Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[CH3:12][NH:13][NH2:14].[OH-].[Na+]>>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([N:13]([CH3:12])[NH2:14])=[N:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CNN
Agent: [Na+]
Agent: [OH-]
Product: CN(N)c1ccc(C(F)(F)F)cn1
Temperature: 90 °C

Procedure:
2-Chloro-5-trifluoromethylpyridine (44.3 g; 0.24 mol) was treated with several portions of methyl hydrazine (33.9 g; 0.74 mol) at room temperature under nitrogen. The mixture was heated at 90° C. for 6 hr. The resulting solid was treated with 3M aqueous NaOH and extracted with ethyl acetate. The organic extracts were dried and evaporated to leave an oil/solid. Distillation of the crude product to remove excess hydrazine gave 1-[5-trifluoromethylpyrid-2-yl]-1-methyl hydrazine as a white solid (44.0 g; 94%), m.pt. 52°-55° C. ##STR14##
Reaction SMILES: N[C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[Br-:12].[Na+].C(ON=O)(C)(C)C>CC#N.[Cu]Br>[Br:12][C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: [Br-]
Reactant: COC(=O)c1nc(N)sc1C
Agent: [Cu]Br
Agent: CC(C)(C)ON=O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1nc(Br)sc1C
Temperature: 80 °C
Yield: 57.1 %

Procedure:
To a stirred suspension of methyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate (5 g, 29.03 mmol, 1 eq.) in 75 ml of MeCN, were added sodium bromide (5.97 g, 58.07 mmol, 2 eq.), Copper (I) bromide (6.08 g, 31.93 mmol, 1.1 eq.) and t-Butylnitrite (90%, 3.65 g, 31.93 mmol, 1.1 eq.). The reaction was slowly heated to 80° C. for 1 h and allowed to cool. MeCN was evaporated and 100 ml DCM were added to the residue. The crude was triturated, filtered through “celite” plug and washed with further 50 ml of EtOAc. The organic layers were combined, dried over MgSO4, and evaporated to give methyl 2-bromo-5-methyl-1,3-thiazole-4-carboxylate (3.91 g, 42% yield) as a yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:21]=[C:22](/[CH:24]=[CH:25]/[C:26]4[CH:35]=[CH:34][C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=4)[N:23]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[N-:36]=[N+:37]=[N-:38].[Na+]>>[NH:36]1[C:19]([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:21]=[C:22](/[CH:24]=[CH:25]/[C:26]5[CH:35]=[CH:34][C:33]6[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=6)[N:27]=5)[N:23]=[C:8]4[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)=[N:20][N:38]=[N:37]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(-c2cnc(N3CCOCC3)c3nc(/C=C/c4ccc5ccccc5n4)cn23)cn1
Agent: [Na+]
Product: C(=C/c1cn2c(-c3ccc(-c4nnn[nH]4)nc3)cnc(N3CCOCC3)c2n1)\c1ccc2ccccc2n1
Reaction time: 0.13 h

