Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH2:5][C:6]#[C:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1)[CH2:3][OH:4].C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:49]([O:51][C:52](=[O:65])[C:53]([O:56][C:57]1[CH:62]=[CH:61][C:60](O)=[CH:59][C:58]=1[CH3:64])([CH3:55])[CH3:54])[CH3:50].C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.C(#N)C>[CH2:49]([O:51][C:52](=[O:65])[C:53]([O:56][C:57]1[CH:62]=[CH:61][C:60]([O:4][CH2:3][C:2]([CH3:19])([CH3:1])[CH2:5][C:6]#[C:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:16])([F:17])[F:18])=[CH:10][CH:9]=2)=[CH:59][C:58]=1[CH3:64])([CH3:54])[CH3:55])[CH3:50]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: CC(C)(CO)CC#Cc1ccc(OC(F)(F)F)cc1
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(OCC(C)(C)CC#Cc2ccc(OC(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
A solution of 0.082 g (0.30 mmol) 2,2-dimethyl-5-(4-trifluoromethoxy-phenyl)-pent-4-yn-1-ol (example 24E]) in 0.3 ml CH2Cl2 was treated at 0° C. with 0.08 ml (0.36 mmol) 2,6-di-tert-butylpyridine and 0.05 ml (0.33 mmol) trifluoromethanesulfonic anhydride. After 2.5 h at 0° C. and 0.5 h at room temperature the solution was evaporated, dissolved in 1 ml acetonitrile and added to a solution of 0.071 g (0.30 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 0.205 g (0.63 mmol) Cs2CO3 in 2 ml acetonitrile. The mixture was stirred for 20 h at room temperature and 1 h at reflux temperature. After filtration, the residue was dissolved in dichloromethane, dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (SiO2, n-heptane/EtOAc 2%) yielded 0.096 g of the title compound as light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][N:20]3[C:26](=[O:27])[CH2:25][C:24]4[CH:28]=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:23]=4[CH2:22][CH2:21]3)[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Se](=O)=[O:37]>O1CCOCC1.O.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH2:16][CH:15]([CH2:19][N:20]3[C:26](=[O:27])[C:25](=[O:37])[C:24]4[CH:28]=[C:29]([O:34][CH3:35])[C:30]([O:32][CH3:33])=[CH:31][C:23]=4[CH2:22][CH2:21]3)[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCN2CCCC(CN3CCc4cc(OC)c(OC)cc4CC3=O)C2)cc1OC
Reactant: O=[Se]=O
Solvent: O
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(CCN2CCCC(CN3CCc4cc(OC)c(OC)cc4C(=O)C3=O)C2)cc1OC

Procedure:
3.8 g (0.0079 mol) of 3-[(N-(2-(3,4-dimethoxy-phenyl)-ethyl)-piperidin-3-yl)-methyl]-7, 8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one are added at 70° C. to a suspension of 1.4 g (0.0128 mol) of selenium dioxide and 0.8 g of kieselguhr in dioxan/water and refluxed for 16 hours. After cooling, the mixture is diluted with a little ethanol and suction filtered The filtrate is evaporated down in vacuo and purified over 310 g of aluminium oxide (neutral, activity II-III) with methylene chloride and increasing amounts of ethanol (up to 1%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][N:5]2[CH:18]=1.C1C(=O)N([I:26])C(=O)C1.C(OCC)(=O)C>C(#N)C>[I:26][C:18]1[N:5]2[N:6]=[C:7]([CH3:17])[CH:8]=[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1I
Reactant: CCCC(CCC)c1cc(C)nn2cc(C)nc12
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCC(CCC)c1cc(C)nn2c(I)c(C)nc12
Yield: 99.8 %

