Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:25]([O-])=O)[C:5]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([N:17]3[CH2:23][CH2:22][CH2:21][N:20]([CH3:24])[CH2:19][CH2:18]3)=[O:16])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[OH-].[K+].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>O>[NH2:25][C:4]1[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([CH2:14][C:15]([N:17]3[CH2:23][CH2:22][CH2:21][N:20]([CH3:24])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH2:13]2)=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: CN1CCCN(C(=O)CC2CCN(c3ncc(Br)cc3[N+](=O)[O-])CC2)CC1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: O
Product: CN1CCCN(C(=O)CC2CCN(c3ncc(Br)cc3N)CC2)CC1
Temperature: 60 °C
Yield: 56.3 %

Procedure:
To a mixture of 0.500 g (1.13 mmol) of 2-(5′-bromo-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-1-(4-methyl-[1,4]diazepan-1-yl)-ethanone in water (25 mL) is added 1.0 g (17 mmol) of potassium hydroxide followed by 1.2 g (11 mmol) of sodium hydrosulfite. The mixture is heated at 60° C. for 4 hours then cooled to room temperature and the pH of the solution adjusted to neutral by the addition of a 2 N solution of hydrochloric acid. The mixture is extracted with a 3:1 mixture of methylene chloride:isopropanol and the combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide 0.261 g (56.0%) of 2-(3′-amino-5′-bromo-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-1-(4-methyl-[1,4]diazepan-1-yl)-ethanone.
Reaction SMILES: [C:1](Cl)(=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br:10][C:11]1[CH:17]=[C:16]([CH3:18])[C:14]([NH2:15])=[C:13]([CH3:19])[CH:12]=1>C(#N)C>[Br:10][C:11]1[CH:17]=[C:16]([CH3:18])[C:14]([NH:15][C:1](=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[C:13]([CH3:19])[CH:12]=1
Reactant: CCCCCCC(=O)Cl
Reactant: Cc1cc(Br)cc(C)c1N
Solvent: CC#N
Product: CCCCCCC(=O)Nc1c(C)cc(Br)cc1C
Temperature: 70 °C
Yield: 32 %

Procedure:
Heptanoyl chloride (16 mg) was added to 4-bromo-2,6-dimethyl-aniline (20 mg) dissolved in acetonitrile and heated to 70° C. for 16 hours. The reaction mixture was concentrated in vacuo, redissolved in dimethyl sulfoxide/methanol (1:1, 0.5 mL) and subjected to preparative LC-MS purification to furnish 10 mg (33% yield) of the title compound as an oil. LC-MS (m/z) 313 (MH+); tR=3.33, (UV, ELSD) 93%, 100%.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:34])([F:33])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]([NH:19][C:20](=[O:32])[N:21]([CH3:31])[C:22]2[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[N:8]=1.[CH3:35]I>C1COCC1>[CH3:35][N:19]([C:9]1[N:8]=[C:7]([O:6][CH2:5][C:4]([F:3])([F:33])[F:34])[CH:12]=[C:11]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[N:10]=1)[C:20](=[O:32])[N:21]([CH3:31])[C:22]1[S:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1
Reactant: CN(C(=O)Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1)c1ccc(C(F)(F)F)s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C(=O)N(C)c1ccc(C(F)(F)F)s1)c1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (18 mg, 0.36 mmol) in anhydrous THF (3 mL) was added a solution of the 3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-methyl-1-(5-(trifluoromethyl)thiophen-2-yl)urea (2) (150 mg, 0.30 mmol). The reaction was stirred for 10 minutes after which time gas evolution had subsided. To the reaction was added methyl iodide (51.2 mg, 0.36 mmol). The reaction was stirred at ambient temperature for 2 h. The reaction was quenched with H2O (5 mL) and extracted with t-butyl ethyl ether (3×5 mL). The organics were combined and extracted with an equal amount of H2O. The organics were dried (MgSO4), filtered and concentrated to afford crude product. The crude material was purified by silica gel chromatography (5% EtOAc in pet ether) to afford 3-methyl-3-(4,6-bis(2,2,2-trifluoroethoxy)pyrimidin-2-yl)-1-methyl-1-(5-(trifluoromethyl)thiophen-2-yl)urea (6) as an off white solid (31 mg, 20%), mp 113-114° C.; 1H NMR (400 MHz, Acetone-d6) δ 7.35-7.24 (m, 1H), 6.73 (d, J=4.2 Hz, 1H), 5.88 (s, 1H), 4.76 (q, J=8.7 Hz, 4H), 3.35 (s, 3H), 3.28 (s, 3H); ESIMS m/z 513 ([M+H]+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.OO.O.C(=O)(O)[O-].[Na+].[ClH:21]>>[Cl:21][C:3]1[CH:4]=[C:5]([C:9]([F:12])([F:10])[F:11])[C:6]([NH2:8])=[N:7][C:2]=1[CH3:1]
Reactant: Cl
Reactant: Cc1ccc(C(F)(F)F)c(N)n1
Agent: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: O
Product: Cc1nc(N)c(C(F)(F)F)cc1Cl
Reaction time: 0.33 h
Yield: 99.2 %

