Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22](Cl)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[CH:45]=[CH:44][C:29]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)=[C:28]([Cl:46])[CH:27]=1>C(O)(C)C>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([NH:25][C:26]3[CH:45]=[CH:44][C:29]([O:30][CH:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[CH2:35][CH2:36]4)=[C:28]([Cl:46])[CH:27]=3)=[N:21][CH:20]=[N:19][C:18]=2[CH:17]=[CH:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2Cl)CC1
Reactant: O=C(OCCOCCn1ccc2ncnc(Cl)c21)c1ccccc1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Nc3ncnc4ccn(CCOCCOC(=O)c5ccccc5)c34)cc2Cl)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
A mixture of 2-[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethoxy]ethyl benzoate (3.46 g), tert-butyl 4-(4-amino-2-chlorophenoxy)piperidine-1-carboxylate (3.27 g) and isopropyl alcohol (50 mL) was stirred at 80° C. overnight. The reaction mixture was concentrated under reduced pressure, water and saturated aqueous sodium hydrogen carbonate solution were added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was subjected to silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→10:90). The object fraction was concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give the title compound (4.70 g) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1)=[O:8].[CH3:29][C:30]([O-])(C)[CH3:31].[K+].C(Br)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][CH:30]([CH3:31])[CH3:29])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(S)cc1)c1cc(Cl)ccc1NS(=O)(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)Br
Solvent: CN(C)C=O
Product: CC(C)Sc1ccc(NC(=O)c2cc(Cl)ccc2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.00 g (2.21 mmol) of 5-chloro-2-(4-chloro-phenylsulfonylamino)-N-(4-mercapto-phenyl)-benzamide were dissolved in 25 ml of dimethylformamide and 0.25 g (2.21 mmol) of potassium tert-butylate were added. The mixture was stirred at room temperature for 15 min, then 0.27 g (2.21 mmol) of isopropyl bromide were added dropwise, and the mixture was heated to 60° C. for 8 h. For working up it was poured onto water and extracted with ethyl acetate. The combined extracts were evaporated and the residue was purified by chromatography over silica with hexane/ethyl acetate (3:1). 420 mg (39%) of the title compound having a melting point of 168-169° C. were obtained.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH:32]([CH3:39])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:30][CH:31]=1.C(N(C(C)C)CC)(C)C.[C:49]([O:52][C:53]1[CH:54]=[C:55]([CH2:62][C:63](O)=[O:64])[CH:56]=[CH:57][C:58]=1[N+:59]([O-:61])=[O:60])(=[O:51])[CH3:50]>CN(C)C=O>[C:49]([O:52][C:53]1[CH:54]=[C:55]([CH2:62][C:63]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([CH:32]([CH3:39])[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[N:30][CH:31]=2)=[O:64])[CH:56]=[CH:57][C:58]=1[N+:59]([O-:61])=[O:60])(=[O:51])[CH3:50]
Reactant: CCOC(=O)CC(C)c1ccc(N)cn1
Reactant: CC(=O)Oc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(OC(C)=O)c2)cn1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
A solution of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (10.95 g) in dry dimethylformamide (20 mL) was added to a solution of (RS) ethyl 3-(5-aminopyrid-2-yl)butanoate (3.0 g, Reference Example 5), diisopropylethylamine (10 mL) and (3-acetoxy-4-nitro-phenyl)acetic acid (6.89 g, Reference Example 17) in dimethylformamide (90 mL) under a nitrogen atmosphere. After stirring at 30° C. for 24 hours the reaction mixture was evaporated and the residue was partitioned between ethyl acetate and 5% aqueous sodium bicarbonate. The organic phase was washed with water, then with brine, then dried over magnesium sulphate, then treated with decolourising charcoal followed by filtration and evaporation of the filtrate to give the title compound as a dark oil.
Reaction SMILES: Br[C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].Cl>CC(=O)OCC.C1(C)C=CC=CC=1.C(O)C>[N:12]1[CH:17]=[CH:16][C:15]([C:2]2[C:6]3[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=3[O:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: O=c1[nH]ccc2occ(Br)c12
Reactant: OB(O)c1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=c1[nH]ccc2occ(-c3ccncc3)c12
Temperature: 130 °C
Yield: 43.4 %