Procedure:
In an oven dried nitrogen purged 25 mL round bottom flask, 0.088 g (0.359 mmol) of 2,6-Dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine, in 5 mL of dry acetonitrile is cooled to 0 C. 0.0.81 g (0.359 mmol) of NIS is added and the bath is allowed to expire. TLC in 1:1 Hexanes:Ethyl Acetate indicates SM is gone. Remove solvents to obtain 0.133 g of the title compound, quantitative yield. MS; 1H NMR (DMSO-d6)=6.985 (s, 1H); 3.262-3.190 (m, 1H); 2.502 (s, 3H); 2.480 (s, 3H); 1.823-1.600 (m, 4H); 1.182-0.985 (m, 4H); 0.804-0.768 (m, 6H) ppm.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[O:11][C:10]=2[CH2:24][O:25][CH2:26][CH3:27])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:31])=O.C(N(CC)CC)C.O>O1CCCC1>[Cl:31][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[O:11][C:10]=1[CH2:24][O:25][CH2:26][CH3:27]
Reactant: CCOCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCOCc1oc(-c2ccc(C(F)(F)F)cc2)cc1C(Cl)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of cyclohexyl{2-(ethoxymethyl)-5-[4-(trifluoromethyl)phenyl]furan-3-yl}methanol (1.8 g) in tetrahydrofuran (30 mL) were added oxalyl chloride (0.6 mL) and triethylamine (1.0 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.9 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:23](OCC)=[O:24])=[CH:4][CH:3]=1.[Al].[Li]>>[CH3:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:23][OH:24])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cc(-c3cccc(C)c3)ccc2n1Cc1ccc(C)cc1
Agent: [Al]
Agent: [Li]
Product: Cc1ccc(Cn2c(CO)cc3cc(-c4cccc(C)c4)ccc32)cc1

Procedure:
The title compound was prepared from ethyl 1-(4-methylbenzyl)5-(3-methylphenyl)-1H-indole-2-carboxylate and lithium aluminum in substantially the same manner, as described in step 3 of Example 1. The product was obtained as a white solid. Mass spectrum (ESI, [M+H]+) m/z 342. 1H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.46 (s, 1H), 7.42 (d, 1H, J=7.79 Hz), 7.37 (d, 1H, J=8.55 Hz); 7.33 (d, 1H, J=8.56 Hz), 7.31 (d, 1H, J=7.02 Hz), 7.29 (d, 1H, J=7.48 Hz), 7.10-7.07 (m, 4H), 6.96 (d, 2H, J=7.94 Hz), 6.48 (s, 1H), 5.54 (s, 2H), 5.33 (s, 1H), 4.60 (s, 2H), 2.36 (s, 3H), and 2.23 ppm (s, 3H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:14]=[CH:13][O:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:16][CH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([N:8]([CH2:9][C:10]1[CH:14]=[CH:13][O:12][CH:11]=1)[CH2:16][CH2:17][OH:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCCBr
Reactant: c1ccc(CNCc2ccoc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN(Cc1ccccc1)Cc1ccoc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 0.641 g (3.423 mmol) of N-benzyl-3-furylmethylamine and 0.64 g (5.1 mmol) of 2-bromoethanol in 30 ml of N,N-dimethylformamide, 0.95 g of potassium carbonate was added, followed by stirring at 80° C. for 2 hours. 0.64 g (5.1 mmol) of 2-bromoethanol was further added, followed by overnight stirring at 80° C. The reaction mixture was poured into water and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to yield 2-[benzyl-(3-furylmethyl)amino]ethanol.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7].[C:14]([O:18][C:19](=[O:27])[CH2:20][CH:21]([NH2:26])[CH:22]([OH:25])[CH2:23][F:24])([CH3:17])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C1COCC1.CN(C1C=CN=CC=1)C>[C:14]([O:18][C:19](=[O:27])[CH2:20][CH:21]([NH:26][C:10](=[O:12])[CH:9]([NH:8][C:6]([C:2]1[NH:1][CH:5]=[CH:4][N:3]=1)=[O:7])[CH3:13])[CH:22]([OH:25])[CH2:23][F:24])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)CC(N)C(O)CF
Reactant: C[C@H](NC(=O)c1ncc[nH]1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(NC(=O)c1ncc[nH]1)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
A solution of (2S)-2-[(1H-imidazole-2-carbonyl)-amino]-propionic acid and 3-amino-5-fluoro-4-hydroxy-pentanoic acid tert-butyl ester (0.254 g) in THF (7 mL) was cooled to 0° C. before addition of DMAP (0.151 g), diisopropylethyl amine (0.56 mL), HOBT (0.16 g) and EDC HCl (0.23 g). The reaction mixture was stirred at ambient temperature for 18 hrs before being concentrated at reduced pressure. The residue was purified by silica gel chromatography (5% methanol in dichloromethane) to afford the sub-title compound as a colourless solid (0.386 g, 97%): 1H NMR 400 MHz CDCl3/CD3OD 1.40 (12H, m), 3.92 (1H, m), 4.20-4.55 (4H, m), 7.11 (2H, d, J 15); 19F NMR CDCl3-229.74 (m), −229.84 (m), −230.54 (m), −230.87 (m).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14](=[O:15])[N:13]([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:12]2[C:7]1=[N:8][C:9]([C:24]1[C:32]3[C:27](=[N:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[F:40])[N:25]=1)=[N:10][CH:11]=2.C([SiH](CC)CC)C.O.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O.C(OCC)(=O)C>[F:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[CH2:33][N:26]1[C:27]2=[N:28][CH:29]=[CH:30][CH:31]=[C:32]2[C:24]([C:9]2[N:8]=[C:7]3[C:12]([N:13]([CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[C:14](=[O:15])[NH:6]3)=[CH:11][N:10]=2)=[N:25]1
Reactant: COc1ccc(Cn2c(=O)n(CCN3CCOCC3)c3cnc(-c4nn(Cc5ccccc5F)c5ncccc45)nc32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=c1[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)ncc2n1CCN1CCOCC1
Yield: 69.8 %

