Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37]Cl)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:73][C:74]1[S:75][C:76]2[C:77]([N:82]=1)=[N:78][CH:79]=[CH:80][CH:81]=2.SC1SC2C=CN=CC=2N=1>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:53]/[O:54][C@H:55]([C:57]([O:59][CH:60]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)[C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)=[O:58])[CH3:56])/[C:27]([NH:29][CH:30]2[C:51](=[O:52])[N:32]3[C:33]([C:39]([O:41][CH2:42][C:43]4[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[CH:45][CH:44]=4)=[O:40])=[C:34]([CH2:37][S:73][C:74]4[S:75][C:76]5[C:77]([N:82]=4)=[N:78][CH:79]=[CH:80][CH:81]=5)[CH2:35][S:36][C@H:31]23)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Sc1nc2ncccc2s1
Reactant: COc1ccc(COC(=O)C2=C(CCl)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Agent: Sc1nc2cnccc2s1
Product: COc1ccc(COC(=O)C2=C(CSc3nc4ncccc4s3)CS[C@@H]3C(NC(=O)/C(=N\O[C@@H](C)C(=O)OC(c4ccccc4)c4ccccc4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Yield: 62.4 %

Procedure:
Using 305 mg of p-methoxybenzyl 7-[(Z)-2-(2-tritylaminothiazol-4-yl)-2-{(S)-1-diphenylmethoxycarbonylethoxyimino}acetamido]-3-chloromethyl-3-cephem-4-carboxylate and 60 mg of 2-mercaptothiazolo[4,5-b]pyridine in place of p-methoxybenzyl 7-{(Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetamido}-3-chloromethyl-3-cephem-4-carboxylate and 2-mercaptothiazolo[4,5-c]pyridine, respectively, the reaction and purification were carried out in the same manner as in Example 1(a) to obtain 215 mg of the title compound in a yield of 62%.
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:15]([O:19][C:20]([N:22]1[CH:26]=[C:25]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=O)[N:24]=[C:23]1[NH2:33])=[O:21])([CH3:18])([CH3:17])[CH3:16].ON1C2C=CC=CC=2N=N1.Cl.C[N:46](C)[CH2:47][CH2:48][CH2:49][N:50]=[C:51]=[N:52]CC>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH:26]=[C:25]([CH2:27][CH2:28][CH2:29][C:30](=[O:32])[NH:52][C:51]2[N:46]=[CH:47][CH:48]=[CH:49][N:50]=2)[N:24]=[C:23]1[NH2:33])=[O:21])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)(C)OC(=O)n1cc(CCCC(=O)O)nc1N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)n1cc(CCCC(=O)Nc2ncccn2)nc1N
Temperature: 25 °C

Procedure:
General EDC/HOBt Procedure: 2-amino-4-(3-carboxy-propyl)-imidazole-1-carboxylic acid tert-butyl ester 22 (100 mg, 0.371 mmol), 1-hydroxybenzotriazole (100 mg, 0.742 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (142 mg, 0.742 mmol) were dissolved in anhydrous DMF (3 mL). The appropriate amine coupling partner (1.48 mmol) was then added and the solution was stirred at ambient temperature until completion was evident by TLC analysis. The reaction was concentrated under reduced pressure and the residue partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was successively washed with water (3×10 mL), a 10% aqueous solution of citric acid (2×10 mL), sat. NaHCO3 (2×10 mL), and brine (10 mL) before being dried (Na2SO4) and evaporated to dryness. The crude product was purified via flash column chromatography (2-10% MeOH/CH2Cl2) to afford the target compound.
Reaction SMILES: [Li+].C[Si]([N-:6][Si](C)(C)C)(C)C.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[N:18].Cl>>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[NH:6])[NH2:18]
Reactant: N#Cc1ccccn1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Product: N=C(N)c1ccccn1
Reaction time: 2 h
Yield: 82549.2 %

Procedure:
To the solution of LiHMDS (5.18 g, 0.026 mmol, 1.3 equiv.) was added picolinonitrile (2.08 g, 0.02 mmol, 1 equiv.) at ice-bath and kept stirred for 2 h. Then, the reaction mixture was acidified with aqueous HCl (4N) to pH2, cooled at ice-bath and kept stirred. Then, the mixture was extracted with EA (200 mL×5). The combined organic phase was washed with brine, dried (Na2SO4), and evaporated to get picolinimidamide (2.0 g, 83%). LC-MS (m/z)=122 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][C@@H:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21]([O:23]C)=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1.[Li+].[OH-].O>O1CCCC1>[F:1][C:2]1[C:3]([NH:18][C@@H:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:20][C:21]([OH:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][CH:9]=2)=[N:6][CH:7]=1
Reactant: COC(=O)C[C@@H](Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F)C(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](CC(=O)O)Nc1nc(-c2c[nH]c3ncc(F)cc23)ncc1F
Temperature: 50 °C

