Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](/[C:38](/[CH3:41])=[CH:39]\[CH3:40])[C:6]2[O:10][C:9]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:37]=1)#[N:2].ClCCl.CO>C(OCC)(=O)C.[Pd]>[CH:38]([C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([C:25]5[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=5)[CH2:21][CH2:20]4)=[O:16])=[CH:35][CH:36]=3)=[N:8][C:7]=2[CH:37]=[C:3]([C:1]#[N:2])[CH:4]=1)([CH2:39][CH3:40])[CH3:41]
Reactant: C/C=C(/C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)oc12
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(c5nccc(C(F)(F)F)n5)CC4)cc3)oc12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a mixture of 4-{5-cyano-7-[(1Z)-1-methylprop-1-en-1-yl]-1,3-benzoxazol-2-yl}-N-({1-[4-(trifluoromethyl)pyrimidin-2-yl]piperidin-4-yl}methyl)benzamide (18 mg) in ethyl acetate (5 ml)/dichloromethane (5 ml)/methanol (5 ml) at 40° C. was added 15 mg of 10% Pd/C and the resulting mixture was degassed and flushed with nitrogen, followed by degassing and flushing with hydrogen using a double balloon. The mixture was stirred under hydrogen at 40° C. overnight, and then filtered, washing with ethyl acetate. The filtrate was concentrated and purified by flash column chromatography on a Biotage Horizon, 25M Si column, eluting with 1 column volume of 10% ethyl acetate in hexanes, followed by a linear gradient of ethyl acetate in hexanes from 10% to 100% over 10 column volumes to afford the title compound. Mass spectrum (ESI) 563.2 (M+1). 1H NMR (500 MHz, CDCl3) δ: 8.47 (d, J=4.8 Hz, 1H), 8.34 (d, J=8.2 Hz, 2H), 7.95 (d, J=8.7 Hz, 2H), 7.49 (s, 1H), 6.73 (d, J=4.8 Hz, 1H), 6.32 (t, J=5.9 Hz, 1H), 4.87 (d, J=13.3 Hz, 2H), 3.44 (t, J=6.7 Hz, 2H), 3.21 (m, 1H), 2.93 (m, 2H), 2.01 (m, 1H), 1.90 (m, 2H), 1.84 (m, 2H), 1.44 (d, J=7.1 Hz, 3H), 1.31 (m, 2H), 0.91 (t, J=8.0 Hz, 3H).
Reaction SMILES: [CH:1]1([O:7][CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][C:16]([SH:18])=[CH:17][C:12]3=[N:11][C:10]=2[CH:19]([CH3:21])[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:29][N:30]([CH3:34])[C:31](Cl)=[O:32].C(=O)([O-])O.[Na+]>ClCCCl>[CH3:29][N:30]([CH3:34])[C:31](=[O:32])[S:18][C:16]1[CH:15]=[CH:14][N:13]2[C:9]([CH2:8][O:7][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:10]([CH:19]([CH3:21])[CH3:20])[N:11]=[C:12]2[CH:17]=1
Reactant: CC(C)c1nc2cc(S)ccn2c1COC1CCCCC1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)c1nc2cc(SC(=O)N(C)C)ccn2c1COC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.6 %

