Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[NH:7][C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([N+:21]([O-:23])=[O:22])[CH:11]=[CH:10][CH:9]=2)([CH3:5])[CH3:4].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[CH:3]([C:6]1[N:7]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:8]2[C:13]([C:14]=1[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:12]([N+:21]([O-:23])=[O:22])[CH:11]=[CH:10][CH:9]=2)([CH3:4])[CH3:5]
Reactant: CCOC(=O)CBr
Reactant: CCOC(=O)Cc1c(C(C)C)[nH]c2cccc([N+](=O)[O-])c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C(C)C)n(CC(=O)OCC)c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium hydride (45 mg of a 60% dispersion in mineral oil, 1.13 mmol) was added to a solution of ethyl (2-isopropyl-4-nitro-1H-indol-3-yl)acetate from Step E (300 mg, 1.03 mmol) in DMF (10 mL). After 5 min, ethyl bromoacetate (0.126 mL, 1.13 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 30 min. The reaction mixture was quenched with saturated aqueous NaHCO3 (10 mL) and extracted with CHCl3 (3×25 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CHCl3:MeOH—100:0 to 95:5, to give the title compound. MS: m/z=377 (M+1).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:44])[CH2:30][CH2:31][N:32]([C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][C:37]=1[NH2:43])[C:33](=[O:35])[CH3:34]>>[CH3:44][N:29]([CH3:28])[CH2:30][CH2:31][N:32]([C:36]1[CH:42]=[CH:41][C:39]([NH:40]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:38][C:37]=1[NH2:43])[C:33](=[O:35])[CH3:34]
Reactant: CC(=O)N(CCN(C)C)c1ccc(N)cc1N
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(CCN(C)C)C(C)=O)c(N)c1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-(N-(2-dimethylamino-ethyl)-N-acetyl-amino)-3-amino-aniline Rf value: 0.5 (aluminium oxide, methylene chloride/methanol=20:1) C29H31N5O4
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:15]1([C:18](Cl)=[O:19])[CH2:17][CH2:16]1>CCOC(C)=O>[CH:15]1([C:18]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=2)=[O:19])[CH2:17][CH2:16]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc(S)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(S)cc1)C1CC1
Reaction time: 8 h
Yield: 88 %

Procedure:
To 4-aminothiophenol (9.4 g, 75.0 mmol, 1.5 equiv) and pyridine (8.09 mL, 100.0 mmol, 2 equiv) at 0° C. was added cyclopropanecarbonyl chloride (4.58 mL, 50.0 mmol, 1 equiv) drop wise. The reaction was stirred from 0° C. to room temperature for overnight, diluted with EtOAc (200 mL), washed with 1 N HCl (50 mL×4), dried over Na2SO4, concentrated, and dried under vacuum to yield the compound 5 as a off-white solid (8.5 g, 88%).
Reaction SMILES: [CH2:1]([N:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH2:5])[CH:2]=[CH2:3].[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[NH:5][C:20](=[O:21])[NH:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(N)CC(=O)OCC
Reactant: O=C=NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCN(CC(=O)OCC)NC(=O)NCc1ccccc1
Yield: 73.6 %

