Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[N:25]([CH3:26])[CH:24]=[CH:23][C:10]3=[N:11][C:12]=2[C@@H:13]([NH:15]C(=O)OC(C)(C)C)[CH3:14])=[C:5]([CH3:27])[NH:4][N:3]=1.[ClH:28]>C1COCC1.O1CCOCC1>[ClH:28].[CH3:27][C:5]1[C:6]([C:7]2[CH:8]=[C:9]3[N:25]([CH3:26])[CH:24]=[CH:23][C:10]3=[N:11][C:12]=2[C@@H:13]([NH2:15])[CH3:14])=[C:2]([CH3:1])[NH:3][N:4]=1
Reactant: Cc1n[nH]c(C)c1-c1cc2c(ccn2C)nc1[C@H](C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: Cc1n[nH]c(C)c1-c1cc2c(ccn2C)nc1[C@H](C)N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl ((1S)-1-(6-(3,5-dimethyl-1H-pyrazol-4-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)carbamate (149 mg, 0.403 mmol) in THF (4 mL) was added dropwise 4 M HCl (1 mL, 4.00 mmol) in dioxane. The mixture was stirred at RT for 2 hours and then concentrated in vacuo to give an HCl salt of the title compound as an off-white solid. ESI-MS m/z [M+H]+ calc'd for C15H19N5, 270.16; found 270.6.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:10]([O:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]([CH2:28][C:29]([N:31]([CH3:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:30])[C:22](=[O:27])[CH2:23][N:24]=[C:25]=[O:26])=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]([CH2:28][C:29]([N:31]([CH3:38])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)=[O:30])[C:22](=[O:27])[CH2:23][NH:24][C:25]([NH:6][C:5]1[CH:7]=[CH:8][CH:9]=[C:3]([CH2:2][OH:1])[CH:4]=1)=[O:26])=[O:14])[CH3:11]
Reactant: CCOC(=O)c1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CN=C=O
Reactant: Nc1cccc(CO)c1
Product: CCOC(=O)c1ccccc1N(CC(=O)N(C)c1ccccc1)C(=O)CNC(=O)Nc1cccc(CO)c1
Yield: 55.2 %

Procedure:
Using a procedure similar to that described in Example 31, but starting with 3-(hydroxymethyl)aniline (0.86 g) and 2-[N-(2-ethoxycarbonylphenyl)isocyanatoacetamido]-N-methyl-N-phenylacetamide (2.9 g), and after recrystallisation in ethyl acetate, 2-[N-(2-ethoxycarbonylphenyl)-2-{3-[3-(hydroxymethyl)phenyl]ureido}acetamido]-N-methyl-N-phenylacetamide (2 g), m.p. 184° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11]C)=O)=[N:4][C:5]([Br:8])=[CH:6][N:7]=1.O.[NH2:14][NH2:15]>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:9]([NH:14][NH2:15])=[O:11])=[N:4][C:5]([Br:8])=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: NN
Solvent: C1COCCO1
Solvent: O
Product: NNC(=O)c1nc(Br)cnc1N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Methyl 3-amino-6-bromopyrazine-2-carboxylate (15 g, 64.6 mmol) was suspended in 150 mL of dioxane at room temperature. Hydrazine hydrate (6.5 g, 130 mmol) was added and the reaction mixture was stirred at 60° C. for 2 hours. Initially the mixture became clear, but after a while a precipitate formed. The mixture was cooled to ambient temperature and crude product filtered off. The solid was washed with TBME and subsequently stirred in water. The material was filtered and washed with acetone to afford 3-Amino-6-bromopyrazine-2-carbohydrazide 4 as slightly yellow solid. The material was dried in vacuo. (10.5 g, 70%).
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([N:23]=[C:24]=[O:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1C=CC=CC=1>[C:1]1([CH2:7][C:8](=[O:13])[CH:9]([C:24](=[O:25])[NH:23][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:26])=[CH:15][CH:16]=2)(=[O:21])=[O:22])[C:10](=[O:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CC(=O)Cc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: c1ccccc1
Product: CC(=O)C(C(=O)Cc1ccccc1)C(=O)NS(=O)(=O)c1ccc(C)cc1

