Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)=[N:4][CH:3]=[N:2]1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[CH:20]=1>>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]3[O:23][N:22]=[C:21]([CH3:24])[CH:20]=3)=[CH:8][CH:7]=2)=[N:4][CH:3]=[N:2]1
Reactant: Cc1cc(CCCCCBr)on1
Reactant: Oc1ccc(-c2ncno2)cc1
Product: Cc1cc(CCCCCOc2ccc(-c3ncno3)cc2)on1

Procedure:
It is further contemplated that 4-(1,2,4-oxadiazol-5-yl)phenol can be caused to react with 5-(5-bromopentyl)-3-methylisoxazole according to the procedure of Example 1 to give 5-{5-[4-(1,2,4-oxadiazol-5-yl)phenoxy]pentyl}-3-methylisoxazole [II; R1 and R2 =H, Het=1,2,4-oxadiazol-5-yl].
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11](N1C2C(=CC=CC=2)CCC1)=[O:12].[F:28][C:29]1[CH:30]=[CH:31][C:32]([O:36][CH3:37])=[C:33]([NH2:35])[CH:34]=1>>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:3]=1[O:4][C:5]1[C:6]([C:11]([NH:35][C:33]2[CH:34]=[C:29]([F:28])[CH:30]=[CH:31][C:32]=2[O:36][CH3:37])=[O:12])=[CH:7][N:8]=[CH:9][CH:10]=1
Reactant: O=C(c1cnccc1Oc1cc(Cl)ccc1Cl)N1CCCc2ccccc21
Reactant: COc1ccc(F)cc1N
Product: COc1ccc(F)cc1NC(=O)c1cnccc1Oc1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared in analogy to Example 1, from 4-(2,5-dichloro-phenoxy)-nicotinic acid (Example 1, intermediate) and 5-fluoro-2-methoxy-phenylamine (commercially available; CAS RN 1978-39-8). White solid (74%). MS (ESI): m/z=407.036 [M+H]+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Cl:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]1[C:14]2[N:15]([C:19]([N:26]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[CH2:27][CH2:28][CH3:29])=[C:20](S(C)(=O)=O)[N:21]=2)[CH:16]=[CH:17][N:18]=1>O>[Cl:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[C:13]1[C:14]2[N:15]([C:19]([N:26]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[CH2:27][CH2:28][CH3:29])=[C:20]([O:2][CH3:1])[N:21]=2)[CH:16]=[CH:17][N:18]=1
Reactant: CCCN(CC1CC1)c1c(S(C)(=O)=O)nc2c(-c3ccc(OC)cc3Cl)nccn12
Reactant: C[O-]
Agent: [Na+]
Solvent: O
Product: CCCN(CC1CC1)c1c(OC)nc2c(-c3ccc(OC)cc3Cl)nccn12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A 28% sodium methoxide solution (5 mL) was added to N-[8-(2-chloro-4-methoxyphenyl)-2-(methylsulfonyl)imidazo[1,2-a]pyrazin-3-yl]-N-cyclopropylmethyl-N-propylamine (80 mg), and the mixture was stirred for 6 hours by heating under reflux. After cooled to room temperature, water was added thereto, which was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The resulting residue was purified by silica gel column chromatography (ethyl acetate:n-hexane=1:5) to give the title compound (23 mg) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([N+:8]([O-])=O)=[CH:6][N:5]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]2)[N:4]=1>[Pd].CO>[NH2:8][C:7]1[C:3]([O:2][CH3:1])=[N:4][N:5]([CH:11]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:12]2)[CH:6]=1
Reactant: COc1nn(C2CN(C(=O)OC(C)(C)C)C2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1nn(C2CN(C(=O)OC(C)(C)C)C2)cc1N
Reaction time: 18 h

Procedure:
