Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])([O-])=O.[Zn+2:9].[N+]([O-])([O-])=O.[P:14](=[O:18])([OH:17])([OH:16])[OH:15]>O>[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Zn+2:9].[P:14]([O-:18])([O-:17])([O-:16])=[O:15].[Zn+2:9].[Zn+2:9]
Reactant: O=P(O)(O)O
Agent: O=[N+]([O-])[O-]
Agent: [Zn+2]
Solvent: O=[N+]([O-])O
Solvent: O
Product: O=P([O-])([O-])[O-]

Procedure:
a phosphatizing solution based on: zinc phosphate diacid, nitric acid, zinc nitrate and phosphoric acid, diluted in water at 5 to 20%, at a temperature of 60 to 85° C. for a time which can vary between 5 and 15 minutes, to produce a zinc phosphate coating which is compact and uniform and has a very fine crystalline structure in order to facilitate the mechanical deformation of the material when cold;
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:15])=O)[C:7]=2[CH:6]=[N:5]1)[CH3:3].[NH2:16][CH2:17][C:18]1[C:19](=[O:32])[NH:20][C:21]([CH3:31])=[CH:22][C:23]=1[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([C:23]1[CH:22]=[C:21]([CH3:31])[NH:20][C:19](=[O:32])[C:18]=1[CH2:17][NH:16][C:13]([C:12]1[C:7]2[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=2[N:9]=[CH:10][CH:11]=1)=[O:15])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cc(Cc2ccccc2)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)ccnc21
Product: Cc1cc(Cc2ccccc2)c(CNC(=O)c2ccnc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described for example 11 from 1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.060 g, 0.292 mmol) and 3(aminomethyl)-6-methyl-4-(phenylmethyl)-2(1H)-pyridinone (0.081 g, 0.307 mmol) wherein the product obtained was further purified by reverse phase HPLC (Gradient B: 5-85%. A:Dichloromethane. B: 10% (2M Ammonia in Methanol) in Chloroform). The isolated product was concentrated from MTBE (2×) to afford a white solid (93 mg, 75%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, J=6.57 Hz, 6 H), 2.10 (s, 3 H), 3.98 (s, 2 H), 4.45 (d, J=5.05 Hz, 2 H), 5.24 (quin, J=6.63 Hz, 1 H), 5.81 (s, 1 H), 7.12-7.30 (m, 5 H), 7.50 (d, J=4.55 Hz, 1 H), 8.33 (s, 1 H), 8.61 (d, J=4.55 Hz, 1 H), 8.88 (t, J=5.05 Hz, 1 H), 11.63 (s, 1 H). LCMS(ES) [M+H]+ 416.0
Reaction SMILES: [CH3:1][C:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:7])[CH2:3][C:4]([OH:6])=O.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[CH3:7][C:2]1([CH3:1])[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:6])[CH2:3]1
Reactant: CC(C)(CC(=O)O)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC1(C)CC(=O)c2ccccc21
Temperature: 25 °C

Procedure:
To a solution of 3-methyl-3-phenyl butanoic acid (17.1 g, 95.5 mmoles) in benzene (70 mL) was added PCl5 (23.0 g, 0.11 mole, 1.15 eq.) portionwise with cooling. Upon completion of the addition, the reaction mixture was refluxed for 30 minutes and cooled to room temperature. Aluminum chloride (13.1 g, 98.3 mmoles) was added in increments and the reaction was heated at reflux for 30 minutes. The reaction mixture was poured onto ice; the oily layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organics were washed with 5% HCl solution, saturated NaHCO3 solution, saturated NaCl solution and dried over MgSO4. The solvent was evaporated in vacuo and the crude product (14.3 g) was vacuum distilled (b.p.=103° C. @ 2.3 mmHg) to obtain 9.98 g of the title C compound as a colorless oil. MS: (M+H)+ @ 161.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:15][C:16](=[O:29])[CH:17]([NH2:28])[C:18]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Br:30][C@H:31]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:32](O)=[O:33].CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>ClCCl.C(OCC)(=O)C.CCCCCC>[CH2:21]([NH:20][C:18](=[O:19])[CH:17]([NH:28][C:32](=[O:33])[C@H:31]([Br:30])[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:16]([NH:15][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:29])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NC(C(=O)NCc1ccccc1)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@H](Br)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CCCCCC
Product: O=C(NCc1ccccc1)C(NC(=O)[C@H](Br)Cc1ccccc1)C(=O)NCc1ccccc1
Reaction time: 18 h