Procedure:
Reaction of equimolar amounts of 1-phenyl-2,4-pentanedione with p-toluenesulfonylisocyanate in benzene according to the procedure of Example 1 affords 1-PHENYL-3-(N-p-TOLUENESULFONYLCARBAMOYL)-2,4-PENTANEDIONE, m.p. 119.5°-120.5° C. (corr.).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:10][CH2:11][CH2:12][NH2:13])[C:7]([OH:9])=[O:8])(=O)C>O.N>[NH2:13][CH2:12][CH2:11][CH2:10][CH:6]([CH2:5][SH:4])[C:7]([OH:9])=[O:8]
Reactant: CC(=O)SCC(CCCN)C(=O)O
Agent: N
Solvent: O
Product: NCCCC(CS)C(=O)O

Procedure:
2-Acetylthiomethyl-5-aminopentanoic acid (1 g.) is dissolved in a mixture of water (12 ml.) and concentrated ammonia (12 ml.) under a blanket of argon. The solution is stored for twenty minutes at room temperature and concentrated to dryness in vacuo. The residue is applied to a column of Dowex 50 in the hydrogen cycle, the column is washed with water and 5-amino-2-mercaptomethylpentanoic acid is eluted with 2 M pyridine-acetate buffer pH 6.5.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=1[CH3:13].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:12][S:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:13][Br:14])[CH:4]=1)(=[O:11])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(OS(C)(=O)=O)ccc1Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CS(=O)(=O)Oc1ccc(Cl)c(CBr)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
To a solution of the product from step A (61.3 g, 301 mmol) in 500 ml of carbon tetrachloride was added N-bromosuccinimide (80.3 g, 451 mmol) and 2,2-azobisisobutyronitrile (7.40 g, 45.0 mmol). The reaction was stirred at 80° C. for 2.5 hr, concentrated in vacuo, and then suspended in 30% EtOAc/Hexane (300 mL). The solution was filtered and concentrated to give crude product. The crude product was purified by silica gel chromatography (20% EtOAc/Hexane) to provide the title product as a yellow oil
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[C:12]([F:15])([F:14])[F:13].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH2:27](O)[CH3:28]>>[CH2:27]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[CH:11][C:3]([CH2:2][Br:1])=[C:4]([C:12]([F:13])([F:14])[F:15])[CH:5]=1)[CH3:28]
Reactant: O=C(O)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(CBr)c(C(F)(F)F)c1
Temperature: 80 °C
Yield: 77 %

Procedure:
4-(bromomethyl)-3-(trifluoromethyl)benzoic acid 35 (650 mg, 2.296 mmol) was dissolved in ethanol (30 mL). Concentrated H2SO4 (1.224 mL, 22.96 mmol) was slowly added. The resulting mixture was heated at 80° C. overnight. The reaction mixture was cooled and neutralized with saturated Na2CO3 Solution. The resulting precipitate was collected to give crude 4-bromomethyl-3-trifluoromethyl-benzoic acid ethyl ester 36 (550 mg, 77%) which was used without further purification. (m/z)=311 an 313 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Na].[CH3:10][O:11][CH2:12][C:13]([C:16]1([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)[CH2:18][O:17]1)([CH3:15])[CH3:14]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][C:16]([OH:17])([C:13]([CH3:15])([CH3:14])[CH2:12][O:11][CH3:10])[CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[N:21]2)=[CH:4][CH:3]=1
Reactant: COCC(C)(C)C1(Cn2cncn2)CO1
Reactant: Oc1ccc(Cl)cc1
Agent: [Na]
Solvent: CCO
Product: COCC(C)(C)C(O)(COc1ccc(Cl)cc1)Cn1cncn1
Yield: 64.5 %

