Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH2:7][CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=O.[C:23]([O:30][CH3:31])(=[O:29])[CH2:24][CH2:25][C:26]([CH3:28])=O.Cl[Si](C)(C)C>CN(C=O)C>[CH3:31][O:30][C:23](=[O:29])[CH2:24][C:25]1[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)=[C:3]2[C:4]3[CH2:10][CH2:9][CH2:8][CH2:7][C:5]=3[S:6][C:2]2=[N:1][C:26]=1[CH3:28]
Reactant: COC(=O)CCC(C)=O
Reactant: Nc1sc2c(c1C(=O)c1cccc(C(F)(F)F)c1)CCCC2
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1cccc(C(F)(F)F)c1)CCCC3
Yield: 62.5 %

Procedure:
This compound was prepared according to the procedure B from (2-amino-4,5,6,7-tetrahydrobenzo[b]thiophen-3-yl)(3-trifluoromethylphenyl)methanone (0.325 g; 1 mmol), methyl levulinate (0.141 mL; 1.1 mmol), chlorotrimethylsilane (0.511 mL; 4 mmol) in DMF (4 mL) for 48 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (3-50%) in heptane furnished 0.262 g (62%) of the title compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.C[Si](C)(C)[C:11]#[C:12][CH3:13].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1(C)C=CC=CC=1.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:4]1[CH:3]=[C:2]([C:11]#[C:12][CH3:13])[CH:7]=[CH:6][N:5]=1
Reactant: CC#C[Si](C)(C)C
Reactant: Clc1cc(Br)ccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC#Cc1ccnc(Cl)c1
Temperature: 100 °C
Yield: 67.2 %

Procedure:
4-Bromo-2-chloropyridine (1.00 g, 5.20 mmol), 1-(trimethylsilyl)-1-propyne (0.846 mL, 5.72 mmol), copper(I) iodide (99 mg, 0.52 mmol), and tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.08 mmol) were taken up in toluene (14 mL) in a microwave vial. Tetra-N-butylammonium fluoride (1M in THF) (6 mL, 6.00 mmol) was added and the reaction vessel was sealed and heated at 100° C. for 20 min in a microwave reactor. After cooling, the mixture was filtered through diatomaceous earth, and then concentrated in vacuo. The product was purified by flash chromatography using a gradient of EtOAc in heptane (0-50%) to give the title compound (530 mg, 67% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 2.11 (s, 3 H), 7.38 (dd, 1 H), 7.51 (s, 1H), 8.37 (d, 1 H); MS (ES+) m/z 152 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[O:5][N:4]=1.[NH:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][N:20]3[CH2:26][CH2:25][CH2:24][N:23]([CH2:2][C:3]4[CH:7]=[C:6]([C:8]5[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=5)[O:5][N:4]=4)[CH2:22][CH2:21]3)[CH:7]=2)[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: COc1cc(-c2cc(CCl)no2)cc(OC)c1OC
Reactant: C1CNCCNC1
Product: COc1cc(-c2cc(CN3CCCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)on4)CC3)no2)cc(OC)c1OC

Procedure:
3-Chloromethyl-5-(3,4,5-trimethoxyphenyl)isoxazole (170 mg) and homopiperazine (30 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [O:1]([C:8]([NH:10][C@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])C1C=CC=CC=1.[C:22]([OH:25])(=[O:24])C>C(#N)C>[C:22]([NH:10][C@H:11]([C:19]([O:21][C:19](=[O:20])[C@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:10][C:8]([OH:1])=[O:9])=[O:20])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([OH:25])=[O:24]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)Oc1ccccc1
Reactant: CC(=O)O
Solvent: CC#N
Product: O=C(O)N[C@@H](Cc1ccccc1)C(=O)OC(=O)[C@H](Cc1ccccc1)NC(=O)O
Temperature: 80 °C
Reaction time: 29 h
Yield: 99 %

