Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][C@@H:15]([C:20]2[S:21][C:22]([C:25]3[C:33]4[C:28](=[N:29][CH:30]=[CH:31][CH:32]=4)[NH:27][CH:26]=3)=[CH:23][CH:24]=2)[CH2:16][C:17](O)=[O:18])=[O:13])[C:7]1=[O:34].CN(C)C=O.[CH2:44]([NH2:46])[CH3:45].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>>[CH2:44]([NH:46][C:17]([CH2:16][C@@H:15]([NH:14][C:12]([C:8]1[C:7](=[O:34])[N:6]([CH2:5][C:4]2[CH:35]=[CH:36][C:37]([F:38])=[C:2]([F:1])[CH:3]=2)[CH:11]=[CH:10][CH:9]=1)=[O:13])[C:20]1[S:21][C:22]([C:25]2[C:33]3[C:28](=[N:29][CH:30]=[CH:31][CH:32]=3)[NH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:18])[CH3:45]
Reactant: CCN
Reactant: O=C(O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CCNC(=O)C[C@@H](NC(=O)c1cccn(Cc2ccc(F)c(F)c2)c1=O)c1ccc(-c2c[nH]c3ncccc23)s1
Reaction time: 2 h

Procedure:
(R)-3-{[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-3-[5-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-yl]-propionic acid (0.040 g, 0.000075 mol;) was dissolved in N,N-Dimethylformamide (3 mL, 0.04 mol;) and Ethylamine (7 mg, 0.0001 mol;) then N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (0.037 g, 0.000097 mol;) was added. The reaction was allowed to stir for 2 hours and LC-MS showed disappearance of starting material and appearance of product at 1.28 562.10. The reaction was purified by Gilson Preparative HPLC and the pure fractions were concentrated. ES (+) MS m/e=562.10; NMR (400 MHz, DMSO-d6) δ ppm 0.92 (t, 3H, J=7 Hz), 2.76 (m, 2H), 2.95 (m, 2H), 5.22 (m, 2H), 5.66 (m, 1H), 6.66 (t, 1H, J=8 Hz), 6.99 (d, 1H, J=3 Hz), 7.14-7.21 (m, 3H), 7.38-7.49 (m, 2H), 7.79 (m, 1H), 8.2-8.25 (m, 2H), 8.29 (m, 1H), 8.4 (dd. 1H), 10.22 (d, 1H), 11.95 (s, 1H)
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:14])O[C:5](=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl.Cl.[CH3:17][N:18]([CH3:27])[C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(O)(=O)C>[Cl:1][C:2]1[C:3](=[O:14])[N:24]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([N:18]([CH3:27])[CH3:17])=[CH:20][CH:21]=2)[C:5](=[O:13])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(C)c1ccc(CN)cc1
Reactant: O=C1OC(=O)C(c2ccccc2)=C1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CN(C)c1ccc(CN2C(=O)C(Cl)=C(c3ccccc3)C2=O)cc1
Temperature: 120 °C

Procedure:
To a solution of 3-chloro-4-phenylfuran-2,5-dione (0.20 mmol, 42 mg) and 4-dimethylaminobenzylamine dihydrochloride (0.20 mmol, 45 mg) in glacial acetic acid (1 mL) was added triethylamine (0.40 mmol). The mixture was heated in a microwave reactor at 120° C. for two min. After cooling, the solvent was evaporated at reduced pressure. The reaction mixture was purified by HPLC (95% 0.1M ammonium acetate buffer: 5% CH3CN→100% CH3CN).
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=2)(=[O:15])=[O:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Cl:25][C:26]1[CH:31]=[C:30]([NH2:32])[CH:29]=[C:28]([Cl:33])[N:27]=1.CC1C=CC(C)=CC=1>ClCCl>[Cl:25][C:26]1[CH:31]=[C:30]([NH:32][C:2]2[C:3]([NH:12][S:13]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-:24])=[O:23])[CH:17]=3)(=[O:14])=[O:15])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:29]=[C:28]([Cl:33])[N:27]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)c1
Reactant: Nc1cc(Cl)nc(Cl)c1
Solvent: Cc1ccc(C)cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(S(=O)(=O)Nc2nc3ccccc3nc2Nc2cc(Cl)nc(Cl)c2)c1
Temperature: 135 °C
Reaction time: 8 h

