Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-])=O.[CH:12]([Mg]Br)=[CH2:13].[Cl-].[NH4+].Cl>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]2[C:3]=1[NH:9][CH:13]=[CH:12]2
Reactant: C=C[Mg]Br
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(Cl)c2[nH]ccc12
Temperature: -50 °C
Reaction time: 2 h

Procedure:
A solution of 5.21 g of 1-chloro-4-methyl-2-nitrobenzene in 150 mL of THF was cooled to −50° C. To the solution was added 95 mL of 1 M vinylmagnesium bromide solution in THF while the inner temperature was kept at −30° C. or lower, and the resulting mixture was stirred at −50° C. for 2 hours. To the solution, 100 mL of the saturated aqueous ammonium chloride solution and 100 mL of 1 M hydrochloric acid were added, then the resulting mixture was warmed to room temperature and stirred for 15 minutes, and then extracted twice with 100 mL of ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane=1:9) to obtain 2.69 g of 7-chloro-4-methylindole as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]([CH3:20])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][NH:18][CH3:19])[C:12](=[O:15])[C:13]=1[OH:14])=[O:8].CCN(CC)CC.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[CH2:5][N:6]([CH3:20])[C:7]([C:9]1[CH2:10][N:11]([CH2:16][CH2:17][N:18]([S:33]([CH3:32])(=[O:35])=[O:34])[CH3:19])[C:12](=[O:15])[C:13]=1[OH:14])=[O:8]
Reactant: CNCCN1CC(C(=O)N(C)Cc2ccc(Cl)c(Cl)c2)=C(O)C1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C1=C(O)C(=O)N(CCN(C)S(C)(=O)=O)C1
Reaction time: 1 h
Yield: 12.9 %

Procedure:
To a stirred solution of 4-hydroxy-1-(2-methylamino-ethyl)-5-oxo-2,5-dihydro-1H-pyrrole-3-carboxylic acid (3,4-dichloro-benzyl)-methyl-amide (Compound 15) (150 mg, 0.367 mmol) in CH2Cl2 (5 mL) was added Et3N (0.14 mL, 1.0 mmol) followed by methanesulfonyl chloride (38 μL, 0.5 mmol) at room temperature. After 1 h, the reaction mixture was concentrated and the resulting residue was dissolved in methanol and purified by preparative HPLC on a C18 column using water/methanol-(0.1% TFA) as eluent. The fractions containing the desired product were combined, concentrated and lyophilized to give the title compound as a white powder (21.3 mg, 13% yield). 1HNMR (500 MHz, CDCl3) δ: 7.42 (1H, d, J=8.2 Hz), 7.35 (1H, s), 7.11 (1H, d, J=8.2 Hz), 4.58 (2H, s), 4.29 (2H, s), 3.71 (2H, t, J=5.8 Hz), 3.38 (2H, t, J=5.8 Hz), 3.02 (3H, s), 2.89 (3H, s), 2.78 (3H, s). HRMS calcd for C17H22Cl2N3O5S (M+H): 450.0657. found: 450.0658.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH:6]([C:14]1([C:28]([CH3:30])=[CH2:29])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]1=[O:27])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH2:4][CH2:5][CH:6]([C:14]1([C:28]([CH3:30])=[CH2:29])[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]1=[O:27])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: C=C(C)C1(C(CCN=[N+]=[N-])C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)C1(C(CCN)C(=O)OC(C)(C)C)CCN(CCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
A solution of tert-butyl α-(2-azidoethyl)-2-oxo-1-(2-phenylethyl)-3-(propen-2-yl)-3-pyrrolidineacetate (2.12 g, 5.14 mmol) and triphenylphosphine (1.48 g, 5.65 mmol) in THF (15 mL) is stirred under N2 for 7 hours. Water (1 mL) is added and the solution stirred overnight at room temperature under N2. The solution is concentrated and purified by silica gel chromatography (75 g SG; EtOAc, 20% MeOH/EtOAc) to provide 1.94 g (97%) of the title compound as a yellow oil:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[Cl:15])[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][S:19][CH2:18][CH2:17]2)[N:3]=1.OO.S([O-])([O-])=[O:25].[Na+].[Na+]>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[Cl:15])[N:5]=[C:4]([N:16]2[CH2:17][CH2:18][S:19](=[O:25])[CH2:20][CH2:21]2)[N:3]=1
Reactant: O=S([O-])[O-]
Reactant: Nc1nc(-c2cc(Cl)ccc2Cl)nc(N2CCSCC2)n1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1nc(-c2cc(Cl)ccc2Cl)nc(N2CCS(=O)CC2)n1
Reaction time: 3 h