Procedure:
Under a nitrogen atmosphere, 571 mg (2 mmol) of N-phenoxycarbonyl-L-phenylalanine, 360 mg (6 mmol) of acetic acid, and 20 mL of acetonitrile were loaded into a two-necked round bottom flask having a volume of 100 mL and mounted with a Dimroth condenser, and then the mixture was stirred at 80° C. for 29 hours. The fact that N-carboxy-phenylalanine anhydride was obtained in a yield of 99% or more was confirmed by subjecting the reaction mixture to NMR determination. After the reaction mixture had been cooled to room temperature, 2 mL of a 1M aqueous solution of hydrochloric acid and 2,400 mg of activated carbon were added to the resultant, and then the mixture was stirred for 1 hour. The activated carbon was removed by filtration, and then the resultant filtrate was concentrated under reduced pressure. Thus, N-carboxy-phenylalanine anhydride was obtained. An isolation amount and an isolation yield were 302.5 mg and 78%, respectively.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17](O)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1.[NH2:29][C:30]1[CH:38]=[C:37]2[C:33]([C:34](=[O:47])[N:35]([CH3:46])[N:36]2[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[CH:32][CH:31]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH:26]([F:28])[F:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH2:21][O:22][CH3:23])[C:17]([NH:29][C:30]3[CH:38]=[C:37]4[C:33]([C:34](=[O:47])[N:35]([CH3:46])[N:36]4[C:39]([O:41][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:40])=[CH:32][CH:31]=3)=[O:18])[C:10](=[O:24])[CH:9]=2)[CH:7]=1
Reactant: Cn1c(=O)c2ccc(N)cc2n1C(=O)OC(C)(C)C
Reactant: COCCC(C(=O)O)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O
Product: COCCC(C(=O)Nc1ccc2c(=O)n(C)n(C(=O)OC(C)(C)C)c2c1)n1cc(OC)c(-c2cc(Cl)ccc2OC(F)F)cc1=O

Procedure:
113 mg (purity 82%, 0.26 mmol) of 2-{4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxy-2-oxopyridin-1(2H)-yl}-4-methoxybutanoic acid (racemate) and 79 mg (0.29 mmol, 1.1 eq.) of tert-butyl 6-amino-2-methyl-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate were reacted according to General Method 5A. Yield: 132 mg (73% of theory)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[CH:16]=[O:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([F:28])[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=2[CH:16]=[O:17])=[C:21]([F:28])[CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1nccc(Br)c1C=O
Reactant: OB(O)c1ccc(Cl)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nccc(-c2ccc(Cl)cc2F)c1C=O
Temperature: 85 °C
Yield: 51.2 %

Procedure:
To a stirred suspension of tert-butyl (4-bromo-3-formylpyridin-2-yl)carbamate (100 mg, 0.332 mmol), (4-chloro-2-fluorophenyl)boronic acid (57.9 mg, 0.332 mmol) and cesium carbonate (216 mg, 0.664 mmol) in THF (50 mL) and water (8 mL), was added Pd(PPh3)4 (19.19 mg, 0.017 mmol) and the reaction mixture was heated to 85° C. overnight (14 h). The reaction mixture was cooled to room temperature, diluted with water (30 mL) and extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (1×25 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified via silica gel chromatography (ethyl acetate/hexanes) to afford tert-butyl 4-(4-chloro-2-fluorophenyl)-3-formylpyridin-2-ylcarbamate (60 mg, 0.17 mmol, 35% yield). LC/MS (ESI) m/e 351.2 [(M+H)+, calcd for C17H17ClFN2O3351.1]. LC/MS retention time (method A): tR=2.07 min.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.Cl.[CH3:31][O:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH:40]2[CH2:45][N:44]3[CH:46]=[C:47]([C:49](O)=[O:50])[N:48]=[C:43]3[CH2:42][CH2:41]2)=[CH:35][C:34]=1[CH3:52].[F:53][C:54]([F:68])([F:67])[C:55]1[CH:56]=[C:57]([N:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH:58]=[CH:59][CH:60]=1>CN(C=O)C>[CH3:31][O:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH:40]2[CH2:45][N:44]3[CH:46]=[C:47]([C:49]([N:64]4[CH2:63][CH2:62][N:61]([C:57]5[CH:58]=[CH:59][CH:60]=[C:55]([C:54]([F:67])([F:68])[F:53])[CH:56]=5)[CH2:66][CH2:65]4)=[O:50])[N:48]=[C:43]3[CH2:42][CH2:41]2)=[CH:35][C:34]=1[CH3:52]
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: COc1c(C)cc(C2CCc3nc(C(=O)O)cn3C2)cc1C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1c(C)cc(C2CCc3nc(C(=O)N4CCN(c5cccc(C(F)(F)F)c5)CC4)cn3C2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
TBTU (240 mg; 0.75 mmol) and N-methylmorpholine (206 μl; 189 mg; 1.87 mmol) were added to a solution of 6-(4-methoxy-3,5-dimethylphenyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride (210 mg; 0.63 mmol) in DMF (1 ml). The reaction mixture was stirred vigorously for 30 min at room temperature and then 1-(3-trifluoromethylphenyl)piperazine (140 μl; 172 mg; 0.75 mmol) was added. The reaction mixture was stirred for 4 h at room temperature, then poured onto water and extracted with chloroform. The organic phase was dried over MgSO4, filtered and concentrated to small volume. The raw product was purified by column chromatography on silica gel (chloroform). Yield: 198 mg (62%).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.CC1(C)O[C@]2(OC[C@@H]3OC(C)(C)O[C@@H]3C2=O)CO1>>[OH:1][C@@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1
Reactant: O=C1CN[C@H](C(=O)O)C1
Agent: CC1(C)O[C@H]2CO[C@@]3(COC(C)(C)O3)C(=O)[C@H]2O1
Product: O=C(O)[C@@H]1C[C@H](O)CN1

