Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([NH2:15])=[CH:13][C:12]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:11]2)=[CH:6][CH:5]=1.C1N=CN([C:26]([N:28]2C=N[CH:30]=[CH:29]2)=[O:27])C=1.[N:33]1[CH:38]=[CH:37][C:36]([O:39][C:40]2[CH:45]=CC(N)=[CH:42][CH:41]=2)=[CH:35][CH:34]=1.CCOC(C)=O>ClCCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14]([NH:15][C:26]([NH:28][C:29]3[CH:30]=[CH:45][C:40]([O:39][C:36]4[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=4)=[CH:41][CH:42]=3)=[O:27])=[CH:13][C:12]([C:16]([CH3:17])([CH3:19])[CH3:18])=[N:11]2)=[CH:8][CH:9]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(Oc2ccncc2)cc1
Reactant: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccncc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a suspension of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)benzoic acid methyl ester (1.89 g, 6.93 mmol) in anhydrous DCE (10 mL) was added CDI (1.24 g, 7.62 mmol), and the mixture was stirred at room temperature for 16 h. A suspension of 4-(pyridin-4-yloxy)phenylamine (1.29 g, 6.93 mmol; Dumas et al., U.S. pat. appl. US2002065296 (2002)) in DCE was then added, and the mixture was stirred at room temperature for 4 h. The reaction was diluted into EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated at reduced pressure. The crude product was purified by MPLC (15% EtOAc/hexane) to give 2.3 g (68%) of the title compound as a white solid. 1H-NMR (acetone-d6) δ 8.64 (s, 1H), 8.44 (d, J=9.0 Hz, 2H), 8.12 (d, J=9.0 Hz, 2H), 8.01 (s, 1H), 7.61 (d, J=9.0 Hz, 2H), 7.81 (d, J=9.0 Hz, 2H), 7.09 (d, J=9.0 Hz, 2H), 6.86 (d, J=6.0 Hz, 2H), 6.48 (s, 1H), 3.91 (s, 3H), 1.34 (s, 9H); MS LC-MS [M+H]+=486, RT=2.50 min.
Reaction SMILES: [F:1][C:2]1([F:40])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@H:28]4[CH2:32][O:31]C(C)(C)[O:29]4)[C:21]([C:35]([CH3:39])([CH3:38])[CH2:36][OH:37])=[CH:20]5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.O.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO>[F:40][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@H:28]([OH:29])[CH2:32][OH:31])[C:21]([C:35]([CH3:38])([CH3:39])[CH2:36][OH:37])=[CH:20]5)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: CC1(C)OC[C@H](Cn2c(C(C)(C)CO)cc3cc(NC(=O)C4(c5ccc6c(c5)OC(F)(F)O6)CC4)c(F)cc32)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CC(C)(CO)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)c(F)cc2n1C[C@H](O)CO
Temperature: 80 °C

Procedure:
(S)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (290 g, 0.5 mmol) was dissolved in methanol (5 mL). Water (0.5 mL) was added followed by p-TsOH.H2O (20 mg, 0.1 mmol). The reaction was heated at 80° C. for 45 minutes. The solution was then partitioned between ethyl acetate and saturated NaHCO3 solution. The ethyl acetate layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography (50-100% ethyl acetate-hexanes) to yield the product as a cream colored foamy solid. (146 mg, 54%, ee >97% by SFC). ESI-MS m/z calc. 520.5, found 521.5 (M+1)+. Retention time 1.67 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.53 (d, J=1.1 Hz, 1H), 7.42-7.37 (m, 2H), 7.33-7.30 (m, 2H), 6.22 (s, 1H), 5.01 (d, J=5.0 Hz, 1H), 4.91 (t, J=5.5 Hz, 1H), 4.75 (t, J=5.8 Hz, 1H), 4.42-4.38 (m, 1H), 4.10 (dd, J=8.8, 15.1 Hz, 1H), 3.90 (s, 1H), 3.64-3.54 (m, 2H), 3.48-3.33 (m, 2H), 1.48-1.45 (m, 2H), 1.35 (s, 3H), 1.32 (s, 3H) and 1.14-1.11 (m, 2H) ppm.
Reaction SMILES: [CH3:1][C@@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1.Cl>CN(C)C1C=CN=CC=1.ClCCl>[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:30])=[CH:24][CH:23]=1
Reactant: CC1(C)C2CC[C@]1(C)C(=O)CC2=O
Reactant: Cc1ccc(N=C=O)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(NC(=O)C2C(=O)C3CC[C@](C)(C2=O)C3(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1S)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.36 g, 2.0 mmole), triethylamine (0.20 g, 2.0 mmole) and 4-(dimethylamino)pyridine (0.24 g, 2.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-methylphenyl isocyanate (0.27 g, 2.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for seven hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a brown solid (0.19 g, 30% yield), mp=80–82° C.; MS (−) ESI m/z=341 (M−H)−; [α]D25=−24.0° (c=1, EtOH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH3:17])[CH:3]=1.[C:27]([O-:30])([O-])=O.[K+].[K+].ClC([O:36][CH2:37][CH3:38])=O>CC(C)=O>[C:37](=[CH:38][CH2:27][O:30][N:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[C:16](=[N:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[CH3:17])[S:9]([C:12]([F:15])([F:13])[F:14])(=[O:11])=[O:10])=[O:36]
Reactant: CC(=NOc1ccc(F)cc1)c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cl
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=NOc1ccc(F)cc1)c1cc(Cl)ccc1N(OCC=C=O)S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 21 h
Yield: 47.8 %

