Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:37][C:6]2[N:7]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[C:8](=[O:21])[N:9]([CH2:12][CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[C:15]3[CH2:19][OH:20])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[C:38]([Si:42](Cl)([CH3:44])[CH3:43])([CH3:41])([CH3:40])[CH3:39].C(N(CC)CC)C>C(Cl)Cl>[Si:42]([O:20][CH2:19][C:15]1[N:14]([CH2:13][CH2:12][N:9]2[C:10](=[O:11])[C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[S:37][C:6]=3[N:7]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]4[C:30]([C:35]#[N:36])=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:25][CH:24]=3)[C:8]2=[O:21])[CH:18]=[CH:17][N:16]=1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:44])[CH3:43]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1cc2c(=O)n(CCn3ccnc3CO)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc2c(=O)n(CCn3ccnc3CO[Si](C)(C)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
A mixture of 4′-{[6-ethyl-3-{2-[2-(hydroxymethyl)-1H-imidazol-1-yl]ethyl}-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g), tert-butyl(chloro)dimethylsilane (0.18 g), triethylamine (0.16 mL) and methylene chloride (20 mL) was stirred at room temperature for 4 hr. The reaction mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.61 g, 99%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:7][C:6]=2[CH:16]=1.[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][CH:25]=1)=[O:20].[Cl-].[Li+]>CN1CCCC1=O.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>[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:7][C:6]=3[CH:16]=2)=[CH:28][CH:29]=1)=[O:20]
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc1
Reactant: CS(=O)(=O)NCc1nc2cc(Br)ccc2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)NCc1nc2cc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc3)ccc2s1
Temperature: 90 °C
Yield: 1.6 %

Procedure:
To a stirred solution of N-(5-Bromo-benzothiazol-2-ylmethyl) methane sulfonamide (0.21 g, 0.656 mmol) and 2,2-Difluoro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-trimethylstannanyl-phenyl)-ethyl]-acetamide (0.404 g, 0.984 mmol) in N-Methyl-2-pyrrolidone (9 mL) is added lithium chloride (0.084 g, 1.968 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 15 minutes then Pd(PPh3)2Cl2 (0.046 g, 0.065 mmol) is added. The reaction mixture heated to 90° C. for 16 hours. Reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulfate, solvent is evaporated in vacuo to give the crude material purified by flash column chromatography using 2.4% methanol in CH2Cl2 as an eluent to give impure compound. The impure compound is again purified by prep-HPLC to give the title compound (5 mg). 1HNMR (400 MHz, DMSO) δ: 3.04 (s, 3H), 4.26-4.33 (m, 1H), 4.41-4.43 (m, 0.5H), 4.44-4.50 (m, 0.5H), 4.62 (s, 2H), 4.65-4.68 (m, 0.5H), 4.75-4.79 (m, 0.5H), 4.87-4.88 (m, 1H), 5.9 (d, J=4.56 Hz, 1H), 6.20 (d, J=56.36 Hz, 1H), 7.45 (d, J=8.24 Hz, 2H), 7.63, (d, J=8.16 Hz, 1H), 7.73 (d, J=8.28 Hz, 2H). 7.81 (d, J1=1.8 Hz, J2=8.52 Hz, 1H), 8.42 (d, J=1.6 Hz, 1H), 8.82-8.83 (m, 2H). LC-Ms (m/z): [M−H]=485.8.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].C(N(CC)CC)C>C(#N)C.[Cu](I)I.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:16]#[C:15][Si:12]([CH3:14])([CH3:13])[CH3:11])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1nc(Br)cnc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1cnc(N)c(C#N)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 3.0 grams (0.015 mole) of 2-amino-3-cyano-5-bromopyrazine and 2.1 grams (0.021 mole) of trimethylsilylacetylene in 50 mL of acetonitrile is stirred, and 10.6 mL of triethylamine, 0.13 gram of copper iodide, and 0.29 gram of bis(triphenylphosphine)palladium(II) chloride are added in order. Upon completion of addition, the reaction mixture is stirred at ambient temperature for about 20 hours. The reaction mixture is warmed to 70° C., where it is stirred for about 7.5 hours. After this time, the reaction mixture is concentrated under reduced pressure to a residue. The residue is dissolved in ethyl acetate, and the solution is washed with 50 mL of aqueous, dilute hydrochloric acid. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel. Elution is accomplished using tetrahydrofuran/methylene chloride combinations. The product-containing fractions are combined and concentrated under reduced pressure, yielding 2-amino-3-cyano-5-(trimethylsilylethynyl)pyrazine.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.Br[CH:11]([CH3:15])[C:12](=O)[CH3:13]>C(O)C>[NH2:8][C:7]1[C:2]2[N:3]([C:11]([CH3:15])=[C:12]([CH3:13])[N:1]=2)[CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1cc(Cl)cnc1N
Reactant: CC(=O)C(C)Br
Solvent: CCO
Product: Cc1nc2c(N)cc(Cl)cn2c1C
Temperature: 25 °C