A nitrogen-flushed round bottom flask was charged with tert-butyl 3-(3-methoxy-4-nitro-1H-pyrazol-1-yl)azetidine-1-carboxylate (188 mg, 0.63 mmol, 1.00 eq), 10% Pd/C (100 mg) and methanol (10 mL). The reaction mixture was sparged with hydrogen for 5 min then stirred vigorously under hydrogen atmosphere for 18 hr. The reaction mixture was then sparged with nitrogen, filtered through Celite®, concentrated, and azeotroped from toluene (2×20 mL) to give an oil that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.04 (s, 1H), 4.82 (tt, J=5.4, 7.9 Hz, 1H), 4.15 (t, J=8.3 Hz, 2H), 4.04-3.95 (m, 2H), 3.79 (s, 3H), 3.44 (br. s., 2H), 1.40 (s, 9H). m/z (APCI+) for C7H13N4O 169.2 (M−Boc+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[C:15]([CH:16]=[CH2:17])=[N:14][N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:8]=2[N:9]=[C:10](Cl)[CH:11]=1)=[O:5])C.[OH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:10]2[CH:11]=[C:6]([C:4]([OH:3])=[O:5])[C:7]3[C:15]([CH:16]=[CH2:17])=[N:14][N:13]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:8]=3[N:9]=2)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: C=Cc1nn(C2CCCCO2)c2nc(Cl)cc(C(=O)OCC)c12
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: C1COCCO1
Product: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)O)c12
Yield: 143.7 %

Procedure:
To a solution of 6-chloro-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (2.00 g, 5.96 mmol), described in example 16.1, in dioxane (54 mL) were added 4-hydroxyphenylboronic acid (0.90 g, 6.55 mmol) and an aqueous solution of cesium carbonate (0.4 M, 27 mL, 10.8 mmol). The resulting solution was degassed using argon, tetrakis(triphenylphosphine)palladium (0.62 g, 0.54 mmol) was then added and the reaction mixture was refluxed overnight. Dioxane was removed under vacuum, water was added and then the mixture was acidified to pH=2. The aqueous phase was extracted with a mixture of tetrahydrofuran and EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, concentrated under vacuum to give the title compound (3.13 g) as a brown foam which was used without further purification.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([O:10][C@@H:11]1[C@H:15]([O:16][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)[C@@:14](COS(C)(=O)=O)([CH2:28][O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[O:13][C@@:12]1([SiH:48]([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[N:40]1[CH:47]=[CH:46][C:44](=[O:45])[NH:43][C:41]1=[O:42])(=O)C.CCOC(C)=O>CO>[C:18]1([CH2:17][O:16][C@@H:15]2[C@@:14]3([CH2:7][O:10][C@H:11]2[C@:12]([SiH:48]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:55]2[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=2)([N:40]2[CH:47]=[CH:46][C:44](=[O:45])[NH:43][C:41]2=[O:42])[O:13]3)[CH2:28][O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(=O)O[C@@H]1[C@H](OCc2cccc3ccccc23)[C@](COC(C)(C)C)(COS(C)(=O)=O)O[C@]1(n1ccc(=O)[nH]c1=O)[SiH](c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC[C@]12CO[C@H]([C@@H]1OCc1cccc3ccccc13)[C@@](n1ccc(=O)[nH]c1=O)([SiH](c1ccccc1)c1ccccc1)O2
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
Solid K2CO3 (11.1 g, 80 mmol) was added to a solution of compound 10 (29.4 g, 38 mmol) in methanol (350 mL). After stirring at room temperature for 5 hours, mixture was poured into EtOAc, washed with aqueous NaHCO3, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to a yellow foam. Purification by silica gel chromatography (1% methanol in CH2Cl2) yielded 20.0 g (83%) of nucleoside 11 as a pale yellow foam.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Br.Br.[NH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][NH:30][C:31]2[S:32][C:33]3[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=3[N:35]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>O.CN(C)C(=O)C>[F:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:23]2[CH2:28][CH2:27][CH:26]([CH2:29][NH:30][C:31]3[S:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=3)[CH2:25][CH2:24]2)=[C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1
