Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH2:5][CH2:6]2)=O.[C:11]([CH2:13]C(O)=O)#[N:12].[OH-].[NH4+].CN(C)C=O>C1C=CC=CC=1>[C:11]([CH2:13][CH:1]=[C:3]1[CH:8]([CH3:9])[CH:7]2[CH2:10][CH:4]1[CH2:5][CH2:6]2)#[N:12]
Reactant: CC1C2CCC(C2)C1C=O
Reactant: N#CCC(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC1C(=CCC#N)C2CCC1C2
Yield: 77 %

Procedure:
A stirred solution of 97 g (0.7 mol) of 2-formyl-3-methylbicyclo[2.2.1]heptane 65 g (0.76 mol) of cyanoacetic acid, 2 ml of ammonium hydroxide (58%), 132 ml of dimethylformamide, and 170 ml benzene was heated to reflux and the water removed with a Dean-Stark trap. The reaction was allowed to continue until the evolution of carbon dioxide ceased (approx. 24 hrs.). Upon completion, the reaction was cooled and the solvent removed under reduced pressure. The residual oil was distilled under vacuum to give 87 g (77% yield) of 2-(2-cyanoethylidene)-3-methylbicyclo[2.2.1]heptane: b.p. 72-85° C/1 mm; ir 2940, 2870, 2220, 1610, 1450, 1380, 830, 740; nmr 0.9-1.1 (3H, m), 1.2-2.8 (9H, m), 2.85-3.2 (2H, m), 4.8-5.4 (1H, m); ms 161.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[C:18]([N:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30](O)=[O:31])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:18]([N:28]1[CH2:35][CH2:34][CH2:33][C@H:29]1[C:30]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)=[O:31])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1)C2
Temperature: 50 °C
Reaction time: 48 h
Yield: 42.1 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.00 g, 8.70 mmol) was dissolved in dimethylformamide (150 ml). To the obtained solution, carbobenzyloxy-L-proline (2.80 g, 11.3 mmol), WSC-HCl (2.00 g, 11.3 mmol) and HOBT (1.53 g, 11.3 mmol) were added, and the mixture was stirred at 50° C. for 48 hours. The reaction mixture was condensed under reduced pressure. The resultant residue was extracted using a solvent mixture (chloroform: methanol=4:1) combined with 1N-HCl. The organic phase was washed with saturated aqueous NaCl solution, followed by drying and condensing under reduced pressure. The resultant residue was purified by silica gel column chromatography (chloroform: methanol=20:1). The crude crystals were subjected to a recrystallizing procedure using chloroform--methanol--ether. As a result, 1.69 g of the title compound was obtained as colorless powdery crystals (42.1%).
Reaction SMILES: COCCOC[O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:10][C:9]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl.CCOC(C)=O.[Zn+2].[Br-].[Br-]>[CH2:21]([O:20][C:11]1[CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]([OH:7])=[C:9]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:10]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCOc1cc(-c2ccccc2)c(OCOCCOC)c(-c2ccccc2)c1
Agent: [Br-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCCOc1cc(-c2ccccc2)c(O)c(-c2ccccc2)c1
Reaction time: 18 h
Yield: 92.7 %

Procedure:
To a stirred solution of (2′-methoxyethoxymethoxy-[1,1′;3′,1″]terphenyl-5′-yloxy)butane (0.237 g, 0.583 mmol) in CH2Cl2 (6 mL) at room temperature was added anhydrous ZnBr2 (0.656 g, 2.92 mmol). After 18 h at this temperature, the resulting mixture was diluted with EtOAc (100 mL). The organic layer was washed with sat. aq. NaHCO3 (10 mL) and brine (10 mL) and then dried (MgSO4). After concentration, the residue was purified by preparatory plate chromatography (10% EtOAc/petroleum ether) to afford the product (0.172 g, 92%) as a solid; 1H NMR (CDCl3) δ 0.97 (t, J=10.9 Hz, 3H), 1.39–1.60 (m, 2H), 1.68–1.87 (m, 2H), 3.97 (t, J=9.5 Hz, 2H), 5.05 (s, 1H), 6.87 (s, 2H), 7.32–7.62 (m, 10H); mass spectrum [(+) ESI], m/z 319 (M+H)+, 341 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12](Cl)(=[O:16])[C:13]([CH3:15])=[CH2:14]>>[CH3:15][C:13](=[CH2:14])[C:12]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[CH3:1])=[O:16]
Reactant: C=C(C)C(=O)Cl
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Product: C=C(C)C(=O)Nc1ccc([N+](=O)[O-])cc1C

Procedure:
2-Methyl-N-(2-methyl-4-nitrophenyl)acrylamide was prepared as described in Example 1a starting from 2-methyl-4-nitroaniline and methacryloyl chloride. 1H NMR (400 MHz, DMSO-d6): 1.98 (3H, s), 2.34 (3H, s), 5.59 (1H, s), 5.91 (1H, s), 7.74 (1H, d, J=8.8 Hz), 8.07 (1H, dd, J=8.8 Hz, J=2.7 Hz), 8.15 (1H, d, J=2.6 Hz), 9.53 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.CS(C)=O.[O:14]1[C:16]2[CH2:17][CH2:18][CH2:19][C:15]1=2>[Pd].O1CCCC1>[NH2:9][C:3]1[C:2]([CH3:1])=[CH:7][N:6]([CH:18]2[CH2:19][CH:15]([OH:14])[CH:16]=[CH:17]2)[C:5](=[O:8])[N:4]=1
Reactant: C1CC2=C(C1)O2
Reactant: Cc1c[nH]c(=O)nc1N
Agent: [Pd]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Cc1cn(C2C=CC(O)C2)c(=O)nc1N
Reaction time: 1.5 h
Yield: 24.4 %

Procedure:
50 g (0.4 mol) of 5-methylcytosine are added to a solution of the palladium(0) catalyst (1.6 mol %) prepared in situ as described above in 200 ml of dry tetrahydrofuran/200 ml of dry dimethylsulfoxide at 5° C. 49.2 g (0.6 mol) of epoxycyclopentene, dissolved in 100 ml of tetrahydrofuran, are added dropwise to this suspension, while stirring (1.5 hours). The mixture is stirred at room temperature for 3 days and then concentrated, and the residue is stirred with 2N sodium carbonate solution, filtered off and washed with water and acetone. 20.2 g (24.4% of theory) of 4-amino-5-methyl-1-[(1RS,4SR)-4-hydroxy-cyclopent-2-en-1-yl]pyrimidin-2(1H)-one of melting point 241°-245° C. are obtained. Chromatography (silica gel, methylene chloride/methanol 3/1) of the neutralized mother liquor gives, in addition to 5-methylcytosine (14.95 g, melting point 264°-269° C.) a further 9.87 g (11.9% of theory) of the title compound; total yield: 36.3% of theory. 1H NMR (270 MHz, d6 -DMSO); δ[ppm]: 7.23 (s, 1H), 7.12 (s, broad, 1H), 6.70 (s, broad, 1H), 6.09 (m, 1H), 5.74 (m, 1H), 5.45 (m, 1H), 5.17 (s, 1H), 4.61 (m, 1H), 2.71 (m, 1H), 1.81 (s, 3H), 1.27 (m, 1H).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.ON1C2N=CC=CC=2N=N1.[CH2:44]([O:51][C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][C:60]=1[CH3:61])[C:55]([OH:57])=O)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.Cl.[NH2:63][C:64]1[C:65]([O:79][CH3:80])=[C:66]([NH:74][S:75]([CH3:78])(=[O:77])=[O:76])[CH:67]=[C:68]([C:70]([CH3:73])([CH3:72])[CH3:71])[CH:69]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:44]([O:51][C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][C:60]=1[CH3:61])[C:55]([NH:63][C:64]1[CH:69]=[C:68]([C:70]([CH3:72])([CH3:73])[CH3:71])[CH:67]=[C:66]([NH:74][S:75]([CH3:78])(=[O:77])=[O:76])[C:65]=1[O:79][CH3:80])=[O:57])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: Cc1ccc(C(=O)O)cc1OCc1ccccc1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(NC(=O)c2ccc(C)c(OCc3ccccc3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