Procedure:
A mixture of 2,3-diamino-5-chloropyridine (5.26 g, 36.64 mmol) and 3-bromo-2-butanone (6.2 g, 41.06 mmol) in ethanol (60 ml) was refluxed overnight. After cooling to room temperature, the crystalline product was filtered and washed with ethanol and ether. The crystals were dissolved in methylene chloride and neutralized by aqueous NaHCO3. The organic layer was separated, dried over Na2SO4 and evaporated in vacuo. Yield 3.0 g.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[OH:5][C:6]1[CH:15]=[C:14]([I:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[I:16][C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([O:5][CH:2]([CH3:4])[CH3:3])[CH:15]=1
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(I)cc1OC(C)C
Yield: 98.3 %

Procedure:
2-Iodopropane (6.42 g) was added at room temperature to a mixture of methyl 2-hydroxy-4-iodobenzoate (7.00 g), potassium carbonate (6.96 g), and DMF (100 mL), and the resultant mixture was stirred at 70 C for 2 days in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The obtained organic layer was washed with water and saturated saline in this order and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (7.92 g)
Reaction SMILES: [C@@H:1]1([NH:10][C:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[N:16][C:17]([Cl:24])=[CH:18][C:19]=3[CH3:23])[NH:14]2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.IC.N1[CH2:28]CCN2CCCCCC=12>CN(C=O)C>[C@@H:1]1([NH:10][C:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[N:16][C:17]([Cl:24])=[CH:18][C:19]=3[CH3:23])[N:14]2[CH3:28])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1cc(Cl)nc2[nH]n(C(=O)N[C@H]3CCc4ccccc43)c(=O)c12
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc(Cl)nc2c1c(=O)n(C(=O)N[C@H]1CCc3ccccc31)n2C

Procedure:
In analogy to example 2, 50 mg (0.146 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydropyrazolo[3,4-b]pyridine-2-carboxylic acid (S)-indan-1-ylamide were reacted with 31 mg (0.22 mmol) of iodomethane in DMF with 2,3,4,6,7,8,9,10-octahydro -pyrimido[1,2-a]azepin (DBU). Yield: 6 mg (12%), M+H+: 357.09.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1[C:32]([Sn](CCCC)(CCCC)CCCC)=[CH:31][N:30]=[CH:29]1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:32]4[N:28]([CH3:27])[CH:29]=[N:30][CH:31]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Cn1cncc1-c1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Yield: 89.8 %