Procedure:
3-Cyclohexyloxymethyl-2-isopropylimidazo[1,2-a]pyridine-7-thiol (210 mg, 0.691 mmol) obtained in step 1 was dissolved in 1,2-dichloroethane (2.0 mL). Under ice-cooled condition, triethylamine (0.140 mL, 1.00 mmol) and dimethylcarbamoyl chloride (0.0770 mL, 0.834 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After adding a saturated sodium hydrogen carbonate aqueous solution to the reaction mixture, the reaction mixture was filtered through a Presep (registered trademark; diatomaceous earth, granular type M, 4.5 g/25 mL). The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30) to give S-3-(cyclohexyloxymethyl)-2-isopropylimidazo[1,2-a]pyridin-7-yl dimethylthiocarbamate (121 mg, yield 47%).
Reaction SMILES: N([O-])=[O:2].[Na+].[CH3:5][C:6]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:7]=1[CH2:8]N.C(O)(=O)C.[OH-].[Na+]>O.CO>[CH3:5][C:6]1[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:7]=1[CH2:8][OH:2]
Reactant: Cc1ccc([N+](=O)[O-])c(CN)c1C
Reactant: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc([N+](=O)[O-])c(CO)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
Sodium nitrite (36.5 g, 0.53 mole) in water (125 ml) was added dropwise to a stirred mixture of 2,3-dimethyl-6-nitrobenzylamine (63.5 g, 0.35 mole), acetic acid (165 mL) and water (165 mL) cooled in an ice bath. After completing the addition, the mixture was stirred for 10 minutes, warmed to room temperature and stirred to a further 10 minutes before being diluted with water (1000 mL). The mixture was extracted with dichloromethane (3×500 mL), the combined extracts dried over magnesium sulfate and concentrated to afford an oil which was dissolved in methanol (400 mL). 1N Sodium hydroxide solution (400 mL) was added dropwise over 20 minutes. The methanol was removed under reduced pressure, and the residue diluted with water (1200 mL) and extracted with dichloromethane (3×700 mL). The combined extracts were dried over magnesium sulfate and the solvent evaporated to afford 2,3-dimethyl-6-nitrobenzyl alcohol (59.3 g, 93%) as brown solid used in Step 3 below without further purification. An analytical sample was prepared by crystallization from hexane/diethyl ether, m.p. 48°-51° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)/[C:35](O)=[O:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:51][C:52]1[S:53][CH:54]=[CH:55][N:56]=1>C(Cl)Cl>[CH:28]1(/[CH:33]=[C:34](\[C:38]2[CH:43]=[CH:42][C:41]([N:44]3[C:48]([CH3:49])=[N:47][N:46]=[N:45]3)=[C:40]([F:50])[CH:39]=2)/[C:35]([NH:51][C:52]2[S:53][CH:54]=[CH:55][N:56]=2)=[O:36])[CH2:29][CH2:30][CH2:31][CH2:32]1
Reactant: Nc1nccs1
Reactant: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)O)cc1F
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnnn1-c1ccc(/C(=C\C2CCCC2)C(=O)Nc2nccs2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 19.6 %

Procedure:
A solution of triphenylphosphine (262 mg, 1 mmol) in methylene chloride (6 mL) was cooled to 0° C. and then treated with N-bromosuccinimide (178 mg, 1 mmol). The reaction mixture was stirred at 0° C. for 30 min and then treated with (E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-acrylic acid (158 mg, 0.5 mmol). The reaction mixture was stirred for 15 min at 0° C. and then allowed to warm to 25° C. where it was stirred for 1.5 h. The reaction mixture was then treated with 2-aminothiazole (150 mg, 1.5 mmol), and the resulting suspension was stirred for 2 d at 25° C. The reaction mixture was then concentrated in vacuo to remove methylene chloride, and the residue was diluted with ethyl acetate (20 mL) and a 1N aqueous hydrochloric acid solution (30 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×15 mL). The combined organic extracts were successively washed with a 1N aqueous hydrochloric acid solution (1×50 mL), a saturated aqueous sodium bicarbonate solution (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded (E)-3-cyclopentyl-2-[3-fluoro-4-(5-methyl-tetrazol-1-yl)-phenyl]-N-thiazol-2-yl-acrylamide (39 mg, 20%) as a white solid: mp 158-162° C.; EI-HRMS m/e calcd for C19H19FN6OS (M+)) 398.1325, found 398.1323.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][CH2:13][CH2:12][C:11]2=O>O.C(O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[O:14][CH2:13][CH2:12][C:11]2=[N:2][OH:3]
Reactant: NO
Reactant: COc1ccc2c(c1)C(=O)CCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)C(=NO)CCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 140 g (2.02 mole) of hydroxylamine hydrochloride in 630 ml of water, contained in a 3-l Erlenmeyer flask, was treated with 560 ml of 10% NaOH, and a solution of 250 g (1.40 mole) of 6-methoxy-4-chromanone in 560 ml of ethanol, all with rapid stirring. The reaction mixture was heated to boiling over 15 min., and continued to boil for 5 min. The mixture was stirred rapidly at room temperature for 3 hrs., refrigerated overnight and filtered. A white crystalline solid was washed with 1-l of water and air dried for 3 days; m.p. 120°-121°, Yield: 266 g (99%).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21].Cl[C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C1COCC1>[C:20]([O:19][C:18]([NH:17][CH:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[CH2:11][NH:10][C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:24])([CH3:21])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC1CCCC1CN
Reactant: CCOC(=O)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(=O)NCC1CCCC1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
iPr2NEt (0.5 mL) was added into a solution of tert-butyl (2-(aminomethyl)cyclopentyl)carbamate (300 mg) and ethyl 2-chloro-2-oxoacetate (191 mg) in THF (10 mL). The reaction was stirred at room temperature for 16 hours before being quenched by water. The aqueous layer was extracted with EtOAc (3×20 mL). The combined organic phase was dried over MgSO4 and concentrated under vacuum to give the crude ethyl 2-(((2-((tert-butoxycarbonyl)amino)cyclopentyl)methyl)amino)-2-oxoacetate which was used as was.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17](Cl)(=[O:19])=[O:18])[CH2:4]1)[CH3:2].[NH2:21][C:22]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]2[C:25]([C@H:26]3[CH2:36][C@H:27]3[CH2:28][O:29]2)=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:21][C:22]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]3[C:25]([C@H:26]4[CH2:36][C@H:27]4[CH2:28][O:29]3)=[CH:24][CH:23]=2)(=[O:19])=[O:18])[CH2:4]1)[CH3:2]
Reactant: COC(=O)c1c(N)ccc2c1OC[C@@H]1C[C@H]21
Reactant: CCN1CCCC(Cc2cc(F)ccc2S(=O)(=O)Cl)C1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CCCC(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OC[C@@H]2C[C@H]32)C1
Yield: 21.5 %