Procedure:
To a mixture of N-{4-chloro-2-[1-(4-fluorophenoxyimino)ethyl]phenyl}trifluoromethanesulfonamide (compound 129) (150 mg, 0.37 mmol) and K2CO3 (151 mg, 1.10 mmol) in acetone (5 mL) was added ethyl chloroformate (105 μL, 1.10 mmol), and the reaction allowed to stir at RT for 21 hours. The reaction mixture was concentrated under vacuum and the residue dissolved in Et2O (50 mL), washed with H2O (40 mL) then brine (40 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by radial thin layer chromatography (eluting with EtOAc/PE, 1:19) to afford N-carbonylethoxy-N-{4-chloro-2-[1-(4-fluorophenoxyimino)ethyl]phenyl}trifluoromethanesulfonamide 310 (85 mg, 63% based on recovered starting material), as a pale yellow oil, 1H n.m.r. (400 MHz, CDCl3) δ 7.52, d, J=2.4 Hz, 1H, 7.45, dd, J=2.4 and 8.8 Hz, 1H, 7.26, d, J=2.4 Hz, 1H, 7.14, m, 2H, 6.98, m, 2H; 4.24, m, 1H, 4.15, m, 1H, 2.41, s, 3H, 1.15, t, J=7.2 Hz, 3H. HRMS (M+) 482.0316.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]3[NH:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:9](=[O:16])[N:8]([CH2:17][O:18][CH3:19])[C:7]=2[CH:20]=1.S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+].[C-:30]#[N:31].[Na+]>ClCCl>[CH3:19][O:18][CH2:17][N:8]1[C:7]2[CH:20]=[C:3]([CH2:2][C:30]#[N:31])[CH:4]=[CH:5][C:6]=2[C:15]2[NH:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]1=[O:16]
Reactant: [C-]#N
Reactant: COCn1c(=O)c2c(c3ccc(CO)cc31)NCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COCn1c(=O)c2c(c3ccc(CC#N)cc31)NCCC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.6 %

Procedure:
8-(hydroxymethyl)-6-(methoxymethyl)-1,2,3,4-tetrahydrobenzo[h][1,6]naphthyridine-5-(6H)-one (100 mg, 0.36 mmol) prepared in step 5 of Example 41 was dissolved in dichloromethane (10 ml), added dropwise with thionylchloride (66 μl, 0.91 mmol) at 0° C. The resulting mixture was stirred at room temperature for 4 hours and poured into saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and concentrated to dryness. The residue was then dissolved in N,N-dimethylformamide (5 ml) and sodium cyanide (55 mg, 1.09 mmol) was added. The resulting mixture was stirred at room temperature overnight and poured into ice water. The mixture was extracted with chloroform and the organic layer was washed with brine. The solution was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was then purified by flash column chromatography (chloroform:methanol=30:1) to obtain the title compound (70 mg, yield: 69%, white solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH:19]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][CH2:19][N:33]3[CH2:32][CH2:31][N:30]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])[CH2:35][CH2:34]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1ccc(C2=NOC(CCCC=O)C2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2=NOC(CCCCN3CCN(c4ccccc4OC)CC3)C2)cc1OC
Yield: 67.2 %