Procedure:
A reaction tube was charged with 3-bromofuro[3,2-c]pyridin-4(5H)-one (1000 mg, 4.67 mmol) and a mixture of 1 mL of ethanol and 1 mL of toluene under argon. To this mixture, pyridin-4-ylboronic acid (574 mg, 4.67 mmol) and a 2 M solution of Na2CO3 (743 mg, 7.01 mmol) were added followed by the addition of tetrakis-(triphenylphoshine)palladium (540 mg, 0.467 mmol). The reaction mixture was heated in a Cem microwave at about 130° C. for about 30 min. After completion of the reaction, EA was added followed by the addition of 2 N HCl. The mixture was extracted twice with EtOAc. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography to give the title compound as dark yellow solid (430 mg, 43.4%).
Reaction SMILES: Cl[C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1.[F:14][C:15]1[CH:16]=[C:17]([CH2:32][OH:33])[CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1>>[F:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:23]=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)[CH2:32][O:33][C:2]1[CH:12]=[C:6]2[N:7]([CH3:11])[CH2:8][CH2:9][CH2:10][N:5]2[C:4](=[O:13])[N:3]=1
Reactant: OCc1ccc(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Reactant: CN1CCCn2c1cc(Cl)nc2=O
Product: CN1CCCn2c1cc(OCc1ccc(Oc3ccc(C(F)(F)F)nc3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 8-chloro-1-methyl-3,4-dihydro-1H-pyrimido[1,6-a]pyrimidin-6(2H)-one and (3-fluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[NH:15][C:16](=[O:33])[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=2)[CH:21]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[N:7]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:21]=3)[CH2:17][C:16](=[O:33])[NH:15][C:9]=2[CH:10]=1
Reactant: Cc1ncccc1-c1cccc(C(=O)CC(=O)Nc2cc(Cl)ccc2NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1-c1cccc(C2=Nc3ccc(Cl)cc3NC(=O)C2)c1

Procedure:
The title compound was prepared from (4-chloro-2-{3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M29) (216 mg, 0.45 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (121 mg).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])[CH:7]=[CH:6][C:5]=1[OH:15].[CH2:17](O)[CH3:18]>>[CH2:17]([O:15][C:5]1[CH:6]=[CH:7][C:8]([S:10](=[O:14])(=[O:13])[NH:11][CH3:12])=[CH:9][C:4]=1[C:3]([OH:2])=[O:16])[CH3:18]
Reactant: CNS(=O)(=O)c1ccc(O)c(C(=O)OC)c1
Reactant: CCO
Product: CCOc1ccc(S(=O)(=O)NC)cc1C(=O)O

Procedure:
Prepared in analogy to Example B13(d-e) from 2-Hydroxy-5-methylsulfamoyl-benzoic acid methyl ester and ethanol. MS (m/e): 257.9 ([M−H]−, 100%)
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([O:14][CH2:15][CH3:16])=[C:6]([C:17](O)=[O:18])[C:5]=1[C:20](O)=[O:21])[CH3:2].[NH2:23][C:24]1[CH:34]=[CH:33][C:27]([CH2:28][S:29]([NH2:32])(=[O:31])=[O:30])=[CH:26][CH:25]=1.O>C(O)(=O)C>[CH2:15]([O:14][C:7]1[C:6]2[C:17](=[O:18])[N:23]([C:24]3[CH:34]=[CH:33][C:27]([CH2:28][S:29]([NH2:32])(=[O:30])=[O:31])=[CH:26][CH:25]=3)[C:20](=[O:21])[C:5]=2[C:4]([O:3][CH2:1][CH3:2])=[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=12)[CH3:16]
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Reactant: CCOc1c(C(=O)O)c(C(=O)O)c(OCC)c2ccccc12
Solvent: O
Solvent: CC(=O)O
Product: CCOc1c2c(c(OCC)c3ccccc13)C(=O)N(c1ccc(CS(N)(=O)=O)cc1)C2=O
Temperature: 120 °C
Yield: 75.6 %

