Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[NH:5][C:6]1[C:7](I)=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].[C:14]([O:18][C:19](=[O:30])[NH:20][C@H:21]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]#[CH:28])[C:22]1=[O:29])([CH3:17])([CH3:16])[CH3:15].C#C.N12CCCN=C1CCCCC2>C(#N)C.CO.CN(C=O)C.O.CCOC(C)=O.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.[Cu](I)I.C(N(CC)CC)C>[CH2:1]([O:3][C:4]([N:5]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH:28]=[C:27]1[CH2:26][N:23]1[CH2:24][CH2:25][C@H:21]([NH:20][C:19]([O:18][C:14]([CH3:16])([CH3:15])[CH3:17])=[O:30])[C:22]1=[O:29])=[O:13])[CH3:2]
Reactant: CCOC(=O)Nc1cccnc1I
Reactant: C#CCN1CC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: C#C
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CC#N
Product: CCOC(=O)n1c(CN2CC[C@H](NC(=O)OC(C)(C)C)C2=O)cc2ncccc21
Temperature: 100 °C
Yield: 10.7 %

Procedure:
A mixture of (2-iodo-pyridin-3-yl)-carbamic acid ethyl ester (0.6 g, 2.05 mmol), (2-oxo-1-prop-2-ynyl-pyrrolidin-3-(S)-yl)-carbamic acid tert-butyl ester (0.49 g, 2.05 mmol), Pd(PPh3)2Cl2 (72 mg), copper iodide (12 mg) and triethylamine (1.1 mL) in 4 mL of acetonitrile is heated in a sealed tube at 100° C. for 18 hours. After cooling, the reaction mixture is diluted with MeOH and filtered through a Celite pad. The filtrate is concentrated in vacuo. The residue is diluted with EtOAc and washed with water (4×). The combined aqueous layers are extracted with EtOAc (2×). The combined organic layers are washed with water, then dried over MgSO4, filtered and concentrated to yield the crude intermediate coupled acetylene. IS MS, [M+H]+=403. The crude acetylene intermediate is dissolved in 16 mL of DMF and treated with 1,8-diazabicyclo[5.4.0]undec-7ene (DBU) (0.58 mL, 4.1 mmol). The mixture is heated at 60° C. for 2 hours. After cooling, the resulting mixture is diluted with water and EtOAc and the layers are separated. The organic layer is washed with water and then dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with 90% EtOAc/CH2Cl2 to yield the title compound (0.07 g, 0.22 mmol) as a beige solid.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][O:9][C:10]([O:21][CH3:22])([O:19][CH3:20])[C:11](=[O:18])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1.[Cl-].[NH4+]>[CH3:22][O:21][C:10]([O:19][CH3:20])([O:9][CH3:8])[C:11](=[O:18])[CH2:12][CH:13]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: BrCc1ccccc1
Reactant: COC(=O)CCC(=O)C(OC)(OC)OC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(CC(=O)C(OC)(OC)OC)Cc1ccccc1
Temperature: -78 °C

Procedure:
To a solution of 0.98 ml diisopropylamine in 13 ml anhydrous tetrahydrofuran 4.29 ml 1.5M n-butyllithium (in hexane solution) was added under nitrogen gas atmosphere, while stirring the solution at -78° C. After the mixture was stirred for 15 minutes, a solution of 1.18 g dimethyl 2-oxoglutarate dimethyl ketal in 7 ml anhydrous tetrahydrofuran was added over a period of 15 minutes, then the resulting mixture was stirred for 15 minutes. A solution of 0.76 ml benzyl bromide and 0.28 ml hexamethylphosphoramide in 7 ml anhydrous tetrahydrofuran was added over a period of 5 minutes, and the resulting mixture was stirred at -78° C. for 30 minutes. The reaction mixture, after raising temperature to -20° C. over a period of 2 hours with stirring, was diluted with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The resulting extract was washed with water and dried (MgSO4), then the solvent was evaporated. The resulting residue was eluted with hexane-ethyl acetate (5:1→2:1) via column chromatography using silica gel to yield 1.64 g dimethyl 4-benzyl-2-oxoglutarate dimethyl ketal in the form of a light yellow oily substance.
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@@H:10]([C@@H:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=2)[CH3:21])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C@H:20]([C@@H:10]2[C@@H:11]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[CH2:12][NH:8][CH2:9]2)[CH3:21])=[N:24][CH:25]=1
Reactant: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(Cl)cc1
Temperature: 100 °C
Yield: 64 %