Procedure:
To the solution of ethyl 2-(1-allylhydrazinyl)acetate (Compound XV-1) 6.9 g (44 mmol) in tetrahydrofuran 40 ml, benzyl isocyanate 6.1 g (46 mmol) was added at 0° C. and at room temperature for 3.5 hours. The reaction mixture was diluted with ethyl acetate 150 ml and washed with water 75 ml and brine 75 ml. The organic phase was dried with magnesium sulfate and filtered. The filtrate was concentrated in vacuo to obtain the title compound 9.43 g (75%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][C:9]([CH3:11])=[O:10].[OH-].[Na+].O>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:8][C:9](=[O:10])[CH:11]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: O=Cc1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1cccs1)C=Cc1cccs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
2-Thiophenecarboxaldehyde (33, 0.50 ml, 5.3 mmol) and acetone (19, 0.20 ml, 2.7 mmol) were combined in ethanol (10 ml) and stirred for 10 min at room temperature. A solution of sodium hydroxide (0.30 g, 7.5 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethanol/water to give 0.55 g (82%) of a yellow solid: mp 115-117° C. [expected mp 115-117° C.]; 1H NMR: δ 6.80 (d, 2H, J=15.5 Hz), 7.06 (dt, 2H, J=3.6, 1.4 Hz), 7.31 (d, 2H, J=3.4 Hz), 7.39 (d, 2H, J=5.0 Hz), 7.82 (d, 2H, J=15.5 Hz); 13C NMR: δ 124.4, 128.2, 128.7, 131.7, 135.5, 140.2, 187.5.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[C:19]([Cl:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:27]3[S:28][CH:29]=[C:30]([CH:32]([CH3:34])[CH3:33])[N:31]=3)[CH:15]=2)[CH2:10][CH:9]1[C:35](=[O:47])[NH:36][C:37]1([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:39][CH:38]1[CH:40]=[CH2:41])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:45]([O:44][C:42]([C:37]1([NH:36][C:35]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[C:23]4[C:18](=[C:19]([Cl:26])[C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:27]4[S:28][CH:29]=[C:30]([CH:32]([CH3:33])[CH3:34])[N:31]=4)[CH:15]=3)[CH2:12][NH:8]2)=[O:47])[CH2:39][CH:38]1[CH:40]=[CH2:41])=[O:43])[CH3:46]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(Oc2cc(-c3nc(C(C)C)cs3)nc3c(Cl)c(OC)ccc23)CN1)C(=O)OCC
Reaction time: 2 h
Yield: 97.2 %

Procedure:
To a stirred solution of 4-[8-chloro-2-(4-isopropylthiazol-2-yl)-7-methoxyquinolin-4-yloxy]-2-(1-ethoxycarbonyl-2-vinylcyclopropylcarbamoyl)pyrrolidine-1-carboxylic acid tert-butyl ester (49, 0.7 g, 1.02 mmol) in CH2Cl2 (8 mL) was added trifluoroacetic acid (2.0 mL). After 2 h at room temperature, the reaction mixture was concentrated and the residue was partitioned between a saturated solution of NaHCO3 and DCM. The organic layer was dried (MgSO4) filtered and concentrated to give 580 mg (97%) of the title product (50) as a colorless oil: m/z=585 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[H-].[Na+].Cl.Cl[CH2:25][CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[O:40][CH3:41])[CH2:30][CH2:29]1.O>CN(C)C=O>[CH3:41][O:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[N:31]1[CH2:30][CH2:29][N:28]([CH2:27][CH2:26][CH2:25][S:20][C:11]2[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH2:33][CH2:32]1
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(CCCSC2=Nc3ccc(Cl)cc3C(c3ccccc3Cl)=NC2)CC1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a solution of 11.5 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in 100 ml of anhydrous dimethylformamide is added under ice cooling with stirring 2.1 g of sodium hydride (50% oily suspension), and the resulting mixture is stirred at 30° C. for 1 hour. To the mixture is added dropwise a solution of 12.5 g of 1-chloro-3-[4-(2-methoxyphenyl)-1-piperazinyl]propane hydrochloride in 50 ml of dimethylformamide over a period of 15 minutes, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into iced water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate and, thereafter, the solvent is distilled off under reduced pressure to obtain an oily 2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propylthio]-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with fumaric acid and recrystallized from isopropyl alcohol to obtain 10.5 g of 2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propylthio]-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate, m.p. 189°-191° C.
Reaction SMILES: [OH:1][C@@H:2]([CH2:24][OH:25])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[C:15]([SH:19])[N:14]=[C:13]([O:20][CH3:21])[C:12]=2[C:22]#[N:23])=[CH:7][CH:6]=1.Cl[CH2:27][C:28]1[N:29]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)[S:31][CH:32]=1.C(=O)(O)[O-].[Na+]>>[Cl:39][C:36]1[CH:35]=[CH:34][C:33]([C:30]2[S:31][CH:32]=[C:28]([CH2:27][S:19][C:15]3[C:16]([C:17]#[N:18])=[C:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][C@@H:2]([OH:1])[CH2:24][OH:25])=[CH:6][CH:7]=4)[C:12]([C:22]#[N:23])=[C:13]([O:20][CH3:21])[N:14]=3)[N:29]=2)=[CH:38][CH:37]=1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Reactant: COc1nc(S)c(C#N)c(-c2ccc(OC[C@@H](O)CO)cc2)c1C#N
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OC[C@@H](O)CO)cc2)c1C#N