Procedure:
8.1 g (0.0633 mol) of 4-chlorophenol were added to a solution of 0.32 g (0.014 mol) of sodium in 100 ml of absolute ethanol. 10.3 g (0.0488 mol) of 2-(methoxy-tert.-butyl)-2-(1,2,4-triazol-1-yl-methyl)-oxirane, dissolved in 300 ml of absolute ethanol, were added, and the reaction mixture was heated under reflux for 48 hours. The reaction mixture was allowed to cool and was concentrated. The residue was taken up in ethyl acetate, and the solution was washed once with water, once with 1N sodium hydroxide solution, again with water, thereafter with 1N hydrochloric acid and 1N sodium hydroxide solution, again with water, and finally with saturated sodium chloride solution. The organic phase was dried over sodium sulphate, and concentrated. 10.7 g (64.6% of theory) of 2-(4-chlorophenoxymethyl)-3,3-dimethyl-4-methoxy-1-(1,2,4-triazol-1-yl)-butan-2-ol of refractive index nD20 =1.531 were obtained.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:30])[C@@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[CH:38]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:41]=[CH:40][C:39]=1[S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl>[CH2:12]([O:19][C:20](=[O:30])[C@@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:22][S:48]([C:39]1[CH:40]=[CH:41][C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:38]=1)(=[O:50])=[O:49])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: N[C@H](Cc1ccccc1)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 93.1 %

Procedure:
A solution of 10 g of (D)-phenylalanine benzyl ester p-toluenesulphonate in 150 ml of methylene chloride is treated with 8.2 ml of triethylamine and cooled to 0° C. 5.8 g of 2-naphthylsulphonyl chloride are added thereto and the mixture is stirred at room temperature for 12 hours. The reaction mixture is evaporated, the residue is taken up in 200 ml of ethyl acetate, the precipitated triethylammonium chloride salt is filtered off under suction and the mother liquor is washed with water. After evaporation of the organic phase and crystallization from hexane there are obtained 9.7 g of N-(2-naphthylsulfonyl) -3-phenyl-D-alanine benzyl ester, m.p. 107° C.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[C:5]([F:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC>C1(C)C=CC=CC=1.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>[Cl:13][C:10]1[C:9]2[C:4](=[C:5]([F:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2c(F)cccc2c1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2c(F)cccc2c1Cl

Procedure:
Prepared according to general Procedure E using 2,4-dichloro-8-fluoro-3-methylquinoline (1.0 g, 4.35 mmol), tetrakis(triphenylphosphine)palladium(0) (251 mg, 0.22 mmol) and 2-tributylstannylpyridine (1.6 mL, 4.35 mmol) in toluene (15 mL) to give 4-chloro-8-fluoro-3-methyl-2-(pyridin-2-yl)quinoline as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=4)=[C:10]3[C@@H:9]3[CH2:22][CH2:23][N:8]3[C:7](=[O:24])[C:6]=2[CH:25]=1.[CH2:26]([NH2:29])[CH2:27][CH3:28]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]4[N:19]=[C:18]([CH2:20][NH:29][CH2:26][CH2:27][CH3:28])[O:17][N:16]=4)=[C:10]3[C@@H:9]3[CH2:22][CH2:23][N:8]3[C:7](=[O:24])[C:6]=2[CH:25]=1
Reactant: O=C1c2cc(Cl)ccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCN12
Reactant: CCCN
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2[C@@H]2CCN2C(=O)c2cc(Cl)ccc2-3)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.2 %

Procedure:
A suspension of 1.13 g (3.0 mmol) of (S)-7-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one in 15 ml of N,N-dimethylformamide was treated with 0.74 ml (9.0 mmol) of propylamine and stirred at room temperature under argon for 3 hrs. The solution was evaporated, the residue was taken up in 20 ml of water and the aqueous phase was extracted with methylene chloride. The combined extracts were washed twice with water, dried with sodium sulfate, filtered and evaporated. The crude product was chromatographed on 30 g of silica gel (methylene chloride/acetone 4:1, then 2:1 and finally methylene chloride/methanol 9:1). There were obtained 840 mg of (S)-7-chloro-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted in acetonitrile in the presence of fumaric acid into the fumarate. By recrystallization from acetonitrile there were obtained 588 mg (35%) of (S)-7-chloro-1-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one fumarate (1:1.4) of m.p. 135°-140° (dec.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>>[CH3:20][S:21]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)(=[O:23])=[O:22]
Reactant: OCCCCc1cccc(OCc2ccccc2)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)OCCCCc1cccc(OCc2ccccc2)c1