Procedure:
A mixture of N-(3-chloroquinoxalin-2-yl)-3-nitrobenzenesulfonamide (1 g), 2,6-dichloropyridin-4-amine (760 mg) and p-xylene (10 mL) was heated at 135° C. with stirring overnight. Upon cooling to room temperature, the mixture was dissolved in dichloromethane, washed with 2 N HCl (2×) and brine, concentrated in vacuo to give a crude product of N-{3-[(2,6-dichloropyridin-4-yl)amino]quinoxalin-2-yl}-3-nitrobenzenesulfonamide. A small portion of this crude product was purified by HPLC to give N-{3-[(2,6-dichloropyridin-4-yl)amino]quinoxalin-2-yl}-3-nitro-benzenesulfonamide. 1H NMR (400 MHz, DMSO) δ 9.71 (s, 1H), 8.90 (s, 1H), 8.50 (d, 2H), 8.8.41 (d, 1H), 8.30 (s, 2H), 7.88-7.78 (m, 27.65 (d, 1H), 7.47-7.37 (m, 2H); MS (EI) m/z for C19H12C12N6O4S: 491.1, 493.1 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Br:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[Br:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1ccccc1Br
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccccc1Br

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-bromoaniline to yield 2-[(2-bromophenyl)amino]phenylacetic acid.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([CH:10]2[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].[F:16][C:17]([F:26])([C:22]([F:25])([F:24])[F:23])[C:18](I)([F:20])[F:19]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>[CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C@H:10]2[CH2:15][CH2:14][C@H:13]([C:18]([F:20])([F:19])[C:17]([F:26])([F:16])[C:22]([F:25])([F:24])[F:23])[CH2:12][CH2:11]2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCC[C@H]1CC[C@H](C2CC=CCC2)CC1
Reactant: FC(F)(F)C(F)(F)C(F)(F)I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(F)(F)C(F)(F)C(F)(F)F)CC2)CC1

Procedure:
A mixture of 0.1 mol of 4-(trans-4-propylcyclohexyl)-cyclohex-1-ene, 0.1 mol of heptafluoropropyl iodide, 10 mol % of tetrakis-(triphenylphosphine)-palladium and 200 ml of hexane is heated under reflux for 24 hours (compare T. Ishihara, Chemistry Letters (1986) 1895). The isomer mixture of the addition product thus formed is, after the catalyst has been filtered off, first heated with tributyl-tin hydride for 90 hours in toluene and reduced. The all-trans product, trans-4-(trans-4-propylcyclohexyl)-1-heptafluoropropylcyclohexane, is finally obtained by separating the thiourea inclusion compound from a solution in methanol.
Reaction SMILES: [CH:1]1[C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]2[C:10]([O:12][C:13](=O)[C:3]=2[CH:2]=1)=[O:11].[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24]C(O)=O)=[CH:20][CH:19]=1)([CH3:17])[CH3:16]>>[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[C:2]2[CH:1]=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=[C:4]3[CH:3]2[CH2:13][O:12][C:10]3=[O:11])=[CH:20][CH:19]=1)([CH3:17])[CH3:16]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: CC(C)c1ccc(CC(=O)O)cc1
Product: CC(C)c1ccc(C=C2C=C(C(=O)O)C=C3C(=O)OCC23)cc1