Procedure:
To a solution of 2-{(S)-1-[(3R,4S)-1-benzyl-4-(4-chloro-phenyl)-pyrrolidin-3yl]-ethoxy}-5-chloro-pyridine 220 mg (0.51 mmol) dissolved in toluene (5 mL) were added 0.17 mL (1.53 mmol) of 1-chloroethyl chloroformate and 0.27 mL (1.53 mmol) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (10 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 110 mg (62%) of the title compound as a light yellow oil. ES-MS m/e: 337.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20]C(C)(C)C)=O)[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29].[C:31](Cl)(=O)C.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:26](=[CH:27][CH:28]=1)[O:25][C:11]1([CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:20])[CH3:31])[CH2:13][CH2:12]1)[CH2:10][C:9]2=[O:29]
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(=O)OC(C)(C)C)CC1)O2
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCCN(C(C)=O)CC1)O2
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A suspension of (±)-(E)-3-[4-oxo-spiro(chromane-2,4′-azepane)-6-yl]acrylic acid methyl ester hydrochloride salt (500 mg, 1.43 mmol, Intermediate 3) in DCM (15 ml) was treated with acetyl chloride (0.121 ml, 1.72 mmol) and DIPEA (0.507 ml, 2.86 mmol) and was stirred at RT for 1. The solution was evaporated under vacuum and the crude product was purified by chromatography column (eluent: DCM/MeOH 95:5) to give (±)-(E)-3-[1′-acetyl-4-oxo-spiro(chromane-2,4′-azepane)-6-yl]-acrylic acid methyl ester (503 mg).
Reaction SMILES: [C:1]([NH2:7])(=[O:6])[CH2:2][C:3]([NH2:5])=[O:4].C[O-].[Na+].CN(C)[CH:13]=[C:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)[CH:15]=O>CO>[O:4]=[C:3]1[C:2]([C:1]([NH2:7])=[O:6])=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=2)=[CH:13][NH:5]1
Reactant: CN(C)C=C(C=O)c1cccc(C(F)(F)F)c1
Reactant: NC(=O)CC(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)c[nH]c1=O

Procedure:
To a solution of 1.1 g. of malonamide and 1.1 g. of sodium methoxide in 50 ml. of methanol is added 2.43 g. of 3-(dimethylamino)-2-[3-(trifluoromethyl)phenyl]-2-propenal. The resulting mixture is heated at reflux temperature for 12 hours. The mixture is cooled, concentrated and acidified with hydrochloric acid to yield 800 mg. of the product of the Example as a yellow solid m.p. 276.5°-278.5° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][N:12]=2)=[O:7])[CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[O:9][C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][N:12]=2)=[O:7])[CH2:3]1)(=[O:29])=[O:28]
Reactant: O=C(c1nnc(-c2ccccc2)o1)N1CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A suspension of 53A (2.00 g, 8.16 mmol) in dichloromethane (200 mL) was cooled in an ice-bath. Triethylamine (1.58 mL, 11.42 mmol) was added followed by methane-sulfonyl chloride (0.85 mL, 11.01 mmol). After the addition, the cooling bath was removed. The mixture was stirred overnight and then transferred to a separatory funnel. The mixture was washed with water and then with aqueous NaHCO3. The organic solution was dried (phase separator) and evaporated. There was obtained 2.58 g (98%) of 53B as a solid. 1H NMR (500 MHz, CDCl3): δ 3.13 (s, 3H), 4.43 (dd, 1H), 4.64 (dd, 1H), 4.87 (dd, 1H), 5.12 (dd, 1H), 5.40 (m, 1H), 7.54 (t, 2H), 7.59 (t, 1H), 8.15 (d, 2H), MS (APCI+) m/z 324 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22]Cl)[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[I:33])[C:28]#[N:29].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][O:24][C:25]1[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[CH:31][C:32]=1[I:33])[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCl)CCC(=O)OCc1ccccc1
Reactant: N#Cc1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)COc1cc(C#N)ccc1I

Procedure:
8.29 g (24.3 mmol) of benzyl (4R)-4-t-butoxycarbonylamino-5-chloropentanoate, 6.9 g (28.0 mmol) of 3-hydroxy-4-iodobenzonitrile, 6.9 g (50 mmol) of potassium carbonate and 4.15 g (25 mmol) of potassium iodide were stirred together in 80 ml of DMF at 70° C. for 3 days. The solvent was evaporated, and the crude product obtained by an ordinary method with ethyl acetate as the extracting solvent was purified by the silica gel chromatography (ethyl acetate/hexane) to obtain the title compound.
Reaction SMILES: O=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[NH:3]1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2[nH]c(=O)[nH]c2c1
Product: COC(=O)c1ccc2nc(Cl)[nH]c2c1