Procedure:
6-Methyl-3-(trifluoromethyl)pyridin-2-amine (59 mg, 335 μmol, Eq: 1.00) was suspended in 37% HCl aq (4.13 ml) and 35% hydrogen peroxide aq (488 mg, 440 μl, 5.02 mmol, Eq: 15) was added dropwise. The mixture was stirred for 20 min. Water (50 ml) was added. The mixture was alkalized by addition of sodium bicarbonate and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to an oil. The product (70 mg, 99.2%) was obtained as a light yellow solid by column chromatography (SiO2, ethyl acetate/n-heptane). MS: m/z=211.2 (M+H+)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=2)[NH:13][C:12]=1[C:22](O)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25]([N:28](C(C)C)CC)(C)C.Cl.CN.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:21][O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:22](=[O:23])[NH:28][CH3:25])=[C:11]2[CH2:10][CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2[nH]c(C(=O)O)c(CCNC(=O)OC(C)(C)C)c2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1[nH]c2ccc(OC)cc2c1CCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-{2-[(tert-butoxycarbonyl)amino]ethyl}-5-methoxy-1H-indole-2-carboxylic acid (500 mg), diisopropylethylamine (1.28 mL), methylamine hydrochloride (303 mg), and N,N-dimethyl formamide (10.0 mL) was added 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (853 mg), followed by stirring at room temperature overnight. To the mixture was added ice water, followed by extraction with ethyl acetate, and the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The insoluble materials were separated by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 20:1) to obtain tert-butyl {2-[5-methoxy-2-(methylcarbamoyl)-1H-indol-3-yl]ethyl}carbamate (520 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18]N=C[CH:15]=2)[CH:13]=1)=[O:7].O=[C:27]1C(C(O)=O)=CC(C2C=NC=CC=2)=N[NH:28]1.C(Cl)(=O)C(Cl)=O.ClC1C=C(Cl)C=CC=1CN>C(N(CC)CC)C.CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:15]=[N:28][CH:27]=[CH:18][CH:19]=2)[CH:13]=1)=[O:7]
Reactant: O=C(O)c1cc(-c2cccnc2)n[nH]c1=O
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Agent: NCc1ccc(Cl)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2cccnc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-3-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 1 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.21 cm3 of 2,4-dichlorobenzylamine and 0.22 cm3 of triethylamine, and after purification by chromatography on silica gel (particle size 40-63 μm, under an argon pressure of 150 kPa), eluting with a mixture of dichloromethane and methanol (90/10 by volume), 0.204 g of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-3-yl-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a cream-colored solid melting at a temperature in the region of 260° C.
Reaction SMILES: [C:1]([O-:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7].C1[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2O)[C@H](O)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O)[C@H](N)[C@H]2O)[C@@H]1N.N[C@H](C(O)=O)[C@H](CC)C.C[C@]1(O)[C@@H]2C(=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3C2)C(=O)C2C(O)=CC=CC1=2>>[C:1]([OH:15])(=[O:14])[CH2:2][CH2:3][NH:4][C:5](=[O:13])[C@@H:6]([C:8]([CH2:11][OH:12])([CH3:10])[CH3:9])[OH:7]
Reactant: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)[O-]
Agent: CC[C@H](C)[C@H](N)C(=O)O
Agent: CN(C)[C@@H]1C(O)=C(C(N)=O)C(=O)[C@@]2(O)C(O)=C3C(=O)c4c(O)cccc4[C@@](C)(O)[C@H]3C[C@@H]12
Agent: NC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O)[C@H](N)[C@H]3O)[C@H](N)C[C@@H]2N)[C@H](O)[C@@H](O)[C@@H]1O
Product: CC(C)(CO)[C@@H](O)C(=O)NCCC(=O)O