Procedure:
Combine N,N′-dibenzyl-2-aminomalonamide trifluoroacetic acid salt (0.41 g, 1.04 mmol), (R)-2-bromo-3-phenylpropionic acid (0.262 g, 1.15 mmol), N-methylmorpholine (0.23 mL, 2.08 mmol), 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloric acid salt (0.22 g, 1.15 mmol), and 1 -hydroxybenztriazole hydrate (0.155 g, 1.15 mmol) in dichloromethane (5 mL). After 18 hours, extract with an aqueous 5% sulfuric acid solution, a saturated sodium bicarbonate solution, and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 ethyl acetate/hexane to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[CH2:6][CH2:7][C:8]1[S:9][C:10]2[N:11]=[C:12]([NH2:23])[N:13]=[C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:15]=2[N:16]=1.[CH3:29][O:30][C:31]1[CH:41]=[CH:40][C:34]([O:35][CH2:36][C:37](O)=[O:38])=[CH:33][CH:32]=1>>[NH2:23][C:12]1[N:13]=[C:14]([N:17]2[CH2:18][CH2:19][N:20]([C:37](=[O:38])[CH2:36][O:35][C:34]3[CH:40]=[CH:41][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)[CH2:21][CH2:22]2)[C:15]2[N:16]=[C:8]([CH2:7][CH2:6][C:5]3[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:3]([O:2][CH3:1])[CH:4]=3)[S:9][C:10]=2[N:11]=1
Reactant: COc1ccc(CCc2nc3c(N4CCNCC4)nc(N)nc3s2)cc1OC
Reactant: COc1ccc(OCC(=O)O)cc1
Product: COc1ccc(OCC(=O)N2CCN(c3nc(N)nc4sc(CCc5ccc(OC)c(OC)c5)nc34)CC2)cc1
Yield: 71 %

Procedure:
This compound was prepared from 2-(3,4-dimethoxyphenethyl)-7-(piperazin-1-yl)thiazolo[5,4-d]pyrimidin-5-amine using 4-methoxyphenoxyacetic acid in a yield of 71%, according to the procedure for the synthesis of example 50.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[CH2:12][C:13]2[CH:22]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:20]=[CH:19][C:14]=2[C:15](OC)=[O:16])=[CH:6][CH:5]=1>O1CCCC1.C(OCC)(=O)C>[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:11](=[O:27])[CH2:12][C:13]3[C:14](=[CH:19][CH:20]=[C:21]([C:23]([O:25][CH3:26])=[O:24])[CH:22]=3)[C:15]2=[O:16])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(CC(=O)Nc2ccc(F)cc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CC(=O)N(c1ccc(F)cc1)C2=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 100.2 %

Procedure:
NaH (0.382 g, 9.56 mmol) was added to a stirred, 0° C. mixture of dimethyl 2-(2-((4-fluorophenyl)amino)-2-oxoethyl)terephthalate (1.65 g, 4.78 mmol) in tetrahydrofuran (100 mL) and the mixture was stirred at 0° C. for 90 min. which turned into a red solution. The mixture was diluted with ethyl acetate (30 mL), washed with hydrochloric acid (0.5 M, 1×15 mL), water (10 mL), and brine (20 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure to give methyl 2-(4-fluorophenyl)-1,3-dioxo-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (1.5 g, 4.79 mmol) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=2)=[N:6][CH:7]=1.[CH3:25][C:26]([CH3:49])([CH2:31][O:32][C:33]1[CH:38]=[C:37]([CH3:39])[C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][N:34]=1)[C:27]([O:29][CH3:30])=[O:28].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)(O)[O-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.O1CCCC1>[CH3:25][C:26]([CH3:49])([CH2:31][O:32][C:33]1[N:34]=[CH:35][C:36]([C:2]2[CH:7]=[N:6][C:5]([C:8]3[N:9]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=3)=[CH:4][CH:3]=2)=[C:37]([CH3:39])[CH:38]=1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)cn1
Reactant: COC(=O)C(C)(C)COc1cc(C)c(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)COc1cc(C)c(-c2ccc(-c3nc(C(F)(F)F)cn3COCC[Si](C)(C)C)nc2)cn1
Temperature: 50 °C
Reaction time: 6 h
Yield: 16.6 %