Procedure:
The (4-benzyloxy-phenyl)-(6-bromoquinazolin-4-yl)-amine (1.0 g, 2.46 mmol), 1-methyl-5-(tributylstannyl)imidazole (prepared according to Gaare, K., et al. Acta Chem. Scand. (1993), 47(1), 57-62) (1.25 g, 3.37 mmol) and bis(triphenylphosphine)palladium (II) chloride (catalytic amount) were reacted according to Procedure B in dioxane (50 ml) for 3 hours. The solvent was removed in vacuo, and the solid was washed with i-hexane. The resulting dark solid was suspended in IMS, and undissolved material removed by filtration. The resulting filtrate was concentrated in vacuo to give the product as a pale baige solid (0.90 g, 2.21 mmol, 90%); δH [2H6]-DMSO 9.69 (1H, b, NH), 8.60 (1H, s, 5-H), 8.55 (1H, s, 2-H), 8.00 (1H, d, 7-H), 7.83 (2H, m, 8-H, imidazole-H), 7.69 (2H, d, 2′-H, 6′-H), 7.52-7.33 (5H, m, 5×Ph-H), 7.22 (1H, s, imidazole-H), 7.09 (2H, d, 3′-H, 5′-H), 5.14 (2H, s, CH2), 3.80 (3H, s, CH3); m/z 408 (M+1)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C@H:9]1[O:38][C@H:37]([CH2:39][O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:10]1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)=O.[N-:48]=[N+:49]=[N-:50].C([N+](CCCC)(CCCC)CCCC)CCC>C(C#N)(C)=O>[CH2:12]([O:11][C@@H:10]1[C@@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@H:28]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@@H:37]([CH2:39][O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[O:38][C@@H:9]1[CH2:8][CH2:7][CH2:6][N:48]=[N+:49]=[N-:50])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCCC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: CC(=O)C#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: [N-]=[N+]=NCCC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl)propyl methanesulfonate (3.78 g, 5.72 mmol) in AcCN (50 mL) was added tetrabutylammonium azide (1.66 g, 5.83 mmol). The resulting mixture allowed to reflux overnight. After cooled to rt, the reaction mixture was concentrated. The residue was dissolved in ether (50 mL), which was washed with water (2×50 mL), brine (25 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (120 g, eluting with 0-30% EtOAc in hexanes) to give the title compound. 1H NMR (CDCl3) δ 1.58-1.68 (m, 2H), 1.74-1.86 (m, 2H), 3.32-3.41 (m, 2H), 3.58-3.76 (m, 4H), 3.76-3.85 (m, 2H), 4.40 (m, 1H), 4.52 (t, J=10.4, 2H), 4.65 (dd, J=11.7, 2.5, 2H), 4.75 (d, J=11.7, 1H), 4.86 (m, 2H), 4.97 (d, J=10.8, 1H), 7.16 (m, 2H), 7.28-7.40 (m, 18H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[CH:12]=[CH:11][NH:10][C:8]=2[N:9]=1.[CH3:13]I>C1COCC1.O>[Cl:3][C:4]1[N:5]=[CH:6][C:7]2[CH:12]=[CH:11][N:10]([CH3:13])[C:8]=2[N:9]=1
Reactant: Clc1ncc2cc[nH]c2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc2cnc(Cl)nc21
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a solution of NaH (106.6 mg, 2.67 mmol) in THF (5 mL) was added 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (500 mg, 2.54 mmol) at 0° C. and stirred for 30 minutes at the same temperature. CH3I (1.5 g, 10.2 mmol) was added at 0° C. and the combined mixture stirred for 3 h at 15° C. After TLC showed the reaction was complete, the mixture was diluted with water 20 mL) and extracted with ethyl acetate EA (2×20 mL) and the combined organic layers were washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound (254 mg, 47.4%) as colorless oil which was used in next step without further purification.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[N:11]([CH:12]2[CH2:15][CH2:14][CH2:13]2)[C:10]([CH3:16])=[N:9][CH:8]=1)=O.Cl.[NH2:19][C:20]([NH2:22])=[NH:21].C[O-].[Na+]>C(O)CCC>[NH2:21][C:20]1[N:22]=[C:5]([C:7]2[N:11]([CH:12]3[CH2:13][CH2:14][CH2:15]3)[C:10]([CH3:16])=[N:9][CH:8]=2)[CH:4]=[CH:3][N:19]=1
Reactant: Cc1ncc(C(=O)C=CN(C)C)n1C1CCC1
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCCCO
Product: Cc1ncc(-c2ccnc(N)n2)n1C1CCC1
Temperature: 25 °C
Yield: 65640 %