Procedure:
Methyl 2-oxo-2,3-dihydro-1H-benzimidazole-6-carboxylate (43 g, 0.22 mol) was charged into phosphorus oxychloride (286 ml). Dry hydrogen chloride was bubbled through the boiling reaction mass for 12 hours. After cooling a reaction mass was poured into a mixture of ice and water (2 kg). Precipitate was filtered out. Filtrate was diluted with water (1.25 1) and ammonia solution (˜800 ml), after that pH was adjusted to 5.6 with ammonia solution. Precipitate was filtered and rinsed with water. Yield was 39.5 g (84%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[CH:12][C:11]([F:22])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:23]C(C)([O-])C.[K+].O1CCCC1.[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:23])[C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[CH:12][C:11]([F:22])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)c1[nH]c2ccc(F)cc2c1Nc1ccncc1
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Nc2ccncc2)c2cc(F)ccc2n1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
Stir at 0° C., a solution of 5-fluoro-3-(4-pyridinylamino)-1H-indole-2-carboxylic ethyl ester (0.195 mg, 0.65 mmol) in dimethylformamide (3.0 mL) and add a solution of 1M potassium tert-butoxide in tetrahydrofuran (0.8 mL, 0.8 mmol). Stir for 0.5 to 1 h at 0° C. and add lodomethane (0.05 mL, 0.78 mmol). After 1 h, add saturated aqueous ammonium chloride solution (5 mL) and ethyl acetate (10 mL). Separate the layers and reextract with ethyl acetate. Combine the organic layers and wash with water (3×'s), brine and dry with MgSO4. Concentrate the extract to obtain 60 mg (30%) of the title compound as a brown solid: ESI/MS 314 (M+H); HPLC: Rt=1.50 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1.[NH2:23][CH2:24][C:25]1[CH:33]=[CH:32][C:28]([C:29]([NH2:31])=[O:30])=[CH:27][CH:26]=1>>[NH2:31][C:29]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:20]([C:17]2[CH:16]=[CH:15][C:14]([C:3]3[CH:4]=[C:5]([C:8]4[O:9][C:10]([CH3:13])=[N:11][N:12]=4)[CH:6]=[CH:7][C:2]=3[CH3:1])=[CH:19][CH:18]=2)=[O:21])=[CH:33][CH:32]=1)=[O:30]
Reactant: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)O)cc3)c2)o1
Reactant: NCc1ccc(C(N)=O)cc1
Product: Cc1nnc(-c2ccc(C)c(-c3ccc(C(=O)NCc4ccc(C(N)=O)cc4)cc3)c2)o1

Procedure:
N-[4-(Aminocarbonyl)benzyl]-2′-methyl-5′-(5methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from 2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxylic acid and 4-aminomethylbenzamide using method H. NMR; δH [2H6]—DMSO 9.20,(1H, t), 8.01,(2H, d), 7.93,(1H, b), 7.89,(1H, dd), 7.83,(2H, d), 7.77,(1H, d), 7.54,(3H, m), 7.39,(2H, d), 7.32,(1H, b), 4.54,(2H, d), 2.56,(3H, s), 2.31,(3H, s). LCMS; retention time 2.82 min, MH+ 427.
Reaction SMILES: BrC1C=CC2N(N=C(N(C)C)N=2)C=1.[C:14]([O:18][C:19](=[O:36])[NH:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([N:27]=[C:28]([N:30]3[CH2:35]COC[CH2:31]3)[N:29]=2)[CH:26]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19](=[O:36])[NH:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([N:27]=[C:28]([N:30]([CH3:31])[CH3:35])[N:29]=2)[CH:26]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Agent: CN(C)c1nc2ccc(Br)cn2n1
Product: CN(C)c1nc2ccc(NC(=O)OC(C)(C)C)cn2n1

Procedure:
Using (6-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-dimethyl-amine, this compound was prepared following the same method as for the synthesis of (2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-carbamic acid tert-butyl ester. Reddish yellow solid (250 mg, 33%). MS: m/z=278 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9](Cl)(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>N1C=CC=CC=1>[Br:1][C:2]1[C:3]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1Br
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ncccc1Br
Temperature: 80 °C

