Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([OH:15])=[O:14])[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30]Br)=[CH:26][CH:25]=1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:12][C@H:11]([C:13]([O:15][CH2:30][C:27]2[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=2)=[O:14])[C:10]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)O)C1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H](C(=O)OCc2ccccc2)C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A stirred solution of (1S,3R)-3-(tert-butoxycarbonylamino)-2,2-dimethylcyclobutanecarboxylic acid (0.5 g, 2.05 mmol) in DMF (about 5 ml), Cs2CO3 (0.804 g, 2.47 mmol) and BnBr (0.3 ml, 2.47 mmol) were added slowly portion wise at about 0° C., then the reaction was stirred at room temperature for about 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water, brine and dried over Na2SO4. The solvent was evaporated and purified by silica gel column (60-120 mesh, elution 4% EtOAc in hexane) to afford title compound as a pale yellow syrup. Wt: 0.35 g; Yield: 51%; 1H NMR (300 MHZ, CDCl3): δ 7.39-7.28 (m, 5H), 5.12 (Brs, 2H), 4.60 (Brs, 1H), 3.88-3.79 (m, 1H), 2.65-2.53 (m, 1H), 2.38-2.27 (m, 1H), 2.01-1.99 (m, 1H), 1.43 (s, 9H), 1.28 (s, 3H), 0.86 (s, 3H); IR (KBr, cm−1): 3387, 2962, 1710, 1523, 1456, 1366, 1253, 1173, 1079, 1009, 979, 746, 698.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]1[N:24]=[C:23](S(C)(=O)=O)[N:22]3[N:29]=[CH:30][CH:31]=[C:21]3[CH:20]=1)[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]([O:36][C:37](=[O:46])[NH:38][C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1)([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37](=[O:46])[NH:38][C:39]1[CH:40]=[CH:41][C:42]([NH:45][C:23]2[N:22]3[N:29]=[CH:30][CH:31]=[C:21]3[CH:20]=[C:19]([C:14]3[CH:13]=[CH:12][C:11]4[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:10]=4)[CH:15]=3)[N:24]=2)=[CH:43][CH:44]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CS(=O)(=O)c1nc(-c2ccc3cc(OCc4ccccc4)ccc3c2)cc2ccnn12
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Product: CC(C)(C)OC(=O)Nc1ccc(Nc2nc(-c3ccc4cc(OCc5ccccc5)ccc4c3)cc3ccnn23)cc1
Temperature: 135 °C
Yield: 45.1 %

Procedure:
A mixture of 5-(6-benzyloxy-naphthalen-2-yl)-7-methanesulfonyl-pyrazolo[1,5-c]pyrimidine (compound D2)(87 mg) and 4-amino-phenyl-carbamic acid tert-butyl ester (208 mg) is heated neat at 130 to 140° C. bath temperature for 20 min. After cooling, the crude product is purified by silica gel flash chromatography. A nearly colorless solid (51 mg, 46%) with melting temperature of 189° C. is obtained.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:9]=2[CH:8]=1.[B:36](OC(C)C)([O:41]C(C)C)[O:37]C(C)C>C1COCC1>[CH2:20]([C:10]1([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:9]2[CH:8]=[C:7]([B:36]([OH:41])[OH:37])[CH:19]=[CH:18][C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(Br)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCC1(CCCCCCCC)c2ccccc2-c2ccc(B(O)O)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
n-BuLi (2.5 M in hexane, 12.0 mL, 30.0 mmol) is slowly added to a solution of 2-bromo-9,9-bis(n-octyl)fluorene (12.0 g, 25.6 mmol) in anhydrous THF (50 mL) at −78° C. At this temperature, the reaction mixture is stirred for 1 h before adding tri-iso-propyl borate (9.0 mL, 7.34 g, 39.0 mmol). The resulting mixture is then warmed to room temperature, stirred overnight followed by quenching with 100 mL HCl (2.0 M), and poured into a large amount of water. After extraction with ethyl ether three times, the organic portions are washed with brine before drying over anhydrous MgSO4. Solid residues collected by evaporating off the solvent are purified by column chromatography on silica gel with petroleum ether/ethyl acetate (2:1) to yield 9,9-bis(n-octyl)fluoren-2-yl-boronic acid (2a) as a white solid (10.0 g, 89%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)[C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].Cl>O1CCCC1>[CH3:11][C:10]1[N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][N:13]=2)[N:8]=[N:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1nnn(-c2ccc(C(F)(F)F)cn2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)nnn1-c1ccc(C(F)(F)F)cn1
Temperature: 80 °C
Reaction time: 9 h
Yield: 64.1 %