Procedure:
The solution from Example 29A is stirred together with 75 mg (0.306 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 93 mg (1.112 mmol) of sodium bicarbonate at room temperature overnight. The reaction mixture is purified by preparative HPLC (acetonitrile/water: 10:90→95:5, with 0.1% TFA added). This gives 33 mg (20% of theory over two steps) of the target compound.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22](OC)=[O:23])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][O:33][CH2:34][CH2:35][CH2:36][NH2:37]>>[CH:1]1([N:7]2[C:11]3[CH:12]=[C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([NH:37][CH2:36][CH2:35][CH2:34][O:33][CH3:32])=[O:23])[CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(C3CCCCC3)c2c1
Reactant: COCCCN
Product: COCCCNC(=O)CCCCCOc1ccc2nc(-c3ccccc3)n(C3CCCCC3)c2c1

Procedure:
1-Cyclohexyl-6-[(5-(methoxycarbonyl)pentyl)oxy]-2-phenyl-benzimidazole is reacted according to general operating instructions 7 with 3-methoxypropylamine. 1-Cyclohexyl-6-[(5-((3-methoxy-propyl)aminocarbonyl)pentyl)oxy]-2-phenyl-benzimidazole is obtained as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15](O)=[O:16])=[CH:9][CH:8]=1.O[N:22]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]([NH2:22])=[O:16])=[CH:9][CH:8]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C#Cc1ccc(OCc2cccc(F)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(=O)C#Cc1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
50 mg (0.19 mmol) of [4-(3-fluoro-benzyloxy)-phenyl]-propynoic acid is dissolved in 3 ml of THF and treated with 27 mg (0.2 mmol) of 1-hydroxybenzotriazole and 37 mg (0.19 mmol) of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride. The resulting mixture is stirred at RT for 30 minutes, cooled to 0° C. and treated with 1 ml of concentrated ammonia. The suspension is stirred overnight at RT, diluted with water and extracted three times with dichloromethane. Flash-chromatography (silica gel, dichloromethane/methanol) yields 29 mg (59%) of a colorless solid. MS: m/e=270.2 (M++H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1.[CH2:16]([O:23][CH2:24][C@H:25]([NH:29]C(OC(C)(C)C)=O)[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:29][C@@H:25]([CH2:24][O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:26]([NH:10][C:9]1[CH:11]=[CH:12][C:6]([O:5][C:4]2[CH:13]=[CH:14][CH:15]=[C:2]([Cl:1])[CH:3]=2)=[CH:7][CH:8]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: Nc1ccc(Oc2cccc(Cl)c2)cc1
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2cccc(Cl)c2)cc1
Yield: 90 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(3-chlorophenoxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-(3-chlorophenoxy)phenyl)propanamide (349 mg, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([NH:14][NH2:15])=[O:13].[C:16](OCC)(OCC)(OCC)[CH3:17]>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]1[O:13][C:16]([CH3:17])=[N:15][N:14]=1
Reactant: NNC(=O)c1cccc2c(Br)cccc12
Reactant: CCOC(C)(OCC)OCC
Product: Cc1nnc(-c2cccc3c(Br)cccc23)o1
Yield: 88 %

Procedure:
5-Bromo-1-napthoic hydrazide (D2) (2.00 g, 7.5 mmol) was stirred at reflux under Ar in triethyl orthoacetate (20 ml) for 20 h. The mixture was cooled in ice, and the solid was filtered off, washed with petroleum ether (b.p. 60-80° C.), and dried in vacuo at 60° C., giving the title compound (1.92 g, 88%) as a light brown powder.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:5][N:4]=1.[CH3:24][CH:25]([OH:33])[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1>>[CH3:24][CH:25]([O:33][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:5][N:4]=1)[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1
Reactant: CC(O)c1ccc(F)cc1
Product: CC(Oc1ncc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1)c1ccc(F)cc1