Procedure:
In 150 ml of acetic acid was dissolved 2.0 g of the compound synthesized in Example 38. To this solution was added 1.3 ml of 30% aqueous solution of hydrogen peroxide dropwise under ice-cooling and the mixture was stirred at the same temperature for 3 hours. The excess of hydrogen peroxide was decomposed with aqueous sodium sulfite solution and the mixture was concentrated. The crystals separated out were collected by filtration, rinsed with water, and dried to provide 1.86 g of the title compound as white crystals. m.p. 267-269° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][CH:8]=[C:9](Br)[CH:10]=1)=[O:4].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([C:22]2[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=2)[CH:8]=[N:7][CH:6]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cncc(-c2ccc(Cl)cc2)c1
Temperature: 80 °C
Yield: 79.4 %

Procedure:
81 mg (0.07 mmol)Pd(PPh3)4 was added under argon at room temperature to a solution of 1.0 g (4.63 mmol) methyl-5-bromo-pyridine-3-carboxylate in 23 ml N,N-dimethylformamide and the mixture was heated to 80° C. Then 2.26 g (6.94 mmol) cesium carbonate and 0.84 g (5.09 mmol) of 4-chlorophenyl boronic acid were added and the mixture was stirred at 80° C. over night. The reaction mixture was cooled to room temperature, filtered, and the filtrate evaporated. The residue was taken up with ethyl acetate, washed twice with water, dried over sodium sulphate and evaporated. Chromatography on silica (eluent: ethyl acetate/n-heptane 1:3) gave 0.91 g (69%) of 5-(4-Chloro-phenyl)-nicotinic acid methyl ester
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[N:5][N:6]=1.[C:12]([C:19](OCC)=[O:20])#[C:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[N:7]1([C:4]2[S:3][C:2]3=[N:1][C:19](=[O:20])[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:6]3[N:5]=2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Nc1nnc(N2CCCC2)s1
Reactant: CCOC(=O)C#CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cc(=O)nc2sc(N3CCCC3)nn12
Reaction time: 8 h

Procedure:
8.5 g of 2-amino-5-pyrrolidino-1,3,4-thiadiazole were added to 300 ml of ethanol and mixed with 8.5 g of diethyl acetylenedicarboxylate. On heating for 10 to 20 minutes to about 50° to 60° C. a clear solution was obtained which after standing overnight at room temperature was evaporated in vacuo to dryness. The residue was triturated with a small amount of cold ethyl acetate, filtered off, washed with ether and then dried. 8.4 g (57.1% of the theoretical yield) of ethyl 2-pyrrolidino-7H-1,3,4-thiadiazolo-[3,2-a]pyrimidin-7-one-5-carboxylate were thus obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[C:13](=[N:14][CH:15]=[N:16][C:17]=2Cl)[N:12]=1.C(O)(=[O:23])C>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[NH:19][C:18]2[C:17](=[O:23])[NH:16][CH:15]=[N:14][C:13]=2[N:12]=1
Reactant: COc1ccc(-c2nc3ncnc(Cl)c3[nH]2)c(OC)c1
Reactant: CC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2nc3nc[nH]c(=O)c3[nH]2)c(OC)c1