Procedure:
Chemical synthesis of 4-ketoproline derivatives from inexpensive achiral starting materials will typically produce a racemic mixture of two enantiomers. It has been reported that hydrogenation of either D- or L-enantiomer of 4-ketoproline derivatives can produce the corresponding cis-4-hydroxyproline derivatives with high selectivity (Kuhn et al., Chem. Ber. 89:1423 (1956)), so an enzymatic resolution of a racemic mixture of D- and L-4-ketoproline derivatives would allow for the hydrogenation of the 4-keto-D-proline derivative to produce CHDP. Chemical or enzymatic racemization of the remaining 4-keto-L-proline derivative to a 50/50 mixture of D- and L-isomers could allow the undesired L-isomer to be recycled back into the resolution step. Alternatively, if the 4-keto-L-proline derivative could be reduced and hydrolyzed to THLP, the THLP is readily converted to CHDP by chemical isomerization.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]1([CH2:17][C:18]([NH2:20])=[NH:19])[CH2:16][CH2:15][CH2:14][CH2:13]1.[C:21]([O:25][C:26]([C:28]1[C:33]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:32]([OH:42])N=C(CC2(C3C=C(Cl)C=CC=3Cl)CCCC2)N=1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26]([C:28]1[C:33]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:32]([OH:42])[N:20]=[C:18]([CH2:17][C:12]2([C:3]3[CH:4]=[CH:5][C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[CH:2]=3)[CH2:16][CH2:15][CH2:14][CH2:13]2)[N:19]=1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)c1nc(CC2(c3cc(Cl)ccc3Cl)CCCC2)nc(O)c1OCc1ccccc1
Reactant: N=C(N)CC1(c2ccc3ccccc3c2)CCCC1
Agent: Cl
Product: CC(C)(C)OC(=O)c1nc(CC2(c3ccc4ccccc4c3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 45.2 %

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-naphthalen-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid tert-butyl ester (217) (4.0 g, 45.2%) was synthesized as a white solid from 2-(1-naphthalen-2-yl-cyclopentyl)-acetamidine hydrochloride (216) (5.0 g, 17.33 mmol) following the procedure described for 5-benzyloxy-2-[1-(2,5-dichlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid tert-butyl ester (204).
Reaction SMILES: [CH:1]([C:3]1[C:4]([NH:12][C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=2)=[N:5][C:6]([S:10][CH3:11])=[N:7][C:8]=1[CH3:9])=O>C1COCC1>[CH2:20]([O:19][C:17](=[O:18])/[CH:16]=[CH:1]/[C:3]1[C:4]([NH:12][C:13]2[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])=[CH:15][CH:14]=2)=[N:5][C:6]([S:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:21]
Reactant: CSc1nc(C)c(C=O)c(Nc2ccc(C(=O)OC(C)(C)C)cc2)n1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(C)nc(SC)nc1Nc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 188.9 %