Procedure:
To a solution of 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (681 mg) in tetrahydrofuran (10 ml) was added 1 N aqueous solution of sodium hydroxide (10 ml) at room temperature, and stirred at 80° C. for 9 hours. After completion of the reaction, 1 N hydrochloric acid aqueous solution (10 ml) was added thereto, and the solvent was evaporated. The obtained residue was washed with water, and dried in vacuo to give the titled compound (396 mg) as a brown solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]2[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][CH2:9][O:8]2)=[C:5]([N+:15]([O-:17])=[O:16])[CH:4]=[N:3]1.C[Si]([N:22]=[N+:23]=[N-:24])(C)C>CC#N>[N:22]([CH:10]1[CH2:9][O:8][CH:7]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:13][C:12](=[O:14])[CH2:11]1)=[N+:23]=[N-:24]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CC(=O)C=CCO1
Solvent: CC#N
Product: Cn1ncc([N+](=O)[O-])c1C1CC(=O)CC(N=[N+]=[N-])CO1
Temperature: 65 °C

Procedure:
To a solution of 2-(2-methyl-4-nitro-pyrazol-3-yl)-3,7-dihydro-2H-oxepin-4-one (440 mg, 0.42 mmol) in MeCN (3 mL) was added Amberlite IRA 900F resin (79 mg, 0.19 mmol) and trimethylsilylazide (1.2 mL, 9.35 mmol). The reaction mixture was heated at 65° C. behind a blast screen for 24 hr, cooled to room temperature and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave pure 6-azido-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-one along with mixed fractions containing product and starting material. These were concentrated under reduced pressure and resubmitted to the same reaction conditions. Final purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 6-azido-2-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-one as a colourless solid (449 mg). To this solid (449 mg, 1.60 mmol) was added deoxo-Fluor® (50% in THF, 5 mL) and the mixture was stirred at room temperature for 18 hr. DCM (50 mL) was added and the reaction mixture cooled to 0° C. Saturated aqueous NaHCO3 (30 mL) was then carefully added. The aqueous layer was extracted with DCM (3×30 mL) and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 5-(6-azido-4,4-difluoro-oxepan-2-yl)-1-methyl-4-nitro-pyrazole (Diastereomer 1-major) as a colourless solid (264 mg, 47% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 5.67-5.58 (m, 1H), 4.18-3.91 (m, 3H), 4.08 (s, 3H), 2.79-2.63 (m, 1H), 2.63-2.40 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20]([CH3:23])(=[O:22])=[O:21])[C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:32]=[C:33]([NH2:37])[CH:34]=[N:35][CH:36]=2)[CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[F:12][C:10]1[CH:9]=[C:8]([F:13])[CH:7]=[C:6]2[C:11]=1[C:2]([NH:37][C:33]1[CH:34]=[N:35][CH:36]=[C:31]([N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)[CH:32]=1)=[C:3]([CH3:24])[C:4]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([CH3:23])(=[O:22])=[O:21])=[N:5]2
Reactant: Nc1cncc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccc2S(C)(=O)=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Essentially prepared according to Procedure H using 4-chloro-5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)quinoline (75.0 mg, 0.20 mmol) and 5-morpholinopyridin-3-amine in toluene to give 5,7-difluoro-3-methyl-2-(2-(methylsulfonyl)phenyl)-N-(5-morpholinopyridin-3-yl)quinolin-4-amine. 1H NMR (CDCl3) δ ppm 8.19 (1H, dd, J=7.9, 1.3 Hz), 7.89 (1H, d, J=2.3 Hz), 7.86 (1H, d, J=2.3 Hz), 7.78 (1H, td), 7.68 (1H, td, J=7.7, 1.2 Hz), 7.49 (1H, ddd, J=9.4, 2.4, 1.3 Hz), 7.42 (1H, dd, J=7.5, 1.3 Hz), 7.02-7.15 (2H, m), 6.55 (1H, t, J=2.3 Hz), 3.79 (4H, t, J=4.8 Hz), 3.09-3.22 (7H, m), 1.88 (3H, s). Mass Spectrum (ESI) m/e=511.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C=O)C>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:18])=[O:7])=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: Cc1ccc(C(=O)O)c(C(F)(F)F)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)Cl)c(C(F)(F)F)c1
Reaction time: 3 h