Procedure:
To a solution of 1,4-diethoxy-2,3-naphthalenedicarboxylic acid (0.75 g, 2.5 mmol, 1.1 eqs) in glacial acetic acid (5 ml) was added 4-amino-benzylsulfonamide (0.43 g, 2.3 mmol). The reaction mixture was heated at 120° C. for 18 h. The reaction mixture was allowed to cool to ambient temperature and then poured into water (5 ml). The precipitate was filtered off, triturated with ethyl acetate/40:60 petroleum ether and then dried in vacuo to give the title compound as a beige solid (790 mg, 69%). δH [2H6]—DMSO 1.48 (6H, t); 4.40 (2H, s); 4.52 (4H, q); 7.00 (2H, s); 7.51 (2H, d, 8.5Hz); 7.56 (2H, d, 8.5 Hz); 7.89 (2H, m); 8.43 (2H, m)
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[O:24][CH:25]=[C:26]([C:28](O)=[O:29])[N:27]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:31]=1.Cl.[CH2:33]([NH2:35])[CH3:34].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>ClCCl.C(Cl)(Cl)Cl>[CH2:33]([NH:35][C:28]([C:26]1[N:27]=[C:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([N:14]3[CH2:13][C@H:12]4[N:8]([CH2:9][CH2:10][CH2:11]4)[C:7]4[N:31]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=4[C:15]3=[O:16])[CH:18]=2)[O:24][CH:25]=1)=[O:29])[CH3:34]
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nc(C(=O)O)co3)c1)C2=O
Reactant: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCNC(=O)c1coc(-c2cccc(N3C[C@@H]4CCCN4c4nc(SC)ncc4C3=O)c2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.7 %

Procedure:
(S)-2-[3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-4-carboxylic acid (105 mg, 0.240 mmol) obtained in Step 1 was dissolved in dichloromethane (5 mL), and the mixture was stirred at room temperature for 5 hours after adding ethylamine hydrochloride (39.0 mg, 0.480 mmol), triethylamine (0.067 mL, 0.480 mmol), 1-ethyl-3-(3dimethylaminopropyl)carbodiimide hydrochloride (92.0 mg, 0.480 mmol), and 1-hydroxybenzotriazole.monohydrate (37.0 mg, 0.240 mmol). The mixture was diluted with chloroform and washed with a saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by silica gel column chromatography to give (S)—N-ethyl 2-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,3-oxazole-4-carboxamide (110 mg, quantitative).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:25][O:26][C:27](=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[CH:30]=1>ClCCl>[CH3:25][O:26][C:27](=[O:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:2]2[C:3]3[C:10]([C:11]4[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=4)=[C:9]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:30]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Cl)c23)cc1
Reactant: COC(=O)Cc1cccc(N)c1
Solvent: ClCCl
Product: COC(=O)Cc1cccc(Nc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)c1