Reactant: c1ccc2sc(NCC3CCNCC3)nc2c1
Reactant: Fc1ccc(OCCCCl)c(OCc2ccccc2)c1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Fc1ccc(OCCCN2CCC(CNc3nc4ccccc4s3)CC2)c(OCc2ccccc2)c1
Temperature: 75 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
A mixture of 3.2 parts of 1-(3-chloropropoxy)-4-fluoro-2-(phenylmethoxy)benzene, 4.1 parts of N-(4-piperidinylmethyl)-2-benzothiazolamine dihydrobromide, 6 parts of sodium carbonate, 0.1 parts of sodium iodide and 67.5 parts of N,N-dimethylacetamide was stirred overnight at 75° C. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The oily residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 3.3 parts (65.2%) of N-[[1-[3-[4-fluoro-2-(phenylmethoxy)phenoxy]propyl]-4-piperidinyl]methyl]-2-benzothiazolamine; mp. 129.5° C. (compound 24).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[CH:12]=[C:11](B3OC(C)(C)C(C)(C)O3)[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)=[N:9]2)=[CH:5][CH:4]=1.[CH3:33][S:34][C:35]1[N:40]=[C:39](Cl)[CH:38]=[CH:37][N:36]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:37]3[CH:38]=[CH:39][N:40]=[C:35]([S:34][CH3:33])[N:36]=3)[C:10]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)=[N:9]2)=[CH:31][CH:32]=1
Reactant: COc1ccc(Cn2cc(B3OC(C)(C)C(C)(C)O3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Reactant: CSc1nccc(Cl)n1
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: C1COCCO1
Solvent: O
Product: COc1ccc(Cn2cc(-c3ccnc(SC)n3)c(-c3cccc([N+](=O)[O-])c3)n2)cc1
Temperature: 100 °C
Yield: 88.4 %

Procedure:
2.6 g (6 mmol) of 1-(4-methoxybenzyl)-3-(3-nitrophenyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole were dissolved in a mixture of 520 ml of dioxane and 130 ml of water under a nitrogen atmosphere. 709 μl (6 mmol) of 2-methylthio-4-chloro-pyrimidine, 3.9 g (12 mmol) of cesium carbonate and 650 mg (0.6 mmol) of palladium tetrakis were added consecutively to the resulting solution under stirring. The reaction mixture was heated at 100° C. for 6 hours, then filtered through a celite pad and concentrated under reduced pressure. The residue was partitioned between dichloromethane and water, the organic layer dried over sodium sulphate and evaporated to dryness. The crude was finally purified by flash-chromatography on a silica gel column (cyclohexane-ethylacetate; from 9/1 to 4/1), giving 2.3 g (88%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][C:6]1[N:7]=[CH:8][N:9](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]=1.Br[CH2:32][C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([F:41])[CH:34]=1>CCOC(C)=O>[C:37]([C:36]1[CH:39]=[CH:40][C:33]([CH2:32][N:7]2[C:6]([CH2:5][CH2:4][C:3]([OH:30])=[O:2])=[CH:10][N:9]=[CH:8]2)=[CH:34][C:35]=1[F:41])#[N:38]
Reactant: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: N#Cc1ccc(CBr)cc1F
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Cn2cncc2CCC(=O)O)cc1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-Trityl-imidazole-4-propionic acid methyl ester (2.15 g, 5.42 mmol) and 4-bromomethyl-2-fluoro-benzonitrile, as described above in Step D, (1.16 g, 5.42 mmol) were dissolved in EtOAc (20 mL) and heated at 60° C. for 3 h. The precipitated solid was filtered off, and the filtrate was concentrated to 10 mL then heating at 60° C. was continued overnight. The precipitate was collected and combined with the first solid and heated at reflux in CH3OH (20 mL) for 5 h. The reaction mixture was concentrated to dryness and triturated with hexane to remove triphenylmethane. The residue was dissolved in THF (10 mL)-H2O (5 mL), treated with 1 N NaOH (5 mL) and stirred at ambient temperature for 16 h. The reaction mixture was neutralized with 1N HCl (5 mL), concentrated to remove the THF, then lyophilized to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:33]=[C:34]([CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1)[CH3:35]>CN(C=O)C.