Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:15][O-:16].[Na+].[C]=O.[BH4-].[Na+]>CN(C=O)C>[CH:4]1[C:5]2[CH:6]([CH2:15][OH:16])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:13][C:14]=2[CH:1]=[CH:2][CH:3]=1
Reactant: C[O-]
Reactant: c1ccc2c(c1)Cc1ccccc1C2
Agent: [BH4-]
Agent: [C]=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: OCC1c2ccccc2Cc2ccccc21
Yield: 83 %

Procedure:
According to the procedure described in Example 3, a mixture of 9.0 grams of 9,10-dihydroanthracene, 3.5 grams of sodium methoxide and 25 cc of DMF was treated with carbon monoxide under an initial pressure of 800 psig. At the end, residual CO (400 psig) was released, and a sodium borohydride solution (1 gram in 10 cc of water) was added to the mixture. Excess hydride was destroyed by adding a hydrochloric acid solution. The mixture was then extracted with ether. An 83% yield of 9,10-dihydro-9-anthracenemethanol was realized. The separation was carried out by evaporating off the solvent, then extracting the desired product from the residue with methanol. Recrystallization from benzene-pentane gave 6.0 grams of white powder, mp=105° C. which was identified as 9,10-dihydro-9-anthracenemethanol. Five grams of this product was mixed with 1.0 grams of silica-alumina (Davison SMR5-1020, 87% SiO2 -13% Al2O3, BET surface area 350 m2 /gr) and heated under a nitrogen flow to 250° C. After cooling, the solid was dissolved in benzene, and methanol was added to recrystallize 4.5 grams of white plates which was identified to be pure 5H-dibenzo(a,d)cycloheptene, i.e. a compound having the structure of compound I.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][CH2:7][CH2:6][CH:5]2[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:32]=[CH:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][N:28]=2)[CH2:23][CH2:22]1>CO.C(Cl)Cl>[Cl:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][CH:5]1[C:4]2[C:9](=[N:10][CH:11]=[C:2]([C:30]3[CH:29]=[N:28][C:27]([N:24]4[CH2:23][CH2:22][N:21]([CH3:20])[CH2:26][CH2:25]4)=[CH:32][CH:31]=3)[CH:3]=2)[NH:8][CH2:7][CH2:6]1
Reactant: CN1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Clc1cccc(OC2CCNc3ncc(Br)cc32)c1
Solvent: CO
Solvent: ClCCl
Product: CN1CCN(c2ccc(-c3cnc4c(c3)C(Oc3cccc(Cl)c3)CCN4)cn2)CC1
Yield: 55 %

