Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:22]=[CH:21][C:13]([C:14]([O:16]C(C)(C)C)=[O:15])=[CH:12][CH:11]=2)[CH2:5][CH2:4]1)=O.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]2[CH2:32][C@H:31]2[NH2:33])=[CH:26][CH:25]=1.[B-]C#N.[Na+].O>CO>[Br:23][C:24]1[CH:25]=[CH:26][C:27]([C@@H:30]2[CH2:32][C@H:31]2[NH:33][CH2:1][CH:3]2[CH2:4][CH2:5][N:6]([CH2:9][C:10]3[CH:11]=[CH:12][C:13]([C:14]([OH:16])=[O:15])=[CH:21][CH:22]=3)[CH2:7][CH2:8]2)=[CH:28][CH:29]=1
Reactant: N[C@@H]1C[C@H]1c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(CN2CCC(C=O)CC2)cc1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccc(Br)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.8 %

Procedure:
To a solution of tert-butyl 4-((4-formylpiperidin-1-yl)methyl)benzoate (250 mg, 0.824 mmol) in methanol (50 mL) was added trans-2-(4-bromophenyl)cyclopropylamine (210 mg, 0.989 mmol). The reaction mixture was refluxed for 2 minutes then cooled down to room temperature. Sodium cyanotrihydroborate (78 mg, 1.236 mmol) was added. The reaction mixture was stirred 1 hour at room temperature. Water (50 mL) was added. The reaction was concentrated and 50 mL of dichloromethane was added. The layers were separated. The organic was washed with 10% acetic acid (50 mL). The layers were separated and 50 mL of brine was added and the formed solid was filtered. The solid was refluxed in 1 M HCl for 30 min, then cooled to 0° C. and after 1 hour the solid was filtered. 4-((4-(((trans-2-(4-bromophenyl)cyclopropyl)amino)methyl)piperidin-1-yl)methyl)benzoic acid (120 mg, 0.221 mmol, 26.8% yield) was isolated as white solid. 1H NMR (400 MHz, METHANOL-d4) δ 8.14 (d, J=8.34 Hz, 2H), 7.71 (d, J=8.34 Hz, 2H), 7.48 (d, J=8.59 Hz, 2H), 7.15 (d, J=8.34 Hz, 2H), 4.44 (br. s., 2H), 3.55 (d, J=10.36 Hz, 2H), 3.06-3.25 (m, 4H), 3.01 (dt, J=3.98, 7.71 Hz, 1H), 2.59 (ddd, J=3.54, 6.63, 10.29 Hz, 1H), 2.02-2.29 (m, 3H), 1.53-1.80 (m, 3H), 1.41 (q, 1H); LC-MS Rt=0.61 min; MS (ESI): 445.2 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([N:14]([CH2:21][CH:22]=[CH2:23])[CH2:15][C:16](OCC)=[O:17])=[O:13])=[CH:7][CH:6]=1)[CH3:4].O(C)[Na]>CO>[CH2:21]([N:14]1[CH2:15][C:16](=[O:17])[N:11]([C:8]2[CH:9]=[CH:10][C:5]([C:3](=[N:2][OH:1])[CH3:4])=[CH:6][CH:7]=2)[C:12]1=[O:13])[CH:22]=[CH2:23]
Reactant: C=CCN(CC(=O)OCC)C(=O)Nc1ccc(C(C)=NO)cc1
Agent: CO[Na]
Solvent: CO
Product: C=CCN1CC(=O)N(c2ccc(C(C)=NO)cc2)C1=O

Procedure:
0.01 mol of this urea is dissolved in 150 mL of CH3OH. The pH is adjusted to approximately 10.0 using 25% NaOCH3 solution in CH3OH. The solution is heated to reflux for 2.5 hours, after which time the solvent is removed in vacuo. The residue is washed with cold water and dried in vacuo to yield crude 1-allyl-3-[4-(1-hydroxyiminoethyl)phenyl]hydantoin. The hydantoin is purified by recrystallization from CH3OH:H2O.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[O:9])[CH:7]=[CH2:8].S(=O)(=O)(O)O>ClCCCl>[S:1]1[CH:5]=[CH:4][C:3]2[CH2:8][CH2:7][C:6](=[O:9])[C:2]1=2
Reactant: C=CC(=O)c1cccs1
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: O=C1CCc2ccsc21
Temperature: 80 °C
Yield: 28 %