Procedure:
Heat 300 mg (0.89 mmol) of 4-chloro-5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidine and 191.3 mg (1.16 mmol) of 3-aminophenylacetic acid methyl ester to 150° C. for 1.5 h. After cooling, add dichloromethane and filter off the resulting solid with suction, wash with dichloromethane and dry at 50° C. under high vacuum overnight. Purify the crude product by chromatography on silica gel (eluent: dichloromethane/ethyl acetate 10:1). 273.2 mg (65.9% of theory) of the target product are obtained as a yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.FC1C(C=O)=C(F)C=CC=1NS(C(C)C)(=O)=O.[F:28][C:29]1[C:34]([CH:35]=[O:36])=[C:33]([F:37])[CH:32]=[CH:31][C:30]=1[NH:38][S:39]([C:42]1[S:43][CH:44]=[CH:45][CH:46]=1)(=[O:41])=[O:40]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:35]([C:34]3[C:29]([F:28])=[C:30]([NH:38][S:39]([C:42]4[S:43][CH:44]=[CH:45][CH:46]=4)(=[O:41])=[O:40])[CH:31]=[CH:32][C:33]=3[F:37])=[O:36])=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: O=Cc1c(F)ccc(NS(=O)(=O)c2cccs2)c1F
Reactant: Clc1cnc2[nH]ccc2c1
Agent: CC(C)S(=O)(=O)Nc1ccc(F)c(C=O)c1F
Product: O=C(c1c(F)ccc(NS(=O)(=O)c2cccs2)c1F)c1c[nH]c2ncc(Cl)cc12

Procedure:
was prepared using the protocol of Steps 3 and 4 of Scheme 17, substituting 5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine 89 with 5-chloro-7-azaindole 80 (see Example 9) and propane-2-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 60 with thiophene-2-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide 512 (see Example 21) in Step 3. MS (ESI) [M+H+]+=451.9.
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:36])[CH:21]([O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][C:26]=2[CH3:35])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:54])[C@@H:15]2[CH2:37][CH2:38][C@H:39]2[O:44][C:43](=[O:45])[CH2:42][C@H:41]([O:46][Si](C(C)(C)C)(C)C)[CH2:40]2)=[CH:10]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C@H:9]1[CH2:18][C@H:17]([O:19][C:20](=[O:36])[CH:21]([O:24][C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][C:26]=2[CH3:35])[CH2:22][CH3:23])[C@H:16]2[C:11]([CH:12]=[CH:13][C@H:14]([CH3:54])[C@@H:15]2[CH2:37][CH2:38][C@H:39]2[O:44][C:43](=[O:45])[CH2:42][C@H:41]([OH:46])[CH2:40]2)=[CH:10]1
Reactant: CCC(Oc1c(C)ccc2ccccc12)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCC(Oc1c(C)ccc2ccccc12)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Yield: 73.6 %

Procedure:
A procedure similar to that described in Example 2, above, was followed, but using 1.52 g of (4R,6R)-6-([1S,2S,6S,8S,8aR]-2-{1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-[(2RS)-2-(2-methyl-1-naphthyloxy)butyryloxy]-2-methyl-1-naphthyl}ethyl)tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example 34, above] and 36.0 ml of a 1.0 molar solution of tetrabutylammonium fluoride in tetrahydrofuran, to give 0.79 g of the title compound as a foam.
Reaction SMILES: C(S([CH:6]1[N:9]([CH:10]([C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[S:25])[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C:8](=[O:35])[CH2:7]1)=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[CH3:34][O:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][C:24]2[S:25][CH:6]3[N:9]([C:8](=[O:35])[CH2:7]3)[C:10]=2[C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=2)=[O:12])=[CH:32][CH:31]=1
Reactant: C=CCS(=O)C1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=S)Oc1ccc(OC)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COc1ccc(OC2=C(C(=O)OCc3ccc([N+](=O)[O-])cc3)N3C(=O)CC3S2)cc1
Yield: 17.2 %