10.59 g of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-uronium hexafluorophosphate, 9.54 ml diisopropylethylamine and 1.26 g 1-hydroxy-7-azabenzotriazole are added to 4.50 g 3-benzyloxy-4-methyl-benzoic acid in 25 ml N,N-dimethylformamide under an argon atmosphere. The mixture is stirred for 15 minutes at ambient temperature, before 5.74 g N-(3-amino-5-tert-butyl-2-methoxyphenyl)methanesulphonamide-hydrochloride are added. The reaction mixture is stirred overnight at 50° C. After cooling to ambient temperature the reaction mixture is diluted with ethyl acetate, washed with water, 1 N hydrochloric acid and saturated aqueous sodium chloride solution, dried on magnesium sulphate and evaporated down. The flask residue is stirred with methanol, and the resulting white precipitate is suction filtered and dried.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.C(OCC)(OCC)OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:33]([C@@H:38]([C@H:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[OH:41])O)([O:35][CH2:36][CH3:37])=[O:34]>C1(C)C=CC=CC=1>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]3[O:41][CH:40]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:38]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[O:8]3)=[CH:5][C:4]=2[O:9]1
Reactant: CCOC(=O)[C@H](O)[C@@H](O)C(=O)OCC
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(OCC)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1OC(c2ccc3c(c2)OCO3)OC1C(=O)OCC
Temperature: 25 °C
Yield: 67 %

Procedure:
A mixture of piperonal (60 g, 0.4 mol), triethyl orthoformate (59.2 g, 0.4 mol), toluene (250 mL) and p-toluenesulfonic acid (2 g, 0.01 mol) was heated at 100°-110° C. for 0.5 h. Diethyl L-tartrate (103 g, 0.5 mol) was added to the hot solution over a 10 min. period. The mixture was then heated at reflux for 2 h. Subsequently over a 3 hour period, distillate (150 mL) was collected (pot temperature 84° C. to 110° C). The mixture was cooled (25° C.) and washed with sodium bicarbonate solution (2×50 mL) and brine (1×50 mL). Evaporation of solvents under reduced pressure provided 130.7 g of crude product. Recrystallization from methanol provided 90 g (67% yield) of (4R,5R)-2-(3,4-methylenedioxyphenyl-4,5-dicarboethoxy-1,3-dioxolane, mp 39°-40° C., [α]D25 -34.8° (c, 1.0 methanol). 1H-NMR (CDCl3)δ7.12 (1H,d,J=1.5 Hz), 7.03 (1H,dd,J= 1.5 Hz and 7.9 Hz), 6.80 (1H,d,J=7.9 Hz), 6.06 (1H,s), 5.97 (2H,s), 4.91 (1H,d,J=4.0 Hz), 4.80 (1H,d,J=4.0 Hz), 4.36-4.26 (4H, 2 q, overlapping, J=7.0 Hz), 1.38-1.30 (6H, 2 t, overlapping, J=7.0 Hz). IR (KBr) 2980, 2900, 1735, 1490, 1445, 1415 cm-1. MS m/e (% abundance) 338 (3), 265 (16), 166 (100), 149 (96), 135 (54), 121 (35), 93 (10), 65 (12), 43 (8).