Procedure:
In substantially the same manner as in Reference Example 85, 4-(3-benzyloxyphenyl)butanol was allowed to react with methanesulfonylchloride to give 4-(3-benzyloxyphenyl)butyl methanesulfonate. The yield was quantative. Oily substance.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH:18]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:24]=[CH:25][C:26]=1[Cl:27].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:16][CH2:17][CH2:18][N:31]2[CH2:30][CH2:29][N:28]([C:23]3[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([Cl:20])[CH:22]=3)[CH2:33][CH2:32]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccccc1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)n1nc(CCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)cc1-c1ccccc1

Procedure:
74 mg (47%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-phenyl-1H-pyrazol-3-yl)propanal (80 mg, 0.312 mmol), 1-(3,4-dichlorophenyl)piperazine (72 mg, 0.312 mmol), DIPEA (82 mL, 0.468 mmol) and NaBH(OAc)3 (198 mg, 0.936 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:13])=[CH:4][CH:3]=1.[CH:16]1([C:21]([N:23]2[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]2)=[O:22])[CH2:20][CH2:19][CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][CH:26]2[CH2:27][CH2:28][N:23]([C:21]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:22])[CH2:24][CH2:25]2)=[CH:4][CH:3]=1
Reactant: O=C1CCN(C(=O)C2CCCC2)CC1
Reactant: Nc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(C1CCCC1)N1CCC(Nc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 100 °C
Yield: 45.7 %