Procedure:
Compound 2c (120 mg, 0.260 mmol) was treated with NaN3 as described in Example 1, Step H. This resulted in 150 mg of crude compound 96, which was then purified by Prep-HPLC under the following conditions: XbridgePrep Shield RP 18, 5 μm, 19*150 mm; mobile phase, water with 0.05% NH4CO3 and CH3CN (30% CH3CN up to 50% in 8 min, up to 100% in 1 min, down to 30% in 1 min); Detector, UV 254 nm. The title compound 96 was obtained as a yellow solid (38.4 mg, 29% yield). 1H-NMR (300 MHz, DMSO-d6) δ (ppm): 9.09 (s, 1H), 8.41-8.33 (m, 4H), 7.95-7.56 (m, 8H), 4.50-4.28 (m, 4H), 4.00-3.71 (m, 4H). Mass Spectrum (LCMS, ESI pos.): Calcd. for C22H22N10O: 503.2 (M+H). Found 503.2.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:44]([O:48][C:49](=[O:69])[NH:50][C@H:51]([CH2:67][NH2:68])[CH2:52][CH2:53][CH2:54][CH2:55][NH:56][C:57]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)=[O:58])([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.CO>[C:44]([O:48][C:49](=[O:69])[NH:50][C@H:51]([CH2:67][NH:68][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:12])[CH2:52][CH2:53][CH2:54][CH2:55][NH:56][C:57]([O:59][CH2:60][C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)=[O:58])([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)OC(=O)N[C@H](CN)CCCCNC(=O)OCc1ccccc1
Reactant: Nc1nc(N)c(C(=O)O)nc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)CNC(=O)c1nc(Cl)c(N)nc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic acid (386 mg, 2.05 mmol) and HATU (781 mg, 2.05 mmol) in DMF (10 mL) is added N-methyl morpholine (831 mg, 8.22 mmol) followed by ((S)-1-aminomethyl-5-benzyloxycarbonylamino-pentyl)-carbamic acid tert-butyl ester (prepared according to the procedure described in WO1997/01204 page 20) (750 mg, 2.05 mmol). The resulting solution is stirred at RT for 18 h and then concentrated in vacuo to afford an orange oil. The oil is dissolved in MeOH (10 mL) and allowed to stand at RT after which time a cream precipitate forms that is collected by filtration and dried under vacuum to yield the title compound. [M+H]+ 536.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[S:43][C:42]([CH3:44])=[N:41][CH:40]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[S:43][C:42]([CH3:44])=[N:41][CH:40]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: Cc1ncc(C2(O)CCC(=O)CC2)s1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(F)(F)F)cc45)C3)CC2)s1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-hydroxy-4-(2-methyl-thiazol-5-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [S-2].[Na+].[Na+].[NH2:4][C:5]1[C:10]([C:11]#[N:12])=[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=2)[C:8]([C:25]#[N:26])=[C:7]([S:27]CC2C=CC=CC=2)[N:6]=1.Cl.O>CN(C=O)C>[NH2:4][C:5]1[C:10]([C:11]#[N:12])=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:17][CH:18]=2)[C:8]([C:25]#[N:26])=[C:7]([SH:27])[N:6]=1
Reactant: CN(C)CCOc1ccc(-c2c(C#N)c(N)nc(SCc3ccccc3)c2C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [S-2]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.97 g (12.41 mmol) of sodium sulphide is added to a solution of 3.56 g (8.28 mmol) of the compound from Example 33A in 13 ml of dry DMF. The reaction mixture is stirred at +80° C. for 2 h. After cooling to RT, 2 ml of 37% strength hydrochloric acid are added to the reaction mixture, whose temperature rises to 65° C. After addition of 2.6 ml of water, the reaction mixture is cooled back to RT. After addition of a further 5 ml of water, the mixture is washed with 5 ml of ethyl acetate and made alkaline by addition of 40% strength sodium hydroxide solution. Yellow crystals precipitate, and these are filtered off with suction, washed with 10 ml of water and 10 ml of diethyl ether and then dried under reduced pressure. The filtrate is concentrated using a rotary evaporator and stirred with a little water. The resulting crystals are filtered off with suction, washed with in each case 10 ml of water and diethyl ether and dried under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1.ON1C(=O)N(O)C(=O)N(O)C1=O.C[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=1[C:30]([OH:32])=[O:31].O=O>[Ti].C([O-])(=O)C.[Co+2].C([O-])(=O)C.O.C(O)(=O)C>[C:30]([OH:32])(=[O:31])[C:29]1[CH:24]=[CH:25][C:26]([C:8]([OH:10])=[O:9])=[CH:27][CH:28]=1.[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccccc1C(=O)O
Agent: [Co+2]
Agent: [Ti]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(C(=O)O)cc1
Temperature: 150 °C
Reaction time: 1 h