Reaction SMILES: [CH2:1]([C:3]([CH3:5])=[O:4])[CH3:2].CO.[OH-].[K+].[CH3:10][C:11]1[C:15]([CH3:17])([CH3:16])[CH:14]([CH2:18][CH:19]=O)[CH2:13][CH:12]=1.S(=O)(=O)(O)O>O>[CH3:2][C:1](=[CH:19][CH2:18][CH:14]1[CH2:13][CH:12]=[C:11]([CH3:10])[C:15]1([CH3:17])[CH3:16])[C:3](=[O:4])[CH3:5]
Reactant: CCC(C)=O
Reactant: CC1=CCC(CC=O)C1(C)C
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)C(C)=CCC1CC=C(C)C1(C)C
Reaction time: 21 h

Procedure:
To a stirred solution of 400 g (6.1 moles) of methyl ethyl ketone, 1025 g (32 moles) of methanol, 30.5 g (0.54 mole) of potassium hydroxide and 380 g of water cooled to -5° to -10° C was added 152 g (1.0 mole) of campholenic aldehyde over 15-30 minutes. The mixture was maintained at 0° to -10° C for 24-36 hours and then at 25°-35° C for 18-24 hours. The mixture was neutralized by addition of 36.8 g of 62.5% sulfuric acid and the unreacted methyl ethyl ketone and excess methanol were removed by atmospheric distillation. The residual liquid was added to 200 ml of hexane and 200 ml of water. The aqueous layer was drawn off and the hexane layer was washed with 200 ml of brine. The hexane was removed by atmospheric distillation and the oil fractionally distilled under vacuum to give 3-methyl-5-(2,2,3-trimethylcyclopent-3-en-1-yl) pent-3-en-2-one and two other isomers in a ratio of ca. 86:6:8 by glc. Yield 140.3 g (85% theory); bp 102°-105° C (1.3 mm); nD20 1.4888; mol wt. 206 (ms); nmr, 0.8δ (3H, s), 1.0 (3H, s), 1.6 (3H, broad s), 1.8 (3H, broad s), 2.3 (3H, s, acetyl CH3), 5.3 (1H, broad multiplet, olefinic H), 6.7 (1H, complex, β-olefinic H of an α,β-unsaturated carbonyl system); ir, 3030, 1670, 1635, 790 cm-1.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.[Al+3].[Cl-].[Cl-].[Cl-]>[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])=[CH:13][CH:12]=1
Reactant: CCCCCC(=O)Cl
Reactant: COc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCC(=O)c1ccc(OC)cc1
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
A procedure similar to step 2 of Example 52 was used. n-Caproyl chloride prepared in the step 1 and methylphenyl ether were used as starting materials, allowed to react in dichloromethane in the presence of AlCl3 catalyst, stirred at −10° C. to −15° C. for 30 minutes and then at room temperature for 3 hours, a crude product was obtained, purified under a reduced pressure by silica gel column chromatography eluted with petroleum ether and ethyl acetate at a ratio of 20:1 to obtain a product as a waxy solid in a yield of 66.2%, mp: 39-40 └. 1H-NMR (CDCl3, 400 MHz) δ: 0.91 (3H, t, J=7.20 Hz, CH3), 1.30˜1.42 (4H, m, CH2CH2), 1.73 (2H, t, J=7.20 Hz, COCH2CH2), 2.91 (2H, t, J=7.20 Hz, COCH2CH2), 3.87 (3H, s, OCH3), 6.93 (2H, d, J=8.80 Hz, ArH), 7.96 (2H, d, J=8.80 Hz, ArH); ESI-MS m/e (%): 206.1 (M, 5), 163.0 (6), 150.0 (58), 135.0 (100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Br:21][C:22]1[CH:23]=[CH:24][C:25]([CH3:30])=[C:26]([CH:29]=1)[CH:27]=[O:28]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:27]([C:26]2[CH:29]=[C:22]([Br:21])[CH:23]=[CH:24][C:25]=2[CH3:30])[OH:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: Cc1ccc(Br)cc1C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(Br)cc1C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of 4-benzyloxybromobenzene (2.63 g, 10 mmol) in THF (50 mL) at −78° C. under nitrogen was slowly added n-butyllithium (2.5 M in hexanes, 4.4 mL, 11 mmol). The reaction was stirred for 30 minutes. 5-Bromo-2-methylbenzaldehyde (32, 1.99 g, 10 mmol) in THF (4 mL plus 1 mL rinse) was added slowly. The reaction was allowed to slowly warm to about 0° C. over 2 hours, then quenched with saturated aqueous NH4Cl, diluted with ether, washed with H2O and brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash chromatography (gradient 0-25% EtOAc/hexanes) to give 3.12 g (82% yield) of the title compound 33 as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.80 (d, J=2.3 Hz, 1 H), 7.36-7.47 (m, 4 H), 7.29-7.36 (m, 2 H), 7.18-7.24 (m, 2 H), 6.99 (d, J=8.1 Hz, 1 H), 6.88-6.97 (m, 2 H), 5.89 (d, J=3.5 Hz, 1 H), 5.06 (s, 2 H), 2.12 (s, 3 H), 2.06 (d, J=3.5 Hz, 1 H); MS (ES+) [M-OH]+=365, 367.