Procedure:
4-Methyl-2-(trifluoromethyl)benzoic acid (1 g, 4.90 mmol, commercially available from e.g. Fluorochem or ABCR) in dichloromethane (DCM) (40 mL) was cooled to 0° C., before oxalyl chloride (0.472 mL, 5.39 mmol) and a few drops of DMF (cat.) were added. The solution was then stirred under argon for 3 hours. The solvent was then evaporated in vacuo and the remaining residue was azeotroped with toluene (2×20 mL) to yield the product in 1.051 g.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4]([NH2:21])[N:3]=1>C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:18][OH:17])[CH2:14][OH:15])=[C:4]([NH2:21])[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(N)nc(N)nc32)CO1
Solvent: CC(=O)O
Product: Nc1nc(N)c2ncn(CCC(CO)CO)c2n1
Yield: 62.8 %

Procedure:
A solution of 2,6-diamino-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (180 mg, 0.6 mmol) in 70% acetic acid (10 ml) was stirred for 1 hour at room temperature. The solvent was removed, the residue was suspended in methanol and sodium methoxide was added to neutralise. Column chromatography on silica gel eluting with chloroformmethanol mixtures (6:1, 4:1 and 3:1) gave 2,6-diamino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (95 mg, 63%), m.p. 187°-190° C.; λmax (H2O, pH6.5) 215 (ε25,500), 255 (ε7,290), and 280 (ε9,170) nm; νmax 3150, 1680, 1650, 1605, 1590, and 1410 cm-1 ; δH [(CD3)2SO] 1.46 (1 H, m, CHCH2CH2), 1.73 (2 H, q, J 7.1 Hz, CHCH2CH2), 3.3-3.5 (4 H, ddd (ABX), JAB 10.6 Hz, JAX 5.5 Hz and JBX 5.9 Hz, 2×CH2O), 4.01 (2 H, t, J 7.3 Hz, CH2N), 4.41 (2 H, br, D2O exchangeable, 2×OH), 5.70 (2 H, s, D2O exchangeable, NH2), 6.56 (2 H, s, D2O exchangeable, NH2), and 7.69 (1 H, s, 8-H) (Found: C, 46.09; H, 6.32; N, 31.69%; C10H16N6O2 0.1CHCl3 requires C, 45.91; H, 6.14; N, 31.81%).
Reaction SMILES: N1(O[C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=2)C2C=CC=CC=2N=N1.[C:28]([NH:31][C:32]1[CH:33]=[C:34]([CH:36]=[CH:37][CH:38]=1)[NH2:35])(=[O:30])[CH3:29].CC1C=CC(S(O)(=O)=O)=CC=1>CN1C(=O)CCC1>[C:28]([NH:31][C:32]1[CH:33]=[C:34]([NH:35][C:11]2[N:16]=[C:15]([NH:17][CH2:18][C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[C:14]([C:25]([NH2:27])=[O:26])=[CH:13][N:12]=2)[CH:36]=[CH:37][CH:38]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: Cn1cc(CNc2nc(On3nnc4ccccc43)ncc2C(N)=O)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCCC1=O
Product: CC(=O)Nc1cccc(Nc2ncc(C(N)=O)c(NCc3cnn(C)c3)n2)c1
Temperature: 100 °C
Yield: 75.1 %

Procedure:
To a solution of 2-(1H-benzo[d][1,2,3]triazol-1-yloxy)-4-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrimidine-5-carboxamide (51 mg, 0.14 mmol) in NMP (0.8 mL) was added 3-acetamidoaniline (24 mg, 0.16 mmol) and pTsOH*H2O (27 mg, 0.14 mmol). The mixture was heated at 100° C. for 2 h, cooled to room temperature, purified by preparative HPLC to give 2-(3-acetamidophenylamino)-4-((1-methyl-1H-pyrazol-4-yl)methylamino)pyrimidine-5-carboxamide (40 mg). MS found for C18H20N8O2 as (M+H)+ 381.5. λ=242.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14](O)=[O:15])[CH:7]=[CH:6]2.C(Cl)(=O)C([Cl:21])=O>CN(C=O)C.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([Cl:21])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2cc([C@H](C)C(=O)Cl)ccc2c1
Reaction time: 0.05 h