Procedure:
A mixture in which tetrahydrofuran (6 mL) was added to 5-bromo-2-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (542 mg), methyl 2,2-dimethyl-3-{[4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-yl]oxy}propanoate (372 mg), potassium phosphate (302 mg), palladium acetate (8 mg) and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (29 mg) was stirred under nitrogen atmosphere at 50° C. for 6 hours. After cooling the mixture to room temperature, a saturated aqueous sodium bicarbonate solution, water and ethyl acetate were added to the mixture and the resulting mixture was stirred. The organic layer was separated, washed with a saturated brine, and the residue obtained by concentrating under reduced pressure was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10 to 60:40) to obtain methyl 2,2-dimethyl-3-({4-methyl-6′-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]-3,3′-bipyridin-6-yl}oxy)propanoate (100 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[NH2:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]
Reactant: COc1ccc(C=O)cc1OC
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NCc1ccc(OC)c(OC)c1
Yield: 63.7 %

Procedure:
Prepared according to the procedure of Example 50 using 3,4-dimethoxybenzaldehyde (1.94 g, 11.6 mmol), 3-amino-4-methoxy-N-phenyl-benzamide (2.8 g, 11.6 mmol), acetic acid (0.69 g, 11.5 mmol), and sodium triacetoxyborohydride (2.6 g, 11.7 mmol) to afford the product (2.9 g); m.p. 187-188° C. after recrystallization from ethanol.
Reaction SMILES: I[As:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:15][C:16]([F:19])([F:18])I>>[C:3]1([As:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]([F:19])([F:18])[F:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: I[As](c1ccccc1)c1ccccc1
Reactant: FC(F)(F)I
Product: FC(F)(F)[As](c1ccccc1)c1ccccc1

Procedure:
R. Cullen in an article "Perfluoroalkyl Arsenicals, Part II The Preparation and Properties of Aryl Perfluoroalkyl Arsenicals", reported in Canadian Journal of Chemistry, Volume 38, 1960, pg. 445-451, describes the reaction of iododiphenylarsine with trifluoroiodomethane to produce diphenyltrifluoromethylarsine. Thermal decomposition of diphenyltrifluoromethylarsine resulted in undisclosed black solid deposit.
Reaction SMILES: [P:1]([O:12][Si](C)(C)C)([O:7][Si](C)(C)C)[O:2][Si](C)(C)C.[C:17](Cl)(=[O:19])[CH3:18]>CO>[OH:19][CH2:17][CH:18]([P:1](=[O:2])([OH:12])[OH:7])[P:1](=[O:12])([OH:7])[OH:2]
Reactant: CC(=O)Cl
Reactant: C[Si](C)(C)OP(O[Si](C)(C)C)O[Si](C)(C)C
Solvent: CO
Product: O=P(O)(O)C(CO)P(=O)(O)O
Reaction time: 0.17 h

Procedure:
Tris(trimethylsilyl) phosphite (2 molar equiv.) in an appropriate dry solvent was added dropwise to a stirred solution of acetyl chloride (1 molar equiv.) in an appropriate dry solvent at room temperature and the mixture stirred for 10 minutes. Excess methanol was then added and the mixture stirred for 5 minutes to decompose the silyl esters. The volatile components in the reaction mixture were then removed under reduced pressure to leave the title compound in good purity.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[C:26]1([NH2:33])[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([NH2:33])=[CH:27][CH:28]=3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Nc1ccc(N)cc1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Nc3ccc(N)cc3)c2c1