Procedure:
To a solution of 1-(thiophen-2-yl)-prop-2-en-1-one (8.5 g; 62 mmoles) of Example 1b in 1,2-dichloroethane (47 mL) a solution of sulphuric acid (47 mL) is added dropwise at room temperature. The mixture is then heated to 80° C. for 75 minutes. Then cooling to room temperature is carried out and the cooled liquid mass is poured in an ice bath. An extraction with dichloromethane (2×20 mL) is then carried out and the organic phase washed with a 5% NaHCO3 solution, anhydrified with sodium sulphate, filtered and concentrated under vacuum. The obtained residue is purified by chromatography on silica gel with a ligroin/ethyl acetate mixture (elution gradient from 10% to 80% ethyl acetate). After solvent removal 2.4 g of 4H-cyclopenta[b]thiophen-6(5H)-one are isolated (yellow solid; yield 28%). Rf=0.54 (ligroin/ethyl acetate 9/7 volume/volume); 1H NMR (CDCl3) δ (ppm): 7.89 (d, 1H, ArH), 7.05 (d, 1H, ArH), 3.01 (m, 4H, CH2); 13C NMR (CDCl3) δ (ppm): 197.3, 169.0, 141.2, 140.5, 124.0, 41.2, 24.0 FT-IR (film) νmax: 3063.8, 1668.5, 1419.1, 1248.1, 960.7, 749.8 cm−1.
Reaction SMILES: [CH:1]1(C2C(OC3C=CC(C4C=CC=CC=4C4N=NNN=4)=CC=3)=C(C(OC(OC(=O)CC)C(C)C)=O)C3C(=CC=CC=3)N=2)C[CH2:2]1.[CH:44]1([C:47]2[C:56]([O:57][C:58]3[CH:63]=[CH:62][C:61]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=4[C:70]4[N:71]=[N:72][N:73]([C:75]([C:88]5[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=5)([C:82]5[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=5)[C:76]5[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=5)[N:74]=4)=[CH:60][CH:59]=3)=[C:55]([C:94]([OH:96])=[O:95])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[N:48]=2)[CH2:46][CH2:45]1.C(I)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH:44]1([C:47]2[C:56]([O:57][C:58]3[CH:59]=[CH:60][C:61]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=4[C:70]4[N:71]=[N:72][N:73]([C:75]([C:88]5[CH:89]=[CH:90][CH:91]=[CH:92][CH:93]=5)([C:76]5[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=5)[C:82]5[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=5)[N:74]=4)=[CH:62][CH:63]=3)=[C:55]([C:94]([O:96][CH2:1][CH3:2])=[O:95])[C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[N:48]=2)[CH2:45][CH2:46]1
Reactant: CCC(=O)OC(OC(=O)c1c(Oc2ccc(-c3ccccc3-c3nn[nH]n3)cc2)c(C2CC2)nc2ccccc12)C(C)C
Reactant: O=C(O)c1c(Oc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C2CC2)nc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCI
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Oc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c(C2CC2)nc2ccccc12
Temperature: 90 °C
Yield: 64 %

Procedure:
A mixture of the title A compound of Example 28, 2-cyclopropyl-3-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5-yl][1,1'-biphenyl]-4-yl]oxy]-4-quinolinecarboxylic acid (372 mg, 0.517 mmol), ethyl iodide (0.13 mL, 254 mg, 1.62 mmol), and potassium carbonate (335 mg, 2.42 mmol) in dimethylformamide (2.5 mL) were heated at 90° C. for 90 minutes. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and rinsed with aq. 5% sodium bisulfite and brine, dried (magnesium sulfate), and concentrated in vacuo to give a crude product (580 mg). Flash chromatography on silica gel (40 g) eluted with 10:1, hexanes:ethyl acetate yielded the title compound (372 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1I.[C:30]1(B(O)O)[CH2:34][CH2:33][CH2:32][CH:31]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:10]([O:20][C@H:21]3[C@H:25]4[O:26][CH2:27][C@@H:28]([OH:29])[C@H:24]4[O:23][CH2:22]3)=[N:9][C:5]2=[N:6][C:7]=1[C:30]1[CH2:34][CH2:33][CH2:32][CH:31]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(I)c(Cl)cc21
Reactant: OB(O)C1=CCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(C3=CCCC3)c(Cl)cc21
Temperature: 85 °C