Procedure:
A mixture of (S)-6-methoxy-α-methyl-2-naphthaleneacetic acid (23.09 g) and THF (41 mL) is agitated until dissolution is achieved. Oxalyl chloride (17.5 mL) is added to the flask followed by DMF (3 drops) and heptanes (50 mL). The mixture is stirred for approximately 2 hours. The resulting slurry is filtered, washed with heptane (15 mL) and aspirated for 3 minutes and vacuum dried to give 17.44 g.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[NH:6][C:7]([CH2:9][C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[H-].[Na+].I[CH2:20][C:21]#[N:22]>CN(C=O)C>[Cl:16][C:15]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([CH2:20][C:21]#[N:22])[C:7]([CH2:9][C:10]([F:12])([F:13])[F:11])=[N:6][C:5]=2[CH:14]=1
Reactant: N#CCI
Reactant: FC(F)(F)Cc1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCn1c(CC(F)(F)F)nc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 5,6-dichloro-2-(2,2,2-trifluoro-ethyl)-1H-benzimidazole (356 mg) in DMF (5 mL) was added sodium hydride (79 mg of 60% in oil) and iodoacetonitrile (331 mg). The resulting mixture was stirred at room temperature overnight. The reaction mixture was quenched with water, extracted with EtOAc, and dried over Na2SO4. The crude product was purified by silica gel chromatography (10%-40% EtOAc/hexanes), followed by washing solid with CH2Cl2 to yield the title compound as a peach-colored solid.
Reaction SMILES: Cl.[CH:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([S:12](Cl)(=[O:14])=[O:13])[C:6]=2[CH:5]=[CH:4][N:3]=1.[N:16]1([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(Cl)Cl>[C:26]([O:25][C:23]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([S:12]([C:7]2[C:6]3[CH:5]=[CH:4][N:3]=[CH:2][C:11]=3[CH:10]=[CH:9][CH:8]=2)(=[O:14])=[O:13])[CH2:18][CH2:17]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCN(S(=O)(=O)c2cccc3cnccc23)CC1
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a stirred suspension of isoquinoline-5-sulfonylchloride hydrochloride (3.00 g, 11.4 mmol) in anhydrous methylene chloride (100 mL) was added tert-butyl 1-homopiperazine carboxylate (3.00 g, 15.0 mmol) and triethylamine (4.36 g, 43.1 mmol). The mixture was stirred for 3 h, evaporated to dryness, mixed with a saturated solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (80 mL×2). The combined extracts were dried, filtered and evaporated to give an oil (4.45 g, 100%). LCMS (+APCI) m/z 392 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[NH:6][CH:5]=1.[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[NH:16][CH:15]=1.C(N(C(C)C)C(C)C)C>C(Cl)(Cl)Cl>[F:13][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[NH:6][CH:5]=[C:4]2[CH2:3][CH2:2][N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[CH:15]1
Reactant: Fc1ccc2[nH]cc(CCBr)c2c1
Reactant: c1ccc2[nH]cnc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Fc1ccc2[nH]cc(CCn3cnc4ccccc43)c2c1

Procedure:
A solution of 3-(2-bromo-ethyl)-5-fluoro-1H-indole (7.26 g, 30 mmol), benz-imidazole (3.54 g, 30 mmol) and ethyl-diisopropylamine (5.1 ml, 30 mmol) in abs. chloroform (80 ml) was boiled under reflux for 20 h. The reaction solution was then washed twice with water, dried over Na2SO4 and concentrated i. vac. and the residue which remained was purified by flash chromatography with CHCl3/MeOH (50:1).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)[CH3:2].[N+](C1C=CC([CH:37]2[S:41]/[C:40](=[N:42]\[C:43](=O)[O-:44])/[N:39]([C:46]3[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=3[CH:53]([CH3:55])[CH3:54])[C:38]2=[O:56])=CC=1)([O-])=O>>[CH2:1]([N:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[CH:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:26])([F:25])[F:27])=[CH:19][CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1)[C:43](/[N:42]=[C:40]1\[S:41][CH2:37][C:38](=[O:56])[N:39]\1[C:46]1[CH:51]=[C:50]([CH3:52])[CH:49]=[CH:48][C:47]=1[CH:53]([CH3:54])[CH3:55])=[O:44])[CH3:2]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)C(c3ccc([N+](=O)[O-])cc3)S/C2=N\C(=O)[O-])c1
Reactant: CCNCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: CCN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)/N=C1\SCC(=O)N1c1cc(C)ccc1C(C)C

Procedure:
The title compound was prepared as described in Example 95 using N-ethyl-2-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl)ethanamine (CB25) and (Z)-4-nitrophenyl(3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a red solid (0.075 g, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:16]([N:24]=[C:25]=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[C:16]([NH:24][C:25]([NH:8][C:5]1[C:4]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[S:26])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: Nc1ncc(Cl)cc1Oc1ccccc1
Solvent: C1CCOC1
Product: O=C(NC(=S)Nc1ncc(Cl)cc1Oc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.1 %