Procedure:
In a 500-ml titanium autoclave equipped with a stirrer and a pressure gauge, 15.36 g of p-toluic acid, 104.0 g of acetic acid, 0.066 g of hexahydro-1,3,5-trihydroxy-1,3,5-triazine-2,4,6-trione (1,3,5-trihydroxyisocyanuric acid) (0.33% by mole relative top-toluic acid), 0.112 g of cobalt (II) acetate 4 H2O and 0.277 g of manganese(II) acetate 4 H2O were placed. The autoclave was charged with 2 MPa of oxygen gas and 2 MPa of nitrogen gas and placed in a heated oil bath. The mixture was stirred at 150° C. for 1 hour. After the completion of the reaction, the autoclave was placed on cold water to cool down the reaction mixture quickly. The resulting mixture was analyzed by high performance liquid chromatography and was found to yield terephthalic acid in 63% yield at 68% conversion of p-toluic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([CH3:12])[CH2:5]2.C(Cl)(Cl)Cl.[N:17]1C2C(=CC=CC=2)C=C[CH:18]=1>>[C:18]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([CH3:12])[CH2:5]2)#[N:17]
Reactant: c1ccc2ncccc2c1
Reactant: CC1Cc2cc(Br)ccc2C1=O
Solvent: ClC(Cl)Cl
Product: CC1Cc2cc(C#N)ccc2C1=O

Procedure:
5-Bromo-2-methyl-1-indanone (2.0 g) and cuprous cyanide (4.0 g) in quinoline (50 ml ) were stirred at 200° for 2 hours. The mixture was cooled, treated with chloroform (100 ml ) and filtered to remove copper salts. The filtrate was then washed with 6N hydrochloric acid (3×100 ml ) and evaporated to give the crude product as a brown gum. Crystallisation from ethanol-water gave 5-cyano-2-methyl-1-indanone (1.46 g, m.p. 90°-1°).
Reaction SMILES: [CH2:1]([NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[CH2:19][N:20]=[C:21]=[S:22]>C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[CH2:19][NH:20][C:21]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[S:22]
Reactant: COc1cccc(CN=C=S)c1
Reactant: CCCCCCCCCCCCN
Solvent: CCO
Product: CCCCCCCCCCCCNC(=S)NCc1cccc(OC)c1
Temperature: 4 °C

Procedure:
Dodecyl amine (4.89 g, 26.4 mmol) in 83 ml ethanol at 50° C. was reacted with 3-methoxybenzyl isothiocyanate (3.97 g, 22.1 mmol) for 6 h under N2 with stirring, and then poured into a 250 ml beaker. Performing this reaction at 40° C. led to a precipitate that was difficult to stir. Crystallization began as soon as the reaction started cooling below 50° C. The reaction mixture was cooled to 4° C. and the crystals were filtered off using Whatman 54 filter paper. The crystals were washed with 15 ml of ethanol. Combined filtrates were evaporated to dryness and taken up in 10 ml ethanol. Cooling the solution to −10° C. gave no crystals. The solution was evaporated to dryness and the solids were weighed. Material recovery was 98.7%, and yield of crystals was 7.62 g, or 94.4% of the theoretical yield. Calculated elemental analysis of 1-(3-methoxybenzyl)-3-dodecyl thiourea: C, 69.18; H, 9.95; N, 7.68; S, 8.79. Found: C, 69.65; H, 10.07; N, 7.67; S, 8.80.
Reaction SMILES: O.[OH-].[Li+].[CH3:4][CH:5]([CH3:42])[CH:6]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:34](=[O:35])[CH2:33][O:32][C:31]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[N:30]2)=[CH:24][CH:23]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[CH2:11]1)=[O:8].Cl>C1COCC1.O>[CH3:4][CH:5]([CH3:42])[CH:6]([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][N:29]2[C:34](=[O:35])[CH2:33][O:32][C:31]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)=[N:30]2)=[CH:24][CH:23]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH:12]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH2:11]1)=[O:8]
Reactant: COC(=O)CCC1CCCC(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C(C)C)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(C(=O)NC1CCCC(CCC(=O)O)C1)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
94 mg (2.25 mmol) of lithium hydroxide monohydrate were added to a solution of 600 mg (1.12 mmol) of methyl 3-{3-[(3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}butanoyl)amino]cyclohexyl}propanoate (Example 142A) in 15 ml of THF and 15 ml of water, and the mixture was stirred at room temperature overnight. The reaction mixture was then adjusted to pH 2 with 1 M hydrochloric acid and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. This gave 573 mg (1.10 mmol, 98% of theory) of the title compound as a mixture of isomers.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[N:21][N:22]=1)C1C=CC=CC=1>C1COCC1.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[O:19][C:20]([CH:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[N:21][N:22]=1
Reactant: CN1CCC(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CN1CCC(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4O)o2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a solution of (2S,5R)-6-(benzyloxy)-2-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (198 mg, 0.50 mmol) in THF (20 mL) was added 10% Pd/C (200 mg). The mixture was stirred under H2 atmosphere at rt for 3 hrs. The reaction mixture was filtered and concentrated to afford (2S,5R)-6-hydroxy-2-(5-(1-methylpiperidin-4-yl)-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (151 mg, 97%), which was used directly in the next step. ESI-MS (EI+, m/z): 308.1 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:18]=[CH:17][C:11]3[NH:12][C:13](=[O:16])[CH2:14][O:15][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:18]=[CH:17][C:11]3[NH:12][C:13](=[O:16])[CH2:14][O:15][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2ccc3c(c2)OCC(=O)N3)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1COc2cc(Oc3ccc(O)cc3)ccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A solution of 7-(4-methoxyphenoxy)-2H-1,4-benzoxazin-3(4H)-one (120 mg; 0.44 mmol) in CH2Cl2 (1 ml) was treated with BBr3 (332 mg; 1.33 mmol). The mixture was stirred at room temperature for 3 hours. After evaporation to dryness the residue was taken up in EtOAc and water. The organic phase was washed with brine and dried over MgSO4. The residue (110 mg) was triturated with EtOAc, filtered and dried to give 7-(4-hydroxyphenoxy)-2H-1,4-benzoxazin-3(4H)-one as a biege solid (85 mg), Melting point 250-251° C.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH3:16])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][CH:28]([OH:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C
Reactant: O=Cc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccccc2)noc1CC(O)c1ccccc1
Temperature: -65 °C
Reaction time: 2 h