Procedure:
5-(3-Dimethylaminoprop-2-en-1-oyl)-1-cyclobutyl-2-methylimidazole (Method 37; 466 mg, 2 mmol) and guanidine hydrochloride (476 mg, 5 mmol) were suspended in 1-butanol (10 ml). Sodium methoxide (432 g, 8 mmol) was added in one portion and the mixture heated under reflux, under an atmosphere of nitrogen, for 2 hours. The reaction mixture was allowed to cool to ambient temperature and was pre-absorbed on to silica gel and purified by column chromatography on silica gel eluting with DCM/2% methanolic ammonia (100:0 increasing in polarity to 97:3) to give the title compound (301 g, 66%). NMR: 1.73 (m, 2H), 2.45 (m, 7H), 5.36 (m, 1H), 6.58 (s, 2H), 6.72 (d, 1H), 7.24 (s, 1H), 8.16 (d, 1H); m/z 230
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[Cl:19])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(C(C)C)CC)(C)C.[CH3:31][C:32]1([CH3:40])[O:36][C@H:35]([CH2:37][O:38][NH2:39])[CH2:34][O:33]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[Cl:1][C:2]1[C:3]([F:21])=[C:4]([F:20])[C:5]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[Cl:19])=[C:6]([CH:10]=1)[C:7]([NH:39][O:38][CH2:37][C@@H:35]1[CH2:34][O:33][C:32]([CH3:40])([CH3:31])[O:36]1)=[O:9]
Reactant: O=C(O)c1cc(Cl)c(F)c(F)c1Nc1ccc(I)cc1Cl
Reactant: CC1(C)OC[C@@H](CON)O1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)OC[C@@H](CONC(=O)c2cc(Cl)c(F)c(F)c2Nc2ccc(I)cc2Cl)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
A 1L single necked round-bottomed flask equipped with a magnetic stirrer was charged with a solution of 5-chloro-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid (59.6 g, 135 mmol) in dry tetrahydrofuran (300 mL). The solution was cooled to 0° C. in an ice-acetone bath. To this solution was added diisopropylethylamine (34.8 g, 270 mmol), (S)-O-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (29.7 g, 202 mmol), 1-hydroxybenzotriazole (30.93 g, 202 mmol), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (89.32 g, 202 mmol). After 30 minutes, the cooling bath was removed, and the reaction was stirred at ambient temperature for 18 hrs. The solvent was evaporated in vacuo, and the residue was dissolved in diethyl ether. The organic solution was washed with 10% aqueous sodium hydroxide (3×500 mL) and brine, and dried (MgSO4). The solution was concentrated to afford 5-chloro-2-(2-chloro-4-iodo-phenylamino)-N-((S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-benzamide (69.9 g) as a pale yellow solid that was used directly in the next hydrolysis reaction.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([Cl:21])=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16])[N:7]=1.[CH3:22][P:23]([C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH2:33][CH3:34])[CH:27]=1)([CH3:25])=[O:24].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C.ClCCl>[Cl:21][C:5]1[N:4]=[N:3][C:2]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([P:23]([CH3:25])([CH3:22])=[O:24])=[CH:27][C:28]=2[CH2:33][CH3:34])=[N:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH:18]([CH3:20])[CH3:19])(=[O:17])=[O:16]
Reactant: CCc1cc(P(C)(C)=O)ccc1N
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)nnc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Solvent: ClCCl
Product: CCc1cc(P(C)(C)=O)ccc1Nc1nnc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Temperature: 25 °C

Procedure:
A mixture of 3,6-dichloro-N-[2-(propan-2-ylsulfonyl)phenyl]-1,2,4-triazin-5-amine (prepared as in Example 106: 0.7 mmol), 4-(Dimethylphosphoryl)-2-ethylaniline (0.7 mmol) and camphorsulfonic acid (0.7 equiv.), is refluxed for 20-48 hours in 2-propanol. The reaction mixture is allowed to cool to room temperature, dissolved in dichloromethane and washed with an aqueous solution of Na2CO3. The dichloromethane extract is dried over MgSO4 and evaporated. The crude product is purified by Prep-HPLC.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=1)=[O:15].CS(C)=O>C(#N)C>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=1)=[O:15]
Reactant: NC(=O)c1ccc(NC(=O)CCCCCCCBr)cc1
Reactant: CNCCO
Solvent: CC#N
Solvent: CS(C)=O
Product: CN(CCO)CCCCCCCC(=O)Nc1ccc(C(N)=O)cc1
Temperature: 25 °C

Procedure:
2-(Methylamino)ethanol (9.5 g, 7 equivalents) is added to a stirred mixture of 4-[(8-bromooctanoyl)amino]benzamide (5.76 g, 16.9 mmol, e.g. which can be as prepared in Intermediate 53 (first or alternative preparation thereof)) and dimethyl sulfoxide (30 mL). The mixture is stirred at 25° C. until the reaction is substantially complete and is then diluted with acetonitrile (115 mL). After stirring for 1 hour the mixture is filtered, washed with ethyl acetate (15 mL) and tert-butyl methyl ether (TBME, 15 mL) before being dried in vacuo to yield the title compound, generally as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]#[CH:10].[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][SH:17])=[CH:14][CH:13]=1.[Na]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]\[CH:16]([S:17][CH:16](/[CH:10]=[CH:9]\[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1)[C:15]1[CH:18]=[CH:19][C:12]([Cl:11])=[CH:13][CH:14]=1
Reactant: C#Cc1ccc(F)cc1F
Reactant: SCc1ccc(Cl)cc1
Agent: [Na]
Product: Fc1ccc(/C=C\C(SC(/C=C\c2ccc(F)cc2F)c2ccc(Cl)cc2)c2ccc(Cl)cc2)c(F)c1