Procedure:
6-Bromo-4-(3-chlorophenoxy)-1,2,3,4-tetrahydro-[1,8]naphthyridine (20 mg) was reacted with 1-methyl-4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridin-2-yl]piperazine (25.0 mg) as in General Procedure 13. Silica gel chromatography using a gradient of 0-20% methanol/CH2Cl2 as the eluting solvent gave the title compound as an orange foam (55% yield). LCMS: m/z=436.12 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.0-2.11 (m, 1H), 2.21-2.32 (m, 1H), 2.36 (s, 3H), 2.54 (t, J=5.0 Hz, 4H), 3.39-3.49 (m, 1H), 3.53-3.68 (m, 1H), 3.59 (t, J=5.0 Hz, 4H), 5.10 (s, 1H), 5.37 (t, J=3.5 Hz, 1H), 6.68 (d, J=8.8 Hz, 1H), 6.90 (dd, J=2.3 and 8.3 Hz, 1H), 6.98-7.07 (m, 2H), 7.20-7.27 (m, 1H), 7.50 (d, J=2.1 Hz, 1H), 7.56 (dd, J=2.5 and 8.8 Hz, 1H), 8.20 (d, J=2.2 Hz, 1H), 8.29 (d, J=2.4 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:14]=O)[CH2:10][CH:11]([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:16][CH:17]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C([BH3-])#N.[Na+]>CO>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:14][NH:16][CH:17]([C:18](=[O:19])[NH:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:30][CH:31]=1)[CH2:10][CH:11]([CH3:12])[CH3:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NC(=O)C(N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)CC(CNC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
A solution consisting of 1.00 g (4.64 mmol) N-tert-butoxycarbonyl-L-leucinal and 1.52 g (4.64 mmol) 2-amino-3-(4-benzyloxy-phenyl)-N-tert-butyl-propionamide (Example 2, Step C) in 20 mL methanol containing 1% acetic acid was stirred at 25° C. for 20 minutes, at which time a solution of 0.614 g (9.29 mmol) sodium cyanotrihydridoborate (Aldrich, Milwaukee, Wis.) in 12 mL methanol was added and the resulting mixture stirred for 24 hours. The reaction was quenched by the addition of 3 M HCl in 3 mL increments until the vigorous bubbling subsided. The mixture was neutralized with saturated NaHCO3 solution then extracted with three 50 mL portions of ethyl acetate. The combined extracts were washed with 100 mL brine, dried over anhydrous sodium sulphate, and evaporated at reduced pressure to give a clear, colorless oil which was chromatographed on a silica gel column using 30% to 40% ethyl acetate:hexane to give 735 mg (30%) of [S-(R*,S*)]-(1-{[2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethylamino]-methyl}-3-methyl-butyl)-carbamic acid tert-butyl ester as a clear foam.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[C:24]1[N:28]([CH3:29])[N:27]=[C:26]([C:30]#[N:31])[CH:25]=1>ClCCCl.ClC(Cl)C>[Cl:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:25]1[C:26]([C:30]#[N:31])=[N:27][N:28]([CH3:29])[C:24]=1[C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[F:16])=[O:9]
Reactant: Cn1nc(C#N)cc1-c1c(F)cccc1F
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: Cn1nc(C#N)c(C(=O)c2ccc(F)cc2Cl)c1-c1c(F)cccc1F
Temperature: 180 °C

Procedure:
To a mixture of aluminum chloride (0.18 g, 1.36 mmol) in 1,2-dichloroethane (2 mL) was added a mixture of 2-chloro-4-fluorobenzoyl chloride (0.26 g, 1.36 mmol) and 5-(2,6-difluorophenyl)-1-methyl-1H-pyrazole-3-carbonitrile (i.e. the product of Step B) (0.15 g, 0.68 mmol) in dichloroethane (1 mL). The reaction mixture was heated at 180° C. in a Biotage Initiator™ microwave apparatus for 30 minutes. The resulting mixture was poured directly onto a Varian Bond Elute SIC) column and eluted with methylene chloride followed by 30% ethyl acetate in hexanes to provide the title compound, a compound of the present invention, as a solid (0.07 g).
Reaction SMILES: [CH3:1][O:2][C:3]1N=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][CH3:12])[N:4]=1.[F:13][CH:14]([F:28])[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23].[CH2:29](Cl)Cl>>[F:28][CH:14]([F:13])[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([NH:25][C:26]([N:11]([C:5]1[N:4]=[C:3]([O:2][CH3:1])[CH:29]=[C:7]([O:9][CH3:10])[N:6]=1)[CH3:12])=[O:27])(=[O:24])=[O:23]
Reactant: CNc1nc(OC)nc(OC)n1
Reactant: O=C=NS(=O)(=O)c1ccccc1SC(F)F
Reactant: ClCCl
Product: COc1cc(OC)nc(N(C)C(=O)NS(=O)(=O)c2ccccc2SC(F)F)n1
Reaction time: 16 h

Procedure:
To 0.80 g of 4,6-dimethoxy-2-methylamino-1,3,5-triazine in 25 ml of dry methylene chloride was added at ambient temperature 1.33 g of 2-difluoromethylthiobenzenesulfonyl isocyanate in 15 ml of methylene chloride. The reaction mixture was stirred for 16 hours and the resultant precipitate removed by filtration. It melted at 158°-164°, showed absorption peaks by Nuclear Magnetic Resonance (60MC) at:
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:26]2[NH:30][N:29]=[C:28]([C:31]([OH:33])=O)[CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][N:55]([C:58](=[O:67])[C:59]2[CH:64]=[C:63]([Cl:65])[CH:62]=[CH:61][C:60]=2[Cl:66])[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[Cl:66][C:60]1[CH:61]=[CH:62][C:63]([Cl:65])=[CH:64][C:59]=1[C:58]([N:55]1[CH2:54][CH2:53][N:52]([C:50](=[O:51])[CH2:49][NH:48][C:31]([C:28]2[CH:27]=[C:26]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:30][N:29]=2)=[O:33])[CH2:57][CH2:56]1)=[O:67]
Reactant: O=C(O)c1cc(-c2ccccc2)[nH]n1
Reactant: NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1)c1cc(-c2ccccc2)[nH]n1
Temperature: 10 °C
Reaction time: 8 h
Yield: 89.47 %