Procedure:
One-half gram of 8-(2,4-dimethoxy-phenyl)-6-chloro-purine is refluxed for seven hours in 30 ml of 2N sodium hydroxide solution. The mixture is acidified with glacial acetic acid, and the precipitate obtained is recrystallized from methanol.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[NH2:15][CH2:16][CH2:17][C:18]([NH:20][C:21]1[CH:22]=[CH:23][C:24]2[NH:25][C:26]3[N:42]=[C:30]([NH:31][C:32]4[CH:33]=[CH:34][CH:35]=[C:36]([CH:41]=4)[CH2:37][CH2:38][C:39]=1[CH:40]=2)[N:29]=[CH:28][C:27]=3[Cl:43])=[O:19].[C:44]1([N:50]=[C:51]=[O:52])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:50]([C:51]([NH:15][CH2:16][CH2:17][C:18]([NH:20][C:21]1[CH:22]=[CH:23][C:24]2[NH:25][C:26]3[N:42]=[C:30]([NH:31][C:32]4[CH:33]=[CH:34][CH:35]=[C:36]([CH:41]=4)[CH2:37][CH2:38][C:39]=1[CH:40]=2)[N:29]=[CH:28][C:27]=3[Cl:43])=[O:19])=[O:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C=Nc1ccccc1
Reactant: NCCC(=O)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCNC(=O)Nc1ccccc1)Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 35 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using 3-amino-N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]propanamide bis(trifluoroacetate) and phenyl isocyanate as starting materials in 35% yield. LCMS for C28H27ClN7O2 (M+H)+: m/z=528.2.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[C:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C1COCC1.CCO>[C:21]1(=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:10]2[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:28])=[O:3])=[CH:8][CH:9]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CCOC(=O)COc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)COc1ccc(C(=C2CCCCCC2)c2ccc(O)cc2)cc1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
Ethyl({4-[cycloheptylidene(4-hydroxyphenyl)methyl]phenyl}oxy)acetate (190) (0.20 g, 0.53 mmol) was dissolved in THF and EtOH (1:1, 6 mL). To the above solution was added 1 N NaOH (2.5 mL) at room temperature. The reaction was heated at 70° C. with stirring for 0.5 h and then cooled at RT. Reaction mixture was acidified with 20% aqueous HCl, and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and concentrated under reduced pressure to afford the crude product. The product was purified by flash column chromatography with chloroform and methanol (9:1 to 4:1) as an eluent to give 0.182 g of compound 191 as an off-white solid. mp 170-171° C. 1H NMR (300 MHz, DMSO-d6): δ 12.92 (s, 1H), 9.25 (s, 1H), 7.00 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 6.81 (d, J=8.7 Hz, 2H), 6.66 (d, J=8.4 Hz, 2H), 4.62 (s, 2H), 2.22 (br s, 4H), 1.5 (br s, 8H). LCMS (ESI): m/z 375.08 (M+Na)+. Anal. Calcd for C22H24O4: C, 74.98; H, 6.86. Found: C, 73.05, H, 6.74.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([C:13]2[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]3[C:20]([C:21]=2[NH2:22])=[CH:19][CH:18]=[C:17]([Cl:23])[CH:16]=3)=[O:12])[O:9][CH:10]=1)(=[O:3])[CH3:2].[C:29](Cl)(=[O:32])[CH2:30][CH3:31]>>[C:1]([O:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([C:13]2[N:14]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:15]3[C:20]([C:21]=2[NH:22][C:29](=[O:32])[CH2:30][CH3:31])=[CH:19][CH:18]=[C:17]([Cl:23])[CH:16]=3)=[O:12])[O:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CCC(=O)Cl
Reactant: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(N)c2ccc(Cl)cc21
Product: CCOC(=O)n1c(C(=O)c2cc(COC(C)=O)co2)c(NC(=O)CC)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) employing 2-(4-acetoxymethyl-2-furoyl)-3-amino-6-chloro-1-(ethoxycarbonyl)indole (Exampe 373, step 2) and propionyl chloride.
Reaction SMILES: CO[CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1.B(Br)(Br)[Br:18]>C(Cl)Cl>[Br:18][CH2:3][C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:10][C:6]=2[CH:5]=1
Reactant: BrB(Br)Br
Reactant: COCc1ccc2oc(S(N)(=O)=O)cc2c1
Solvent: ClCCl
Product: NS(=O)(=O)c1cc2cc(CBr)ccc2o1
Temperature: -30 °C

Procedure:
A suspension of 5-methoxymethyl-2-sulfamoylbenzo[b]furan in dry methylene chloride cooled to -30° C. is treated with boron tribromide to provide the title compound.
Reaction SMILES: [C:1]1([C:11](=[CH2:15])[C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH2:21]([O:13][C:12](=[O:14])[C:11]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)=[CH2:15])[CH3:22]
Reactant: CCO
Reactant: C=C(C(=O)O)c1cccc2ccccc12
Agent: O=S(=O)(O)O
Product: C=C(C(=O)OCC)c1cccc2ccccc12
Yield: 94 %