Procedure:
(R)-Methyl 3-((5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl)amino)-4,4-dimethylpentanoate, 9a, (18.4 g, 47.1 mmol) was dissolved in tetrahydrofuran (275 mL) and aqueous 1M LiOH (141 mL) was added. The mixture was heated to 50° C. for 3.5 h. The reaction mixture was cooled to room temperature and 180 mL of water was added. The tetrahydrofuran was removed under reduced pressure and the residue was then flushed twice with hexanes. Diethylether (60 mL) was added and the layers separated. The pH of the aqueous layer was adjusted to 6 with 1N HCl. Ethyl acetate (540 mL) was added, the layers were separated and the aqueous layer was extracted with ethyl acetate (720 mL), then again with ethyl acetate (300 mL). The organic layers were combined, washed with brine (100 mL) and dried (Na2SO4). The solvents were removed while flushing with heptanes to provide the desired product, 2, (17.5 g): 1H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 12.03 (s, 1H), 8.68-8.52 (m, 1H), 8.27 (s, 1H), 8.19 (d, J=2.5 Hz, 1H), 8.13 (d, J=4.0 Hz, 1H), 7.39 (d, J=9.2 Hz, 1H), 4.83 (t, J=9.3 Hz, 1H), 2.71-2.51 (m, 2H), 0.97 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 min, C18/ACN, RT=1.96 minutes (M+H) 377.02.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:28][CH2:29][C@H:30]([OH:45])[CH2:31][O:32][C:33]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]2[C:34]=1[CH2:35][CH2:36][C:37](=[O:44])[NH:38]2>>[OH:45][C@H:30]([CH2:31][O:32][C:33]1[CH:42]=[CH:41][C:40]([OH:43])=[C:39]2[C:34]=1[CH2:35][CH2:36][C:37](=[O:44])[NH:38]2)[CH2:29][NH:28][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1ccc(O)c2c1CCC(=O)N2
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)c5c4CCC(=O)N5)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidine-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and 5-(3-amino-(2S)-2-hydroxy-propoxy)-8-hydroxy-3,4-dihydro-1H-quinolin-2-one (which was obtained in Example 12) according to the procedure of Example 278 as a white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2H), 1.75-1.90 (m, 2H), 2.05 (s, 3H), 2.39 (t, J=7.5 Hz, 2H), 2.50-2.80 (m, 5H), 2.83 (t, J=7.5 Hz, 2H), 3.40-3.55 (m, 2H), 3.70-3.85 (m, 3H), 6.44 (d, J=8.7 Hz, 1H), 6.60 (d, J=8.7 Hz, 1H), 6.76 (d, J=9.0 Hz, 2H), 6.85 (d, J=9.0 Hz, 2H), 7.58 (d, J=9.0 Hz, 2H), 7.67 (d, J=9.0 Hz, 2H), 8.72 (s, 1H), 10.27 (s, 1H); MS (ES) m/z: 623.9 (MH+); HRMS Calcd. for C31H38N5O7S(MH+): 624.2492. Found: 624.2469.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[O:13].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]=O)[CH:15]=1.N1CCCC1>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][C:7](=[CH:20][C:16]1[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=1)[C:6]2=[O:13]
Reactant: COc1ccc2c(c1)C(=O)CCO2
Reactant: O=Cc1cccnc1
Solvent: C1CCNC1
Solvent: CO
Product: COc1ccc2c(c1)C(=O)C(=Cc1cccnc1)CO2
Temperature: 25 °C
Reaction time: 60 h
Yield: 57 %

