Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:19](NOC4CCCCO4)=[O:20])[C:15]([CH2:16][CH2:17][OH:18])=[C:10]3[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3[C:10](=[C:15]4[CH2:16][CH2:17][O:18][C:19](=[O:20])[C:14]4=[N:13][CH:12]=3)[CH:9]=[CH:8]2)=[CH:29][CH:30]=1
Reactant: O=C(NOC1CCCCO1)c1ncc2c(ccn2Cc2ccc(F)cc2)c1CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1OCCc2c1ncc1c2ccn1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.8 %

Procedure:
To a stirred solution of 1-(4-fluorobenzyl)-4-(2-hydroxyethyl)-N-(tetrahydro-2H-pyran-2-yloxy)-1H-pyrrolo[2,3-c]pyridine-5-carboxamide (0.16 g, 0.39 mmol) and triphenylphosphine (0.12 g, 0.46 mmol) in THF (10 mL), was added dropwise diisopropylazodicarboxylate (0.09 mL, 94 mg, 0.46 mmol) in THF (1 mL) was added. The resulting mixture was stirred at room temperature for 1 hour, and the solvent was evaporated. Purification by Biotage chromatography provided 0.12 g of a crude material that was used without further purification in the next step. LCMS (APCl, M+H+): 396.2.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[CH3:30][O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)=[CH:28][CH:27]=1
Reactant: COc1ccc(CC[C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(CC[C@H]2CNCCN2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
Combine (S)-1,4-dibenzyl-2-(2-(4-methoxy-phenyl)-ethyl)-piperazine (1.34 g, 3.33 mmol), ammonium formate (1.05 g, 16.67 mmol), 5% Pd/C (161.2 mg), and ethanol (100 mL). Stir and heat the mixture at reflux. After 3 hours, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and purify it on silica gel using dichloromethane/2N ammonia in methanol (80:20) to give (689.3 mg, 94%) of the title compound as a white solid: mp 125–130° C.; mass spectrum (ion spray): m/z=221.1 (M+1); Analysis for C13H20N2O: calcd: C, 70.87; H, 9.15; N, 12.72; found: C, 70.58; H, 9.05; N, 12.61.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:17]2[CH2:21][CH:20]([CH2:22][N:23]=[N+]=[N-])[O:19][C:18]2=[O:26])[CH:5]=[C:6]([F:16])[C:7]=1[N:8]1[CH2:13][CH2:12][S:11](=[O:15])(=[O:14])[CH2:10][CH2:9]1.N(C[C@@H]1OC(=O)N(C2C=C(F)C(N3CCS(=O)(=O)CC3)=C(F)C=2)C1)=[N+]=[N-]>>[O:15]=[S:11]1(=[O:14])[CH2:10][CH2:9][N:8]([C:7]2[C:6]([F:16])=[CH:5][C:4]([N:17]3[CH2:21][C@@H:20]([CH2:22][NH2:23])[O:19][C:18]3=[O:26])=[CH:3][C:2]=2[F:1])[CH2:13][CH2:12]1
Reactant: [N-]=[N+]=NCC1CN(c2cc(F)c(N3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: [N-]=[N+]=NC[C@H]1CN(c2cc(F)c(N3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Product: NC[C@@H]1CN(c2cc(F)c(N3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Yield: 85.2 %