Procedure:
Benzene-1,2,4-tricarboxylic anhydride and p-isopropylphenylacetic acid are reacted together as described in Example IA to give a mixture of benzylidenephthalide carboxylic acids. Fractional crystallization of this mixture from aqueous ethanol yields 2-(p-ispropylbenzylidene)phthalide-5-carboxylic acid as the less soluble isomer, and 4-(p-isopropylbenzylidene)phthalide-6-carboxylic acid as the more soluble isomer. By following the rest of the procedure set forth in part A of this example, 2-carboxy-7-isopropyl-10,11-dihydro-5-oxo-5H-dibenzo[a,d]cycloheptene was obtained with a m.p. of 178°-182° C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH2:14]([N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][CH2:36][CH2:37]Cl)[CH:29]=2)=[C:20]([NH:39][C:40]([NH:42][C:43]2[C:48]([CH:49]([CH3:51])[CH3:50])=[CH:47][CH:46]=[CH:45][C:44]=2[CH:52]([CH3:54])[CH3:53])=[O:41])[C:19]1=[O:55])[CH2:15][CH2:16][CH3:17]>CN(C=O)C.O>[CH2:14]([N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][N:26]=2)[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][CH2:36][CH2:37][N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:29]=2)=[C:20]([NH:39][C:40]([NH:42][C:43]2[C:48]([CH:49]([CH3:51])[CH3:50])=[CH:47][CH:46]=[CH:45][C:44]=2[CH:52]([CH3:53])[CH3:54])=[O:41])[C:19]1=[O:55])[CH2:15][CH2:16][CH3:17]
Reactant: c1c[nH]cn1
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCCCl)c2)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCCn3ccnc3)c2)c2cccnc21
Reaction time: 10 h
Yield: 38.7 %

Procedure:
To a suspension of imidazole (97 mg, 1.43 mmol), potassium carbonate (246 mg, 1.78 mmol) and sodium iodide (35 mg) in DMF (20 ml) was added N-[1-(butyl-4-{3-(3-chloropropoxy)phenyl}-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (700 mg, 1.19 mmol), and the mixture was stirred at 50°-60° C. for 10 hours. After allowed to stand for cooling, the mixture was poured into water, extracted with ethyl acetate, and the extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The residue was concentrated under reduced pressure, and purified by silica gel column chromatography (5% methanol in chloroform) to give the title compound (286 mg, 0.46 mmol).
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:11])[CH:10]=1)=[O:5].[CH2:13]([Mg]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH3:11][N:9]1[CH:10]=[C:6]([C:4](=[O:5])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:7]=[N:8]1
Reactant: CON(C)C(=O)c1cnn(C)c1
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1cc(C(=O)Cc2ccccc2)cn1
Reaction time: 3 h
Yield: 73.4 %

Procedure:
To a solution of N-methoxy-N,1-dimethyl-1H-pyrazole-4-carboxamide (4.6 g, 27.2 mmol) in anhydrous THF (50 mL) was added benzylmagnesium chloride (2.0 M in THF, 16.7 mL, 32.6 mmol) at −78° C. under N2, then stirred at the same temperature for 3 hours. The mixture was quenched with saturated NH4Cl solution, followed by a standard aqueous/EtOAc procedure. The crude was purified by silica gel column chromatography (PE:EtOAc=10:1) to give Intermediate 4 (4.0 g, yield 74%).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH2:14][OH:15]>C1(C)C=CC=CC=1.[O-2].[Mn+4].[O-2]>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]=[O:15]
Reactant: Cc1cccc2nc(CO)c(Br)c(=O)n12
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: Cc1cccc2nc(C=O)c(Br)c(=O)n12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-bromo-2-(hydroxymethyl)-6-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (2.7421 g, 10.19 mmol, Prepared in Example 1) and manganese(IV) oxide (8.86 g, 102 mmol) in toluene (67.9 mL) was heated to reflux. After 3 h, the mixture was cooled to rt and filtered through a pad of Celite™, The filtrate was concd under reduced pressure to give 3-bromo-6-methyl-4-oxo-4H-pyrido[1,2-a]-pyrimidine-2-carbaldehyde as a bright yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.07 (1 H, s), 7.81 (1 H, dd, J=9.0, 7.0 Hz), 7.60 (1 H, dd, J=9.0, 0.8 Hz), 7.10-7.15 (1 H, m), 2.96 (3 H, s); Mass Spectrum (ESI) m/e=267.0 [M+1 (79Br)] and 268.9 [M+1 (81Br)].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:7](=[O:9])[C:6]2[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[OH:11])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: Cc1ccc(O)c(C(=O)O)c1
Product: Cc1ccc(O)c(C(=O)Nc2cc(Cl)cc(Cl)c2)c1
Yield: 71 %