Procedure:
To a 25° C. mixture of 20.0 g (0.112 mol) of 6-methoxy-4-chromanone and 18.09 g (0.169 mol) of 3-pyridinecarbaldehyde in 100 ml of methanol was added 14.1 ml (0.169 mol) of pyrrolidine. The resultant solution was allowed to stir 60 hours at 25° C., cooled to 0° C. and filtered to yield 17.07 g (57%) of the title compound, mp 127°-131° C.; MS (m/e) 267 (M+), 238, 161, 150 (100%), 135 and 107. IR (CHCl3) 1671 (C=O), 1614, 1589 and 1566 cm-1. 1H-NMR (CDCl3) delta (ppm): 3.79 (s, OCH3), 5.23 (d, J=1.5 Hz, CH2), 6.86 (d, J=8 Hz, C-8 H), 7.06 (dd, J=8, 2 Hz, C-7 H), 7.37 (d, J=1.5 Hz, vinyl H), 7.36, 7.58, 7.75, 8.52 and 8.57 (multiplets, 5 ArH). Anal. C 71.72, H 4.85, N 5 16, calcd. C 71.90 , H 4.90, N 5.24.
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]4[CH:26]=[CH:27][C:28]([C:30]5[CH:35]=[CH:34][C:33]([C:36]([N:38]6[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]6)=[O:37])=[CH:32][CH:31]=5)=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:17][C:16]=2[F:44])=[O:13])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[CH3:45][C:46]([CH3:48])=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:25]4[CH:26]=[CH:27][C:28]([C:30]5[CH:35]=[CH:34][C:33]([C:36]([N:38]6[CH2:39][CH2:40][N:41]([CH:46]([CH3:48])[CH3:45])[CH2:42][CH2:43]6)=[O:37])=[CH:32][CH:31]=5)=[CH:29][C:24]4=[N:23][CH:22]=3)=[CH:17][C:16]=2[F:44])=[O:13])[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cnc4cc(-c5ccc(C(=O)N6CCNCC6)cc5)ccn34)cc2F)no1
Reactant: CC(C)=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)N1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(NC(=O)Nc6cc(C(C)(C)C)on6)c(F)c5)cnc4c3)cc2)CC1
Reaction time: 0.08 h
Yield: 6.5 %

Procedure:
Dissolve 1-(5-tert-butyl-isoxazol-3-yl)-3-(2-fluoro-4-{7-[4-(piperazine-1-carbonyl)-phenyl]-imidazo[1,2-a]pyridin-3-yl}-phenyl)-urea hydrochloride (0.290 g, 0.469 mmol) in methanol (5 mL) and acetone (0.041 mL, 0.563 mmol). Add acetic acid (0.032 mL, 0.563 mmol); stir the mixture for five minutes. Add sodium cyanoboro-hydride (0.053 g, 0.845 mmol). Stir the mixture at room temperature for 14 hours. Concentrate to dryness and quench with 1 N HCl (5 mL). Partition between ethyl acetate and 1 N NaOH, wash with aqueous saturated sodium chloride, dry the organics over magnesium sulfate, filter, and concentrate. Purify by column chromatography (hexanes→5% methanol in dichloromethane→10% methanol in dichloromethane→10% 2 M NH3 in methanol in dichloromethane) to afford product (0.019 g, 7%). MS(ES), m/z 624 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH3:13])=O)=[CH:4][CH:3]=1>O1CCCC1.CO.Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:11][CH2:12][CH3:13])=[CH:6][CH:7]=1
Reactant: CCNC(=O)Cc1ccc(Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CCNCCc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A mixture of 2-(4-chloro-phenyl)-N-ethyl-acetamide (preparation 80), (437 mg, 2.22 mmol) and borane tetrahydrofuran complex (1M, 8.88 mL, 8.88 mmol) in tetrahydrofuran was heated under reflux for 18 hours. The cooled reaction mixture was then diluted with methanol (5 mL) and 12M hydrochloric acid (2 mL) and the re-heated to reflux for a further hour. The mixture was cooled to room temperature and concentrated in vacuo. Trituration of the residue with ethyl acetate afforded the title compound as a colourless solid in 99% yield, 403 mg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C([O-])([O-])=O.[Cs+].[Cs+].[CH:23]1([C:27]#[C:28][Si](C)(C)C)[CH2:26][CH2:25][CH2:24]1.N#N>[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].CC(N(C)C)=O>[CH:23]1([C:27]#[C:28][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[CH:5]3)[CH2:26][CH2:25][CH2:24]1
Reactant: C[Si](C)(C)C#CC1CCC1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Agent: [Cu]I
Agent: [Fe+2]
Agent: [Pd+2]
Solvent: CC(=O)N(C)C
Product: C(#CC1CCC1)c1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Yield: 70.7 %