Procedure:
HOBt (24 mg, 0.18 mmol) and DIPEA (74 mg, 0.57 mmol) were added to a stirred solution of 5-phenyl-1H-pyrazole-3-carboxylic acid; hydrochloride (32 mg, 0.14 mmol) in DMF (1.0 mL). The mixture was then cooled to 10° C. and EDCI.HCl (34 mg, 0.18 mmol), followed by 2-amino-1-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-ethanone hydrochloride (50 mg, 0.14 mmol) were added. The reaction mixture was then stirred at room temperature overnight. Water was added, and the resulting precipitate was isolated by filtration and dried under reduced pressure to afford 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2,5-dichloro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide as a solid in 89.47% Yield. LC-MS purity: 92.226%. 1H-NMR (DMSO): δ 8.6 (s, 1H), 8.1 (t, 1H), 7.8 (m, 2H), 7.6 (m, 3H), 7.45 (m, 4H), 7.1 (s, 1H), 3.9 (m, 2H), 3.4 (m, 6H), 3.2 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[N:12]=2)[N:3]=1.[H-].[Na+].[C:30](N1C=CN=C1)(N1C=CN=C1)=[O:31].O>C1COCC1>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][N:13]1[C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[C:11]([C:4]2[N:3]=[C:2]3[NH:1][C:30](=[O:31])[NH:10][C:8](=[O:9])[C:7]3=[CH:6][N:5]=2)=[N:12]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)c2cnc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2[nH]1
Reaction time: 0.42 h

Procedure:
70 mg (0.19 mmol) of 4-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidine-5-carb oxamide (example 104A) were initially charged in 7 ml of THF and, while cooling with ice, 30.8 mg (0.77 mmol) of sodium hydride (60% in mineral oil) were added over a period of 5 min. The mixture was stirred for 25 min, then 46.9 mg (0.29 mmol) of 1,1′-carbonyldiimidazole were added with ice cooling over 5 min. Conversion was effected at room temperature for 1 h and at reflux temperature for 90 min. After cooling, the mixture was hydrolyzed with 2 ml of water. The precipitate formed was filtered off and then stirred in 7 ml of methanol/water (5/2). The remaining precipitate was filtered off and dried under high vacuum. Thus, 26 mg (35% of theory) of the target compound were obtained.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]([CH2:17][C:18]3[N:19]=[C:20]([CH2:23][CH2:24][CH2:25][CH:26]=O)[S:21][CH:22]=3)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[N:28]1([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([NH2:40])[CH:35]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C1COCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(Cl)[Cl:61]>>[ClH:61].[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C@@H:10]([CH2:17][C:18]3[N:19]=[C:20]([CH2:23][CH2:24][CH2:25][CH2:26][NH:40][C:36]4[CH:35]=[C:34]([N:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH:39]=[CH:38][N:37]=4)[S:21][CH:22]=3)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CCOC(=O)C[C@H](Cc1csc(CCCC=O)n1)c1ccc2c(c1)OCO2
Reactant: Nc1cc(N2CCOCC2)ccn1
Reactant: ClCCl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C[C@H](Cc1csc(CCCCNc2cc(N3CCOCC3)ccn2)n1)c1ccc2c(c1)OCO2
Product: Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Dissolve (3S)-Ethyl 3-(1,3-benzodioxol-5-yl)-4-[2-(4-oxobutyl)-1,3-thiazol-4-yl]butanoate (230 mg, 0.6 mmol) and 4-morpholin-4-ylpyridin-2-amine (88 mg, 0.5 mmol) prepared according to Scheme 6, Example 1, in CH2Cl2. Add 3 mL THF and add NaBH(OAc)3. Stir at room temperature for 18 hours. Add 1.0 eq NaBH(OAc)3 and stir 24 hrs. The reaction was concentrated in vacuo and purified via reverse phase HPLC using a gradient of 10–60% CH3CN/H2O/0.5% HCl over 30 minutes to obtain the crude desired product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH3:12])=[CH:6][N:5]=[C:4]2[N:14]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[S:33]([NH2:36])(=[O:35])=[O:34])=[CH:23][CH:22]=3)[C:15]([CH2:17][CH2:18][CH3:19])=[N:16][C:3]=12.Cl[C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39].ClC(OCCCC)=O>>[CH3:1][C:2]1[C:7]([NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH3:12])=[CH:6][N:5]=[C:4]2[N:14]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[S:33]([NH:36][C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])(=[O:35])=[O:34])=[CH:25][CH:26]=3)[C:15]([CH2:17][CH2:18][CH3:19])=[N:16][C:3]=12
Reactant: CCCC(=O)Nc1cnc2c(nc(CCC)n2Cc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c1C
Reactant: O=C(Cl)OCc1ccccc1
Agent: CCCCOC(=O)Cl
Product: CCCC(=O)Nc1cnc2c(nc(CCC)n2Cc2ccc(-c3ccccc3S(=O)(=O)NC(=O)OCc3ccccc3)cc2)c1C