Procedure:
2-(1-Ethylpiperidin-3-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 222, 0.21 g) was added to a solution of methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42A 0.290 g) in DCM (10 mL) and pyridine (2 mL) and the resultant mixture was stirred at room temperature for 4 hours. The mixture was evaporated to dryness and the residue was partitioned between DCM and water. The organic layer was dried (Na2SO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica eluting with a mixture of 2M ammonia in methanol and DCM with a gradient of 0-15% to give methyl (1aR,7bS)-5-[2-(1-ethylpiperidin-3-ylmethyl)-4-fluoro-benzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.071 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([OH:26])=[CH:10][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:12][C:13]=2[O:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[S:32](Cl)(=[O:34])=[O:33]>>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH2:15][CH3:16])=[CH:12][C:11]([CH2:17][C:18]3[C:19]([NH2:25])=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)=[CH:10][C:9]=2[O:26][S:32]([C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)(=[O:34])=[O:33])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(O)c1-c1cccc(N)c1
Reactant: O=S(=O)(Cl)c1cccs1
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OS(=O)(=O)c2cccs2)c1-c1cccc(N)c1
Yield: 51.7 %

Procedure:
Starting from 3′-amino-4-(2,4-diamino-pyrimidin-5-ylmethyl)-6-ethoxy-biphenyl-2-ol (100 mg; 0.28 mmol) and 2-thienylsulfonyl chloride (94 mg; 0.51 mmol), 72 mg of the title compound are isolated as a yellow foam.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:21])=[CH:19][CH:20]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH2:13]([O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)=[CH:19][CH:20]=1)[CH3:12]
Reactant: Oc1cccc2ccccc12
Reactant: CCOc1ccc(N)cc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CCOc1ccc(Nc2cccc3ccccc23)cc1
Temperature: 220 °C
Yield: 97 %

Procedure:
288 parts of α-naphthol, 411 parts of p-phenetidine and 10 parts of triphenyl phosphite are mixed and heated to 220° C. At this temperature, the elimination of water commences. In the course of 8 hours, the reaction temperature rises to 250° C, at which stage the reaction has ended. 36 parts of water are removed. After removing excess p-phenetidine, N-p-ethoxy-phenyl-α-naphthylamine distils at a boiling point of 233° - 235° C/5 mm Hg. 510 parts of end product of melting point 73° - 75° C are obtained. This corresponds to a yield of 97% of theory.
Reaction SMILES: [S:1](=[N:4][C:5]([NH2:7])=[O:6])(=[O:3])=[O:2].C(OC(=O)[N:14]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:33]=[CH:32][C:31](N)=[CH:30][CH:29]=1)[CH:20]=[CH:19]2)C)(C)(C)C.[C:36]1(S(N)(=O)=O)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[NH2:14][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[F:26])[C:22](=[O:27])[N:21]([C:28]1[CH:33]=[CH:32][C:31]([NH:7][C:5]([NH:4][S:1]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)(=[O:3])=[O:2])=[O:6])=[CH:30][CH:29]=1)[CH:20]=[CH:19]2
Reactant: NC(=O)N=S(=O)=O
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)c1cc2ccn(-c3ccc(N)cc3)c(=O)c2cc1F
Product: Nc1cc2ccn(-c3ccc(NC(=O)NS(=O)(=O)c4ccccc4)cc3)c(=O)c2cc1F