Procedure:
A 100 mL round bottom flask was charged with 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (6.8 g, 24.2 mmol; Intermediate 1), DMA (30 mL), CuI (0.46 g, 2.4 mmol), Pd(OAc)2 (0.55 g, 2.4 mmol), dppf (1.35 g, 2.4 mmol), Cs2CO3 (11.2 g, 34.4 mmol), and (cyclobutylethynyl)trimethylsilane (5.2 g, 34.1 mmol; Intermediate 42) sequentially while N2 was bubbled through the mixture. The resulting mixture was heated at 80° C. under N2 atmosphere for 2 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL) and H2O (100 mL) and filtered. The organic layer of the filtrate was separated, and the aqueous layer was extracted with additional EtOAc (2×50 mL). The combined organic layers were washed with brine (3×100 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified on a silica gel column using 0˜10% EtOAc in petroleum ether to afford the title compound as yellow oil (4.8 g, 71%). 1H NMR (DMSO-d6): δ 8.08 (s, 1H), 7.82 (s, 1H), 7.68 (d, 1H), 7.39 (dd, 1H), 5.82 (dd, 1H), 3.89-3.85 (m, 1H), 3.76-3.69 (m, 1H), 3.30-3.24 (m, 1H), 2.39-2.26 (m, 3H), 2.19-2.09 (m, 2H), 2.03-1.84 (m, 4H), 1.75-1.70 (m, 1H), 1.58-1.55 (m, 2H); LCMS: 281 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:17]=[C:18]([CH3:20])[CH3:19]>S(=O)(=O)(O)O.O1CCOCC1.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:4]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(C)(C)C
Temperature: -78 °C
Reaction time: 144 h
Yield: 62 %

Procedure:
Concentrated sulfuric acid (10 drop) was added to a solution of 3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (500 mg, 2.15 mmol) in 20 ml of dioxane/chloroform (2:3) in a sealed tube. After cooling the solution at −78° C., put 20 ml of isobutene gas. The sealed tube was closed and then the reaction mixture was stirred for 6 days at 60° C. The solvent was removed and then partitioned between 15 ml of sat. Na2CO3 solution and 15 ml of EtOAc. The organic layer was separated, the aqueous phase was washed twice with ethyl acetate and the combined ethyl acetate layer was dried (MgSO4), concentrated and the residue was purified by flash chromatography (5% EtOAc/Hexane) to obtain 385 mg (62%) of 3-tert-Butylamino-5-phenyl-thiophene-2-carboxylic acid methyl ester. NMR 1H (CDCl3, 400 MHz): 7.65 ppm (d, 2H, Haro); 7.44-7.38 ppm (m, 3H, Haro); 7.07 ppm (s, 1H, Haro); 3.86 ppm (s, 3H); 1.48 ppm (s, 9H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:19]=[C:18]([C:20](=[O:22])[CH3:21])[C:17]([NH2:23])=[C:16]([F:24])[C:15]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1[F:33].C(OC(=O)C)=O>C1COCC1>[CH3:11][O:12][C:13](=[O:34])[C:14]1[CH:19]=[C:18]([C:20](=[O:22])[CH3:21])[C:17]([NH:23][CH:1]=[O:3])=[C:16]([F:24])[C:15]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][C:27]=1[F:33]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1cc(C(C)=O)c(N)c(F)c1Nc1ccc(Br)cc1F
Agent: CC(=O)OC=O
Solvent: C1CCOC1
Solvent: O=CO
Product: COC(=O)c1cc(C(C)=O)c(NC=O)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To acetic anhydride (1.30 equiv.) is added formic acid (1.60 equiv.) at room temperature. The resulting mixture is stirred at 65 OC under N2 atmosphere for 2 hours, cooled to room temperature, and diluted with THF. To a solution of 5-acetyl-4-amino-2-(4-bromo-2-fluorophenylamino)-3-fluorobenzoic acid methyl ester (1.00 equiv.) in THF at 0° C. is added the above solution of acetic formic anhydride in THF. After stirring 30 minutes at 0° C., the reaction is quenched with MeOH. The reaction mixture is concentrated under reduced pressure to give the crude material that is purified by trituration or flash column chromatography to yield the desired product as necessary.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[C@H:2]1[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10])=[O:28]
Reactant: O=C(O)c1ccccc1-c1cccs1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1ccccc1-c1cccs1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 2-Thiophen-2-yl-benzoic acid. LC-MS (basic): tR=1.33 min; [M+H]+=463.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[CH:28][C:10]=1[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:41](O)[CH3:42]>>[CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[CH:28][C:10]=1[C:11]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:41][CH3:42])=[O:26])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CCCCCCCCCCCNC(=O)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CCCCCCCCCCCNC(=O)c1cc(OCc2ccccc2)ccc1OCc1ccccc1
Reaction time: 4.5 h
Yield: 64 %