Procedure:
Using 5-methylsalicylic acid and 3,5-dichloroaniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: C([O:4][C:5]1[C:10](=[O:11])[N:9]([CH:12]([CH3:14])[CH3:13])[C:8](=[O:15])[N:7]2[CH:16]([CH2:29][CH2:30][N:31]([C:33](=[O:35])[CH3:34])[CH3:32])[CH2:17][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19](=[O:20])[C:6]=12)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:18]2[CH2:17][CH:16]([CH2:29][CH2:30][N:31]([CH3:32])[C:33](=[O:35])[CH3:34])[N:7]3[C:8](=[O:15])[N:9]([CH:12]([CH3:14])[CH3:13])[C:10](=[O:11])[C:5]([OH:4])=[C:6]3[C:19]2=[O:20])=[CH:27][CH:26]=1
Reactant: CC(=O)Oc1c2n(c(=O)n(C(C)C)c1=O)C(CCN(C)C(C)=O)CN(Cc1ccc(F)cc1)C2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(=O)N(C)CCC1CN(Cc2ccc(F)cc2)C(=O)c2c(O)c(=O)n(C(C)C)c(=O)n21
Reaction time: 1.5 h

Procedure:
To a stirred solution of 4-{2-[acetyl(methyl)amino]ethyl}-2-(4-fluorobenzyl)-7-isopropyl-1,6,8-trioxo-1,3,4,6,7,8-hexahydro-2H-pyrazino[1,2-c]pyrimidine-9-yl acetate (28 mg, 0.057 mmol) in MeOH (2 mL) at ambient temperature under inert atmosphere was added potassium carbonate (48 mg, 0.344 mmol). After 1.5 h, the solvent was removed in vacuo and the residue treated with 1 N aqueous HCl solution and MeOH. The solvent was again removed in vacuo and the residue suspended in CH2Cl2. The mixture was filtered through a cotton plug, and the filtrate was concentrated in vacuo to give an orange oil. Purification by reverse phase chromatography [95:5 water (+0.1% TFA)/MeCN (+0.1% TFA) to 5:95 water (+0.1% TFA)/MeCN (+0.1% TFA)] afforded the title compound as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 11.76 (br s, 1H), 7.39-7.36 (m, 2H), 7.09-7.05 (m, 2H), 5.16 (dt, J=6.8, 13.6 Hz, 1H), 4.97 (d, J=14.0 Hz, 1H), 4.43 (d, J=11.2 Hz, 1H), 4.35 (d, J=14.4 Hz, 1H), 3.84 (br s, 1H), 1.77-1.70 (m, 1H), 1.46 (dd, J=1.6, 6.8 Hz, 6H). HRMS (FT/ES) M+H: calcd for (C22H27FN4O5)+ 447.2038. found 447.2031.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH3:11])(=[O:3])[CH3:2].[N:12](OC(C)(C)C)=O.C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[N:4]1([C:1](=[O:3])[CH3:2])[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:10]2[CH:11]=[N:12]1
Reactant: CC(C)(C)ON=O
Reactant: CC(=O)Nc1cnccc1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1ncc2ccncc21
Temperature: 25 °C