Procedure:
3-Bromopyridin-2-amine (500 mg, 2.89 mmol) and pivaloyl chloride (420 mg, 3.48 mmol) were added to a 50 mL round-bottomed flask. Pyridine (10 mL) was then added and the mixture stirred and heated at 80° C. for 4 h. The reaction was then cooled to rt and stirred overnight. The reaction mixture was then concentrated to dryness and the resultant residue subjected to FCC to provide the title compound. MS (ESI): mass calcd. for C10H13BrN2O, 256.02; m/z found, 257.1 [M+H]+.
Reaction SMILES: C([O:3]P(OCC)OCC)C.[OH-].[K+].[CH3:13][N:14]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=[C:15]1[CH:22]([CH3:24])[CH3:23].O=O>O=P(N(C)C)(N(C)C)N(C)C.O.C(O)(=O)C>[OH:3][C:22]([C:15]1[N:14]([CH3:13])[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]=1)([CH3:24])[CH3:23]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)c1ncc([N+](=O)[O-])n1C
Agent: O=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: Cn1c([N+](=O)[O-])cnc1C(C)(C)O
Reaction time: 2.5 h
Yield: 21.6 %

Procedure:
A total of 11.2 ml of triethylphosphite and 6 g of powdered potassium hydroxide were added to a solution of 8.5 g of 1-methyl-2-isopropyl-5-nitroimidazole in 40 ml of hexametapol while cooling in an ice-bath. While the solution was further cooled with ice, oxygen was conducted through the solution with vigorous stirring. After 2.5 hours, 6.1 ml of glacial acetic acid were added and the mixture was then poured into 600 ml of water and extracted four times with 150 ml portions of ether. The ether extracts were washed with a small amount of water, evaporated on a rotary evaporator and finally dried at 85°/0.5 Torr. The residue was crystallized from 15 ml of isopropyl ether. There were obtained 2.0 g of 2-(2-hydroxy-2-propyl)-1-methyl-5-nitroimidazole, melting point 102°-107°. The yield was 21.6%.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:21][CH2:22][CH2:23][NH:24]C(OCC1C=CC(OC)=CC=1)=O)[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])=[O:8])(=[O:3])[CH3:2].[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[C:1]([S:4][CH2:5][CH:6]([CH2:21][CH2:22][CH2:23][NH2:24])[C:7]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:16])[NH2:17])=[O:8])(=[O:3])[CH3:2]
Reactant: COc1ccc(COC(=O)NCCCC(CSC(C)=O)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)SCC(CCCN)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O

Procedure:
A solution of Nα -[2-acetylthiomethyl-5-(p-methoxybenzyloxycarbonylamino)pentanoyl]-L-arginine (1 g) in trifluoroacetic acid (10 ml) is stored at room temperature for fifteen minutes, and then concentrated to dryness in vacuo to yield Nα -(2-acetylthiomethyl-5-aminopentanoyl)-L-arginine trifluoroacetate.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:4][C:3]=1[OH:13].[C:14](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:9][CH2:10][CH2:11][O:12]2)[CH:5]=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: Oc1ccc(C2OCCO2)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COc1ccc(C2OCCO2)cc1Br
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
A mixture of 2-bromo-4-(1,3-dioxolan-2-yl)phenol (3a, 2.0 g, 8.2 mmol) and oven-dried potassium carbonate (2.7 g, 20.0) in dry acetone (20 mL) was stirred for 10 min. Dimethyl sulfate (0.9 mL, 10.0 mmol) was added dropwise to the reaction mixture and the mixture was stirred at room temperature for 18 h. Excess potassium carbonate was filtered off and washed with acetone (3×10 mL). Solvent was evaporated under reduced pressure and water (25 mL) was added. The mixture was extracted with chloroform (3×100 mL) and the organic phase was dried over Na2SO4 and evaporated under reduced pressure. The residue was column chromatographed on silica gel eluting with 20% ethyl acetate in hexanes to afford compound 4b (1.9 g, 91% yield) as a colorless oil. Rf=0.51 (25% EtOAc-hexanes); 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J=2.1 Hz, 1H), 7.33 (dd, J=8.4, 2.1 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H), 5.68 (s, 1H), 4.02 (m, 4H), 3.84 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 156.3, 131.3, 126.8, 111.3, 102.6, 65.1, 56.1.
Reaction SMILES: O[C:2]1[N:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.P(Cl)(Cl)([Cl:12])=O>>[Cl:12][C:2]1[N:3]=[N:4][CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cnnc(O)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cnnc(Cl)c1
Temperature: 75 °C
Reaction time: 0.03 h
Yield: 78.2 %