Procedure:
1-Naphthylacrylic acid (9.5 g), conc. sulfuric acid (1 ml) and ethanol (100 ml) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(a) to obtain the title compound (10.2 g, 94%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH:21]=[O:22].C[Li].[CH3:25]COCC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)/[C:7](=[CH:11]\[C:12]1[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=1)/[C:6]([CH3:20])=[C:5]2[CH:21]([OH:22])[CH3:25]
Reactant: CSc1ccc(/C=C2/C(C)=C(C=O)c3cc(F)ccc32)cc1
Reactant: CCOCC
Agent: [Li]C
Solvent: C1CCOC1
Product: CSc1ccc(/C=C2/C(C)=C(C(C)O)c3cc(F)ccc32)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of aldehyde from Example 9, Step 2 (1.5 g, 4.8 mmol) in THF (25 mL) at 0° C. there was added methyl lithium (1.4M) in ether (3.8 mL, 5.3 mmol) and the mixture stirred at 0° C. for 45 minutes; it was then quenched with saturated aqueous ammonium chloride and extracted with ether to afford crude material which was chromatographed on silica gel to provide the title compound as a reddish syrup.
Reaction SMILES: OS(O)(=O)=O.[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][N:7]=1.C1C(=O)N([Br:27])C(=O)C1>>[Br:27][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[C:9]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][N:7]=[CH:6]2
Reactant: COC(=O)c1cncc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1cncc2cccc(Br)c12
Reaction time: 8 h
Yield: 90.2 %

Procedure:
To a mixture of conc. H2SO4 (16 mL) and methyl isoquinoline-4-carboxylate (Intermediate-15) (2.8 g, 15 mmol) at 0° C. was added, NBS (3.3 g, 18.7 mmol) slowly and the reaction mixture was allowed to come to RT and stirred overnight. After completion (TLC), it was quenched with ice, neutralized (NaHCO3) and extracted with EtOAc (50 mL×3). The organic phase was separated, dried (Na2SO4) and concentrated to give dark brown oil (3.6 g) as crude product that was purified by flash column chromatography (25% EtOAc in Hexanes) to furnish the desired compound (1.4 g, 35%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([S:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=O)=[CH:23][CH:22]=1)[CH2:17][CH2:18][CH3:19].[N:30]([C:33]1[CH:38]=[CH:37][C:36]([SH:39])=[CH:35][CH:34]=1)=[C:31]=[S:32]>ClCCl>[CH2:16]([S:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([S:39][C:36]2[CH:37]=[CH:38][C:33]([N:30]=[C:31]=[S:32])=[CH:34][CH:35]=2)=[O:27])=[CH:28][CH:29]=1)[CH2:17][CH2:18][CH3:19]
Reactant: S=C=Nc1ccc(S)cc1
Reactant: CCCCSc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCSc1ccc(C(=O)Sc2ccc(N=C=S)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N'-dicyclohexylcarbodiimide (1.95 g, 0.009 mol), was added in one portion to a stirred solution of compound 2 (1.67 g, 0.008 mol), compound 3 (1.59 g, 0.009 mol) and 4-(N-pyrrolidino)pyridine (0.39 g, 0.003 mol) in dry dichloromethane (50 ml) at room temperature. The reaction mixture was stirred at room temperature overnight. The product was extracted into ether (200 ml) and was washed with aqueous potassium hydroxide solution (5%, 2×250 ml). The ether layer was evaporated in vacuo and the product was purified by column chromatography [silica gel/petroleum fraction (bp 40°-60° C.), dichloromethane, 1:1] and was recrystallised from cyclohexane to afford a white solid which was dried in vacuo.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:24]=[CH:23][C:10]([O:11][CH2:12][C:13]2[N:14]([CH3:22])[C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:9][CH:8]=1.O.[OH-].[Na+].CN(C)[CH:30]=[O:31]>>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][C:13]2[N:14]([CH3:22])[C:15]3[C:20]([C:21]=2[CH:30]=[O:31])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:23][CH:24]=1
Reactant: CN(C)C=O
Reactant: Cn1c(COc2ccc(Cl)cc2)cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(COc2ccc(Cl)cc2)c(C=O)c2ccccc21
Temperature: 55 °C