Procedure:
To a suspension of 3-acetylamino-4-methylpyridine (301.5 Mg, 2.0 Mmol, 1 equiv) in toluene (3 mL) was added tert-butyl nitrite (t-BuONO) (420 μL, 3.2 Mmol, 1.6 equiv), acetic anhydride (560 μL, 6.0 mmol, 3 equiv) and potassium acetate (235.2 Mg, 2.4 Mmol, 1.2 equiv). The resultant mixture was heated at 80° C. for 2 hours, cooled to room temperature, and diluted with ethyl acetate (200 mL). The mixture was washed with saturated sodium bicarbonate solution (50 mL), water (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide a crude residue. The residue was purified by flash chromatography (silica, 15% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give 1-pyrazolo[3,4-c]pyridin-1-yl-ethanone (20.2 Mg) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([NH:12][C:13](=O)[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:4]([OH:21])[CH:3]=1.O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][C:5]2[N:12]=[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)[O:21][C:4]=2[CH:3]=1
Reactant: O=C(Nc1cc(C(F)(F)F)c(Cl)cc1O)c1ccncc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc2nc(-c3ccncc3)oc2cc1Cl
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a mixture of 1.01 g of N-[4-chloro-2-hydroxy-5-(trifluoromethyl)phenyl]isonicotinamide, 10 ml of tetrahydrofuran and 0.92 g of triphenylphosphine, 1.53 g of 40% toluene solution of diethyl azodicarboxylate was added dropwise at room temperature, and the reaction mixture was stirred for two hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and the resultant crystals washed with methanol to give 0.66 g of 6-chloro-2-(pyridin-4-yl)-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 80”).
Reaction SMILES: [CH:1]([O-])=[O:2].[Na+].[C]=O.Br[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[CH:10][CH:9]=1>CN(C=O)C>[CH:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])=[CH:10][CH:9]=1)=[O:2]
Reactant: O=C[O-]
Reactant: O=C(OCc1ccccc1)N1CCCC1c1ccc(Br)cc1
Agent: [C]=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(C2CCCN2C(=O)OCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a 50 mL round-bottomed flask were placed Pd (PPh3)2Cl2 (70 mg, 0.1 mmol), and sodium formate (510 mg, 7.5 mmol) and purged with carbon monoxide. DMF (7 mL) and benzyl 2-(4-bromophenyl)pyrrolidine-1-carboxylate (1.8 g, 5 mmol) were added via syringes. The mixture was vigorously stirred at 100° C. under carbon monoxide atmosphere for 8 hrs. Then the reaction mixture was cooled to room temperature and partitioned between ether (100 mL) and water (15 mL). The organic phase was washed with water (3×15 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc:hexane=1:10) to give the title compound (0.31 g, yield 20%) as a colorless oil. LC-MS (ESI) m/z: 309 (M+1)+; 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.73-1.88 (m, 3H), 2.31-2.41 (m, 1H), 3.57-3.67 (m, 2H), 4.84-5.06 (m, 3H), 6.84-6.86 (m, 1H), 7.12-7.34 (m, 4H), 7.41-7.43 (d, J=8.0 Hz, 2H), 7.85-7.87 (d, J=8.0 Hz, 2H), 9.98-9.99 (d, J=6.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:48][C:49]1([C:52]2[CH:61]=[CH:60][C:55]([C:56]([O:58][CH3:59])=[O:57])=[CH:54][CH:53]=2)[CH2:51][CH2:50]1.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:48][C:49]1([C:52]2[CH:61]=[CH:60][C:55]([C:56]([O:58][CH3:59])=[O:57])=[CH:54][CH:53]=2)[CH2:51][CH2:50]1)=[O:8]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Nc2ccc(F)cc2F)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(F)cc4F)C3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 173.5 %

Procedure:
A mixture of 5-chloro-2-(3-((2,4-difluorophenyl)amino)azetidin-1-yl)nicotinic acid (D118) (40 mg, 0.118 mmol), 1-Hydroxybenzotriazole hydrate (18 mg, 0.118 mmol) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (34 mg, 0.177 mmol) in dimethylformamide (5 ml) was stirred 10 min at room temperature. A solution of methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (32.2 mg, 0.141 mmol) and triethylamine (0.02 ml, 0.141 mmol) in dry dimethylformamide (2 ml) was added and the mixture was stirred 24 h at room temperature. After solvent evaporation, water (10 ml) was added and the formed precipitate was filtered off and purified by Biotage SNAP-Si (10 g) cartridge eluting with a mixture dichloromethane/methanol from 100/0 to 80/20. Collected fractions, after solvent evaporation afforded the title compound (D169) (105 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:13])[CH2:11][C:10](=[O:12])[O:9][C:7]1=[O:8].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>O>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:10]([CH2:11][C:6]([CH3:13])([CH3:5])[C:7]([OH:9])=[O:8])=[O:12])=[CH:17][CH:16]=1
Reactant: CC1(C)CC(=O)OC1=O
Reactant: Clc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(CC(=O)c1ccc(Cl)cc1)C(=O)O
Temperature: 25 °C