Reaction SMILES: [CH2:1]([N:3]([CH2:18]C)[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])=[CH:9][CH:8]=1)C.CN(C)CCOC1C=CC(C(=O)CCC)=CC=1>>[CH3:18][N:3]([CH3:1])[CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([NH2:17])[CH2:14][CH2:15][CH3:16])=[CH:11][CH:12]=1
Reactant: CCCC(N)c1ccc(OCCN(CC)CC)cc1
Agent: CCCC(=O)c1ccc(OCCN(C)C)cc1
Product: CCCC(N)c1ccc(OCCN(C)C)cc1
Yield: 73 %

Procedure:
The title compound was prepared by using a similar procedure as described for the preparation of 25 except that 1-(4-(2-(dimethylamino)ethoxy)phenyl)butan-1-one (22) was used instead of 1-(4-(2-(diethylamino)ethoxy)phenyl)butan-1-one (21). This produced crude 26 (410 mg, 73%) as a yellow oil: MS (ES+) m/z 237.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=2)[N:5]=[C:4]([CH3:15])[C:3]=1[C:16](=O)[CH3:17].[CH3:19][CH:20]([NH:22][C:23]([C:25]1[S:26][C:27]([C:30]([NH:32][NH2:33])=[O:31])=[CH:28][CH:29]=1)=[O:24])[CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[CH:20]([NH:22][C:23]([C:25]1[S:26][C:27]([C:30]([NH:32][NH:33][C:16](=[C:3]2[C:2](=[O:1])[N:6]([C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([CH3:14])[CH:8]=3)[N:5]=[C:4]2[CH3:15])[CH3:17])=[O:31])=[CH:28][CH:29]=1)=[O:24])([CH3:21])[CH3:19]
Reactant: CC(C)NC(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1c(C)nn(-c2ccc(C)c(C)c2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CC1=NN(c2ccc(C)c(C)c2)C(=O)C1=C(C)NNC(=O)c1ccc(C(=O)NC(C)C)s1
Temperature: 90 °C
Yield: 43 %

Procedure:
1-(5-Hydroxy-3-methyl-1-(3,4-dimethylphenyl)-1H-pyrazol-4-yl)-ethanone (30 mg, 0.123 mmol, synthesized in accordance with patent document 25), 5-hydrazinocarbonyl-thiophene-2-carboxylic acid 2-propylamide prepared in Reference Synthetic Example 1 and p-toluenesulfonic acid monohydrate (2 mg) in isopropanol (1 mL) were heated at 90° C. overnight under reflux. After cooling, chloroform-ether was added, and the resulting crystals were collected by filtration, washed with chloroform-ether and dried to give 24 mg of the desired product (yield 43%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](OS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (S)-3-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (0.750 g, 4.00 mmol) in DCM (10 mL) was cooled to 0° C. and charged with triethylamine (0.67 mL, 4.8 mmol), methanesulfonyl chloride (0.34 mL, 4.4 mmol), and 4-dimethylaminopyridine (0.005 g, 0.04 mmol) and stirred at ambient temperature for 6 h. The reaction mixture was partitioned between CHCl3 and sat. NaHCO3 and separated. The aqueous layer was re-extracted with CHCl3 (3×) and the combined organic fractions were washed with sat. NaHCO3 (2×), brine (2×), dried over Na2SO4, filtered and concentrated in vacuo to give the title compound as a pale yellow oil. This material was taken on to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.47 (s, 9H), 2.05-2.36 (m, 2H), 3.05 (s, 3H), 3.43-3.74 (m, 4H), 5.24-5.30 (m, 1H).