Procedure:
The title compound was prepared from 7-methyl-2-propyl-3-[2'-(aminosulfonyl)[1,1']-biphenyl-4-yl]methyl-6-[(1-oxobutyl)amino]-3H-imidazo[4,5-b]pyridine as described in Example 30 substituting the reagent benzyl chloroformate for butyl chloroformate in Step 5. FAB MS for C35H37N5SO5 : M+ +1=640.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[CH2:8](O)[CH3:9]>>[CH3:1][C:2]([CH3:7])=[CH:3][C:4]([O:6][CH2:8][CH3:9])=[O:5]
Reactant: CC(C)=CC(=O)O
Reactant: CCO
Product: CCOC(=O)C=C(C)C

Procedure:
Ten grams 3,3-dimethylacrylic acid was dissolved in 100 ml absolute ethanol and 0.5 ml concentrated (37% approx.) hydrochloric acid added. The reaction mix was refluxed for 24 to 48 hours with a Dean-Stark trap filled with activated molecular sieves inserted between the reaction vessel and the condenser. After cooling, the solvent was removed by rotary evaporation under reduced pressure at 50° C. to yield 6.3 g of a cloudy, yellow oil (ethyl 3-methyl-2-butenoate.)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.[NH2:33][C:34]1[S:35][C:36]([C:39]([NH2:41])=[O:40])=[CH:37][N:38]=1.CN(C)C=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)/[C:13]([NH:33][C:34]2[S:35][C:36]([C:39]([NH2:41])=[O:40])=[CH:37][N:38]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)O)cc1Cl
Reactant: NC(=O)c1cnc(N)s1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCCC2)C(=O)Nc2ncc(C(N)=O)s2)cc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 21.9 %

Procedure:
(E)-(3-chloro-4-methanesulfonyl-phenyl)-cyclohexyloxyimino-acetic acid (prepared as in Example 9, 112 mg, 0.31 mmol), N,N-diisopropylethylamine (163 μL, 0.94 mmol) and 2-amino-thiazole-5-carboxylic acid amide (54 mg, 0.38 mmol) were combined in methylene chloride (1.5 mL) and cooled to 0° C. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (118 mg, 0.31 mmol) was added and the cooling bath was removed. After stirring 16 h, thin layer chromatography analysis showed no reaction. N,N-dimethylformamide (1 mL) was added and the methylene chloride was removed in vacuo. The reaction mixture was stirred 20 h more then concentrated in vacuo and purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 2% methanol/chloroform) to afford (E)-2-[2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclohexyloxyimino-acetylamino]-thiazole-5-carboxylic acid amide (33 mg, 22%) as a white solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C19H21ClN4O5S2 [M+] 484.06, found 485 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.26-1.79 (m, 8H, 4×CH2), 2.00 (m, 2H, 2×CH of CH2), 3.32 (s, 3 H, SO2CH3), 4.40 (m, 1 H, OCH), 5.82 (brs, 2 H, NH2), 7.64 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.74 (d, Jm=1.5 Hz, 1 H, Ar), 7.96 (s, 1H, Ar), 8.23 (d, Jo=8.2 Hz, 1 H, Ar), 10.23 (s, 1 H, NH).
Reaction SMILES: Cl.CO[C:4](=[O:17])[C@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].[N:18]1C=CC=CC=1>ClCCl>[NH2:6][C@H:5]([C:4]([NH2:18])=[O:17])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12