Procedure:
A suspension of 75 grams (0.348 mole) of 3-phenyl-5,N-dimethyl-isoxazole-4-carboxamide in 1 liter of tetrahydrofuran is cooled to -65° C. and 478 milliliters of 1.6M n-butyllithium in hexane (0.765 mole) is added dropwise maintaining the temperature between -60° C. and -70° C. After the addition is complete, the orange suspension is stirred for 11/2 hours at -60° C. to -70° C., and then 37.2 grams (0.350 mole) of benzaldehyde in 375 milliliters tetrahydrofuran is added dropwise maintaining the temperature between -60° C. and -70° C. After addition is complete, the mixture is stirred 11/2 hours at -60° C. to -70° C. and then warmed to -30° C. and quenched by the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50 percent brine, and once with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid residue is triturated with a 50:50 mixture of ether:petroleum ether, filtered and washed with cold ether to give 3-phenyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide, m.p. 183° - 184° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10]Br)=[O:9])=[CH:4][CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([CH2:10][C:8](=[O:9])[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.5 %

Procedure:
2-Bromo-4-methylacetophenone (572 mg, 2.68 mmol) was added to a solution of piperazine-1-carboxylic acid tert-butyl ester (500 mg, 2.68 mmol) in dichloromethane (5 ml) and triethylamine (0.45 ml, 3.22 mmol). The mixture was stirred for 3 days at room temperature and solvents were removed in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 40% hexane:60% EtOAc) to yield the title compound (661 mg, 77%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[C:10]=1[CH3:11].C1C=C(O[C:19](OC2N=CC=CC=2)=[S:20])N=CC=1>ClCCl>[N:1]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[C:10]=1[CH3:11])=[C:19]=[S:20]
Reactant: Cc1c(N)ccc2ocnc12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Solvent: ClCCl
Product: Cc1c(N=C=S)ccc2ocnc12
Reaction time: 2 h
Yield: 89.8 %

Procedure:
A solution of 5-amino-4-methylbenzoxazole (0.59 g, 3.98 mmol) in dichloromethane (100 mL) is treated with di-2-pyridyl thionocarbonate (1.02 g, 4.39 mmol). The mixture is stirred for two hours. The reaction mixture is concentrated under reduced pressure to yield a brown residue. This material is purified by chromatography (silica-gel, 20% ethyl acetate/hexanes) to afford 0.68 g of 5-isothiocyanato-4-methylbenzoxazole as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:16])=[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:10][CH:9]=2)[CH:15]=1
Reactant: IC1CCCC1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: Clc1ccc(Br)cc1Cc1ccc(OC2CCCC2)cc1
Temperature: 60 °C