Procedure:
To a solution of 2-(4-chlorophenoxy)phenylamine (100 mg, 0.45 mmol), 1-cyclopentylcarbonyl-4-piperidone (144 mg, 0.735 mmol) and acetic acid (147 mg, 2.45 mmol) in DCE (1.5 ml) was added sodium triacetoxyborohydride (260 mg, 1.23 mmol). This solution was then heated at 100° C. for 15 minutes in a CEM discover microwave (fixed hold time set to on). The reaction mixture was then quenched with saturated aqueous sodium bicarbonate solution (5 ml) and extraction with ethyl acetate (3×5 ml) followed. The combined organics were concentrated in vacuo and purification by flash chromatography proceeded (eluant: 8:2 hexane:ethyl acetate) to provide the title compound as a transparent oil (82 mg, 43%). 1H NMR (300 MHz, CDCl3): δ 1.16-1.36 (2H, m, 2×CH), 1.47-1.56 (2H, m, 2×CH), 1.59-1.78 (6H, m, 6×CH), 1.93-2.08 (2H, m, 2×CH), 2.76-2.87 (2H, m, 2×CH), 3.07-3.18 (1H, m, CH), 3.43-3.52 (1H, sept, J=3.9 Hz, CH), 3.78-3.89 (1H, bd, J=13.8 Hz, CH), 3.97-4.10 (1H, m, CH), 4.31-4.42 (1H, bd, J=13.5 Hz, NH), 6.55-6.62 (1H, td, J=1.5, 1.2, 1.2, 7.7 Hz, ArH), 6.68-6.71 (1H, dd, J=1.5, 8.1 Hz, ArH), 6.73-6.77 (1H, dd, J=1.5, 8.1 Hz, ArH), 6.79-6.84 (2H, m, ArH), 6.95-7.01 (1H, td, J=1.5, 0.6, 1.5, 7.7 Hz, ArH), 7.16-7.22 ppm (2H, m, ArH). 13C NMR (67.93 MHz, CDCl3): δ 19.5, 19.6, 30.2, 32.2, 33.2, 40.6, 44.1, 49.9, 112.2, 117.2, 118.8, 119.6, 125.3, 127.9, 129.8, 138.9, 143.1, 156.1, 175.4 ppm LCMS: M+H, 421.46 HPLC: 98.41% (3.124 min, isocratic 90% acetonitrile, 10% water at 1 ml/min).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([OH:15])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[CH3:17][N:18]1[CH2:22]C[C@@H:20](O)[CH2:19]1>C1(C)C=CC=CC=1>[CH3:17][N:18]1[CH2:19][CH2:20][C@@H:1]([O:2][C:3](=[O:16])[C:4]([OH:15])([C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)[C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:22]1
Reactant: CN1CC[C@@H](O)C1
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Solvent: Cc1ccccc1
Product: CN1CC[C@@H](OC(=O)C(O)(c2cccs2)c2cccs2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 g of 2-Hydroxy-2,2-dithien-2-ylacetic acid methyl ester (0.0039 mol) was dissolved in 30 ml of toluene. To this solution were added 0.394 g (0.0039 mol) of (3R)-1-methylpyrrolidin-3-ol (Intermediate I-19), and 0.078 g (0.00195 mol) of HNa (60% dispersion in mineral oil). The mixture was stirred 30 min at room temperature, refluxed for 1 hour, and then refluxed with continuous removal of distillate with replacement with fresh toluene when necessary for 2 hours. The cooled mixture was extracted with 2N HCl, the aqueous layer was washed with a small volume of ethyl acetate, basified with solid K2CO3 and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The yield was 0.73 g (58%) of the title product (structure confirmed by 1H-NMR). This product was purified by chromatography on silica gel eluting with chloroform/ethanol/NH4OH (200:8:1). Appropriate fractions were combined and evaporated to give the title compound.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[NH2:6][C:7]1[CH:8]=[C:9]([C:14]2[S:18][C:17]([NH:19][C:20](=[O:22])[CH3:21])=[N:16][C:15]=2C)[CH:10]=[N:11][C:12]=1[Cl:13].[CH3:24][C:25]1[S:26][C:27]([C:31](O)=[O:32])=[C:28]([CH3:30])[N:29]=1>C(#N)C>[C:20]([NH:19][C:17]1[S:18][C:14]([C:9]2[CH:8]=[C:7]([NH:6][C:31]([C:27]3[S:26][C:25]([CH3:24])=[N:29][C:28]=3[CH3:30])=[O:32])[C:12]([Cl:13])=[N:11][CH:10]=2)=[CH:15][N:16]=1)(=[O:22])[CH3:21]
Reactant: Cc1nc(C)c(C(=O)O)s1
Reactant: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N)c2)s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(=O)Nc1ncc(-c2cnc(Cl)c(NC(=O)c3sc(C)nc3C)c2)s1
Temperature: 25 °C
Yield: 66.2 %

Procedure:
Phosphorus oxychloride (296 mg) was added to a stirred mixture of N-[5-(5-amino-6-chloropyridin-3-yl)-4-methyl-1,3-thiazol-2-yl]acetamide (180 mg), 2,4-dimethylthiazole-5-carboxylic acid (J. Med. Chem., 1999, 42, 5064; 109 mg) and acetonitrile (10 mL) that had been heated to reflux. The resultant mixture was stirred and heated to reflux for 1 hour. The mixture was cooled to room temperature and the precipitate was collected by filtration, washed with acetonitrile and dried under vacuum. There was thus obtained the title compound (172 mg); 1H NMR Spectrum: (DMSOd6) 2.16 (s, 3H), 2.39 (s, 3H), 2.62 (s, 3H), 2.68 (s, 3H), 8.21 (s, 1H), 8.40 (s, 1H); Mass Spectrum: M+H+ 422.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[O:9]=[C:10]1[C:23]2[CH:22]=[C:21]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:19][C:18]=2[C:17](=[O:28])[C:16]2[C:11]1=[CH:12][C:13]([S:29](Cl)(=[O:31])=[O:30])=[CH:14][CH:15]=2>N1C=CC=CC=1.C(Cl)Cl>[OH:8][C:4]1[CH:3]=[C:2]([NH:1][S:29]([C:13]2[CH:14]=[CH:15][C:16]3[C:17](=[O:28])[C:18]4[C:23](=[CH:22][C:21]([S:24]([NH:1][C:2]5[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[CH:3]=5)(=[O:26])=[O:25])=[CH:20][CH:19]=4)[C:10](=[O:9])[C:11]=3[CH:12]=2)(=[O:31])=[O:30])[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1c2ccc(S(=O)(=O)Cl)cc2C(=O)c2cc(S(=O)(=O)Cl)ccc21
Reactant: Nc1cccc(O)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1c2ccc(S(=O)(=O)Nc3cccc(O)c3)cc2C(=O)c2cc(S(=O)(=O)Nc3cccc(O)c3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 28 %