Procedure:
A solution of the active ester VIII (0.035 g, 0.06 mmol), L-tryptophan methyl ester hydrochloride (0.049 g, 0.19 mmol) and pyridine (0.015 g, 0.19 mmol) in dichloromethane (20 ml) was stirred overnight. The solvent was removed under reduced pressure and the residue purified by column chromatography (ethyl acetate elution) to yield the trytophan amide as a dark red crystalline solid.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.F[C:17]1[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=1[C:19]([OH:21])=[O:20].C(O)(=O)C.Cl>>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:17]2[N:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:18]=2[C:19]([OH:21])=[O:20])=[CH:11][CH:10]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COc1cnc(F)c(C(=O)O)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cnc(Oc2ccc(Br)cc2)c(C(=O)O)c1
Temperature: 0 °C
Reaction time: 0.03 h

Procedure:
To a slurry of sodium hydride (60% dispersion) (21.74 g, 543 mmol) in DMF (351 mL, 175 mmol) at 0° C. was added 4-bromophenol (60.7 g, 351 mmol) over the course of 5 minutes. Stirred at 0° C. for two minutes then removed from the ice bath and stirred for an additional 5 minutes at room temperature. Added 2-fluoro-5-methoxynicotinic acid (30 g, 175 mmol) portionwise over 10 minutes and heated the resulting slurry at 140° C. After cooling to room temperature the mixture was then poured onto 1 kg of ice and was quenched with acetic acid (50.2 mL, 877 mmol) and then 75 mL of 6 N HCl. Stirred vigorously for 1 hour, leading to the formation of a red slurry containing a very fine white precipitate. Filtered the slurry to provide 2-(4-bromophenoxy)-5-methoxynicotinic acid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:14]([O-:16])=[O:15])=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6](=[O:13])[NH:5]2.[Br:17]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:17][C:11]1[CH:10]=[C:9]2[C:4]([NH:5][C:6](=[O:13])[C:7](=[O:12])[NH:8]2)=[C:3]([N+:14]([O-:16])=[O:15])[C:2]=1[Cl:1]
Reactant: O=c1[nH]c2ccc(Cl)c([N+](=O)[O-])c2[nH]c1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]c2cc(Br)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 28 °C
Reaction time: 120 h
Yield: 40.1 %

Procedure:
To a stirred solution of 6-chloro-5-nitro-1,4-dihydroquinoxaline-2,3-dione (35 mg, 0.14 mmol) in DMF (0.35 mL), N-bromosuccinimide (39 mg, 0.22 mmol) was added and the solution was stirred at 28° C. for 5 days. The resulting solution was then diluted with water (3.5 mL) and the yellow solid was filtered, washed with water (2.0 mL) and dried to obtain 42 mg crude product as a yellow powder. It was purified by successive crystallization (three times) from DMSO-water (3:1) to furnish 18 mg (44%) of pure title compound as shining yellow flakes, m.p.>350° C.; 1H NMR (DMSO-d6): δ7.483 (s, 1H), 12.222 (s, 1H), 12.323 (br s, 1H); IR (KBr, cm-1): 3418, 3118, 1700, 1550, 1400, 1350, 1006, 675, 562.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:14][C:15]1([CH3:25])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH2:17][CH2:16]1.C(N(CC)CC)C.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([Cl:13])=[CH:4][C:5]([F:12])=[C:6]([S:8]([N:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15]([CH3:25])([CH3:14])[CH2:16][CH2:17]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: CC1(C)CCNc2ccccc21
Reactant: O=S(=O)(Cl)c1cc(Br)c(Cl)cc1F
Solvent: CCN(CC)CC
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CCN(S(=O)(=O)c2cc(Br)c(Cl)cc2F)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.5 %