Procedure:
A solution of compound G (28.8 g; 0.0801 mol) and Ph3PCHCOOEt (34 g; 0.0976 mol) in 400 mL of anhydrous THF was stirred under reflux for 2 h 30′. The reaction mixture was cooled to room temperature, filtered and concentrated. The crude mixture was purified by silica gel column chromatography (eluant: n-hexane/ethyl acetate=3/1 to 1/1) to yield compound H (32.5 g; 94.4%) as a yellow solid.
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[F:12][CH:13]([F:25])[CH:14]([C:16]1[N:17]([CH3:24])[CH:18]=[CH:19][C:20](=[O:23])[C:21]=1[OH:22])O>C(#N)C>[F:25][CH:13]([F:12])[CH2:14][C:16]1[N:17]([CH3:24])[CH:18]=[CH:19][C:20](=[O:23])[C:21]=1[OH:22]
Reactant: Cn1ccc(=O)c(O)c1C(O)C(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cn1ccc(=O)c(O)c1CC(F)F
Reaction time: 2 h
Yield: 24 %

Procedure:
To 10 mL of acetonitrile at ice-water bath was added DMF (0.14 mL, 1.8 mmol) followed by oxalyl chloride (0.15 mL, 1.8 mmol) dropwise. To this resulting suspension was added 2-(2,2-difluoro-1-hydroxyethyl)-3-hydroxy-1-methylpyridin-4(1H)-one (0.30 g, 1.5 mmol) in one portion, and the resulting mixture was stirred for 2 h. A solid was collected by filtration, and it was dissolved in 150 mL of acetonitrile. To this resulting solution was added Pd/C (10%, wet, 0.20 g, 66.7% w/w), and the mixture was subjected to hydrogenation under 40 psi hydrogen pressure for 2 h. The catalyst was filtered off, and the filtrate was evaporated to dryness. The residue was dissolved in de-ionized water, and the pH was adjusted to 5-6 using a 6N NaOH solution. The precipitate was collected via suction filtration to afford the crude product (100 mg) as an off-white solid. The crude was further purified by Biotage using reversed phase C18 cartridge to afford the title compound, Apo7080 (66 mg) as white solid. Yield=24%; 1H NMR (400 MHz, CD3OD) δ (ppm): 7.65 (d, J=7.2 Hz, 1H), 6.41 (d, J=7.2 Hz, 1H), 6.19 (tt, J=56.5, 4.7 Hz, 1H), 3.83 (s, 3H), 3.51 (dt, 3J=15.9 Hz, 2J=4.6 Hz, 2H); MS m/z 190 [M+1]+, 188 (100%).
Reaction SMILES: [F:1][CH:2]([F:32])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH2:24][NH:25][CH2:26][CH2:27][CH2:28][F:29])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[F:32][CH:2]([F:1])[C:3]([NH:5][C@@H:9]([CH2:10][F:11])[C@@H:8]([C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[N:20][C:21]([CH2:24][NH:25][CH2:26][CH2:27][CH2:28][F:29])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)[OH:7])=[O:4]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(CNCCCF)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(N[C@@H](CF)[C@H](O)c1ccc(-c2ccc(CNCCCF)nc2)cc1)C(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 33 %