Procedure:
101 mg (0.16 mmol) of the compound from example 87A were dissolved in 10 ml of trifluoroacetic acid, 188 mg (1.62 mmol) of triethylsilane were added and the mixture was heated to reflux for 18 h. The reaction mixture was admixed with water and ethyl acetate, and neutralized with saturated aqueous sodium hydrogencarbonate solution. The organic phase was dried over sodium sulfate and concentrated on a rotary evaporator. The residue was dried under high vacuum, and purified by means of preparative HPLC (eluent: methanol/water with 0.1% trifluoroacetic acid, gradient 30:70→90:10). 53 mg of the title compound were obtained (69% of theory).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@@H:11]([CH3:12])[O:10]1.[SH:19][CH2:20][CH2:21][CH2:22][OH:23]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([S:19][CH2:20][CH2:21][CH2:22][OH:23])[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: OCCCS
Product: C[C@@H](SCCCO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 61.5 %

Procedure:
Following a procedure similar to that described in Example 1, but using 50 mg of (2R*,3R*)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane [prepared as described in Chem. Pharm. Bull., 38, 2476 (1990), Oida et al.] and 54 mg of 3-mercaptopropanol, 42 mg of the title compound, melting at 119°-120° C. (after recrystallization from a mixture of ethyl acetate and benzene), were obtained.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:21]5[CH:22]=[C:23]([NH:28][C:29](=[O:40])[C:30]6[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=6)[CH:24]=[CH:25][C:26]=5[CH3:27])[CH:19]=[CH:18][N:16]4[N:17]=3)[CH:10]=[N:9]2)=CC=1>FC(F)(F)C(O)=O>[CH3:27][C:26]1[CH:25]=[CH:24][C:23]([NH:28][C:29](=[O:40])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:37])([F:38])[F:39])[CH:31]=2)=[CH:22][C:21]=1[N:20]1[C:15]2[N:16]([N:17]=[C:13]([C:11]3[CH:12]=[N:8][NH:9][CH:10]=3)[CH:14]=2)[CH:18]=[CH:19]1
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cccc(C(F)(F)F)c6)ccc5C)ccn4n3)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-n1ccn2nc(-c3cn[nH]c3)cc12

Procedure:
At 80° C., 25 mg (0.025 mmol, 57% pure) of the compound from Example 50A were stirred in 0.5 ml of trifluoroacetic acid for 6 h. After concentration of the mixture under reduced pressure, the residue was purified by preparative HPLC (Method 11). This gave 6.0 mg (53% of theory) of the title compound.
Reaction SMILES: [C:1]([O:9]CC)(=O)[CH2:2][C:3]([O:5]CC)=O.[Na].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1>C(O)C>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:1](=[O:9])[CH2:2][C:3](=[O:5])[NH:21]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: NNc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Product: O=C1CC(=O)N(c2ccc(Cl)cc2)N1
Reaction time: 0.25 h

Procedure:
The starting material is prepared as follows: 20.0 g of diethyl malonate are added to 5.8 g of sodium metal dissolved in 100 ml of absolute ethanol. After stirring for 15 minutes, 17.8 g of p-chlorophenylhydrazine are added, and the resulting mixture is stripped to remove excess ethanol. The residue is heated at 110° to 120° for 4.5 hours, then quenched with 500 ml of ice-water. The resulting mixture is washed twice with diethyl ether and the aqueous layer is acidified with conc. hydrochloric acid to a pH below 2. The resulting solid is recrystallized from toluene, to give the 1-(p-chlorophenyl)-pyrazolidin-3,5-dione melting at 189°-193°.
Reaction SMILES: C([O-])C.[Na+].[CH3:5][C:6]1[S:10][C:9]([C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:7]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].O>C(O)C>[CH3:5][C:6]1[S:10][C:9]([C:11]([CH:12]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:18])=[CH:8][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(C)s1
Reactant: CCOC(=O)CBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC(C(=O)OCC)C(=O)c1ccc(C)s1
Reaction time: 8 h