Procedure:
The title compound was prepared in analogy to Example 15-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1 1) and benzene-1,4-diamine. MS obsd. (ESI+) [(M+H)+] 445, 1H NMR (400 MHz, DMSO-d6) δ ppm 8.21 (s, 1 H), 7.92-7.83 (m, 2 H), 7.63-7.55 (m, 1 H), 7.53-7.46 (m, 1 H), 7.34 (d, J=8.34 Hz, 1 H), 7.27 (dd, J=8.59, 1.52 Hz, 1 H), 7.15 (d, J=7.58 Hz, 1 H), 6.91 (m, J=8.34 Hz, 2 H), 6.77 (m, J=8.59 Hz, 2 H), 5.97 (s, 1 H), 5.20-5.12 (m, 2 H), 4.76 (brs, 2 H), 3.57 (brs, 2 H), 2.37 (s, 3 H).
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][CH2:7][C@@:8]32[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]3)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([Cl:26])[CH:25]=1.COCCOC>O>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:18]=[C:17]3[C:5]([CH2:6][CH2:7][C@@:8]43[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]4)=[CH:4][CH:3]=2)[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: NC1=N[C@@]2(CCc3ccc(Br)cc32)C(F)(F)CO1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Solvent: COCCOC
Solvent: O
Product: NC1=N[C@@]2(CCc3ccc(-c4cc(Cl)cc(Cl)c4)cc32)C(F)(F)CO1
Yield: 15 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-6-bromo-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.5) with 3,5-dichlorophenylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as the solvent yielded the title compound (15% yield) as an off-white solid. MS (ISP): m/z=382.8 [M+H]+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:11][C:12]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([CH3:21])[C:13]=2[N:14]=1.O1CCOCC1.[ClH:28]>>[Cl:28][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[C:10]1[NH:11][C:12]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([CH3:21])[C:13]=2[N:14]=1
Reactant: Cl
Reactant: COc1nccc(I)c1-c1nc2c(C)cc(C#N)cc2[nH]1
Solvent: C1COCCO1
Product: Cc1cc(C#N)cc2[nH]c(-c3c(Cl)cc[nH]c3=O)nc12
Temperature: 80 °C

Procedure:
A suspension of 2-(4-iodo-2-methoxy-pyridin-3-yl)-7-methyl-3H-benzimidazole-5-carbonitrile (1.8 g, 4.63 mmol) in 4 M HCl dioxane (40 mL) was heated to 80° C. for 6 h and cooled to room temperature. The precipitate was filtered and dried. The crude product (1.08 g, 82%) was used for the next step without purification. LRMS (neg. ESI, (M−H)−) m/z 283.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[NH:9][CH:8]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:6](=O)[CH:5]=1)[CH3:3]>P(Cl)(Cl)(Cl)=O>[CH3:13][O:12][CH2:10][CH2:7][CH2:8][NH:9][C:6]1[CH:5]=[C:4]([CH:2]([CH3:3])[CH3:1])[N:9]=[CH:8][C:7]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1c[nH]c(C(C)C)cc1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc(C(C)C)cc1NCCCOC
Temperature: 120 °C
Reaction time: 3 h
Yield: 187.8 %

Procedure:
Ethyl 6-(1-methylethyl)-4-oxo-1,4-dihydropyridine-3-carboxylate (209 mg) was suspended in phosphorus oxychloride (2 ml), and the mixture was stirred at 120° C. for 3 hr. Phosphorus oxychloride was evaporated under reduced pressure, and the mixture was cooled to 0° C. The mixture was neutralized with saturated aqueous sodium hydrogen carbonate and water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was dissolved in 2-propanol (5 ml), 3-methoxypropylamine (307 μl) and triethylamine (517 μl) were added, and the mixture was stirred with heating to reflux for 15 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography, and the fraction eluted with acetic acid was concentrated under reduced pressure to give the object compound (263 mg).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH-:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N.[C:18](=O)([O-])[O-:19].[K+].[K+].C=O>>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH:13][CH2:18][OH:19])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [NH-]C(=O)c1cccc(Oc2ccccc2)c1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: N
Agent: [K+]
Product: O=C(NCO)c1cccc(Oc2ccccc2)c1
Yield: 267.2 %