Procedure:
The formation of pantothenate by the C. glutamicum strains ATCC13032ΔilvA/pND-D2 and ATCC13032ΔilvA/pND-D2, pT-pfkAexp was tested in medium CGXII (Keilhauer et al., 1993, Journal of Bacteriology, 175:5595-5603; table 1), which had been supplemented with 25 μg/ml kanamycin, 2 mM isoleucine and in the case of the strain ATCC13032ΔilvA/pND-D2, pT-pfkAexp with additionally 10 μg/ml tetracycline.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH2:39][CH2:40][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCC1
Product: CCN(Cc1ccc(OCCN2CCCC2)cc1)c1cc(OC)ccc1[C@H]1CCc2cc(O)ccc2C1
Yield: 42.6 %

Procedure:
Synthesized from pivalic acid (S)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-pyrrolidin-1-ylethanone (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (8.5 mg) was obtained.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.[NH:14]1[CH2:18][CH2:17][C:16]2([C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:27])[CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.O1CCCC1.C(OCC)(=O)C>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:14]3[CH2:18][CH2:17][C:16]4([C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[NH:20][C:19]4=[O:27])[CH2:15]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Reactant: O=C1Nc2ccccc2C12CCNC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1noc(-c2ccc(N3CCC4(C3)C(=O)Nc3ccccc34)nn2)n1
Temperature: 120 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
3-Chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (690 mg) obtained in Example 43(2), spiro[indole-3,3′-pyrrolidin]-2(1H)-one (800 mg), potassium carbonate (500 mg) and tetrabutylammonium iodide (130 mg) were suspended in N,N-dimethylformamide-tetrahydrofuran (1:1, v/v, 50 mL), and the suspension was stirred at 120° C. overnight. The mixture was cooled to room temperature, diluted with ethyl acetate, and washed with aqueous sodium carbonate solution. The organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. Ethyl acetate was added and the resulting precipitate was collected by filtration, and recrystallized from ethyl acetate to give the object product (750 mg, 62%).
Reaction SMILES: C1(N)CCCC1.BrC1C(Cl)=NC(Cl)=NC=1.[Cl:16][C:17]1[N:18]=[CH:19][C:20]2[CH:25]=[C:24]([CH3:26])[N:23]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])[C:21]=2[N:22]=1>>[Cl:16][C:17]1[N:18]=[CH:19][C:20]2[CH:25]=[C:24]([CH3:26])[N:23]([CH:27]3[CH2:30][CH2:31][CH2:29][CH2:28]3)[C:21]=2[N:22]=1
Reactant: CCC(CC)n1c(C)cc2cnc(Cl)nc21
Agent: Clc1ncc(Br)c(Cl)n1
Agent: NC1CCCC1
Product: Cc1cc2cnc(Cl)nc2n1C1CCCC1

Procedure:
2-Chloro-7-cyclopentyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidine is prepared from cyclopentyl amine and 5-bromo-2,4-dichloropyrimidine using a method similar to that for the preparation of 2-chloro-7-(1-ethyl-propyl)-6-methyl-7H-pyrrolo[2,3-d]pyrimidine. given in example 328.
Reaction SMILES: Cl.[NH:2]1[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:5]2([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[O:4][C:3]1=[O:17].Cl[C:19]1[N:24]=[CH:23][N:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH3:39])[C:29]3[N:33]=[C:32]([CH2:34][CH2:35][O:36][CH3:37])[NH:31][C:30]=3[CH:38]=2)[CH:20]=1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C>[CH3:37][O:36][CH2:35][CH2:34][C:32]1[NH:31][C:30]2[CH:38]=[C:26]([O:25][C:21]3[N:22]=[CH:23][N:24]=[C:19]([N:14]4[CH2:13][CH2:12][C:5]5([O:4][C:3](=[O:17])[NH:2][C:7]6[N:8]=[CH:9][CH:10]=[CH:11][C:6]5=6)[CH2:16][CH2:15]4)[CH:20]=3)[CH:27]=[C:28]([CH3:39])[C:29]=2[N:33]=1
Reactant: COCCc1nc2c(C)cc(Oc3cc(Cl)ncn3)cc2[nH]1
Reactant: O=C1Nc2ncccc2C2(CCNCC2)O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCc1nc2c(C)cc(Oc3cc(N4CCC5(CC4)OC(=O)Nc4ncccc45)ncn3)cc2[nH]1

