2)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 5-chloro-2-nitro-1,4-phenylenediamine [CAS-no. 26196-45-2] (4.69 g, 25 mmol), 2,5-dimethoxytetrahydrofuran (4.2 mL, 32.5 mmol) in HOAc (150 mL) at 95° C. for 2 h according to the general procedure F. Obtained as a red solid (4.10 g).