Procedure:
Palladium tetrakistriphenylphosphine (41.7 mg, 0.036 mmol) was added to a stirred suspension of (3R,3aR,6R,6aR)-6-((6-chloro-5-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridin-2-yl)oxy)hexahydro furo[3,2-b]furan-3-ol (Intermediate 3, 100.0 mg, 0.181 mmol), cyclopent-1-en-1-ylboronic acid (30.3 mg, 0.270 mmol), and potassium phosphate tribasic (115.0 mg, 0.542 mmol) in degassed 20% water in dioxane (1.85 mL). The reaction mixture placed under N2 before being heated to 85° C. for 10 h. The reaction mixture was cooled to room temperature. The lower aqueous layer drawn off and discarded. The remaining reaction mixture was evaporated under reduced pressure. Flash chromatography utilizing a 12 g silica RediSep Rf® Gold column and employing a 0-100% EtOAc/hexane gradient afforded the title compound. LC-MS: calculated for C23H32ClN3O5Si 493.18 observed m/e: 494.23 (M+H)+ (Rt 1.67/2.0 min)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:36])[C:19](=[O:35])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])[O:24][CH2:23][C:22]2[N:17]3[C@H:18]([CH3:36])[C:19](=[O:35])[NH:20][N:21]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(C4=CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: [Pd]
Solvent: CO
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 50 °C
Reaction time: 8 h
Yield: 79.6 %

Procedure:
To a suspension of Pd/C (10%, 0.324 g, 3.05 mmol) in MeOH (30 mL) was added 4-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.5 g, 3.05 mmol) and the reaction mixture was stirred at 50° C. under H2 (50 psi) overnight. The reaction mixture was cooled to ambient temperature, filtered and the filtrate was concentrated in vacuo to give 4-[(R)-7-(2-fluoro-phenyl)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 80%) as a yellow solid. 1H NMR (400 MHz, methanol-d4) δ 7.49-7.38 (m, 1H), 7.31-7.16 (m, 3H), 7.09 (s, 1H), 6.82 (s, 1H), 5.00-4.94 (m, 1H), 4.68-4.57 (m, 2H), 4.24-4.07 (m, 2H), 2.58 (m, 3H), 1.76 (m, 2H), 1.67-1.56 (m, 2H), 1.50-1.46 (m, 12H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]([NH:19][C:20](=[O:26])[O:21]C(C)(C)C)[C@@H:9]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])O)[C:5]([F:27])=[CH:4][N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>FC(F)(F)C(O)=O.O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]([C@@H:8]2[C@@H:9]([C:11]3[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=3[F:18])[O:21][C:20](=[O:26])[NH:19]2)[C:5]([F:27])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cc(Br)ncc1F)[C@H](O)c1cc(F)ccc1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: O=C1N[C@H](c2cc(Br)ncc2F)[C@@H](c2cc(F)ccc2F)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Optically-enriched tert-butyl (1R,2R)-1-(2-bromo-5-fluoropyridin-4-yl)-2-(2,5-difluorophenyl)-2-hydroxyethylcarbamate (253 mg, 0.283 mmol) was dissolved in trifluoroacetic acid (10% in dichloromethane, 10 mL) and stirred at room temperature overnight. In the morning, the reaction was concentrated and loaded onto a strong cation exchange cartridge. The cartridge was flushed with several volumes of methanol which were discarded. The crude aminoalcohol was eluted with 2M ammonia in methanol and concentrated to give 53 mg as a solid. The crude solid was dissolved in tetrahydrofuran (5 mL), cooled to 0° C., and treated with carbonyldiimidazole (45.9 mg, 0.283 mmol). After 5 min, the ice bath was removed, and stirring continued for 1 h. The reaction was quenched by addition of 2M ammonia in methanol. The reaction was concentrated and purified by column chromatography (25%→50% EtOAc/Hex) to give 20 mg (9.5%). Mass spec.: 373.1 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.Br[CH2:13][CH2:14][O:15][CH3:16].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH2:13][CH2:14][O:15][CH3:16])[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COCCn1c(=O)oc2ccc(Br)cc21
Temperature: 60 °C