Procedure:
29 mg (0.11 mmol) spiro[piperidin-4,4′-pyrido[2,3-d][1,3]oxazin]-2′(1′H)-one hydrochloride, 29 mg (0.09 mmol) 6-(6-chloropyrimidin-4-yloxy)-2-(2-methoxyethyl)-4-methyl-1H-benzo-[d]imidazole and 50 μL (0.39 mmol) DIPEA in 2.0 mL DMF were stirred overnight at 50° C. The reaction mixture was purified by chromatography. The fractions containing product were combined and evaporated down i.vac. to leave the aqueous residue. This was neutralised with a 1M aqueous NaOH solution. The precipitate formed was suction filtered, washed and dried.
Reaction SMILES: [OH:1][CH:2]=[C:3]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=CN=1)=[O:5].ClC1C=C[C:23]([NH2:24])=CC=1.C(O)(=O)C.[OH-].[Na+]>CS(C)=O>[OH:1][CH:2]=[C:3]([C:13]1[O:17][N:16]=[C:15]([CH3:18])[CH:14]=1)[C:4]([NH:6][C:7]1[CH:23]=[N:24][CH:10]=[CH:11][CH:12]=1)=[O:5]
Reactant: Cc1cc(C(=CO)C(=O)Nc2ccccn2)on1
Reactant: Nc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: Cc1cc(C(=CO)C(=O)Nc2cccnc2)on1

Procedure:
General method for the synthesis of α-[4-(chlorophenylamino)methylene]-3-methyl-N-pyridyl-5-isoxazoleacetamide: α-Hydroxymethylene-3-methyl-N-pyridyl-5-isoxazoleacetamide (0.25 g, 1.0 mmol) was stirred with 4-chloroaniline (0.13 g, 1.0 mmol) and acetic acid (200 μL) in DMSO (3 mL) at rt for 24 h. The resulting solution was mixed with 10 mL of an aqueous 0.5 N NaOH solution and extracted with CH2Cl2. The organic layer was dried over Na2SO4 filtered and concentrated. The residue was then recrystallized from MeOH.
Reaction SMILES: C(O[C:6](=[O:26])[NH:7][C@@H:8]([CH2:14][NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[C@@H:9]([OH:13])[C:10]#[C:11][CH3:12])(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)C(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.[C:53]([NH:60][C@H:61](C(O)=O)[CH2:62][CH2:63][S:64][CH3:65])([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:19]([O:18][C:16](=[O:17])[NH:15][CH2:14][C@H:8]([NH:7][C:6](=[O:26])[C@@H:61]([NH:60][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:62][CH2:63][S:64][CH3:65])[C@@H:9]([OH:13])[C:10]#[C:11][CH3:12])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC#C[C@H](O)[C@H](CNC(=O)OCc1ccccc1)NC(=O)[C@H](CCSC)NC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 78.2 %

Procedure:
A solution of [1S,2S]-[1-(Benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-carbamic acid tert-butyl ester (1.19 g, 3.29 mmol, prepared as described in WO PCT 0250019) was dissolved in CH2Cl2 (20 mL) and treated with TFA (10 mL). The solution was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in CH2Cl2 and concentrated in vacuo; this procedure was repeated. The residue was dissolved in CH2Cl2 (30 mL). The resultant solution was charged sequentially with N, N-diisopropylethylamine (2.3 mL, 13.2 mmol), HOBt (466 mg, 3.45 mmol), N-Boc methionine (820 mg, 3.29 mmol), and BOP (1.53 g, 3.45 mmol). The reaction was stirred for 12 h and partitioned between EtOAc and sat. NH4Cl. The organic phase was washed with sat. NaHCO3 and brine, and then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford [2S,3S]-[2-[(2S)-(2-tert-butoxycarbonylamino-4-methylsulfanyl-butyrylamino)]-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (1.27 g, 78% yield). MS found: (M+Na)+=516.3.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:8][C:7]1[C:2]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc(OCC(F)(F)F)c(Cl)c1
Temperature: 0 °C
Yield: 85 %