Procedure:
An analogous sulfonylurea coupling and de-protection procedure to that described in Example 29 was performed on [2-(4-Amino-phenyl)-7-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-methyl-carbamic acid tert-butyl ester (Example 9) and benzenesulfonamide to give N-({[4-(6-amino-7-fluoro-1-oxoisoquinolin-2(1H)-yl)phenyl]amino}carbonyl)-benzenesulfonamide. ES-MS (M+H)+=467.1; 1H-NMP (ΔMΣO-66) δ (ppm): 9.13-9.06 (bs, 1H), 7.98-7.92 (d, J=8.4 Hz, 2H), 7.70-7.56 (m, 4H), 7.44-7.37 (d, J=8.8 Hz, 2H), 7.39-7.24 (d, J=8.8 Hz, 2H), 7.21-7.18 (d, J=7.3 Hz, 1H), 6.74-6.66 (d, J=8.4 Hz, 1H), 6.56-6.48 (bs, 1H), 6.49-6.46 (d, J=7.7 Hz, 1H), 2.82-2.76 (bd, J=4.4 Hz, 3H).
Reaction SMILES: [Na+].[Cl-].C[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)=[C:9]([OH:11])[CH:10]=1.[CH3:22]C(C)=CCC1C=C2C(=CC=1O)OC(C1C=C(O)C=C(O)C=1)=C2>CO>[CH3:22][O:11][C:9]1[CH:10]=[C:5]([OH:4])[CH:6]=[CH:7][C:8]=1[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1
Reactant: COc1ccc(CCCc2ccc(O)cc2)c(O)c1
Reactant: CC(C)=CCc1cc2cc(-c3cc(O)cc(O)c3)oc2cc1O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(O)ccc1CCCc1ccc(O)cc1

Procedure:
Colorless needles; mp 88-89° C.; UV (MeOH) λmax (log ε) 266 (3.11), 239 (3.10) nm; IR (NaCl) γmax 3335, 2954, 1614, 1508, 1456 cm−1; 1H NMR (CD3OD, 300 MHz) δ 1.76 (2H, m, H-2), 2.49 (4H, m, H-1 and H-3), 3.74 (3H, s, OCH3), 6.29 (1H, dd, J=2.4 and 8.1 Hz, H-5′), 6.38 (1H, d, J=2.4 Hz, H-3′), 6.68 (2H, d, J=8.5 Hz, H-3″), 6.86 (1H, d, J=8.1 Hz, H-6′), 6.98 (2H, d, J=8.5 Hz, H-2″); 13C NMR (CD3OD, 75 MHz) δ 30.3 (C-1), 33.5 (C-2), 35.8 (C-3), 55.6 (OCH3), 99.7 (C-3′), 107.5 (C-5′), 116.0 (C-3″), 122.8 (C-1′), 130.3 (C-2″), 131.1 (C-6′), 134.8 (C-1″), 156.1 (C-4″), 157.6 (C-4′), 159.6 (C-2′); EIMS m/z 258 (M+, 52), 151 (18), 137 (100), 134 (20), 107 (48).
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:33]2=[O:46])[S:27][C:28]=1[C:29]([OH:31])=O.[NH2:47][CH2:48][C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][CH2:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:33]2=[O:46])[S:27][C:28]=1[C:29]([NH:47][CH2:48][C:49]1[CH:50]=[N:51][CH:52]=[CH:53][CH:54]=1)=[O:31]
Reactant: Cc1nc(N2CCN(CCCc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CCCc3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 62 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(3-phenylpropyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 62% yield: mp 127-128° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) 8.57 (s, 1H), 8.45 (d, J=4.2 Hz, 1H), 7.66 (d, J=7.5 Hz, 1H), 7.22-7.07 (m, 6H), 6.51 (t, J=5.7 Hz, 1H), 4.54 (d, J=5.7 Hz, 2H), 3.98-3.92 (m, 2H), 3.49-3.43 (m, 2H), 3.31 (t, J=6.9 Hz, 2H), 2.61-2.50 (m, 5H), 1.91-1.82 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.4, 155.3, 153.6, 149.0, 148.6, 141.0, 135.8, 134.2, 128.4, 128.2, 126.1, 123.6, 116.7, 43.6, 42.1, 41.9, 41.3, 33.0, 28.7, 17.3; MS (ES+) m/z 436.3 (M+1).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH2:11]([C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH2:20])=[C:15]([O:27][CH3:28])[CH:14]=1)[CH3:12]>C1COCC1>[CH2:11]([C:13]1[CH:26]=[CH:25][C:16]([O:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[NH:20][CH:1]=[O:3])=[C:15]([O:27][CH3:28])[CH:14]=1)[CH3:12]
Reactant: CCc1ccc(Oc2ccccc2N)c(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: CCc1ccc(Oc2ccccc2NC=O)c(OC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 126.4 %