Procedure:
A mixture of 422 mg of 4-nitrobenzyl 2-(4-allylsulphinylazetidin-2-on-1-yl)-3-(4-methoxyphenoxy)-3-thioxopropanate, 214 mg of triphenylphosphine, and dioxan was heated under an argon atmosphere at 100° for 15 minutes. Then, the mixture was evaporated in vacuo to dryness, and the resulting oil was chromatographed on silica gel. Elution with ethyl acetate-hexane mixtures afforded 60 mg of the title compound (22% of the theoretical yield).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[N:11][C:12]([C:29]([NH2:31])=[O:30])=[C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][N:20]3[CH2:25][CH2:26][O:27][CH3:28])[N:14]=1.[C:32](OC(=O)N[C@H]1CCCCC[C@H]1N)(C)(C)C.C(OC(=O)N[C@H]1CCCC[C@H]1N)(C)(C)C>>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:32][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[N:11][C:12]([C:29]([NH2:31])=[O:30])=[C:13]([NH:15][C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH:18]=[CH:19][N:20]3[CH2:25][CH2:26][O:27][CH3:28])[N:14]=1
Reactant: COCCn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)nnc3C(N)=O)cccc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCC[C@H]1N
Agent: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Product: COCCn1ccc2c(Nc3nc(N[C@@H]4CCCCC[C@@H]4N)nnc3C(N)=O)cccc21

Procedure:
In accordance with Example 3 (Steps 1 to 4), 1-(2-methoxyethyl)-1H-indol-4-amine obtained in Example 46 was used instead of 1-methyl-1H-indol-4-amine, and tert-butyl((1S,2R)-2-aminocycloheptyl)carbamate obtained in the above-described Step was used instead of tert-butyl((1S,2R)-2-aminocyclohexyl)carbamate to obtain the titled compound as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:7])[NH:5][N:6]=1.O=[C:9]([CH3:15])[CH2:10][C:11](OC)=[O:12].O>Cl>[CH3:15][C:9]1[CH:10]=[C:11]([OH:12])[N:1]=[C:2]2[NH:6][N:5]=[C:4]([OH:7])[C:3]=12
Reactant: Nc1cc(O)[nH]n1
Reactant: COC(=O)CC(C)=O
Agent: Cl
Solvent: O
Product: Cc1cc(O)nc2[nH]nc(O)c12