Procedure:
1.54 g of sodium ethanolate (22.6 mmol), 4.00 g ethyl 3-(5-methylthiophen-2-yl)-3-oxopropanoate (2) and 6.67 g of ethyl bromoacetate are suspended under argon in absolute ethanol at 0° C. The mixture is stirred overnight. Water is added, ethanol is evaporated and the aqueous solution is extracted with diethyl ether. The organic phase is washed with water containing few drops of concentrated HCl, dried and evaporated to provide diethyl 2-(5-methylthiophene-2-carbonyl)succinate (3) which is used without further purification. A mixture of compound 3 and 11.64 g of ammonium acetate in glacial acetic acid is stirred at 120° C. under argon for 4 hours. After cooling to room temperature, the mixture is poured into water. The precipitate formed is isolated by filtration, washed with water and diethyl ether to provide compound 4. 1H NMR (300 MHz, CDCl3) δ 9.57 1H s, 7.61 1H d, 6.81 1H m, 4.24 2H q, 3.53 2H s, 2.54 3H large s, 1.31 3H t.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH3:17])[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[N:27]=[C:28]=[O:29]>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[NH:27][C:28](=[O:29])[N:16]([C:14]1[CH:15]=[C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([N:2]([CH3:1])[CH3:18])[CH:4]=2)[N:11]=[CH:12][N:13]=1)[CH3:17]
Reactant: CNc1cc(Nc2cccc(N(C)C)c2)ncn1
Reactant: O=C=Nc1c(Cl)cccc1Cl
Solvent: CN(C)C=O
Product: CN(C)c1cccc(Nc2cc(N(C)C(=O)Nc3c(Cl)cccc3Cl)ncn2)c1
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A mixture of N-(3-dimethylamino-phenyl)-N′-methyl-pyrimidine-4,6-diamine (243.3 mg, 1 mmol), 2,6-dichlorophenyl isocyanate (188 mg, 1 mmol) in dry dimethylformamide (2.5 mL) is shaken for 14 h at 90° C. Two additional portions (188 mg, 1 mmol each) of 2,6-dichlorophenyl isocyanate are added after 14 h and 26 h. After 38 h the reaction mixture is evaporated in vacuo and the residue is distributed between ethyl acetate and half-saturated K2CO3 solution. The organic layer is dried over Na2SO4, evaporated, and the residue purified by flash chromatography (hexane/ethyl acetate). The combined pure fractions are evaporated, the residue triturated with CH2Cl2 and the solid filtered off and dried in vacuo to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]([OH:10])=[O:9])[N:6]=1.[C:18](OC(=O)C)(=[O:20])C>C(O)=O>[CH:18]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:8]([OH:10])=[O:9])[N:6]=1)=[O:20]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCON=C(C(=O)O)c1csc(N)n1
Solvent: O=CO
Product: CCCCCON=C(C(=O)O)c1csc(NC=O)n1
Yield: 88.4 %

Procedure:
2-(2-Aminothiazol-4-yl)-2-pentyloxyiminoacetic acid (syn isomer, 15 g.), acetic anhydride (23.8 g.) and formic acid (10.7 g.) were treated in a similar manner to that of Example F-(5) to give 2-(2-formamidothiazol-4-yl)-2-pentyloxyiminoacetic acid (syn isomer, 14.7 g.), mp 125° C. (dec.).
Reaction SMILES: [CH:1]([C:4]1[C:9]2[C:10](=[O:15])[NH:11][S:12](=[O:14])(=[O:13])[C:8]=2[CH:7]=[C:6]([O:16][CH3:17])[CH:5]=1)([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[C:27]([O:33][CH2:34]Cl)(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]>C(#N)C>[C:27]([O:33][CH2:34][N:11]1[C:10](=[O:15])[C:9]2[C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]([O:16][CH3:17])=[CH:7][C:8]=2[S:12]1(=[O:14])=[O:13])(=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)NC2=O
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)C(C)(C)C)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a suspension of 4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1.020 kg, 4.2 mol) in 6 L of acetonitrile was added diisopropylethylamine (543 g, 4.2 mol) and the reaction mixture was stirred at ambient temperature for 30 minutes. At the end of this period, chloromethyl pivalate (633 g, 4.2 mol) was added in one portion and the resulting solution was refluxed on a steam bath for 20 hours. The acetonitrile was removed under vacuum and the residue was stirred with 6 L of water for 30 minutes. The off-white solid was collected by filtration, washed first with 6 L of water, followed by 3 L of hexane. The product was dried at 70° C. under vaccum for 18 hours to give 1.33 kg (91%) of 2-(pivaloyloxymethyl)-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, m.p. 178°-179° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[NH2:9][CH2:10][CH2:11][CH2:12][OH:13]>C1COCC1.CCOC(C)=O>[Br:8][C:4]1[N:3]=[C:2]([NH:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:7]=[CH:6][CH:5]=1
Reactant: NCCCO
Reactant: Brc1cccc(Br)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCCNc1cccc(Br)n1