[Cu]I>[CH:36]1(/[C:34](/[CH3:35])=[CH:33]\[N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(=CBr)C1CCCCC1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C/n1c2c(c3cc(C)ccc31)CN(C)CC2)C1CCCCC1
Temperature: 85 °C

Procedure:
2,3,4,5-Tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (100 mg, 0.5 mmol) was dissolved in DMF (3 mL) and potassium phosphate (212.4 mg, 1 mmol), copper(I) iodide (9.5 mg, 0.05 mmol) and L-proline (11.51 mg, 0.1 mmol) was added in to it. (1-bromoprop-1-en-2-yl)cyclohexane (121.8 mg, 0.6 mmol) was dissolved in DMF (2 mL) and added dropwise. Nitrogen was purged for 2 min and the reaction mixture was heated at 85° C. overnight (prolonged heating was required in some cases). DMF was evaporated and water was added. The precipitate obtained was filtered and purified by silica gel chromatography (100-200 mesh) using 0-3% MeOH:DCM as eluent. The compound was further purified through reverse phase purification. Yield: 0.45 mg. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.25 (s, 1H), 7.0 (m, 2H), 6.42 (s, 1H), 4.70 (m, 1H), 4.35 (m, 1H), 3.85 (m, 1H), 3.58 (m, 1H), 3.12 (s, 3H), 3.05 (m, 2H), 2.42 (s, 3H), 2.30 (m, 1H), 1.90 (m, 5H), 1.78 (m, 1H), 1.50-1.30 (m, 7H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[NH:21][CH:22]=[CH:23][C:16]=34)=[CH:13][N:12]([CH2:24][C:25]([OH:27])=[O:26])[N:11]=2)=[CH:6][CH:5]=1)([O-])=O.[Sn].Cl.[C:30]1([N:36]=[C:37]=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(O)C>[C:30]1([NH:36][C:37]([NH:1][C:4]2[CH:9]=[CH:8][C:7]([C:10]3[C:14]([C:15]4[CH:20]=[CH:19][N:18]=[C:17]5[NH:21][CH:22]=[CH:23][C:16]=45)=[CH:13][N:12]([CH2:24][C:25]([OH:27])=[O:26])[N:11]=3)=[CH:6][CH:5]=2)=[O:38])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(O)Cn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: O=C=Nc1ccccc1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: O=C(O)Cn1cc(-c2ccnc3[nH]ccc23)c(-c2ccc(NC(=O)Nc3ccccc3)cc2)n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A heterogeneous mixture of [3-(4-nitrophenyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]acetic acid (31.0 mmol), elemental tin dust (5.30 mmol), 6.0N aqueous hydrochloric acid (5.3 mL) and absolute ethanol (5.3 mL) was stirred at 70° C. for 1 h. The solution was filtered through Celite and concentrated in vacuo. The resulting aniline was dissolved in anhydrous pyridine (10 mL) and phenyl isocyanate (11.17 mmol) added dropwise. The reaction mixture was stirred at room temperature for 4 h. After concentration in vacuo, purification by Gilson reverse phase HPLC afforded the title compound as a white solid (93%). ESMS [M+H]+: 453.2
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][CH:7]=1.[Br-].[S:14]1[CH:18]=[CH:17][N:16]=[C:15]1[Zn+].C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:15]2[S:14][CH:18]=[CH:17][N:16]=2)=[CH:6][CH:7]=1
Reactant: [Zn+]c1nccs1
Reactant: COC(=O)c1nc(Br)ccc1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Br-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2nccs2)ccc1N