Procedure:
To 5-bromo-4-chloro-2-fluorobenzenesulfonyl chloride (3.15 g, 10.8 mmol) in dry DCM (40 mL), was added 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (1.50 g, 9.3 mmol) and triethylamine (2.15 mL, 15.5 mmol). The mixture was stirred at ambient temperature for 16 hrs. Additional sulfonyl chloride (0.93 g, 3.2 mmole) was added and the mixture was stirred an additional 72 hrs. The mixture was washed with 1N hydrochloric acid solution, saturated sodium bicarbonate solution and brine. The organic layer was dried over MgSO4 and the filtrate evaporated. The residue was purified by silica gel chromatography [eluent: 5% ethyl acetate in hexane] to give 1-(5-bromo-4-chloro-2-fluoro-benzenesulfonyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline as a yellow solid (3.6 g). tR=2.82 min (method 1).
Reaction SMILES: [Na].[CH2:2]([C:7]1([CH3:18])[O:12][C:11](=[O:13])[CH:10]([CH2:14][C:15]([OH:17])=[O:16])[S:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6].Br[CH2:20][CH2:21][CH3:22]>C(O)C.C(OCC)C>[CH2:20]([O:16][C:15](=[O:17])[CH2:14][CH:10]1[S:9][CH2:8][C:7]([CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([CH3:18])[O:12][C:11]1=[O:13])[CH2:21][CH3:22]
Reactant: CCCBr
Reactant: CCCCCC1(C)CSC(CC(=O)O)C(=O)O1
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCCCCC1(C)CSC(CC(=O)OCCC)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.41 g of the sodium salt of 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid and 0.63 g of 1-bromopropane are boiled for 1 hour in a mixture of 15 ml of dry ethanol and 5 ml of dry diethyl ether. The mixture is further stirred for 1 hour at room temperature. It is permitted to stand for about 12 hours at 0° and filtered. After distilling off the solvent, 6-pentyl-6-methyl-2-oxo-1,4-oxathiane-3-acetic acid n-propyl ester is obtained.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:18])[CH3:17])[CH:11]=1.Cl>[OH-].[Na+].O.CCO>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1/[CH:1]=[CH:17]/[C:16]([C:12]1[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=1)=[O:18]
Reactant: CC(=O)c1cccnc1
Reactant: O=Cc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccccc1O)c1cccnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a vigorously stirred solution of salicylaldehyde (45 mL, 0.42 mol) in 2.5 M NaOH (330 mL) at 0° C. was added 1-(pyridin-3-yl)ethanone (46.2 mL, 0.422 mol) dropwise over 50 min. After stirring at 0° C. for 2 h, the reaction mixture was diluted with water (150 mL) and EtOH (150 mL). The mixture was acidified with conc. HCl to pH=3. The resulting yellow solid was filtered and dried to give (2E)-3-(2-hydroxyphenyl)-1-pyridin-3-ylprop-2-en-1-one (69.8 g, 73%) which was used without further purification. LCMS: (FA) ES+ 226.2, ES-224.2.
Reaction SMILES: [Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15]/[C:16](=[N:19]/[H])/[NH:17][OH:18])[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1.CC[O-].[Na+].[S:31]1[CH:35]=[CH:34][N:33]=[C:32]1[C:36](OCC)=O>CCO>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[N:7]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]3[N:19]=[C:36]([C:32]4[S:31][CH:35]=[CH:34][N:33]=4)[O:18][N:17]=3)[C:6](=[O:21])[N:5]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:4]=2[N:3]=1
Reactant: CCOC(=O)c1nccs1
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCCC)c1=O)NO
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCn1c(=O)n(CCCCc2noc(-c3nccs3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 170 °C

Procedure:
A solution of (1Z)-5-(8-chloro-2,6-dioxo-3-pentyl-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (50 mg, 0.13 mmol) in EtOH (1.5 ml) was treated with a 21% solution of NaOEt in EtOH (50 μl, 0.13 mmol) and ethyl 1,3-thiazole-2-carboxylate (18 mg, 0.11 mmol). The mixture was heated in the microwave at 170° C. for 10 min. After cooling, the reaction was partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated then concentrated and purified by the MDAP. The title compound was obtained as a white solid (13 mg, 21%).