Procedure:
A mixture of 5-bromobenzo[d]oxazol-2(3H)-one (2.06 g), 1-bromo-2-methoxyethane (1.085 mL) and potassium carbonate (3.99 g) in acetonitrile (15 mL) was heated at 60° C. for 16 h. Water was added and the mixture was extracted with ethyl acetate (3 times). The organic layers were dried over magnesium sulfate, evaporated and purified by flash silica chromatography eluting with 5:1 isohexane/acetone to give the subtitle compound (1.359 g).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]([CH3:43])([CH2:41][CH3:42])[CH2:8][C:9](=O)[CH2:10][NH:11][C:12]([C:14]1([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=3)=[CH:29][CH:28]=2)[CH2:18][CH2:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=O>C(OCC)(=O)C.O>[CH3:6][C:7]([CH3:43])([CH2:41][CH3:42])[CH2:8][C:9]1[N:5]=[C:12]([C:14]2([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][N:34]=4)=[CH:29][CH:28]=3)[CH2:18][CH2:17][CH2:16][N:15]2[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[NH:11][CH:10]=1
Reactant: [NH4+]
Reactant: CCC(C)(C)CC(=O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CCCN1C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(C)(C)Cc1c[nH]c(C2(Cc3ccc(-c4ccc(F)cn4)cc3)CCCN2C(=O)OC(C)(C)C)n1
Temperature: 160 °C
Reaction time: 8 h

Procedure:
Ammonium acetate (1.47 g, 19 mmol) was added to an ambient temperature solution of tert-butyl 2-{[(4,4-dimethyl-2-oxohexyl)amino]carbonyl}-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1-carboxylate (200 mg, 0.38 mmol) in xylenes (10 mL). After stirring at 160° C. in a sealed tube overnight, the reaction mixture was diluted with ethyl acetate and water. The organic phase was dried (magnesium sulfate), filtered, and concentrated in vacuo. Chromatography over silica eluting with 0-100% ethyl acetate/hexane followed by high pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid afforded tert-butyl 2-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1-carboxylate.
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[C:13](=[O:21])[N:12]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[C:11]=2[C:33](=[O:36])[CH2:34][CH3:35])=[CH:6][CH:5]=1.[OH-].[Na+].Cl>CO>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:21])[N:12]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=1)[C:11]([C:33](=[O:36])[CH2:34][CH3:35])=[C:10]2[C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=1
Reactant: CCC(=O)c1c(-c2ccc(C(=O)OC)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(=O)c1c(-c2ccc(C(=O)O)cc2)c2cc(Cl)ccc2c(=O)n1Cc1ccc(S(C)(=O)=O)cc1
Yield: 43.1 %

Procedure:
To a solution (2.0 ml) of 4-[6-chloro-2-(4-methanesulfonylbenzyl)-1-oxo-3-propionyl-1,2-dihydroisoquinolin-4-yl]benzoic acid methyl ester (100 mg) in methanol was added 1N sodium hydroxide (0.28 ml) at room temperature with stirring, and the mixture was stirred for 18 hrs. at the same temperature. The reaction mixture was neutralized with 1N hydrochloric acid and concentrated under reduced pressure. The residue was purified by preparative HPLC, and crystallized from methanol to give the title compound (42 mg) in beige crystals. 1H NMR (CDCl3) δ: 0.56 (3H, t, J=6.9 Hz), 1.79 (2H, q, J=6.9 Hz), 3.02 (3H, s), 5.36 (2H, s), 7.22 (1H, d, J=2.1 Hz), 7.40-7.49 (4H, m), 7.56 (1H, dd, J=2.1, 8.7 Hz), 7.91 (2H, d, J=8.7 Hz), 8.24 (2H, d, J=8.7 Hz), 8.50 (1H, d, J=8.7 Hz). HPLC analysis: purity 99.9% (retention time: 3.92 min). MS (ESI+): 524.0 (M+H), 526.0.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:12](OCC)(OCC)OCC>>[F:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:5])[NH:6][CH:12]=[N:1][C:2]=2[N:10]=1
Reactant: NC(=O)c1ccc(F)nc1N
Reactant: CCOC(OCC)OCC
Product: O=c1[nH]cnc2nc(F)ccc12
Temperature: 25 °C
Yield: 96 %