Procedure:
To a solution of 2,2-Difluoro-1-[(4S,5R)-4-fluoromethyl-5-(4-{6-[(3-fluoro-propylamino)-methyl]-pyridin-3-yl}-phenyl)-2,2-dimethyl-oxazolidin-3-yl]-ethanone (0.113 g, 0.249 mmol) in CH2Cl2 (5 mL) is added trifluoroacetic acid (1.0 mL) at 0° C. The resulting reaction mixture is stirred at room temperature for 5 hours. Solvent is evaporated under reduced pressure and the crude residue is diluted with aqueous bicarbonate solution and extracted with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by combi-flash chromatography using 15% methanol in CH2Cl2 as eluent. Obtained solid is further washed with n-pentane and diethyl ether to give the title compound (0.034 g). 1H NMR (400 MHz, DMSO-d6) δ: 1.84-1.93 (m, 2H), 2.50-2.54 (m, 2H), 2.76 (bs, 1H), 3.99 (bs, 2H), 4.29-4.31 (m, 1.5H), 4.40-4.48 (m, 1.5H), 4.54-4.60 (m, 1.5H), 4.65-4.68 (m, 0.5H), 4.87 (bs, 1H), 5.92 (d, J=4.52 Hz, 1H), 6.20 (t, J=53.64 Hz, 1H), 7.46 (d, J=8.24 Hz, 2H), 7.52 (d, J=8.12 Hz, 1H), 7.70 (d, J=8.24 Hz, 2H), 8.08-8.10 (dd, J1=2.36 Hz, J2=8.2 Hz, 1H), 8.85 (m, 2H). LC-MS (m/z): [M+H]=414.1.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5]NC(=N)N.N[CH2:14]C(N)=O>>[NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH:4]([CH3:14])[CH3:5]
Reactant: NCC(N)=O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
Arg.Pro.Gly-NH2 (nafarelin, as its acetate; RS-94991-298).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)/[CH:7]=[N:8]/[OH:9].C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:22][CH:23]([C:26]#[N:27])[C:24]#[N:25]>CC(O)C>[NH2:27][C:26]1[C:23]([C:24]#[N:25])=[N:22][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][N+:8]=1[O-:9]
Reactant: N#CC(N)C#N
Reactant: O=C(/C=N/O)c1ccco1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: N#Cc1nc(-c2ccco2)c[n+]([O-])c1N
Temperature: 25 °C
Reaction time: 70 h
Yield: 92 %

Procedure:
A mixture of (E)-2-(furan-2-yl)-2-oxoacetaldehyde oxime 54 (2.52 g, 18.12 mmol) and aminomalononitrile p-toluenesulfonate (4.59 g, 18.12 mmol) in 2-Propanol (35 mL) was stirred at rt for 70 h. Cooled down with ice bad with stirring. The resulting precipitate was collected by filtration, washed with 2-propanol and dried to give 2-amino-3-cyano-5-(furan-2-yl)pyrazine 1-oxide 55 (3.37 g, 92%). NMR (400 MHz, DMSO-d6) 6.65 (m, 1H), 7.10 (m, 1H), 7.83 (m, 1H), 8.09 (br s, 2H), 8.87 (s, 1H).
Reaction SMILES: [N:1]1([S:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=2Cl)(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[OH2:21]>>[N:1]1([S:5]([C:8]2[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-:17])=[O:16])[C:9]=2[OH:21])(=[O:7])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCC2)c1Cl
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)N2CCC2)c1O
Yield: 50 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, 1-(azetidin-1-yl)sulfonyl-2,6-dichloro-3-nitrobenzene (510 mg, 1.64mmol), 60% NaH (197 mg, 4.92 mmol) and water (35 μL, 1.97 mmol) were reacted to form the desired product (240 mg, 50%). 1H NMR (MeOD-d4): δ 8.09 (d, 1H), 7.25 (d, 1H), 4.15 (t, 4H), 2.29 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:14].C(N(CC)CC)C.[S:22]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23]1>C(#N)C>[S:22]1[CH:26]=[CH:25][C:24]([S:27]([O:1][C:2]2[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:14])(=[O:29])=[O:28])=[CH:23]1
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: COc1cc(I)c2c(c1O)CNC2=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cc(I)c2c(c1OS(=O)(=O)c1ccsc1)CNC2=O
Yield: 80.6 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-5-methoxy-7-iodoisoindolinone (0.265 g, 0.869 mmol) was dissolved in acetonitrile (8.0 mL), and the solution was treated with triethylamine (0.242 mL, 1.74 mmol) and 3-thiophenesulfonyl chloride (0.191 g, 1.04 mmol) to obtain 4-(3-thiophenesulfonyloxy)-5-methoxy-7-iodoisoindolinone (0.316 g, yield 81%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[NH:12]([C:14]([S:16][C:17]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20]([OH:27])=[C:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:18]=1)=[S:15])[NH2:13].C(N(CC)C(C)C)(C)C.Cl>O1CCCC1.O.C(OCC)(=O)C>[CH3:31][C:28]([C:19]1[CH:18]=[C:17]([S:16][C:14]2[S:15][C:1](=[O:2])[NH:13][N:12]=2)[CH:22]=[C:21]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:20]=1[OH:27])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1cc(SC(=S)NN)cc(C(C)(C)C)c1O
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(Sc2n[nH]c(=O)s2)cc(C(C)(C)C)c1O
Reaction time: 0.17 h
Yield: 43 %