Procedure:
4-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]butanal (26.7 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.6 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 26.5 mg (62.5%) of the target compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:14]([F:17])([F:16])[F:15])[NH:8]2)=[CH:4][C:3]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30].[H-].[Na+].I[CH2:37][CH3:38].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11](=[O:28])[NH:12][CH:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:27])[F:26])[CH:19]=3)[C:14]([F:15])([F:17])[F:16])[N:8]2[CH2:37][CH3:38])=[CH:4][C:3]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)[nH]c2cc1Cl
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(C(=O)NC(c3cccc(C(F)(F)F)c3)C(F)(F)F)n(CC)c2cc1Cl
Yield: 64.7 %

Procedure:
Ethyl 6-chloro-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate (1.00 g, 2.03 mmol) was dissolved under argon at 0° C. in N,N-dimethylformamide (20 ml). Sodium hydride (60%; 0.079 g, 1.97 mmol) was added and the mixture was stirred while cooling with ice for 2 h. Subsequently, iodoethane (0.15 ml, 1.93 mmol) was added dropwise. The reaction mixture was thawed while stirring within 36 h. Water and ethyl acetate were added and the phases were separated. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulphate, and the solvent was removed under reduced pressure. The residue was chromatographed with cyclohexane/ethyl acetate (4/1) and gave 0.65 g (64% of theory) of ethyl 6-chloro-1-ethyl-2-({2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}carbamoyl)-1H-indole-5-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12](I)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:26]4[CH:27]=[N:22][CH:23]=[N:24][CH:25]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(I)ccc1Oc1ncc(Br)cc12
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncnc3)ccc1Oc1ncc(Br)cc12
Temperature: 110 °C

Procedure:
A 10-20 mL microwave vial was charged with (S)-3-bromo-7-iodo-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (503 mg, 1.098 mmol), pyrimidin-5-ylboronic acid (143 mg, 1.153 mmol), pd(ph3p)4 (127 mg, 0.110 mmol). The vial was flushed with Ar(g), then THF (5489 μL, 1.098 mmol) and potassium carbonate (1.5 M) (1464 μL, 2.195 mmol) (aq. solution) were added in sequence. The vial was sealed and heated at 110° C. for 2 hours. The mixture was diluted with water and extracted with 10% i-PrOH/EtOAc (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 100-g SNAP column, eluting with 0-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to provide (S)-3-bromo-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as an off-white solid.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=O)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([N:23]1[C:31]2[N:30]=[C:29]([C:32]([F:35])([F:34])[F:33])[NH:28][C:27]=2[C:26](=[O:36])[NH:25]/[C:24]/1=[N:37]\[NH2:38])[CH2:19][CH2:20][CH2:21][CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[CH2:1]([C:8]1[N:12]=[C:11]([CH2:13][CH2:14][C:15]([NH:38]/[N:37]=[C:24]2\[NH:25][C:26](=[O:36])[C:27]3[NH:28][C:29]([C:32]([F:35])([F:34])[F:33])=[N:30][C:31]=3[N:23]\2[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:17])[O:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCn1/c(=N/N)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Reactant: O=C(O)CCc1nc(Cc2ccccc2)no1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCn1/c(=N/NC(=O)CCc2nc(Cc3ccccc3)no2)[nH]c(=O)c2[nH]c(C(F)(F)F)nc21
Yield: 98.5 %