Yield: 51 %

Procedure:
A solution of methyl 3-amino-6-bromopicolinate (1.0 equiv.), 2-thiazolylzinc bromide 0.5 M solution in THF (3.0 equiv.), and Pd(dppf)Cl2-DCM (0.05 equiv.) was stirred at 80° C. for 1.5 hours. The reaction was filtered and washed with EtOAc. The organic was washed with H2O (100 mL), and further washed with NaCl(sat.) (50 mL), dried over MgSO4, and the volatiles were removed in vacuo. The product was crystallized with hexane/EtOAc (1:1) to yield methyl 3-amino-6-(thiazol-2-yl)picolinate (51%). LCMS (m/z): 236.1 (MH+); LC Rt=2.3 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[N:11]1([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(-n2cncn2)cc1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
4Fluoronitrobenzene (2 g, 0.014 mol), 1,2,4-triazole (1 g, 0.014 mol), potassium carbonate (1.96 g, 0.014 mol) were dissolved in DMSO (50 ml) and stirred at 90° C. for 24 h under dry conditions. The yellow suspension was poured into water (150 ml), extracted (EtOAc), dried (Na2SO4) and evaporated under reduced pressure to afford an orange solid which was purified by flash column chromatography on silica eluting with n-pentane/ethyl acetate (50-100%) to afford a white solid (2.57 g 97%).
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Br[C:61]1[C:65]2[N:66]=[CH:67][N:68]=[C:69]([NH:70][CH:71]([CH3:73])[CH3:72])[C:64]=2[S:63][CH:62]=1.CC1(C)C(C)(C)OB([C:82]2[CH:87]=[CH:86][C:85]([OH:88])=[CH:84][CH:83]=2)O1>>[CH:71]([NH:70][C:69]1[C:64]2[S:63][CH:62]=[C:61]([C:82]3[CH:87]=[CH:86][C:85]([OH:88])=[CH:84][CH:83]=3)[C:65]=2[N:66]=[CH:67][N:68]=1)([CH3:73])[CH3:72]
Reactant: CC(C)Nc1ncnc2c(Br)csc12
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: CC(C)Nc1ncnc2c(-c3ccc(O)cc3)csc12

Procedure:
The title compound 69B was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with compound 69A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 9.49 (s, 1H), 8.50 (s, 1H), 8.10 (s, 1H), 7.88-7.91 (m, 2H), 7.57 (d, J=7.67 Hz, 1H), 6.83-6.86 (m, 2H), 4.44-4.53 (m, 1H), 1.25 (d, J=6.75 Hz, 6H). ESI (+)/MS: 286 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[N:10]([CH2:22][OH:23])[CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1.[Cl-]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:24])[N:10]([CH2:22][O:23][C:9](=[O:24])[CH2:8][CH:5]([CH3:6])[CH3:4])[CH:11]=[C:12]3[C:17]=2[NH:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=2[S:13]3)=[CH:4][CH:3]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccccc1N2
Agent: [Cl-]
Solvent: c1ccncc1
Product: CC(C)CC(=O)OCn1cc2c(c(-c3ccc(Cl)cc3)c1=O)Nc1ccccc1S2
Reaction time: 0.58 h
Yield: 36 %

Procedure:
To 2.5 g. of 4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (7.0 mmol.) in 25 ml. of pyridine at 0° C. was added 2.5 ml. of isovalery chloride (20.5 mmol.). After stirring for 35 minutes, the mixture was poured onto ice-water and allowed to stand for 16 hours at room temperature. The crude product which formed as an orange precipitate was collected, washed with water, air-dried, and purified using flash chromotography on silica gel, using a mixture of 5% ethyl acetate: 95% methylene chloride as the eluent. Fractions containing the product were combined and triturated with ether to yield 4-(4-chlorophenyl)-2-[(3-methyl-1-oxobutoxy)methyl]-5H-pyrido-[3,4-b][1,4]benzothiazin-3(2H)-one as a yellow solid (1.1 g; 36% yield) having the structural formula, ##STR16## a melting point in the range of 163°-171° C. and the following elemental analysis:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:8]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].BrC1C(C=O)=CC(OCC2C=CC=CC=2)=C(C=1)C(OCC1C=CC=CC=1)=O.S(=O)(=O)(O)N.CC(CC)=C.