Procedure:
A suspension of (5R) 3-[3,5-difluoro-4-(1,1-dioxo-4-thiomorpholinyl)phenyl]-5-(azidomethyl)-oxazolidin-2-one (Intermediate 10) (0.82 g, 2.11 mmol) and polystyrene triphenylphosphine (5.6 g, 8.5 mmol) was reacted as described for Example 9 to give the intermediate amine, (5R)-3-[4-(1,1-Dioxo-4-thiomorpholinyl)-3,5-difluorophenyl]-5-(aminomethyl)-oxazolidin-2-one (0.65 g), which was used directly for the next step. This amine (0.63 g, 1.75 mmol) was reacted with diisopropylethylamine (0.9 ml, 5.2 mmol) and α,α-dichloroacetone tosylhydrazone (0.77 g, 2.62 mmol) as described for Example 3. Chromatography on silica gel eluting with 5% methanol in dichloromethane gave the title compound (350 mg).
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[C:17]([NH:19][C:20]4[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][N:21]=4)[CH:16]=[C:15]([CH3:30])[CH:14]=3)=[CH:11][N:12]=2)[CH2:5][CH2:4][CH:3]1[C:31](O)=[O:32].C(Cl)CCl.C1C=CC2N(O)N=[N:45]C=2C=1.[Cl-].[NH4+].C(N(C(C)C)C(C)C)C>CN(C)C=O.CS(C)=O>[CH3:1][C:2]1([CH3:34])[CH2:7][CH:6]([C:8]2[S:9][C:10]([C:13]3[CH:18]=[C:17]([NH:19][C:20]4[N:25]=[C:24]([C:26]([F:27])([F:29])[F:28])[CH:23]=[CH:22][N:21]=4)[CH:16]=[C:15]([CH3:30])[CH:14]=3)=[CH:11][N:12]=2)[CH2:5][CH2:4][CH:3]1[C:31]([NH2:45])=[O:32]
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3CCC(C(=O)O)C(C)(C)C3)s2)c1
Reactant: On1nnc2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3CCC(C(N)=O)C(C)(C)C3)s2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Step 3 was taken up in N,N-dimethylformamide (2.9 ml) and EDC (66.1 mg, 0.35 mmol), HOBT (52.8 mg, 0.35 mmol), ammonium chloride (55.3 mg, 1.04 mmol), and N-ethyl-N-(propan-2-yl)propan-2-amine (301 μl, 1.724 mmol) were added. The mixture was stirred at room temperature overnight. The mixture was then diluted with 1 mL of DMSO and directly purified by reverse phase HPLC (acetonitrile/water+0.1% TFA modifier). The desired fractions were combined, diluted with ethyl acetate and washed once with saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was subject to purification by chiral supercritical fluid chromatography (4/6 2-Propanol/CO2 with a flow rate of 60 mL/min and a 19 minute run time) to afford the four stereoisomers of 2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxamide.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C:20]=2[OH:32])=[O:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[OH:32][C:20]1[C:21]([CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[C:17](=[O:18])[CH2:16][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=1
Reactant: COc1ccc(C(=O)C=Cc2ccc(OCc3ccccc3)cc2)c(O)c1CC=C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)CCc2ccc(O)cc2)c(O)c1CCC(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 87.9 %

Procedure:
Then, an ethyl acetate solution of 24.5 g of 4-benzyloxy-2'-hydroxy-4'-methoxy-3'-(3-methyl-2-butenyl)chalcone was added to an ethyl acetate suspension of 5% palladium-carbon, which a hydrogen gas had been sufficiently absorbed in advance, and the mixture was stirred at room temperature in a hydrogen atmosphere for 3.5 hours. After the reaction, the reaction mixture was filtered and the solvent was removed by distillation, and the obtained residue was subjected to the silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=5/1) to obtain 17.2 g of 1-(2-hydroxy-4-methoxy-3-isopentylphenyl)-3-(4-hydroxyphenyl)-1-propanone in the form of a colorless oil.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH2:6][O:5][C:4]1=[O:16].Cl.[N:18]([O-])=O.[Na+]>O>[ClH:1].[CH3:2][N:3]1[C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][NH2:18])=[CH:11][CH:10]=2)[CH2:6][O:5][C:4]1=[O:16]
Reactant: O=N[O-]
Reactant: CN1C(=O)OC[C@@H]1Cc1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN1C(=O)OC[C@@H]1Cc1ccc(NN)cc1
Reaction time: 0.5 h

Procedure:
A solution of the product from step (b) (4.1 g) in water (24 ml) was cooled to -5° C. and c.HCl (40 ml) added. A solution of sodium nitrite (1.2 g) in water (12 ml) was then added and stirring continued for 0.5 hour. The resulting solution was added dropwise at -5° C. to a stirred solution of stannous chloride dihydrate (18.8 g) in c.HCl (34 ml). The resulting mixture was stirred at 0° C. for 2.5 hours, then evaporated in vacuo. The residue was taken up in water, brought to pH 2.5 using 10N aqu. NaOH and filtered. The filtrate was evaporated in vacuo and the residue triturated with ethanol and filtered. The filtrate was evaporated in vacuo to give the desired product as a froth.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]([C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)(O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]([C:28]2[CH:33]=[CH:32][C:31]([Br:34])=[CH:30][CH:29]=2)([F:11])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Br)cc2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90.4 %