Procedure:
2-Methylthio-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with α-methyl-4-fluorobenzyl alcohol according to the procedure described in Example 59 to afford 2-(α-methyl-4-fluorobenzyloxy-)-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine. (HRf): HPLC/MS: m/e=473 (M++1); Rt=4.91 min; 1H-NMR 400 MHz (CDCl3): δ 1.78 (d, J=9 Hz, 3H), 6.22-6.30 (dd, J=6 Hz, J=9 Hz, 1H), 7.02 (m, 3H), 7.20-7.25 (m, 5H), 7.50-7.59 (m, 3H), 8.40 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([CH2:14][CH3:15])[CH2:9][C:10](OC)=[O:11])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:16]2[C:24]3[C:19](=[C:20]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])[CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17]2)([CH2:14][CH3:15])[CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1
Reactant: CCC(CC(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CCO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 1 h

Procedure:
To a solution of the product of Step H (60 mg, 0.138 mmol) in THF (5 mL) was added LiAlH4 (10.4 mg, 0.276 mmol) at 0° C. The mixture was stirred for 1 h and quenched with H2O (2 mL), extracted with ethyl acetate, and washed with brine (5 mL), dried over sodium sulfate, then filtered. After removing the organic solvent, the residue was purified by silica gel chromatography (EA/PE=1:3) to afford the title racemic compound. The racemic compound was submitted to chiral SFC separation using AS-H column (50% EtOH/CO2, 4.6×250 mm, 39.3° C.) to give two separated enantiomers. LC/MS m/z=406.9[M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1)[CH2:6][C:5]2=[O:18].[C:19]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)#[N:20]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:18]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:25]3[CH:26]=[C:21]([CH:22]=[CH:23][CH:24]=3)[C:19]#[N:20])[CH:3]=2)[O:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:6]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C1CC(c2ccccn2)Oc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC(c2ccccn2)O3)c1
Temperature: 120 °C
Yield: 33.7 %

Procedure:
Pd(PPh3)2Cl2 (20 mg) in a 10 mL flask under Ar was treated sequentially with 6-bromo-2-(pyridin-2-yl)chroman-4-one (300 mg, 1 mmol) in [1,4]dioxane (40 mL), Cs2CO3 (2 N, 5 mL) and 3-cyanophenylboronic acid (250 mg, 1 mmol). The mixture was heated at 120° C. under Ar in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give 3-(4-oxo-2-(pyridin-2-yl)chroman-6-yl)benzonitrile (110 mg, 60%). 1H-NMR (CDCl3): 3.13 (m, 2H), 5.61 (m, 1H), 7.13 (m, 1H), 7.27 (m, 1H), 7.49 (m, 1H), 7.58 (m, 2H), 7.68 (m, 1H), 7.79 (m, 3H), 8.09 (d, 1H), 8.58 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][C:7]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N+:6]([O-])[CH:5]=1.O=P(Cl)(Cl)[Cl:26]>>[CH3:1][O:2][C:3](=[O:23])[C:4]1[C:9]([CH2:10][CH3:11])=[CH:8][C:7]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:6][C:5]=1[Cl:26]
Reactant: CCc1cc(-c2c(CC)cccc2CC)[n+]([O-])cc1C(=O)OC
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1cc(-c2c(CC)cccc2CC)nc(Cl)c1C(=O)OC
Temperature: 80 °C

Procedure:
A mixture of 6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester N-oxide (1.7 g) and POCl3 (10 mL) is heated at 80° C. for 2 hours. The volatile material is removed in vacuo. Ice water and ether is added to the residue. The organic layer is separated and the aqueous layer is extracted with ether. The combined extract is washed with brine, dried, and concentrated to give 2-chloro-6-(2,6-diethyl-phenyl)-4-ethyl-nicotinic acid methyl ester. 1H NMR (CDCl3) 7.26 (t, 1H), 7.12 (d, 3H), 4.02 (s, 3H), 2.69 (q, 2H), 2.32 (m, 4H), 1.25 (t, 3H), 1.07 (t, 6H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[Cl:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[C:16]([Cl:24])[C:15]=1[O:25][C:26]1[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[NH:28][N:27]=1.Cl>C(OCC)(=O)C>[Cl:24][C:16]1[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[CH:19]=[C:14]([Cl:13])[C:15]=1[O:25][C:26]1[CH:30]=[C:29]([C:31]([O:33][CH3:34])=[O:32])[N:28]([C:11](=[O:12])[NH:10][CH2:8][CH3:9])[N:27]=1
Reactant: COC(=O)c1cc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reactant: CCN=C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1nc(Oc2c(Cl)cc(C(F)(F)F)cc2Cl)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 23.5 %