Procedure:
To acetic anhydride (0.53 mmol; 51 μL) under argon, at 0° C., was added formic acid (0.66 mmol; 25 μL). The reaction was stirred 2 hours at 60° C. After cooling to 0° C., the mixture was diluted with 1 mL of dry THF, followed by a solution of 2-(4-ethyl-2-methoxyphenoxy)aniline (0.21 mmol; 50 mg) in dry THE (1 mL). The reaction was stirred 2 hours at room temperature. The mixture was concentrated in vacuo to give the title compound (72 mg; quantitative) as a brown oil, used without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[N:10]=[C:4]2[N:3]=1.Cl.[F:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C>CN(C=O)C>[F:16][CH:17]1[CH2:22][CH2:21][N:20]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[N:10]=[C:4]3[N:3]=2)[CH2:19][CH2:18]1
Reactant: FC1CCNCC1
Reactant: Brc1ccn2c(n1)nc1ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: FC1CCN(c2ccn3c(n2)nc2ccccc23)CC1
Temperature: 25 °C

Procedure:
To a microwave vial equipped with a magnetic stir bar, containing DMF (1 mL) was placed 2-bromobenzo[4,5]imidazo[1,2-a]pyrimidine (0.02 g, 0.089 mmol, 1.0 equiv), 4-fluoropiperidine hydrochloride (0.019 g, 0.133 mmol, 1.5 equiv) and triethylamine (0.037 ml, 0.266 mmol, 3.0 equiv). The suspension was irradiated in a Biotage Initiator microwave reactor (250 W) at 100° C. for 15 min. After cooling to room temperature, the crude product was purified by HPLC to afford 0.015 g (63%) of T777 as an off-white solid. MS (ESI, Pos.) m/z: 271.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[O:24]1[CH2:29][CH2:28][CH:27]([C:30]2([NH2:33])[CH2:32][CH2:31]2)[CH2:26][CH2:25]1>>[OH:1][C:2]1[N:6]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:33][C:30]3([CH:27]4[CH2:28][CH2:29][O:24][CH2:25][CH2:26]4)[CH2:32][CH2:31]3)=[O:12])=[CH:9][N:8]=2)[N:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cc(-c2cnn(-c3ccc(C(=O)O)cn3)c2O)ccn1
Reactant: NC1(C2CCOCC2)CC1
Product: COc1cc(-c2cnn(-c3ccc(C(=O)NC4(C5CCOCC5)CC4)cn3)c2O)ccn1