Procedure:
[Bis(2-Methoxyethyl)amino]sulfur trifluoride (2.1 mL, 11.4 mmol) was added to a stirred solution of 4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (810 mg, 2.28 mmol) in anhydrous DCM (25 mL), at −78° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 72 h. The reaction mixture was quenched by the addition of saturated aqueous potassium carbonate (10 mL) and extracted into DCM (3×10 mL). The combined organic phase was concentrated in vacuo and the residue purified by flash chromatography (silica, 40 g column, ISCO, 0-100% ethyl acetate in cyclohexane) to afford the title compound as a colourless oil (738 mg, 91%). 1H NMR (CDCl3, 300 MHz): 7.50 (d, J=8.5 Hz, 2H), 7.24 (d, J=8.5 Hz, 2H), 4.19-4.05 (m, 2H), 3.29-3.05 (m, 2H), 2.04-1.84 (m, 4H), 1.49 (s, 9H). LCMS (Method B): RT=4.55 min.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([CH2:54][C:55]2[CH:60]=[CH:59][C:58]([CH2:61][CH3:62])=[CH:57][CH:56]=2)=[CH:6][C:7]([C@H:15]2[C@H:20]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@@H:19]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:18]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C@@H:17]([CH2:45][O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[O:16]2)=[C:8]([CH:14]=1)[CH2:9][O:10][CH2:11][CH:12]=[O:13]>C1COCC1>[Cl:3][C:4]1[C:5]([CH2:54][C:55]2[CH:60]=[CH:59][C:58]([CH2:61][CH3:62])=[CH:57][CH:56]=2)=[CH:6][C:7]([C@H:15]2[C@H:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[C@@H:19]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:18]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C@@H:17]([CH2:45][O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[O:16]2)=[C:8]([CH:14]=1)[CH2:9][O:10][CH2:11][CH2:12][OH:13]
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(COCC=O)cc2Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(COCCO)cc2Cl)cc1
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
NaBH4 (13 mg, 0.34 mmol) was added into a solution of 2-(5-chloro-4-(4-ethylbenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyloxy)acetaldehyde (intermediate O-2) (140 mg, 0.17 mmol) in THF (10 mL) and stirred for 1.5 h. The reaction mixture was quenched by MeOH (2 mL), then evaporated to dryness. The residue was purified by preparative TLC, which afforded 2-(5-chloro-4-(4-ethylbenzyl)-2-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-yl)benzyloxy)ethanol (intermediate O-3) (135 mg, 0.169 mmol, yield 96.2%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([OH:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[C:1]([C:3]1[CH:4]=[C:5]([C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)CC(O)c1cccc(C#N)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COC(=O)CC(=O)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
To a solution of methyl 3-(3-cyanophenyl)-3-hydroxypropionate (2.22 g, 10.8 mmol) in 30 mL of methylene chloride was added activated manganese dioxide (4.7 g, 54.0 mmol). This mixture was allowed to stir at 25° C. for 16 h. The reaction mixture was filtered through a pad of celite and concentrated in vacuo. The residue was purified by flash chromatography (elution with 2:1 hexanes/ethyl acetate) to afford 0.9 g (41%) of the title compound along with 0.8 g (36%) of recovered starting material. MS for title compound (H2O GC-MS) 204 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]O)#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(Br)(Br)(Br)[Br:42]>ClCCl>[C:20]([C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36][Br:42])#[C:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: BrC(Br)(Br)Br
Reactant: CCCCCCCCCCCC#Cc1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCCCCCCC#Cc1cccc(CBr)c1
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Triphenyl phosphine (1.5 g, 5.7 mmole) was added in small portions to a stirred solution of 3-(Tridec-1-ynyl)benzyl alcohol (1.34 g, 4.7 mmol, from example 34) and carbon tetrabromide (1.87 g, 5.7 mmole) in dichloromethane (20 ml) at 0° C., and the mixture was stirred for a further 3 hr at this temperature. After removing all the solvent under reduced pressure, n-hexane (20 ml) was added and the precipitate of triphenylphosphine oxide removed by filtration. Removal of the hexane under reduced pressure gave an oil which was distilled to give the desired product, (1.49 g, 91%) B.p. 170° C. at 0.05 mmHg., νmax 690, 790, 1210, 1460, 1480, 1600, 2220, 2850, 2920 cm-1, δ(CDCl3) 0.7 (3H, distorted t, terminal CH3), 1.2 (18H, m, alkylene chain), 2.16 (2H, t J=7 Hz, CH2 adjacent to acetylene), 4.15 (CH, s, benzylics), 7.06 (4H, m, aromatics).
Reaction SMILES: C(OC([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([S:18][CH2:19][CH3:20])=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=O)(C)(C)C.Cl>>[ClH:17].[Cl:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][C:12]=1[S:18][CH2:19][CH3:20])[CH2:9][NH:8][CH2:16]2
Reactant: CCSc1cc2c(cc1Cl)CN(C(=O)OC(C)(C)C)C2
Agent: Cl
Product: CCSc1cc2c(cc1Cl)CNC2