Procedure:
Under a nitrogen atmosphere a round bottom flask was charged with 0.63 ml of anhydrous N,N-dimethylformamide. The reaction vessel was placed in a −20° C. bath and then phosphorous oxychloride (0.187 ml, 0.310 g, 2.02 mmol) was carefully added. The resulting mixture was stirred in an ice bath for about twenty minutes and 2-[(4-chlorophenoxy)methyl]-1-methyl-1H-indole (0.50 g, 1.84 mmol) in 3.4 ml of N,N-dimethylformamide, was added. The resulting mixture was stirred at room temperature for about ninety minutes. The reaction mixture was then placed over an oil bath and heated to 55° C. and maintained at this temperature for about one hour. The reaction mixture was then permitted to cool to room temperature and was then poured into water. Sodium hydroxide (10 ml of a 5.0 N solution) was added and heated to reflux. The resulting mixture was cooled and the solids were then collected by filtration.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C[Al](C)C.C[Al](C)C.C1N2CCN(CC2)C1.C[O:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][N:33]=[C:32]([C:35]3[N:40]=[C:39]([NH2:41])[N:38]=[C:37]([N:42]([CH3:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:36]=3)[N:31]=2)=[CH:26][N:25]=1)=O>C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:1][N:2]([CH3:3])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]2[O:34][N:33]=[C:32]([C:35]3[N:40]=[C:39]([NH2:41])[N:38]=[C:37]([N:42]([CH3:49])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[N:36]=3)[N:31]=2)=[CH:26][N:25]=1)=[O:21]
Reactant: CNC
Reactant: COC(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Agent: C1CN2CCN1CC2
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)c1ccc(-c2nc(-c3nc(N)nc(N(C)c4ccccc4)n3)no2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 12 %

Procedure:
Dimethylamine (248 μL, 0.495 mmol) and bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]-octane (128 mg, 0.495 mmol) were stirred together in anhydrous toluene (2 mL) at 40 C under nitrogen for 1 h. 5-{3-[4-Amino-6-(methyl-phenyl-amino)-[1,3,5]triazin-2-yl]-[1,2,4]oxadiazol-5-yl}-pyridine-2-carboxylic acid methyl ester (prepared in an analogous manner to Example 279, 80 mg, 0.198 mmol) was added and the reaction stirred at 80 C for approximately 18 h. The mixture was then allowed to cool to room temperature and diluted with EtOAc (20 mL). The solution was then washed with 2M HCl (2×6 mL), saturated aq. sodium bicarbonate (2×6 mL), dried over sodium sulfate and evaporated under vacuum. The crude residue was purified by flash chromatography (0-3% MeOH in DCM) and the material obtained was then further purified by flash chromatography (0-80% EtOAc in heptane) to afford the title compound (10 mg, 12%).
Reaction SMILES: [Cl:1][C@@H:2]([C@H:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:14](=O)(O)[O-].[Na+]>CO>[Cl:1][C@@H:2]([C@H:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH3:14])=[O:4]
Reactant: O=C(O)[C@@H](Cl)[C@H](O)c1ccccc1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](Cl)[C@H](O)c1ccccc1
Reaction time: 1 h

Procedure:
A mixture of (2S,3R)-2-chloro-3-hydroxy-3-phenyl propionic acid (CIV, EXAMPLE 3, 2 g, 10 mmol) in methanol (20 ml, saturated with hydrochloric acid) is stirred at 25° for 1 hr. The reaction mixture is poured into a saturated aqueous sodium bicarbonate (20 ml) and extracted with ethyl acetate (20 ml×3). The combined organic phases are washed with water (20 ml) and dried over magnesium sulfate. Filtration and solvent removal under reduced pressure gives the title compound, [α]25D=−5.0° (c=1.5, CHCl3); NMR (300 MHz, CDCl3) 7.41-7.35, 5.19, 4.51 and 3.70 δ; CMR (300 MHz, CDCl3) 168.4, 138.1, 128.7, 128.5, 126.5, 74.4, 62.8 and 53.0 δ.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[C:7]([CH3:9])[CH:8]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: CCOC(=O)CCc1cc(C)cc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCc1cc(C)cc(O)c1
Temperature: -5 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a solution of ethyl 3-(3-methoxy-5-methylphenyl)propanoate (2.00 g) in dichloromethane (30 mL) was added a 1.0 M solution (13.5 mL) of boron tribromide in dichloromethane at −5° C., and the mixture was stirred at −5° C. for 2 hr. Water (20 mL) was added dropwise to the reaction mixture over 30 min, and the mixture was extracted with dichloromethane. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.00 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([Cl:15])=[C:11](Cl)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[C:17]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[Cl:15][C:12]1[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:10][C:11]=1[N:27]1[CH2:26][CH2:25][N:24]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=c1c(Cl)c(Cl)cnn1-c1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2cnn(-c3ccc(Cl)cc3)c(=O)c2Cl)CC1

Procedure:
By general method 1 from 20.66 g (75 mmol) of 2-(4-chlorophenyl)-4,5-dichloropyridazin-3-one with 25.14 g (135 mmol) of Boc-piperazine.