Procedure:
A flask was charged with 3-phenoxybenzoylamide (2.07 g, 9.8 mmol)(prepared from the corresponding acid chloride and concentrated ammonia), potassium carbonate (1.3 mL, 4% aqueous solution, 3.8 mmol), and aqueous formaldehyde (1.1 mL, 37% aqueous solution, 13.6 mmol). The resulting suspension was heated to reflux to give a two-phased solution. Addition of more aqueous formaldehyde (3 mL, 37 mmol) gave a homogeneous solution which was heated at reflux for 4 h. The reaction solution was cooled and partitioned between brine and ethyl acetate. The aqueous layer was dram off and extracted with ethyl acetate (2×). The combined organic layers were washed (2×, brine), dried (Na2SO4), and concentrated under vacuum to provide 2.47 gms of a viscous oil which solidified after vacuum drying. Recrystallization from cold ethyl acetate:hexanes provided the title compound as a colorless solid (1.38 g, 58%), mp 112.5-113° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([OH:15])(=[O:14])[C:11]([CH3:13])=[O:12].[OH-].[K+:17]>CO>[K+:17].[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:13][C:11](=[O:12])[C:10]([O-:15])=[O:14])=[CH:4][CH:3]=1
Reactant: CC(=O)C(=O)O
Reactant: O=Cc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([O-])C(=O)C=Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
To a mixture of 4-bromobenzaldehyde (35.0 g, 189.0 mmol) and pyruvic acid (15.8 mL, 227.0 mmol) in methanol (100.0 mL), was slowly added a solution of potassium hydroxide (19.0 g, 340.0 mmol) in methanol (100.0 mL) at 0° C. The reaction mixture was stirred at room temperature for 16 hours and then filtered. The resulting solid was washed with diethyl ether to give 48.0 g of the titled compound as a pale yellow solid.
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[O:18][C:19]5[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[N:31]1([CH2:37][CH2:38][NH2:39])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[N:31]1([CH2:37][CH2:38][NH:39][C:26]([C:23]2[CH:24]=[CH:25][C:19]3[O:18][C:17]([CH2:16][O:15][C:14]4[CH:13]=[CH:12][C:11]([C:1]56[CH2:10][CH:5]7[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]7)[CH2:8]5)[CH2:2]6)=[CH:30][CH:29]=4)=[N:21][C:20]=3[CH:22]=2)=[O:27])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Reactant: NCCN1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN1CCCCC1)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
To solution of 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (70.2 mg, 0.17 mmol) and 2-piperidine-1-yl-ethylamine (0.049 ml, 0.35 mmol) in DMF 5.0 mL was added HBTU (132.7 mg, 0.35 mmol) and DIPEA (0.061 ml, 0.35 mmol). After stirring at room temperature, the mixture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (CH2Cl2:MeOH=20:1) to give 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (2-piperidine-1-yl-ethyl)-amide as a white foam (18.9 mg, 22% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[NH:11][CH:12]=O)=[CH:9][C:4]=2[O:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.N1C(C)=CC=CC=1C.C(=O)([O-])O.[Na+]>C1COCC1>[N+:11]([CH:10]([S:14]([C:17]1[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=1)(=[O:16])=[O:15])[C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)#[C-:12]
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc3c(c2)OCO3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: [C-]#[N+]C(c1ccc2c(c1)OCO2)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.6 %

Procedure:
To a solution of N-[benzo[1,3]dioxol-5-yl-(toluene-4-sulfonyl)-methyl]-formamide (740 mg, 2.22 mmol) in THF (50 mL) was slowly added phosphorous oxychloride (0.41 mL, 4.44 mmol, 2 equiv). The resulting reaction mixture was stirred at ambient temperature for 2 hours, cooled to 0° C. and slowly treated with 2,6-lutidine (1.55 mL, 13.32 mmol, 6 equiv). The reaction mixture was stirred at ambient temperature for 48 hours, treated with saturated aqueous sodium hydrogen carbonate (80 mL), and then extracted with ethyl acetate (50 mL). The organics were dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography (20% ethyl acetate in hexane) provided 5-[Isocyano-(toluene4-sulfonyl)-methyl]-benzo[1,3]dioxole as a white solid (200 mg, 29%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].Cl[CH2:14][CH:15]=O>C1(C)C=CC=CC=1>[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:14]=[CH:15][N:12]=2)[CH:11]=1)([O:3][CH2:1][CH3:2])=[O:5]
Reactant: O=CCCl
Reactant: CCOC(=O)c1ccc(N)nc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc2nccn2c1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
A mixture of 2-amino-5-pyridine carboxylic acid ethyl ester (4.5 g, 27.1 mmol), chloroacetaldehyde (5.7 ml, 40.6 mmol, 45% w/w in water) and toluene (125 ml) was heated to reflux and water was collected in a Dean Stark trap. After 3 hours at reflux the reaction mixture was cooled to room temperature and the resulting precipitate was collected by filtration and washed with ether. The solid was dissolved in water and the solution was neutralized by the addition of concentrated aqueous ammonium hydroxide. The aqueous layer was extracted with chloroform, the organic layer was washed with brine and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate, treated with charcoal and passed through a plug of silica. Removal of the solvent in vacuo afforded 3.1 g (60%) of 6-carboethoxy imidazo[1,2-a]-pyridine as an off-white solid, m.p. 93°-94° C. when recrystallized from tert-butylmethyl ether and dried for 16 hours at 50° C. in high vacuum.