Procedure:
Prepared in analogy to Example A3(e) from 5-Chloro-6-ethylsulfanyl-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester and HCl. Off-white solid. MS (m/e): 216.2 ({37Cl}M+H+, 42%), 214.2 ({35Cl}M+H+, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]=[O:10])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1.[BH4-].[Na+]>CO>[NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][OH:10])=[C:4]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1
Reactant: CCCCCNc1nc(N)nc(C)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCNc1nc(N)nc(C)c1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the product from step (ii) (4 g) in MeOH (50 ml), sodium borohydride (0.7 g) was added portionwise over 5 min. The mixture was stirred at rt for 1 h then the solvent removed under reduced pressure. The residue was partitioned between EtOAc and water, the organics were separated, dried and evaporated under reduced pressure to give the subtitle compound, 3.89 g.
Reaction SMILES: FC(F)(F)[C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1.C(Br)C1C=CC=CC=1.[CH3:21][C:22]1[CH:26]=[C:25]([N:27]2[CH2:31][CH2:30][NH:29][C:28]2=[O:32])[S:24][C:23]=1[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:7]([N:29]1[CH2:30][CH2:31][N:27]([C:25]2[S:24][C:23]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[C:22]([CH3:21])[CH:26]=2)[C:28]1=[O:32])[C:6]1[CH:5]=[CH:4][CH:3]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: BrCc1ccccc1
Product: CCOC(=O)c1sc(N2CCN(Cc3ccccc3)C2=O)cc1C
Yield: 94 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with benzyl bromide to react with ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate, the title compound was obtained as a colorless solid in 94% yield: 1H NMR (300 MHz, CDCl3) δ 7.39-7.25 (m, 5H), 6.15 (s, 1H), 4.48 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.83-3.75 (m, 2H), 3.48-3.40 (m, 2H), 2.49 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 345.3 (M+1).
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2].[OH-].[Na+].Cl>O1CCCC1>[CH:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)cc1
Temperature: 65 °C
Yield: 97.3 %

Procedure:
To a solution of 52 (0.75 g, 2.12 mmol) in tetrahydrofuran (10 mL) was added aqueous sodium hydroxide (5 mL, 2N). The reaction mixture was heated at 65° C. for 2 days, allowed to cool to room temperature and then acidified to pH 5 with aqueous hydrochloric acid (2N) and extracted with tetrahydrofuran (3×5 mL). The combined organic phases were dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a golden oil (0.7 g), which later solidified. A portion of the crude residue was purified by preparative HPLC to afford the title compound as a white solid (129 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:13][CH:14]=1)=[O:7])([O-])=O>CCOC(C)=O.CCO.[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:21][C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:13][CH:14]=1)=[O:7]
Reactant: O=C(Nc1cnc(-c2ccccc2)nc1)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(N2CCCCC2)cc1C(=O)Nc1cnc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.4 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 2-nitro-N-(2-phenylpyrimidin-5-yl)-5-(piperidin-1-yl)benzamide (100 mg, 0.25 mmol, 1.00 equiv) in EtOAc/EtOH (5/5 mL). The mixture was treated with Pd/C (10 mg) and stirred under a hydrogen atmosphere for 2 h at room temperature. The solids were filtered out. The resulting mixture was concentrated under vacuum to yield 90 mg (97%) of product as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[N:12]2[CH:13]=[CH:14][N:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.[N:16]1([CH:22]=[C:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:29])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C1CCN2C(=NCCC2)CC1.O>CN(C)C=O>[N:16]1([CH:22]=[C:23]2[S:27][C:26](=[O:28])[N:25]([CH2:2][CH2:3][CH2:4][CH2:5][S:6][C:7]3[N:12]4[CH:13]=[CH:14][N:15]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[C:24]2=[O:29])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: ClCCCCSc1cccc2nccn12
Reactant: O=C1NC(=O)C(=CN2CCCCC2)S1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1SC(=CN2CCCCC2)C(=O)N1CCCCSc1cccc2nccn12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 241 mg (1.0 mmol) of 5-(4-chlorobutylthio)imidazo[1,2-a]pyridine and 212 mg (1.0 mmol) of 5-(piperidin-1-yl)methylene-thiazolidine-2,4-dione in 10 ml of N,N-dimethylformamide, 0.15 ml (1.0 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene was added, followed by stirring at 80° C. for 3 hours. After the reaction mixture was cooled, water was added; the mixture was extracted with ethyl acetate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, n-hexane/ethyl acetate=1/4→ethyl acetate) to yield 330 mg (79.2%, white powder) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:25])=[CH:5][C:6]([CH2:12][C:13]2[C:14]([CH3:24])=[N:15][N:16]([CH2:19][CH2:20][C:21]([OH:23])=O)[C:17]=2[CH3:18])=[C:7]2[C:11]=1[CH2:10][CH2:9][CH2:8]2.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH:38]([NH2:41])([CH3:40])[CH3:39].O>O1CCCC1.CCCCCC>[CH:38]([NH:41][C:21](=[O:23])[CH2:20][CH2:19][N:16]1[C:17]([CH3:18])=[C:13]([CH2:12][C:6]2[CH:5]=[C:4]([CH3:25])[C:3]([O:2][CH3:1])=[C:11]3[C:7]=2[CH2:8][CH2:9][CH2:10]3)[C:14]([CH3:24])=[N:15]1)([CH3:40])[CH3:39]
Reactant: CC(C)N
Reactant: COc1c(C)cc(Cc2c(C)nn(CCC(=O)O)c2C)c2c1CCC2
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C)cc(Cc2c(C)nn(CCC(=O)NC(C)C)c2C)c2c1CCC2
Temperature: 72.5 °C
Yield: 72.3 %