Procedure:
A suspension of 2-amino-6-fluoronicotinamide (0.74 g, 4.77 mmol) in triethyl orthoformate (25 mL) is heated at reflux for 8 h. After cooling to room temperature the precipitate is filtered off and washed well with petroleum ether to give 7-fluoropyrido[2,3-d]pyrimid-4(3H)-one (0.76 g, 96%),. 1H NMR (DMSO) δ 12.75 (1H, brs), 8.66 (1H, dd, J=10.4, 8.4 Hz), 8.38 (1H, s), 7.33 (1H, dd, J=8.4, 2.6 Hz).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([NH:14][C:15]([O:17]CC1C=CC=CC=1)=O)[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25]O>[Pd]>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]([NH:14][C:15](=[O:17])[CH3:25])[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)(C)OC(=O)NC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Product: CC(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C

Procedure:
To a solution of N-(t-butoxycarbonyl)-2(S)-benzyloxycarbonylamino-β-alanine (6.15 g) in methanol (120 ml) was added 10% Pd—C (50% wet, 1.2 g). The mixture was stirred vigorously, and hydrogen gas was bubbled for 1 hour. The catalyst was removed by filtration, and the filtrate was evaporated in vacuo. The residue was dissolved in tetrahydrofuran (70 ml) and cooled to 0° C. with ice bath. 1N NaOH (36 ml) was added, then acetic anhydride (3.77 ml) was added dropwise under stirring. The mixture was stirred for additional 1 hour at 0° C., then the pH of the mixture was adjusted to 2.5 with aqueous 20% KHSO4. The resultant mixture was extracted with ethyl acetate-tetrahydrofuran (200 ml-100 ml) twice times. The combined organic layer was dried over Na2SO4 and evaporated in vacuo. The residue was recrystallized from diethyl ether to give N-(t-butoxycarbonyl)-2(S)-acetylamino-β-alanine (3.17 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:17]3[N:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCCC3N
Reactant: Clc1ncccn1
Product: Cc1ccc2[nH]c3c(c2c1)CCCC3Nc1ncccn1

Procedure:
6-Methyl-N-pyrimidin-2-yl-2,3,4,9-tetrahydro-1H-carbazol-1-amine was prepared from 6-methyl-2,3,4,9-tetrahydro-1H-carbazol-1-amine and 2-chloropyrimidine in a similar manner as described above to give 5 mg (4%) of a yellow solid. 1H-NMR (CDCl3): δ 8.63 (s, 1H), 8.40 (d, 1H), 7.32 (d, 2H), 7.24 (d, 1H), 7.01 (d, 1H), 6.64 (t, 1H), 5.47 (d, 1H), 5.24 (q, 1 h), 2.74 (m, 2H), 2.44 (s, 3H), 2.36 (t, 1H), 2.00 (m, 3H); MS m/z 279 (M+1).
Reaction SMILES: CC(O)=[O:3].[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([CH:17]2[CH2:19][O:18]2)[CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].O>C1(C)C=CC=CC=1>[C:5]([O:9][C:10]([N:12]1[CH2:16][CH2:15][C@H:14]([C@H:17]([OH:3])[CH2:19][OH:18])[CH2:13]1)=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C2CO2)C1
Reactant: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)CO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R,R)-(−)-N,N′-Bis(3,5-di-t-butylsalicylidene)-1,2-cyclohexanediaminocobalt (II) (32.6 mg, 53.9 mmol) was dissolved in toluene (2.0 mL). AcOH was added (6.1 μL), and the resulting mixture was stirred at room temperature for 1 hour under air. The mixture was then concentrated and dried under high vacuum. (S)-3-Oxiranylpyrrolidine-1-carboxylic acid t-butyl ester (2.3 g, 10.8 mmol) was added, followed by water (97.1 μL), and the resulting mixture was stirred vigorously for 6 hours. Hexanes (15 mL) was added. The resulting solid was manually crushed and additional hexanes was added and stirred until the red solid became a yellowish precipitate. The precipitate was filtered and washed with 2 portions of hexanes. The precipitate was dried under vacuum to yield (S)-3-((S)-1,2-dihydroxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester as an off-white solid (1.3 g). The filtrate was concentrated and purified by SiO2 flash chromatography (0-100% EtOAc in hexanes) to yield (S)—(R)-3-oxiranylpyrrolidine-1-carboxylic acid t-butyl ester as an oil (970 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[O:16])[NH:11]2.[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=O)[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18].N1CCCCC1>C(O)C>[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[NH:11][C:10]2=[O:16])[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18]
Reactant: O=C1Cc2c(cccc2-c2ccccn2)N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccccn4)c32)c1CCCN1CCN(C)CC1
Temperature: 70 °C