[CH:66]([N:69](C(C)C)[CH2:70]C)(C)C.Cl.CNC.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C)C=O.O.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([C:4]([N:69]([CH3:70])[CH3:66])=[O:5])=[CH:7][C:8]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:9]([CH:10]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(O)c1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1Br
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: Cl
Agent: NS(=O)(=O)O
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(OCc2ccccc2)c(C(=O)OCc2ccccc2)cc1Br
Reaction time: 18 h

Procedure:
To a solution of 2-bromo-5-[(phenylmethyl)oxy]-4-{[(phenylmethyl)oxy]carbonyl}benzoic acid (may be prepared as by oxidation of phenylmethyl 5-bromo-4-formyl-2-[(phenylmethyl)oxy]benzoate—may be prepared as described in Description 24—with sulfamic acid in the presence of 2-methyl-1-butene; 436 mg, 0.99 mmol) in N,N-dimethylformamide (5 ml) was added diisopropylethylamine (0.35 ml, 1.98 mmol), dimethylamine hydrochloride (121 mg, 1.48 mmol), 1-hydroxy-7-azabenzotriazole (188 mg, 1.38 mmol) and EDC (379 mg, 1.98 mmol). The solution was stirred for 18 hours. Ethyl acetate (10 ml) and water (10 ml) were added and the organic layer separated and washed further with water (2×10 ml), dried (MgSO4) and the solvent removed in vacuo. Purification by column chromatography (SiO2, 1:1 ethyl acetate/cyclohexane) gave the title compound as an orange gum. 195 mg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:8][NH:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)[CH2:6][CH3:7])[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:8][N:9]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14]1)[CH2:6][CH3:7])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(CC)CNC1CCCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(CC)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
A solution of 1.07 g (0.005 mole) of (rac)-2-cyclopentylaminomethyl-butanoic acid ethyl ester in 25 mL of water was added dropwise to a solution of 0.97 g (0.005 mole) of 2,4-dichloro-5-nitro-pyrimidine in 25 mL of ethyl ether. At 0 degrees, 1.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-80:20) gave 1.3 g of (rac)-2-{[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]-methyl}-butanoic acid ethyl ester (IV-12).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[CH:4]=[CH:5][C:6](=[O:8])[CH:7]=1.[Cl:10][C:11]1([Cl:20])[C:15]([Cl:16])=[C:14]([Cl:17])[C:13]([Cl:18])=[C:12]1[Cl:19]>C1(C)C=CC=CC=1>[Cl:16][C:15]12[C:11]([Cl:10])([Cl:20])[C:12]([Cl:19])([CH:4]3[CH:5]1[C:6](=[O:8])[CH:7]=[C:2]([CH3:1])[C:3]3=[O:9])[C:13]([Cl:18])=[C:14]2[Cl:17]
Reactant: ClC1=C(Cl)C(Cl)(Cl)C(Cl)=C1Cl
Reactant: CC1=CC(=O)C=CC1=O
Solvent: Cc1ccccc1
Product: CC1=CC(=O)C2C(C1=O)C1(Cl)C(Cl)=C(Cl)C2(Cl)C1(Cl)Cl
Temperature: 25 °C

Procedure:
To a mixture of methyl-p-benzoquinone (60 g.), and hexachlorocyclopentadiene (140 g.), was added 20 ml. of toluene. This reaction mixture was then heated at 130°-140° C. for 3 hours. Upon cooling to room temperature the mixture solidified. This solid was washed with Skelly "B" solvent several times on a Buchner funnel and recrystallized from a Skelly "B"-benzene mixed solvent (20/80). Pale yellow crystals were obtained, m.p. 163°-165° C.