Procedure:
20 g (201.8 mmol) of 5-amino-2H-pyrazol-3-ol and 26 g (224 mmol) of methyl 3-oxo-butyrate were heated under reflux in 63 ml of conc. hydrochloric acid and 17 ml of water for 1 h. After cooling, the product crystallized and was filtered off with suction and dried. Yield: 16.54 g (50%), M+H+: 166.07.
Reaction SMILES: [F:1][C:2]([F:52])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH:49]=[CH:48][N:47]=[CH:46]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].[OH-]>O1CCOCC1>[F:52][C:2]([F:1])([F:51])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:26]4[CH:27]=[C:28]([C:34]5[CH:43]=[CH:42][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=5[CH3:44])[CH:29]=[N:30][C:31]=4[O:32][CH3:33])=[CH:24][N:23]=[C:22]([N:45]4[CH:49]=[CH:48][N:47]=[CH:46]4)[N:21]=3)[C@H:14]2[CH3:50])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(-n4ccnc4)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ncc(-c2ccc(C(=O)O)cc2C)cc1-c1cnc(-n2ccnc2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Methyl 4-{5-[4-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-2-(1H-imidazol-1-yl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (Step A, 99 mg, 0.136 mmol) was dissolved in 1,4-dioxane (2.4 mL). Added 0.5N LiOH (1.20 mL, 0.600 mmol), and stirred at room temperature for 2.5 hrs, at which time LCMS indicates the reaction was complete, but not clean. The reaction was quenched with 0.6 mL of 1N HCl, then diluted with pH 7 buffer and extracted twice with ethyl acetate. The organic was washed again with buffer, dried over sodium sulfate filtered and the filtrate evaporated. The crude was taken up in 1.5-2 mL of acetonitrile, and after about 15 minutes white solid came out of solution. The suspension was filtered and a second crystallization set up from the mother liquor. The combined solid recovery was 51 mg of ≧95% pure product. LCMS (M+H)+: 713.1. 1H NMR (CDCl3, 500 MHz): δ 8.75 (br s, 1H), 8.57 (s, 1H), 8.32 (d, 1H), 8.04 (s, 1H), 7.99 (d, 1H), 7.93 (br s, 1H), 7.90 (s, 1H), 7.77 (s, 2H), 7.59 (d, 1H), 7.36 (d, 1H), 7.26 (s, 1H, (under CHCl3)), 5.82 (d, 1H), 4.93 (d, 1H), 4.48 (m, 1H), 4.21 (d, 1H), 4.04 (s, 3H), 2.40 (s, 3H), 0.81 (d, 3H). RTA IC50: 109 nM
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1B(O)O.Br[C:15]1[CH:20]=[CH:19][C:18]([CH:21]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH2:39][CH2:40][O:41][C:42]3[C:47]([Cl:48])=[CH:46][C:45]([CH3:49])=[CH:44][C:43]=3[Cl:50])=[CH:34][CH:33]=2)[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:17]([CH3:51])[CH:16]=1>>[Cl:48][C:47]1[CH:46]=[C:45]([CH3:49])[CH:44]=[C:43]([Cl:50])[C:42]=1[O:41][CH2:40][CH2:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH:21]([C:18]2[CH:19]=[CH:20][C:15]([C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=3[CH2:4][CH2:3][O:2][CH3:1])=[CH:16][C:17]=2[CH3:51])[CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[CH:33][CH:34]=1
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(Br)cc3C)cc2)c(Cl)c1
Reactant: COCCc1ccccc1B(O)O
Product: COCCc1ccccc1-c1ccc(C(CNC(=O)OC(C)(C)C)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)c(C)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 1, step 1 using [2-(2-methoxyethyl)phenyl]boronic acid from step 3 and tert-butyl (2-(4-bromo-2-methylphenyl)-3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}propyl)carbamate from step 2 as starting materials.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([NH:15][C:16](=[O:30])[C:17]2[CH:22]=[C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:20]=[C:19]([F:29])[CH:18]=2)=[CH:7][CH:6]=1.[OH:31][CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(OCC)(=O)C>CC(C)=O.CS(C)=O>[F:29][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:20]=1)[C:16]([NH:15][C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]([O:4][CH2:3][CH2:2][N:35]2[CH2:36][CH2:37][CH:32]([OH:31])[CH2:33][CH2:34]2)=[CH:6][CH:7]=1)=[O:30]
Reactant: O=C(Nc1ccc(OCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Reactant: OC1CCNCC1
Solvent: CS(C)=O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(OCCN2CCC(O)CC2)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Temperature: 25 °C
Yield: 14.8 %

Procedure:
N-[4-(2-Chloroethoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide (100 mg, 234 mmol) and 4-hydroxypiperidine (118 mg, 1.17 mmol) in acetone (3 ml) and dimethylsulfoxide (1 ml) are heated to 180° C. with microwave irradiation for 20 min. After cooling to room temperature the mixture is poured into ethyl acetate (100 ml) and washed with water (100 ml). The organic layer is dried over anhydrous sodium sulfate and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with ethyl acetate followed by 10% methanol in dichloromethane to give 3-fluoro-N-{4-[2-(4-hydroxypiperidin-1-yl)-ethoxy]-naphthalen-1-yl}-5-piperidin-1-yl-benzamide as a colorless foam (85 mg). 1H NMR 300 MHz (CDCl3) 8.31(dd, 1H, J=1.8 and 8.4 Hz), 7.9(s, 1H), 7.83(d, 1H, J=7.2 Hz), 7.71(d, 1H, J=8.4 Hz), 7.53(m, 2H), 7.31(s, 1H), 6.98(d, 1H, J=9 Hz), 6.83(d, 1H, J=8.4 Hz), 6.76(d, 1H, J=12.3 Hz), 4.23(t, 2H, J=5.7 Hz), 3.74(m, 1H), 3.01(s, 4H), 2.98(m, 4H), 2.42(t, 2H, J=9.5 Hz), 1.95(m, 2H), 1.57-1.71(m, 8H).