Reaction SMILES: [Cl:1]C1[CH:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]23[CH2:21][CH:16]4[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]4)[CH2:13]2)[CH2:19]3)=[O:9])[C:5]([Cl:22])=[CH:4][N:3]=1.C(O[C:28]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)=O)(C)(C)C.Cl>CS(C)=O.CO.O1CCOCC1>[ClH:1].[Cl:22][C:5]1[C:6]([C:8]([NH:10][CH2:11][C:12]23[CH2:13][CH:14]4[CH2:15][CH:16]([CH2:17][CH:18]([CH2:20]4)[CH2:19]2)[CH2:21]3)=[O:9])=[CH:7][C:28]([N:30]2[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]2)=[N:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Cl)ncc1Cl
Agent: Cl
Solvent: CO
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(N2CCNCC2)ncc1Cl
Yield: 51.8 %

Procedure:
A solution of 2,5-dichloro-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-pyridine-4-carboxamide (0.30 g, Example 1a) and 1-t-butoxycarbonylpiperazine (0.344 g) in dimethylsulfoxide (3 ml) was heated at 160° C. for 40 min. The solution was cooled and partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane and the organic layer dried over magnesium sulphate. Concentration in vacuo and chromatography on silica gave a colourless solid. This was redissolved in methanol and treated with 4M HCl in dioxan (4 ml). Once deprotection was complete the solution was partially concentrated in vacuo then diluted slowly with diethyl ether with rapid stirring. The resulting white precipitate was filtered, washed with diethyl ether and dried to afford the title compound (0.195 g).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=1.[BH4-].[Na+].[Cl-].[NH4+]>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH:9]([OH:16])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:4]=1
Reactant: CSc1cc(C(=O)c2ccccc2)ncn1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CSc1cc(C(O)c2ccccc2)ncn1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To 2 ml of ethanol was suspended 0.3 g of 6-methylthio-4-benzoylpyrimidine, to which 0.07 g of sodium borohydride was added, followed by stirring at 0° C. for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined and washed with a saturated aqueous sodium chloride solution, and the combined organic layer was dried over anhydrous magnesium sulfate and then concentrated to give 6-methylthio-4-(α-hydroxybenzyl)pyrimidine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[C:22](Cl)([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[N:6][CH:7]=1
Reactant: Brc1ccc(C2CCCN2)nc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCCC1c1ccc(Br)cn1
Reaction time: 2 h

Procedure:
To a suspension of 5-bromo-2-(pyrrolidin-2-yl)pyridine (2.67 g, 11.8 mmol) in DCM (20 mL) at 0° C. was added DIEA (1.5 eq), followed by CbzCl (1.1 eq). The resulting clear solution was warmed to it and stirred for 2 h. The reaction mixture was washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-50% EtOAc/Hexanes, Rf=0.35 in 50% EtOAc) to afford the titled compound as a brownish oil (3.63 g).
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[C:17]([F:32])=[C:18]([C:23]2[C:24]([C:30]#[N:31])=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)[C:19]([F:22])=[CH:20][CH:21]=1>>[F:1][C:2]1[C:3]2[N:4]([C:12]([C:20]3[C:19]([F:22])=[C:18]([C:23]4[C:24]([C:30]#[N:31])=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[C:17]([F:32])=[CH:16][CH:21]=3)=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9]
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Reactant: N#Cc1cc(F)ccc1-c1c(F)ccc(Br)c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(F)cc4C#N)c3F)cnc2c1F
Yield: 36.4 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol (194 mg, 1.0 mmol) and 3′-bromo-4,2′,6′-trifluorobiphenyl-2-carbonitrile (343 mg, 1.1 mmol) were coupled following the procedure in Example 6 to afford 3′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]-4,2′,6′-trifluorobiphenyl-2-carbonitrile (155 mg, 36%) as a white solid: δH (360 MHz, CDCl3) 1.74 (6H, s), 2.07 (1H, s), 7.19-7.26 (2H, m), 7.41-7.49 (1H, m), 7.54-7.65 (3H, m), 7.73 (1H, s), 7.93 (1H, dd, J 7 and 7); m/z (ES+) 426 (100%, [MH]+).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1/[CH:4]=[N:5]/[NH:6][C:7]1[CH:12]=[CH:11][C:10]([I:13])=[CH:9][CH:8]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:3]=1[C:4]([Cl:20])=[N:5][NH:6][C:7]1[CH:8]=[CH:9][C:10]([I:13])=[CH:11][CH:12]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Fc1cccc(Cl)c1/C=N/Nc1ccc(I)cc1
Solvent: c1ccccc1
Product: Fc1cccc(Cl)c1C(Cl)=NNc1ccc(I)cc1
Yield: 76.4 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-1 using (1E)-1-(2-chloro-6-fluorobenzylidene)-2-(4-iodophenyl)hydrazine (1.2 g, 3.20 mmol), PCl5 (0.990 g, 4.8 mmol) and benzene (20 mL) to afford 1.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 7.00 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 1H), 7.48-7.60 (m, 4H), 10.22 (s, 1H).