Procedure:
To the solution of 3-[4-(7-Methoxy-6-methyl-indan-4-ylmethyl)-3,5-dimethyl-pyrazol-1-yl]-propionic acid (1.0 gm, 0.00292 mole) in Tetrahydrofuran (20 ml), Carbonyl-diimidazole (0.62 gm, 0.0038 mole) was added at 20-30° C. The reaction mixture was heated and stirred for an hour at 70-75° C. A solution of Isopropyl amine (0.3 ml, 0.00367 mole) in Tetrahydrofuran (5 ml) was added at 20-30° C. The reaction mixture was further stirred at 70° C. for 4 hours. The reaction mixture was cooled and poured into water (50 ml) and extracted with Ethyl acetate (2×100 ml). The Ethyl acetate layer was dried over Sodium sulphate, distilled under vacuum to get a crude product which was stirred in Hexane (20 ml) and filtered to give 810 mg of desired product as a solid.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.CCN(C(C)C)C(C)C.[CH3:26][O:27][CH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>CS(C)=O>[CH3:26][O:27][CH2:28][C@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[C:2]1[C:3](=[O:16])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2[nH]c(=O)c(Cl)nc2c1
Reactant: COC[C@H]1CCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC[C@H]1CCCN1c1nc2cc(C(=O)OC)ccc2[nH]c1=O
Temperature: 75 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a solution of methyl 3-chloro-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (600 mg, 2.51 mmol) in DMSO (8 mL) was added DIEA (650 mg, 5.03 mmol), and (2R)-2-(methoxymethyl)pyrrolidine (318 mg, 2.76 mmol). The solution was stirred for 4 h at 75° C. Then the reaction was quenched by the addition of water (50 mL) to give the precipitate, which was collected by filtration to afford methyl 3-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate as a gray solid (650 mg, 81%).
Reaction SMILES: CC(O)C.O.C([C@@](C(O)=O)(O)[C@@](C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[O:32]=[C:33]([N:47]1[CH2:52][CH2:51][N:50]2[C:53]([C:56]([F:59])([F:58])[F:57])=[N:54][N:55]=[C:49]2[CH2:48]1)[CH2:34][CH:35]([NH2:46])[CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=1[F:45].C(O)=O>CO>[O:32]=[C:33]([N:47]1[CH2:52][CH2:51][N:50]2[C:53]([C:56]([F:59])([F:58])[F:57])=[N:54][N:55]=[C:49]2[CH2:48]1)[CH2:34][C@@H:35]([NH2:46])[CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=1[F:45]
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: O=C(O)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)O)C(=O)c1ccccc1
Solvent: O
Solvent: CO
Solvent: O=CO
Product: N[C@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 62.5 °C
Reaction time: 1 h

Procedure:
In a 50 mL three neck flask IPA (5 mL) and Dibenzoyl-L-tartaric acid monohydrate (0.925 g) were taken. It was heated to 60-65° C. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (2.0 g, % purity-93.8%) dissolved in methanol (6 mL) and formic acid (0.112 g) was added into reaction mixture at 60-65. It was stirred for 60 min. at 60-65° C. Solid salt was precipitated. It was gradually cooled to room temperature over a period of 2-3 h. The salt was filtered and washed with a mixture of IPA: MeOH (2:1). An enantiomerically enriched desired Dibenzoyl-L-tartaric acid salt of mixture of (2R) and (2S)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine was obtained (Wt.-1.32 g, % Y-34.6%, Purity by HPLC-99.6%, % Chiral purity by HPLC of R-isomer 75.7%).