Procedure:
To a mixture of 40.0 g 4-(5-bromo-2-chloro-benzyl)-phenol and 71.0 g cesium carbonate in 300 mL ethanol are added 23 mL iodocyclopentane. The mixture is stirred at 60° C. over night and then cooled to ambient temperature. The ethanol is evaporated, and water is added to the residue. The resulting mixture is extracted with ethyl acetate, the combined extracts are dried over sodium sulfate, and the solvent is removed. The residue is filtered through silica gel (cyclohexane/ethyl acetate 100:1→10:1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH3:23])=[O:21])=[N:11][C:12](Br)=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[NH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44].O>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([C:20]([O:22][CH3:23])=[O:21])=[N:11][C:12]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:41]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:47])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NCCCCCCN
Reactant: COC(=O)c1nc(Br)c2cccnc2c1OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1nc(NCCCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Methyl 8-(benzyloxy)-5-bromo-1,6-naphthyridine-7-carboxylate (Example 1; 5.50 g; 14.7 mmol) was dissolved in DMA (300 ml). DIPEA (5.14 ml; 29.5 mmol) was added at room temperature. The reaction mixture was stirred for 5 min at room temperature. tert-Butyl 6-aminohexylcarbamate (4.95 ml; 22.1 mmol) was added and the reaction mixture was stirred at 100° C. for 12 hours. The reaction mixture was cooled. Water and ethyl acetate were added. The organic layer was separated and washed with water (×2) and with brine. The organic layer was dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent: hexane/EtOAc from 10:1 to 1:1). The product fractions were collected and the solvent evaporated.
Reaction SMILES: Br[C:2]1[C:3]([CH3:20])=[N:4][N:5]2[C:10]3[N:11]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:12][CH2:13][C:9]=3[C:8]([CH3:19])=[N:7][C:6]=12.[O:21]1[C:25]([Sn](CCCC)(CCCC)CCCC)=[CH:24][C:23]2[CH:39]=[CH:40][CH:41]=[CH:42][C:22]1=2.C(OCC)(=O)C.O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[C:25]([C:2]2[C:3]([CH3:20])=[N:4][N:5]3[C:10]4[N:11]([CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:12][CH2:13][C:9]=4[C:8]([CH3:19])=[N:7][C:6]=23)=[CH:24][C:23]2[CH:39]=[CH:40][CH:41]=[CH:42][C:22]1=2
Reactant: CCC(CC)N1CCc2c(C)nc3c(Br)c(C)nn3c21
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccccc2o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCC(CC)N1CCc2c(C)nc3c(-c4cc5ccccc5o4)c(C)nn3c21
Yield: 33.3 %

Procedure:
A solution of 3-bromo-8-(1-ethylpropyl)-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (300 mg, 0.89 mmol), benzo[b]furan-2-yl(tributyl)tin (0.72 g, 1.78 mmol) and Pd(PPh3)4 (103 mg, 0.90 mmol) in N,N-dimethylformamide (15 mL) was stirred at 120° C. for one day. Ethyl acetate and water were added thereto, followed by filtering through Celite. The organic layer of the filtrate was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (0-5% ethyl acetate/hexane), to give the title compound (111 mg) as white crystals.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[N:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:15]([CH3:25])[N:14]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[CH3:25][C:15]1[N:14]=[C:13]([CH2:12][N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:27])[C:7]=3[CH2:8]2)[CH:18]=[N:17][C:16]=1[O:19][CH2:20][C:21]([F:24])([F:23])[F:22]
Reactant: O=COc1ccccc1
Reactant: Cc1nc(CN2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Product: Cc1nc(CN2Cc3c(ccnc3C(=O)Oc3ccccc3)C2=O)cnc1OCC(F)(F)F
Yield: 76 %

Procedure:
The title compound is prepared in 76% yield (250 mg, brown solid) from 4-chloro-2-((6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)methyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (270 mg, 0.72 mmol, Intermediate-84) and phenyl formate (180 mg, 1.4 mmol) in a similar manner to Intermediate-91.