Procedure:
To a solution of 4 g (7.5 mmol) of 12-{N-[2,5-di(benzyloxy)benzoyl]amino}dodecanoic acid (compound of Example 6) in 23 ml of anhydrous ethanol, 7.5 mmol of 20% ethanolic hydrogen chloride solution were added and the reaction mixture was stirred for 4.5 hours. After cooling the precipitate was filtered, washed with ether and dried to give 2.69 g (64%) of the aimed compound, m.p.: 70°-71° C.
Reaction SMILES: C([C:4]1([CH2:8][O:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([N:16]3[C:21](=[O:22])[C:20]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]5[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=5)=[CH:26][C:25]=4[F:38])=[C:19]([CH2:39][CH2:40][CH3:41])[N:18]4[N:42]=[CH:43][N:44]=[C:17]34)[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5]1)(=O)C.O.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:51].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[F:38][C:25]1[CH:26]=[C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:28]=[CH:29][C:24]=1[CH2:23][C:20]1[C:21](=[O:22])[N:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([O:9][CH2:8][C:4]3([OH:51])[CH2:7][CH2:6][CH2:5]3)[CH2:11][CH2:12]2)[C:17]2[N:18]([N:42]=[CH:43][N:44]=2)[C:19]=1[CH2:39][CH2:40][CH3:41]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC3(C(C)=O)CCC3)CC2)c2ncnn12
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2CC[C@H](OCC3(O)CCC3)CC2)c2ncnn12
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a mixture of 4′-[(4-{trans-4-[(1-acetylcyclobutyl)methoxy]cyclohexyl}-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile (0.3 g), 30% hydrogen peroxide water (2.1 g) and chloroform (10 mL) was gradually added trifluoroacetic acid anhydride (2.1 mL) at room temperature, and the reaction mixture was warmed to 60° C. and stirred for 24 hr. Saturated aqueous sodium hydrogen carbonate and sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (5 mL) and methanol (5 mL), 1N aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 30 min. 1N Aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.19 g, 65%).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C[N:32]1[CH2:36][CH2:35][CH2:34][C@@H:33]1[CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:32]5[CH2:36][CH2:35][CH2:34][C@@H:33]5[CH3:37])[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Reactant: C[C@H]1CCCN1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCC[C@@H]5C)c4)cc23)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 17.3 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (600 mg, 1.348 mmol) in dimethyl sulfoxide (10 mL) was added of 20 drops of acetic acid and (2S)-1,2-dimethylpyrrolidine (1.37 mL, 13.483 mmol). The resulting mixture was stirred at room temperature for 6 h followed by an addition of sodium triacetoxyborohydride (2.858 g, 13.483 mmol). The reaction was stirred at room temperature overnight then purified by SFC. This compound was separated by RTP CASS Group. The fraction of enantiomer #1 is 99.7% chirally pure to give 119.9 mg of the title compound (17.3%).
Reaction SMILES: [CH:1]1[C:6](Br)=[CH:5][C:4]2[C:8]([CH2:11][CH2:12][OH:13])=[CH:9][NH:10][C:3]=2[CH:2]=1.[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.O>[N:14]1[CH:19]=[CH:18][C:17]([C:6]2[CH:5]=[C:4]3[C:3](=[CH:2][CH:1]=2)[NH:10][CH:9]=[C:8]3[CH2:11][CH2:12][OH:13])=[CH:16][CH:15]=1
Reactant: OB(O)c1ccncc1
Reactant: OCCc1c[nH]c2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCCc1c[nH]c2ccc(-c3ccncc3)cc12

Procedure:
5-Bromotryptophol (1.05 g, 4.39 mmol; see Table 1 and 2) and pyridine-4-boronic acid (10 mg, 6.59 mmol) were suspended in tetrahydrofuran (65 ml), and Na2CO3 solution (4.65 g, 43.9 mmol) in 44 ml of H2O) were added. Bistriphenylphosphinepalladium dichloride (456.2 mg, 0.65 mmol) was then added. The reaction mixture, which was clear when hot, was boiled at 65° C. for 14 h, while stirring. The course of the reaction was monitored by TLC. For working up, the reaction solution was filtered. The filtrate comprised two phases. The organic phase was separated off. The solvent was distilled off on a rotary evaporator. The viscous residue was purified by flash chromatography [silica gel 60 (45 g); eluent: EtOAc (800 ml)].