Procedure:
A solution of 2,6-dibromopyridine (10 g, 42 mmol) and 3-aminopropanol (3.5 mL, 46 mmol) in THF (60 mL) was stirred at reflux for 48 h. The reaction mixture was diluted with EtOAc and washed with H2O and brine, dried (MgSO4) and concentrated in vacuo to give 3-(6-bromo-pyridin-2-ylamino)-propan-1-ol as a light-yellow oil which crystallized on standing at RT to a white solid. MS m/z: 232.0 (M+H). Calc'd for C8H11BrN2O 231.09.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([O:12][CH2:13][C:14]([O:16]CC3C=CC=CC=3)=[O:15])=[O:11])=[CH:8][C:7]=2[O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:3][CH2:2]1>CO.CCOC(C)=O.[Pd]>[CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]([C:10]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[O:11])=[CH:8][C:7]=2[O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:3][CH2:2]1
Reactant: CS(=O)(=O)Oc1cc(C(=O)OCC(=O)OCc2ccccc2)ccc1OCC1CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1cc(C(=O)OCC(=O)O)ccc1OCC1CC1
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A mixture of 2-(benzyloxy)-2-oxoethyl 4-(cyclopropylmethoxy)-3-(methylsulfonyloxy)benzoate (0.238 g, 0.548 mmol) and 10% w/w Pd/C (0.030 g, 0.028 mmol) in MeOH (17 ml) and EtOAc (3 ml) was hydrogenated at 20 psi for 2 hours. The catalyst was filtered off, and the solvent was removed under vacuum affording 2-(4-(cyclopropylmethoxy)-3-(methylsulfonyloxy)benzoyloxy)acetic acid (0.178 g, 0.517 mmol, 94% yield, MS/ESI+ 344.9 [MH]+). The product was used without any further purification.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.CC([O-])=O.[K+].C(Cl)Cl.[Br:35][C:36]1[CH:41]=[CH:40][C:39](I)=[C:38]([F:43])[CH:37]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:35][C:36]1[CH:41]=[CH:40][C:39]([C:2]2[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=2)=[C:38]([F:43])[CH:37]=1
Reactant: Nc1cnc(Br)cn1
Reactant: Fc1cc(Br)ccc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1cnc(-c2ccc(Br)cc2F)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 14.9 %

Procedure:
To a solution of 5-bromopyrazin-2-amine (1.74 g, 10.0 mmol) in 1,4-dioxane (40 mL) were added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.65 g, 10.5 mmol) and KOAc (1.96 g, 20.0 mmol). The mixture was sparged with N2 several times before adding Pd(dppf)Cl2.CH2Cl2 (0.41 g, 0.5 mmol). The resultant mixture was stirred at 90° Celsius for 60 hours under N2. After cooling to rt, 4-bromo-2-fluoro-1-iodobenzene (4.5 g, 15.0 mmol), K2CO3 (2.76 g, 20.0 mmol) and another portion of Pd(dppf)Cl2.CH2Cl2 (0.41 g, 0.5 mmol) were added. The resultant mixture was sparged with N2 again, and stirred at 80° Celsius for 48 hours under N2. The mixture was then cooled to rt, diluted with THF (30 mL) and filtered. The filtrate was concentrated to dryness and the residue purified by FCC to give 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine (0.4 g, 15%). 1H NMR (300 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.01 (s, 1H), 7.82 (m, 1H), 7.63 (dd, J=11.1, 2.1, 1H), 7.50 (dd, J=8.4, 2.1, 1H), 6.75 (s, 2H).