Procedure:
3-Hydroxy-5-methoxypyridazine (629.6 g, 4.99 moles) and phosphorus oxychloride (2.5 L, 27 moles) were added to a 5 L round bottomed flask equipped with a heating mantle and a mechanical stirrer. The resulting stirred slurry was rapidly heated (<30 min) to 75° C. At this temperature the heating mantle was removed. The reaction mixture continued to exotherm to a final temperature of 82.3° C. After the solids had dissolved in the darkening reaction mixture, stirring was continued an additional 2 minutes. The homogeneous reaction mixture was then rapidly cooled to room temperature with an ice/water bath. The reaction mixture was concentrated via rotary evaporator using pump vacuum and a water bath temperature of 45° C. The residue was taken up in 2 L of CH2Cl2 and slowly poured into a stirring mixture of 2 L CH2Cl2 and 6 L of H2O chilled to 10° C. The layers were separated and enough 50% NaOH was added to the aqueous phase to give a pH of 2-4. The aqueous phase was extracted with additional CH2Cl2 (2×2 L). The combined organic layers were washed with 4 L of H2O and dried (MgSO4). The solution was vacuum filtered through 1 kg of silica gel. The silica gel was washed with 4 L of ethyl acetate/hexane (1:1). The filtrate was concentrated in vacuo to afford 564 g (78% yield) of 3-chloro-5-methoxypyridazine as a pale yellow solid. The product was stored in a freezer to prevent gradual decomposition. The product was recrystallized from ethyl acetate/cyclohexane to give a white solid, mp=98°-100° C.
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].CCN(CC)CC.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)(=O)C>[CH3:34][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O:16]/[CH:1]=[CH:2]\[CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCC/C=C\CCCO
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC=CC/C=C\OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 84.7 %

Procedure:
A 10 mL round bottom flask was charged with 21 (0.48 g, 2.12 mmol), Et3N (590 μL, 4.24 mmol), 4-dimethylaminopyridine (0.03 g, 0.21 mmol), and CH2Cl2 (5 mL) under an argon atmosphere. The solution was cooled to 0° C., and a solution of 4-toluenesulfonyl chloride (0.61 g, 3.18 mmol) in CH2Cl2 (1 mL) was added drop wise. The mixture was stirred vigourously for 4 hours at room temperature. The reaction mixture was treated with saturated aqueous NaHCO3 (10 mL). After stirring at room temperature for 20 minutes, ethyl acetate (20 mL) was added. The organic layer was separated and washed with water (3×100 mL) and brine (50 mL), and dried over MgSO4. The solution was filtered and the solvent was removed in vacuo. Flash chromatography of the residue (SiO2, using a gradient of 2:1 hexanes/CH2Cl2 to 1:1 hexanes/CH2Cl2) provided 22 (0.68 g, 84% yield, 84% Z as determined by 13C-NMR) as a colorless oil; 1H NMR (CDCl3): δ 7.79 (2H, d, J=8.3 Hz), 7.33 (2H, d, J=8.9 Hz), 5.19-5.40 (2H, m), 4.02 2H, t, J=6.4 Hz), 2.44 (3H, s), 1.91-2.08 (4H, m), 1.66-1.71 (2H, m), 1.25 (16H, m), 0.88 (3H, t, J=7.0 Hz); 13C NMR (100 Hz, CDCl3): δ 144.8, 144.7, 133.3, 131.8, 129.9, 128.0, 127.8, 127.4, 70.2, 32.6, 32.0, 29.7 (2C), 29.6 (2C), 29.5, 29.4, 29.0, 27.3, 23.1, 22.8, 14.3; HRMS (FAB): 381.2477, [C22H36O3S+H]+ requires 381.2458.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14]C)=[CH:11][CH:12]=2)[N:7]([CH2:16][CH3:17])[C:6]=1[CH3:18])=[O:4].B(Br)(Br)Br>>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[N:7]([CH2:16][CH3:17])[C:6]=1[CH3:18])=[O:4]
Reactant: CCn1c(C)c(C(=O)NC)c2ccc(OC)cc21
Agent: BrB(Br)Br
Product: CCn1c(C)c(C(=O)NC)c2ccc(O)cc21
Yield: 84.9 %

Procedure:
This material was prepared from 1-ethyl-6-methoxy-2-methyl-1H-indole-3-carboxylic acid methylamide 71d (350 mg, 1.42 mmole) by treatment with BBr3 in a manner as previously described for example 1d to give 280 mg product as white solid (85% yield). 1H NMR (400 MHz, CDCl3) δ7.48 (1H, d, J=8.3 Hz), 6.73-6.77 (2H, m), 6.01 (1H, bs), 4.04 (2H, q, J=7.2 Hz, 3.03 (3H, d, J=4.9 Hz), 2.66 (3H, s), 1.31 (3H, t, J=7.2 Hz).