Procedure:
Finely powdered aluminium chloride (29.35 g), 2,2-dimethylsuccinic anhydride (13.9 g) and chlorobenzene (45 ml) were mixed, then stirred and heated on a boiling-water bath for 1.5 hours. The resulting mixture was cooled to room temperature and then poured onto a mixture of ice and water containing a little hydrochloric acid. The resulting mixture was extracted with ether. The ethereal layer was shaken with 2N sodium hydroxide and the resulting aqueous layer washed with ether, acidified with concentrated hydrochloric acid and then extracted with ether. The ethereal layer was washed with water and brine, and finally dried over magnesium sulphate. Removal of the solvent in vacuo gave 13.9 g of 3-(4-chlorobenzoyl)-2,2-dimethylpropionic acid. I.R. (Nujol Mull): 1680 cm-1 (s), 1590 cm-1 (s).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)=[N+:2]=[N-:3].[F:13][C:14]([F:36])([F:35])[C:15]1[N:20]=[CH:19][C:18]([CH2:21][C@H:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:24][C:25]#[CH:26])=[CH:17][CH:16]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.[O-]S([O-])(=O)=O.[Cu+2]>[NH:9]1[C:10]2[C:6](=[CH:5][C:4]([N:1]3[CH:26]=[C:25]([CH2:24][CH2:23][C@@H:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:21][C:18]4[CH:19]=[N:20][C:15]([C:14]([F:13])([F:36])[F:35])=[CH:16][CH:17]=4)[N:3]=[N:2]3)=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: C#CCC[C@H](Cc1ccc(C(F)(F)F)nc1)NC(=O)OC(C)(C)C
Reactant: [N-]=[N+]=Nc1ccc2[nH]ncc2c1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)N[C@H](CCc1cn(-c2ccc3[nH]ncc3c2)nn1)Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-azido-1H-indazole (126 mg, 789 μmol), (R)-tert-butyl 1-(6-(trifluoromethyl)pyridin-3-yl)hex-5-yn-2-ylcarbamate (270 mg, 789 μmol), CuSO4 (6.3 mg, 39 μmol), and sodium ascorbate (16 mg, 79 μmol) in t-BuOH/H2O (1:1, 2 mL) was stirred at room temperature for 8 hours. The mixture was partitioned between saturated aqueous NaCO3 (15 mL) and DCM (15 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×15 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting yellow solid was dissolved in MeOH/DCM, absorbed onto silica gel, and purified by flash chromatography (silica gel, 3% to 8% MeOH/DCM) to deliver tert-butyl(R)-4-(1-(1H-indazol-5-yl)-1H-1,2,3-triazol-4-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ylcarbamate (85 mg, 21%) as a light yellow solid. LCMS (API-ES) m/z: 502.1 (M+H+).
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=O>>[CH2:1]([O:8][CH:9]1[CH2:10][O:11][CH:19]([C:18]2[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH3:14])[CH:17]=2)[O:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(C=O)c1
Reactant: OCC(CO)OCc1ccccc1
Product: COc1cccc(C2OCC(OCc3ccccc3)CO2)c1
Yield: 86.6 %

Procedure:
Using the method of Example 16, 2-benzyloxy-1,3-propane-diol (18.0 g, 0.1 mole), and 3-methoxybenzaldehyde (13.6 g, 0.1 mole) were reacted to give 26.0 g of oil which was distilled at 1 × 10-4 mm to give 20.2 g of product which distilled at a pot temperature of 200°-206° C. nmr analysis of this product indicated it to contain 37% cis-5-benzyloxy-2-(3-methoxyphenyl)-1,3-dioxane.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([O:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][O:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: [H][H]
Reactant: CN(C)CCOC1CCN(Cc2ccccc2)C1
Solvent: CCO
Product: CN(C)CCOC1CCNC1

Procedure:
A solution of 10.0 g. (0.0402 mole) of 1-benzyl-3-(2-dimethylaminoethoxy)pyrrolidine in ethanol containing 10% palladium on charcoal was shaken at 60° C. in about three atmospheres of hydrogen until the theoretical amount of hydrogen was used. The cooled filtered solution was concentrated at reduced pressure to give a quantitative yield of oily product. The structure was confirmed by its nuclear magnetic resonance spectrum.