Procedure:
The mixture of 3-(3-benzyl-1,2,4-oxadiazol-5-yl)propanoic acid (100.0 mg, 0.431 mmole), (2E)-3-pentyl-8-(trifluoromethyl)-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (144.1 mg, 0.474 mmole), BOP (209.5 mg, 0.474 mmole) and triethylamine (0.120 ml, 0.861 mmole). in DMF (4 ml) was stirred at room temperature overnight. The mixture was diluted with EtOAc (100 ml) and washed with water, then brine. The organic phase was dried over Na2SO4, filtrated and concentrated to give the desired product (220.1 mg, 98.6%) as yellowish oil. LCMS calculated for C23H26F3N8O3 (M+H): m/z=5192. Found 519.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[C:31]12([N:38]3[CH2:42][CH2:41][CH2:40][CH:39]3[CH2:43][NH2:44])[CH2:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][CH2:32]2>O.CC(C)=O>[C:31]12([N:38]3[CH2:42][CH2:41][CH2:40][CH:39]3[CH2:43][NH:44][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=[CH:11][C:3]=3[O:2][CH3:1])[CH2:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][CH2:32]2
Reactant: COc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: NCC1CCCN1C12CCC(CC1)C2
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: COc1ccc(S(C)(=O)=O)cc1C(=O)NCC1CCCN1C12CCC(CC1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
69 g of 2-methoxy-5-methylsulphonylbenzoic acid (0.30 mole), 360 ml of acetone, 120 ml of water and 30.3 g of triethylamine (0.30 mole) are placed in a 1 liter flask fitted with an agitator, thermometer, a condenser and a dropping funnel. The solution is chilled to 0° C., then 40.8 g of isobutyl chloroformate (0.30 mole) is added drop by drop. The mixture is agitated for 30 minutes at room temperature, then chilled to 0° C. again, and 58.2 g of 1-norbornyl-2-aminomethyl pyrrolidine (0.30 mole) is poured in drop by drop. The reaction mixture is agitated for 3 hours at room temperature then evaporated dry. The residue is dissolved in 500 ml of water and 80 ml of hydrochloric acid (density 1.18). The solution is filtered with acticarbone 3S and the filtrate is made alkaline with 120 ml of soda lye. A thick oil is decanted off, washed with 500 ml of water then dissolved hot, at about 60° C., in 90 ml of ethyl acetate. The product crystallises. The crystals are frozen, filtered and washed in water and dried in an oven at 60° C. 72 g of product is obtained (melting point 125° C.). This is re-crystallised in 150 ml of isopropanol to give 62 g (51%) of amide melting at 132° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([F:12])[CH:3]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[N:18][CH:19]=1.N1C=CC=CC=1.Cl>ClCCl.CCCCCC>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[N:18][CH:19]=2)=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: O=C(Cl)c1cc(Cl)c(Cl)cc1F
Reactant: COC(=O)c1ccc(N)cn1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCCCCC
Product: COC(=O)c1ccc(NC(=O)c2cc(Cl)c(Cl)cc2F)cn1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
A solution of 4,5-dichloro-2-fluoro-benzoyl chloride (4.35 g, 19.13 mmol) in dichloromethane (40 mL) was added drop-wise to a mixture of methyl 5-aminopyridine-2-carboxylate (2.91 g, 19.13 mmol), pyridine (4.64 mL, 57.39 mmol) and dichloromethane (60 mL) at 0° C. The reaction was stirred and allowed to warm up to room temperature over 2 hours. The mixture was poured into 1N HCl (50 mL) and dichloromethane (50 mL). The two layers were separated. The aqueous layer was extracted with dichloromethane (3×200 mL). The combined organic layer was washed with water (1×150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was slurried in hexanes to remove impurities. The solid was isolated by filtration using hexane to yield methyl 5-[(4,5-dichloro-2-fluoro-benzoyl)amino]pyridine-2-carboxylate (5.33 g, 81%) as a cream color solid. 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.94 (d, J=2.5 Hz, 1H), 8.36 (dd, J=8.6, 2.5 Hz, 1H), 8.12 (d, J=8.6 Hz, 1H), 8.08 (d, J=6.6 Hz, 1H), 7.95 (d, J=9.6 Hz, 1H), 3.87 (s, 3H) ppm. ESI-MS m/z calc. 342.00. found 343.1 (M+1)+; Retention time: 1.72 minutes (3 minutes run).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11]([C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]1)=[O:12].[CH:19]1([CH2:25][S:26](Cl)(=[O:28])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>ClCCl>[CH:19]1([CH2:25][S:26]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C@H:13]2[C:11]([O:10][CH3:9])=[O:12])(=[O:28])=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)[C@@H]1CCCCN1
Reactant: O=S(=O)(Cl)CC1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCCN1S(=O)(=O)CC1CCCCC1
Reaction time: 18 h
Yield: 70.5 %