Procedure:
A mixture of 4-pyridin-2-yl-1,3-dihydroindol-2-one (31.5 mg, 0.15 mmol), 5-formyl-2-methyl-4-[3-(4-methylpiperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (48.2 mg, 0.15 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated in a sealed tube at 70° C. for 6 hours. The reaction was concentrated and the residue was re-crystallized from ethyl acetate and hexane to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.FC(F)(F)S(O[CH2:34][C:35]([CH2:46]OS(C(F)(F)F)(=O)=O)([C:41]([O:43][CH2:44][CH3:45])=[O:42])[C:36]([O:38][CH2:39][CH3:40])=[O:37])(=O)=O>CC#N>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@H:2]4[N:1]3[CH2:46][C:35]([C:41]([O:43][CH2:44][CH3:45])=[O:42])([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:34]3)[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: CCOC(=O)C(COS(=O)(=O)C(F)(F)F)(COS(=O)(=O)C(F)(F)F)C(=O)OCC
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Solvent: CC#N
Product: CCOC(=O)C1(C(=O)OCC)CN([C@@H]2CCc3c(-c4noc(-c5ccc(OC(C)C)c(C#N)c5)n4)cccc32)C1
Temperature: 25 °C
Yield: 28 %

Procedure:
To a solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (247 mg, 0.62 mmol) in CH3CN (2 mL) at −10° C., under N2, was added diethyl 2,2-bis((((trifluoromethyl)sulfonyl)oxy)methyl)malonate INT-26 (3 mL of 0.25 mmol solution in CH3CN). The resulting mixture was warmed to room temperature over 30 min, then heated to 70° C. for 18 h. The mixture was concentrated, dissolved in DCM, and washed with water. The organic layer was dried over Na2SO4 and concentrated to provide 93 mg (28%) of crude (R)-diethyl 1-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)azetidine-3,3-dicarboxylate INT-27, which was used in the next step without further purification. LCMS-ESI (m/z) calculated for C30H32N4O6: 544.6; found 545.2 [M+H]+, tR=3.03 min.
Reaction SMILES: S([O-])(=O)(=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:17][C@@H:16](OS(C)(=O)=O)[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[C:33]=1[SH:39]>>[C:6]([O:10][C:11]([N:13]1[CH2:17][C@H:16]([S:39][C:33]2[C:34]([Cl:38])=[CH:35][CH:36]=[CH:37][C:32]=2[Cl:31])[CH2:15][C@H:14]1[C:23](=[O:30])[NH:24][C:25]1([C:28]#[N:29])[CH2:27][CH2:26]1)=[O:12])([CH3:8])([CH3:9])[CH3:7]
Reactant: Sc1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)N1C[C@@H](OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Agent: CS(=O)(=O)[O-]
Product: CC(C)(C)OC(=O)N1C[C@H](Sc2c(Cl)cccc2Cl)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The reaction of the mesylate from experiment A2 with 2,6-dichlorothiophenol yielded (2S,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-(2,6-dichloro-phenylsulfanyl)-pyrrolidine-1-carboxylic acid t-butyl ester as a white solid. MS: 454.4 [M−H]−.