Procedure:
A solution of 2,4-difluorophenylacetylene (0.02 mol), 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-2,4-difluorostyryl-4-chlorobenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [F:1][CH:2]([F:9])[C:3](=[O:8])[CH2:4][C:5](=O)[CH3:6].O.[NH2:11][NH2:12]>O1CCCC1>[F:1][CH:2]([F:9])[C:3]1([OH:8])[NH:12][N:11]=[C:5]([CH3:6])[CH2:4]1
Reactant: CC(=O)CC(=O)C(F)F
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: CC1=NNC(O)(C(F)F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1,1-difluoropentane-2,4-dione (2.5 g, 0.018 mol) in tetrahydrofuran (32 mL) was added hydrazine hydrate (0.98 mL, 0.020 mol) in tetrahydrofuran (32 mL) dropwise. The reaction was stirred at 25° C. for 16 hours and then concentrated in vacuo. The residue was used in the next reaction without further purification. 1H NMR (CDCl3): δ 5.68-5.96 (t, 1H), 5.50-5.80 (br s, 1H), 2.98 (dd, 1H), 2.68 (dd, 1H), 2.01 (s, 3H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C1COCC1.[Li+].CC([N-]C(C)C)C.[Br:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>CN(P(N(C)C)(N(C)C)=O)C>[Br:22][CH2:23][CH2:24][CH2:25][CH2:26][C:2]([C:1]([O:6][CH2:7][CH3:8])=[O:5])([CH3:4])[CH3:3]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCCCBr
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
In a 1-L 3-neck round-bottomed flask fitted with condenser, dropping funnel pressure equalizer and magnetic stirrer, purged with argon and maintained under argon, were added ethyl isobutyrate (84 ml, 0.63 mol) and THF (120 ml). The mixture was cooled to −78° C., when a solution of LDA (300 ml, 2.0 M in THF/heptane) was added dropwise with a syringe. After the addition was complete, the reaction mixture was stirred at −78° C. for 1 hr. To this mixture, 1,4-dibromobutane (105 ml, 0.84 mol) was added at −78° C., followed by HMPA (90 ml). The reaction mixture was stirred for 30 min at −78° C., then the cooling was stopped. The reaction was left to warm to room temperature, and was quenched with a saturated NH4Cl solution (1.8 L). The aqueous layer was extracted with ethyl acetate (3×100 ml), the organic extracts combined were washed with brine (100 ml), 5% HCl (100 ml) and saturated NaHCO3 (100 ml). The organic phase was dried (MgSO4) and the solvent was evaporated under vacuum. The residue was distilled under reduced pressure to provide the above-titled compound (105.2 g, 70%) (bp 65° C./0.15 mmHg). 1H NMR CDCl3, δ (ppm): 4.15 (q, J=4 Hz, 2H), 3.41 (t, J=5.3 Hz, 2H), 1.85 (qv, J=4 Hz, 2H), 1.60-1.45 (m, 2H), 1.40-1.30 (m, 2H), 1.28 (t, J=4 Hz, 3H), 1.20 (s, 6H); 13C NMR CDCl3, δ (ppm): 177.3, 60.0, 41.8; 39.4, 33.2, 32.9, 24.9, 23.34, 14.02.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[SH:5][CH:6]([CH2:14][CH2:15][SH:16])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:16][CH2:15][CH2:14][CH:6]([SH:5])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: O=C(O)CCCCC(S)CCS
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCCC(S)CCCCC(=O)O
Reaction time: 0.25 h
Yield: 5.4 %

Procedure:
Acetyl chloride (0.30 g, 3.8 mmol) in 4 mL of dry methylene chloride was added dropwise under a nitrogen atmosphere over 10 min to a stirred solution of 6,8-bismercaptooctanoic acid (0.80 g, 3.8 mmol) and triethylamine (1.16 g, 11.5 mmol) at 0. The solution was stirred at 0 a further 15 min then at room temperature for 2 hr. The solution was diluted to 75 mL with methylene chloride and extracted with 2×50 mL of 10% aqueous citric acid, then washed with 30 mL of saturated brine. The organic phase was dried (MgSO4), filtered and the solvent evaporated. The oil remaining was dissolved in 8 mL of 2-propanol and 8 mL of water added. The mixture was stirred under nitrogen at 40 for 4.5 hr. The solvent was evaporated in vacuo and the crude product mixture separated by column chromatography on silica gel first using ethyl acetate-hexane-acetic acid (100:100:1, v/v) as the eluting solvent, and then rechromatographed using hexane-ethyl acetate-acetic acid (150:100:1, v/v) as the solvent yielding 51 mg (5%) of pure 8-acetylmercapto-6-mercaptooctanoic acid as a colorless oil.