Procedure:
Triethylamine (22.15 ml) was added to a solution of (2S)-2-(methoxycarbonyl)piperidine hydrochloride (10 g) [see Preparation 24] and cyclohexylmethanesulfonyl chloride (16.42 g) [King. J. F. et al,. J. Am. Chem. Soc., 1992, 114(5), 1743-9] in dichloromethane (100 ml). The reaction mixture was stirred for 18 hours after which time the solvent was removed under reduced pressure and the residue diluted with ethyl acetate. The organic layer was washed with water, brine, dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with a solvent gradient of 95:5 changing to 80:20, by volume, hexane:ethyl acetate to afford methyl (2S)-1-[(cyclohexylmethyl)sulfonyl]-2-piperidinecarboxylate (11.9 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.Br[CH:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:16]=O.C([O-])(O)=O.[Na+].O>O1CCOCC1>[C:18]1([C:15]2[N:3]3[CH:4]=[CH:5][C:6]([C:8]4[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=4)=[CH:7][C:2]3=[N:1][CH:16]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CC(Br)c1ccccc1
Reactant: Nc1cc(-c2ccncc2)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-c2cnc3cc(-c4ccncc4)ccn23)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the solution of 2-amino-4,4′-bipyridine (0.482 g, 2.815 mmol, 1 equiv) in dioxane (14 mL) was added bromophenylacetaldehyde (0.897 g, 4.50 mmol, 1.6 equiv) and NaHCO3 (0.473 g, 5.63 mmol, 2 equiv). The suspension was stirred at rt for 30 min and then heated to 80° C. for 6 h. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layer was dried, concentrated and purified by flash column chromatography (5% MeOH in CH2Cl2 ) to give 3-phenyl-7-(4-pyridyl)imidazo[1,2-a]pyridine as a solid. 1H NMR (CDCl3) δ 8.72 (d, 2H, J=6.1), 8.45 (d, 1H, J=7.3), 8.00 (s, 1H), 7.80 (s, 1H), 7.61–7.55 (m, 6H), 7.48–7.44 (m, 1H), 7.14 (d, 1H, J=7.3); LRMS m/z (M+H) Calcd: 272.3, found: 272.2.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([C:12]23[CH2:18][CH:16]([CH2:17]2)[C:15](=[O:19])[NH:14][C:13]3=[O:20])=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH2:21](I)[CH3:22].C(OCC)(=O)C.CCCCCC>CN(C)C=O>[CH2:21]([N:14]1[C:15](=[O:19])[CH:16]2[CH2:17][C:12]([C:9]3[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[CH:11][CH:10]=3)([CH2:18]2)[C:13]1=[O:20])[CH3:22]
Reactant: O=C1NC(=O)C2(c3ccc([N+](=O)[O-])cc3)CC1C2
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN1C(=O)C2CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.36 g of sodium hydride is added to a solution of 2.46 g of 1-(4-nitrophenyl)-3-azabicyclo[3.1.1]heptane-2,4-dione in 25 ml of N,N-dimethylformamide and the whole is stirred at room temperature for 30 minutes. 2.33 g of ethyl iodide dissolved in 10 ml of N,N-dimethylformamide are then added dropwise thereto. When the reaction is complete, the reaction mixture is freed of N,N-dimethylformamide. The residue is partitioned between ethyl acetate and water, and the organic phase is dried over magnesium sulphate and, after concentration by evaporation, the product is obtained in the form of a solid. Melting point 175°-179°. Rf (ethyl acetate/hexane 4:1)=0.52.
Reaction SMILES: [C:1](#[N:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH2:17])[CH:13]=1.[NH:18]1[CH2:23][CH2:22][S:21][CH2:20][CH2:19]1>>[CH3:11][C:12]1[NH:16][N:15]=[C:14]([NH:17][C:3]2[CH:2]=[C:1]([N:18]3[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)[N:10]=[C:1]([CH:2]=[CH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:10]=2)[CH:13]=1
Reactant: N#CC=Cc1ccccc1
Reactant: Cc1cc(N)n[nH]1
Reactant: C1CSCCN1
Product: Cc1cc(Nc2cc(N3CCSCC3)nc(C=Cc3ccccc3)n2)n[nH]1

Procedure:
Example 83 was synthesized via Scheme 6 according to the general scheme provided above with the appropriate starting materials cinnamonitrile, 5-methyl-1H-pyrazole-3-amine, and thiomorpholine. Structure of the target was confirmed by 1H-NMR. The 1H-NMR is attached.