Procedure:
5-chloro-3-phenoxypyridin-2-amine (8.493 g, 38.490 mmol) and benzoyl isothiocyanate (6.9096 g, 42.339 mmol) were placed in THF (200 mL) and stirred at room temperature for 2 hours. THF was removed. A suspension was made by adding Hexanes:EtOAc (9:1). The suspension was filtered and the solid was washed with hexanes then dried to afford the title compound (13.752 g, 93.1% yield) as a yellow solid. 1H NMR (d6-DMSO) δ 12.35 (s, 1H), 11.84 (s, 1H), 8.34 (d, 1H), 7.95 (d, 2H), 7.66 (t, 1H), 7.53 (t, 2H), 7.44 (m, 3H), 7.24 (t, 1H), 7.18 (m, 2H); Mass spectrum (apci) m/z=383.1 (M+H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:18])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3.[CH3:19][S-:20].[Na+].O>CN(C)C=O>[CH3:17][O:16][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[O:13][C:14]1[CH:15]=[C:2]([S:20][CH3:19])[CH:3]=[CH:4][C:5]=1[C:6]2=[O:18]
Reactant: COc1cccc2c(=O)c3ccc(Cl)cc3oc12
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc2c(=O)c3ccc(SC)cc3oc12

Procedure:
A suspension of 3-chloro-5-methoxyxanthone (5 g.) in dimethylformamide is added to a solution of excess sodium thiomethoxide in dimethylformamide (prepared from methyl mercaptan and sodium hydride). After 1 hour the reaction mixture is poured into water and extracted with ether, giving on evaporation 5-methoxy-3-(methylthio)xanthone, m.p. 201°-203° C. on recrystallisation from methanol.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].[F:18][C:19]([F:36])([F:35])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32](O)=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1>>[CH3:1][C:2]1[N:6]2[CH:7]=[C:8]([NH:11][C:32]([C:29]3[CH:28]=[CH:27][C:26]([C:23]4[CH:24]=[CH:25][C:20]([C:19]([F:18])([F:35])[F:36])=[CH:21][CH:22]=4)=[CH:31][CH:30]=3)=[O:33])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1nc2ccc([N+](=O)[O-])cn2c1C
Reactant: O=C(O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: COC(=O)c1nc2ccc(NC(=O)c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)cn2c1C

Procedure:
Operations similar to those of Example 1 were conducted using methyl 3-methyl-6-nitroimidazo[1,2-a]pyridine-2-carboxylate and 4′-(trifluoromethyl)[1,1′-biphenyl]-4-carboxylic acid, to provide methyl 3-methyl-6-({[4′-(trifluoromethyl)[1,1′-biphenyl]-4-yl]-carbonyl}amino)-imidazo[1,2-a]pyridine-2-carboxylate as white solid.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH:6]1[CH2:9][NH:8][CH2:7]1.[CH3:16][N:17]=[C:18]=[O:19]>C1C=CC=CC=1>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH:6]1[CH2:9][N:8]([C:18]([NH:17][CH3:16])=[O:19])[CH2:7]1
Reactant: FC(F)(F)c1ccccc1OC1CNC1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)N1CC(Oc2ccccc2C(F)(F)F)C1
Reaction time: 0.5 h

Procedure:
To 4.5 g (0.02 mole) of 3-[2-(trifluoromethyl)phenoxy]azetidine stirring in 50 ml of dry benzene, was added slowly 1.2 g (0.02 mole) of methyl isocyanate at room temperature. Stirring was continued for 30 minutes. A solid formed, and after filtration was recrystallized from benzene to yield 3.5 g (68%), mp 134°-136°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([O:21][CH2:22][CH3:23])=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13]CC2C=CC=CC=2)[CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH:5]([O:21][CH2:22][CH3:23])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(=Cc1cccc(OCc2ccccc2)c1)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cccc(O)c1)OCC
Yield: 92.4 %

Procedure:
3-(3-Benzyloxyphenyl)-2-ethoxyacrylic acid ethyl ester (10.4 g; 31.8 mmole) was hydrogenated at atmospheric pressure in ethyl acetate using Pd/C (dry, 10%) as catalyst. The reaction mixture was filtered through celite and the solvent was evaporated in vacuo. The starting material was not completely consumed, therefor the hydrogenation was repeated to give 7 g (yield 92%) of 2-ethoxy-3-(3-hydroxyphenyl)propanoic acid ethyl ester.