Procedure:
Triethylamine (0.20 g, 2.0 mmol) and ethyl isocyanate (0.14 g, 2.0 mmol) were added to a solution of methyl 3-(2,6-dichloro-4-trifluoromethylphenyloxy)pyrazole-5-carboxylate (0.53 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (chloroform), to give a white solid of methyl 3-(2,6-dichloro-4-trifluoromethylphenyloxy)-1 (N-ethylcarbamoyl)pyrazole-5-carboxylate (0.15 g, yield: 23.5%). mp: 88-90° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.20 (t, J=7.3 Hz, 3H), 3.37 (dq, J=6.0 and 7.3 Hz, 2H), 3.95 (s, 3H), 6.21 (s, 1H), 6.40-6.60 (m, 1H), 7.68 (d, J=0.5 Hz, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].N1CCCCC1>C(O)C>[CH:4]1[C:5](/[CH:6]=[C:14]2\[C:13]([NH:12][C:11]([S:10]\2)=[O:16])=[O:15])=[CH:8][CH:9]=[C:2]([OH:1])[CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)/C(=C\c2ccc(O)cc2)S1

Procedure:
4-(Thiazolidin-2,4-dione-5-ylidinemethyl)-phenol (38) was synthesized by the condensation of 4-hydroxy benzaldehyde (36) with commercially available 2,4-thiazolidinedione (37) using piperidine as base in refluxing ethanol, according to a known procedure (Momose, Y.; Meguro, K.; Ikeda, H.; Hatanaka, C.; Oi, S.; Sohda, T. Chem. Pharm. Bull. 1991, 39, 1440.) (Scheme 2)
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].C(O[CH:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])C>CCO>[NH2:14][C:13]1[N:4]([CH2:3][CH2:2][OH:1])[N:5]=[CH:9][C:10]=1[C:11]#[N:12]
Reactant: NNCCO
Reactant: CCOC=C(C#N)C#N
Solvent: CCO
Product: N#Cc1cnn(CCO)c1N
Temperature: 25 °C
Yield: 70.3 %

Procedure:
A solution of 2-hydroxyethylhydrazine (38.9 g.) in EtOH (425 ml.) was heated to 50° while a solution of ethoxymethylenemalononitrile (52 g.) in warm EtOH (250 ml.) was added over a period of ten minutes. The last of this material was washed into the reaction flask with EtOH (50 ml.), and the mixture was heated under reflux for 2.5 hours. The resulting solution was allowed to cool to room temperature overnight. The golden-brown crystals which formed were collected by filtration, washed with ether, and dried in vacuo at room temperature to give 5-amino-4-cyano-1-(2-hydroxyethyl)pyrazole (45.57 g.): m.p. 158°-160 °.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26](/[CH:33]=C/N(C)C)[N:25]=[C:24]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:45].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:26]([CH:33]=[O:45])[N:25]=[C:24]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)c1c(/C=C/N(C)C)nc(N2CCOCC2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)c1c(C=O)nc(N2CCOCC2)nc1Nc1ccc(CN2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(E)-ethyl 4-(4-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)phenylamino)-6-(2-(dimethylamino)vinyl)-2-morpholinopyrimidine-5-carboxylate (0.2 g, 0.336 mmol) was dissolved in methanol (4 mL) and to this mixture at room temperature was added a solution of sodium periodate (0.21 g, 1 mmol) in methanol (4 mL). The mixture was stirred at room temperature for 3 hours and the precipitate filtered. The filtrate was evaporated, diluted with water and extracted with EtOAc. The organic layer was dried over Na2SO4 and evaporated in vacuum. The crude product was purified by column chromatography over silica gel using acetone/dichloromethane as eluent. (0.11 g). 1H NMR (400 MHz, DMSO-d6): δ 10.07 (s, 1H), 10.02 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 4.31 (q, J=6.8 Hz, 2H), 3.83 (s, 2H), 3.75-3.65 (m, 8H), 3.33 (m, 4H), 2.32 (m, 4H), 1.38 (s, 9H), 1.31 (t, J=6.8 Hz, 3H); MS m/z 555.5 (M+1).