Procedure:
A solution of 2,3-dichloro-5-nitro-pyridine (5 g, Synthesis, 1990 (6), 499-501), 2,2,2-trifluoroethanol (2.6 g) and potassium carbonate (5.4 g) in N,N-dimethylformamide (50 ml) was stirred at 80° C. for 1 hour. The reaction mixture was poured into ice water. The precipitate was isolated by filtration and dried under high vacuum to afford 3-chloro-5-nitro-2-(2,2,2-trifluoro-ethoxy)-pyridine (5.65 g).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[H-].[Na+].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16](Cl)(=[O:18])=[O:17]>>[Br:8][C:3]1[C:4]([CH3:7])=[N:5][O:6][C:2]=1[NH:1][S:16]([C:12]1[O:11][CH:15]=[CH:14][CH:13]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1ccco1
Reactant: Cc1noc(N)c1Br
Agent: [H-]
Agent: [Na+]
Product: Cc1noc(NS(=O)(=O)c2ccco2)c1Br
Yield: 20 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)furan-2-sulfonamide was prepared by the method of Example 1 with 5-amino-4-bromo-3-methylisoxazole (0.266 g, 1.5 mmol), NaH (60% oil dispersion) (0.15 g, 3.8 mmol) and furan-2-sulfonyl chloride (Example 36A) (0.30 mg, 1.8 mmol). Flash chromatography (50% EtOAc/hexane) and recrystallization from CHCl3 and hexane provided 90 mg (20% yield) of light yellow crystals (m.p. 117-119° C.).
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]O.C1C=CC(P([N:24]=[N+:25]=[N-:26])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.Cl.CCOCC>[N:24]([CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[I:1])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1ccccc1I
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOCC
Product: [N-]=[N+]=NCc1ccccc1I
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
To a solution of 2-iodobenzyl alcohol (6.0 g, 25.4 mmol) and DPPA (6.8 mL, 30.5 mmol) in toluene (65 mL) was added DBU (5.0 mL, 33.0 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with 3M HCl (60 mL) and ether (150 mL). The organic phase was separated and the aqueous phase was extracted with ether (×3). The combined organic extracts were washed with water (×2) and and then with brine. The solution was dried over anhydrous Na2SO4 and concentrated in vacuo. Silica gel column chromatography using 95:5 hexanes:EtOAc afforded 6.1 g (93%) of 1-azidomethyl-2-iodo-benzene.
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]2[N:8]=[CH:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[CH3:12].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Cl.[OH-].[Na+]>C(O)C>[CH3:12][C:3]1[N:4]=[C:5]2[CH:11]=[CH:10][CH:9]=[N:8][C:6]2=[N:7][C:2]=1[S:1][CH2:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=1
Reactant: ClCc1ccccn1
Reactant: Cc1nc2cccnc2nc1S
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cccnc2nc1SCc1ccccn1
Yield: 79.7 %

Procedure:
To 1.67 g of 3-mercapto-2-methylpyrido[2,3-b]pyrazine were added 10 ml of ethanol and a solution of 1.15 g of 2-picolyl chloride hydrochloride and 0.67 g of sodium hydroxide. The obtained mixture was heated under refluxing for 1.5 hrs, and then the solvent was removed under reduced pressure. The residue was extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution, and dried over sodium sulfate. The sodium sulfate was removed by filtration, and the filtrate was placed under reduced pressure to remove the solvent. The residue was dissolved in 20 ml of acetonitrile, and the insolubles were removed by filtration. The filtrate was concentrated to give 1.5 g of 2-methyl-3-(2-pyridylmethylthio)pyrido[2,3-b]pyrazine as a brown oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[CH:14].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O.[Cu]I.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>[C:15]1([C:13]#[C:14][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1[nH]nc(C#Cc2ccccc2)c2ccccc12

Procedure:
A mixture of 4-chlorophthalazin-1(2H)-one, ethynylbenzene, triethylamine, copper(I) iodide, and Pd(PPh3)4 in DMF was microwaved at 185° C. for 30 minutes, diluted with EtOAc, washed with water and saturated aqueous NH4Cl, and chromatographed to give impure 4-(phenylethynyl)phthalazin-1(2H)-one, which was used without further purification. This material was treated with O-(diphenylphosphoryl)hydroxylamine as in Example 1B to give impure 2-amino-4-(phenylethynyl)phthalazin-1(2H)-one.
Reaction SMILES: [CH:1]([NH:3][C:4]1(NC)[CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[S:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]1=2)=O.Cl.[OH-].[Na+].C(Cl)Cl>O>[CH3:1][NH:3][C:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[S:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CNC1(NC=O)c2ccccc2SC1c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CNc1c(-c2ccccc2)sc2ccccc12

Procedure:
34.2 g (0.13 mol) of 3-formamido-3-methylamino-2-phenyl-benzo(b)thiophene are refluxed with stirring for 4 hours with 300 milliliters of HCl at 25%. After cooling, it is diluted in water, made alkaline by sodium hydroxide solution and stirred with CH2Cl2. After the organic phase has been extracted several times 2 N NaOH 7.4 g (26% of theory) of 2-phenyl-thioindole are isolated. By evaporating the solution of CH2Cl2 dried over K2CO3, the 3-methylamino-2-phenyl-benzo(b)thiophene is obtained in the form of a crude oily product. It is dissolved in a little CHCl3 and converted into the hydrochloride by hydrochloric gas: 20.2 g (57% of theory) of colourless prisms in a mixture of ethanol and ether, decomposition from 198° C. (in a sealed tube).