Procedure:
The title compound was prepared in a manner similar to Example 227 using 6-(5-hydroxy-4-(2-methoxypyridin-4-yl)-1H-pyrazol-1-yl)nicotinic acid and 1-(tetrahydro-2H-pyran-4-yl)cyclopropanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.82-1.03 (m, 5H) 1.25 (s, 1H) 1.45-1.67 (m, 3H) 1.74 (d, J=12.4 Hz, 2H) 3.37 (t, J=11.6 Hz, 2H) 4.03 (dd, J=11.4, 3.5 Hz, 2H) 4.09 (s, 3H) 7.22 (s, 1H) 7.31 (d, J=6.1 Hz, 1H) 7.41 (s, 1H) 7.83 (d, J 8.6 Hz, 1H) 7.90 (s, 1H) 8.13 (d, J=6.1 Hz, 1H) 8.37 (dd, J=8.7, 2.1 Hz, 1H) 8.83 (d, J=1.8 Hz, 1H). MS m/z [M+H]+ 436.4.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=O.[Cl:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11](I)=[CH:10][N:9]=1.C1N2CCN(CC2)C1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:7][C:8]1[N:9]=[CH:10][C:11]2[CH:4]=[C:2]([C:1]([OH:6])=[O:5])[NH:14][C:12]=2[CH:13]=1
Reactant: Nc1cc(Cl)ncc1I
Reactant: CC(=O)C(=O)O
Agent: [Pd+2]
Agent: C1CN2CCN1CC2
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: O=C(O)c1cc2cnc(Cl)cc2[nH]1
Temperature: 145 °C

Procedure:
Pyruvic acid (0.86 mL, 12.4 mmol) was added to a solution of 2-chloro-5-iodo-pyridin-4-ylamine (Preparation 115, 1.05 mg, 4.13 mmol), palladium acetate (56 mg, 0.25 mmol) and DABCO (1.39 g, 12.4 mmol) in anhydrous DMF (30 ml). The reaction mixture was degassed with argon for 20 min, then heated to 145° C. for 2 h. The solvent was removed in vacuo and the residue taken up in water (200 mL). The suspension was made alkaline (pH 9–10) with dilute NaOH solution (1M) and filtered through Celite. After washing of the filtrate with ethyl acetate (50 mL) and ether (50 mL) the pH was adjusted to 3 with dilute HCl solution (1M). Extraction with ethyl acetate (5×50 mL), drying of the combined extracts (MgSO4) and concentration gave the title compound. δH (d6 DMSO): 7.24 (1H, s), 7.42 (1H, s), 8.80 (1H, s); m/z (ES−)=195.02 [M−H]−; RT=2.36 min.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C@H:7]([N:10]([CH2:18][C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=2)[OH:20])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][OH:9])=[CH:4][CH:3]=1.[C:30]1([C:36]2[C:37]([C:41](O)=[O:42])=[CH:38][NH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O.C(OCC)(=O)C>[Cl:27][C:23]1[CH:22]=[C:21]([C@@H:19]([OH:20])[CH2:18][N:10]([C@@H:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:41]([C:37]3[C:36]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:40][NH:39][CH:38]=3)=[O:42])=[CH:29][CH:28]=2)[CH2:8][OH:9])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:14])[CH3:15])[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(O)c1c[nH]cc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)c1cccc(Cl)c1)[C@H](CO)Cc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C[C@H](O)c1cccc(Cl)c1)[C@H](CO)Cc1ccc(NC(=O)c2c[nH]cc2-c2ccccc2)cc1
Reaction time: 8 h
Yield: 9.5 %

Procedure:
To a solution of tert-butyl N-[(1S)-1-(4-aminobenzyl)-2-hydoxyethyl]-N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]carbamate (120 mg) in N,N-dimethylformamide (2.0 ml) was added successively 4-phenyl-1H-pyrrole-3-carboxylic acid (64.0 mg) and 1-hydroxybenzotriazole hydrate (46.2 mg). To the mixture was added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (65.6 mg) at room temperature and the mixture was stirred overnight. The mixture was diluted with ethyl acetate (20 ml) and washed with water (20 ml×2), a saturated aqueous sodium hydrogencarbonate solution (20 ml×1) and brine (20 ml×1) successively. The organic solution was dried over magnesium sulfate, filtered, and evaporated to give a yellow solid. The crude product was purified by a recycling preparative high pressure liquid chromatography equipped with a gel permeation chromatography column (eluent: chloroform) to give tert-butyl N-[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]-N-[(1S)-2-hydroxy-1-[4-[[(4-phenyl-1H-pyrrol-3-yl)carbonyl]amino]benzyl]ethyl]carbamate (16 mg) as a yellow foam.