Procedure:
3-aminophenol (0.76 g, 7 mmol) in pyridine (10 ml) was treated with the product from Example 10A in methylene chloride. The mixture was stirred at room temperature for 18 hours and the solvents removed under reduced pressure. The residue was taken up in ethyl acetate, washed three times with 1N hydrochloric acid, dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was filtered through a pad of silica gel with 5% methanol in methylene chloride. The filtrate was concentrated under reduced pressure and the residue was taken up in a mixture of ethyl acetate:hexanes (1:1). The mixture was washed three times with water, dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure. The residue was titurated with methylene chloride and the orange solid collected by filtration to provide the title compound (0.47 g, 28% yield for 2 steps). 1H NMR (CD3OD) δ 7.16 (d, 2H, J=1.5 Hz), 6.86 (d, 2H, J=6 Hz), 6.69 (dd, 2H, J1=6 Hz, J2=1.5 Hz), 5.55-5.47 (m, 2H), 5.20-4.95 (m, 6H); MS (ESI−) 549 (M−H)−.
Reaction SMILES: [CH2:1]([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[F:14].IC>C1COCC1>[CH3:1][C:9]1[C:8]([F:14])=[C:7]([Br:6])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: Fc1ccc(Br)c(F)c1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(F)ccc(Br)c1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diisoproplylamine (11.9 ml, 85 mmol) is dissolved in 50 ml of anhydrous THF and cooled in a dry ice/acetone bath. n-Butyllithium (34 ml of a 2.5 M solution in hexanes, 85 mmol) is added dropwise. After 15 minutes, a solution of 1-bromo-2,4-difluorobenzene (16 g, 83 mmol) in 8 ml of TBF is added at a rate to keep the temperature below −65° C. The reaction is stirred for 2.5 hours then a solution of iodomethane (10.3 ml, 166 mmol) in 8 ml of TBF is added to the reaction. The ice bath is removed and the reaction is allowed to warm to room temperature. After 2 hours the reaction is quenched with water and 1N HCl. The aqueous layer is extracted twice with ether. The combined organics are washed with brine and dried over Na2SO4. Removal of the solvent affords the desired product.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([O:15][C:16](=[O:18])[CH3:17])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:19]([OH:22])(=O)=[O:20])[CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:24].O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:14]([O:15][C:16](=[O:18])[CH3:17])=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([S:19]([Cl:24])(=[O:22])=[O:20])[CH:11]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2ccc(S(=O)(=O)O)cc2cc1OC(C)=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)Oc1cc2ccc(S(=O)(=O)Cl)cc2cc1OC(C)=O
Temperature: 80 °C
Yield: 15.6 %

Procedure:
To a suspension of the crude 2,3-diacetoxy-6-naphthalenesulphonic acid (973 mg) in CCl4 (3 ml) was added phosphorus pentachloride (750 mg). The mixture was heated at 80° C. for 20 minutes, cooled, and water added cautiously. The CCl4 was separated from the aqueous layer and the latter was extracted with CH2Cl2. The organic extracts were combined, washed with water and dried over magnesium sulphate. Evaporation of the solvent yielded 2,3-diacetoxy-6-naphthalenesulphonyl chloride (160 mg, yield: 15%). NMR in CDCl3 : 2.37(s,6H); 7.82(s,1H); 7.87(s,1H); 7.99(s,1H); 8.01(s,1H); 8.54(br.s,1H).