Procedure:
A 12.5% solution of phosgene in toluene (8.6 mL, 9.6 mmol) is added dropwise to a -78° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl hydrazinecarbodithioate (1.5 g, 4.8 mmol) and N,N-diisopropylethylamine (3.3 mL, 19.2 mmol) in tetrahydrofuran (150 mL). The reaction mixture is stirred for 10 minutes then poured into a separatory funnel containing ethyl acetate and water. The pH of the aqueous phase is adjusted to 3 with 1N hydrochloric acid. The organic phase is washed twice with water, then with a saturated solution of sodium bicarbonate followed by brine. Drying over magnesium sulfate and evaporation of the solvents gives a solid which is crystallized twice from isopropyl ether/hexane to afford 0.7 g (43%) of 5-[[3,5-bis(1,1-dimethylethyl) -4-hydroxyphenyl]thio]-1,3,4-thiadiazol-2(3H)-one, mp 194°-197° C. (dec).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11]N)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[F:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20](=O)[CH3:21])=[CH:16][CH:15]=1.P(Cl)(Cl)Cl>C1C=CC=CC=1>[F:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][C:19]2[C:8]3[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:10][CH:9]=3)[NH:11][C:20]=2[CH3:21])=[CH:16][CH:15]=1
Reactant: CC(=O)COc1ccc(F)cc1
Reactant: CS(=O)(=O)c1cccc(NN)c1
Solvent: ClP(Cl)Cl
Solvent: c1ccccc1
Product: Cc1[nH]c2cc(S(C)(=O)=O)ccc2c1Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5.2 %

Procedure:
To the solution of (3-methanesulfonyl-phenyl)-hydrazine (1.35 g) and 1-(4-fluoro-phenoxy)-propan-2-one (1.01 g) in benzene at RT was added equimolar amount of PCl3. The reaction mixture was stirred at RT for 1 hour and the solvent was removed in vacuo. The residue was purified by Biotage chromatography, eluted with 10-30% EtOAc/Hexane to yield 0.1 g of 3-(4-fluoro-phenoxy)-6-methanesulfonyl-2-methyl-1H-indole 401 as a light orange powder, MS: 320 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH2:22]([NH2:26])[CH:23]([CH3:25])[CH3:24].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:26][CH2:22][CH:23]([CH3:25])[CH3:24])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: CC(C)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(NCC(C)C)cc2OC1C(F)(F)F
Temperature: 90 °C
Yield: 75.6 %

Procedure:
A mixture of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Example 7a, Step 2) (0.5 g, 1.54 mmole) and isobutylamine (0.15 mL, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), which was warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The mixture was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil. The oil was purified by flash chromatography (silica gel) with 40% methylene chloride in hexane to give a light yellow oil (0.44 g, 76%): GCMS m/z 377.00 (M+). 1H NMR (CDCl3/400 MHz) 7.57 (s, 1H), 7.09 (s, 1H), 6.30 (s, 1H), 5.63 (q, 1H, J=7.0 Hz), 4.27 (m, 2H), 3.00 (m, 2H), 1.95 (m, 1H), 1.31 (m, 3H), 1.00 (m, 6H).