Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[CH:4][C:3]=1[N:10]1[CH2:15][CH:14]=[CH:13][CH2:12][CH2:11]1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>Cl.O>[CH:16](=[N:9][NH:8][C:5]1[N:6]=[N:7][C:2]([Cl:1])=[C:3]([N:10]2[CH2:11][CH:12]=[CH:13][CH2:14][CH2:15]2)[CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NNc1cc(N2CC=CCC2)c(Cl)nn1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: O
Product: Clc1nnc(NN=Cc2ccccc2)cc1N1CC=CCC1
Temperature: 50 °C
Yield: 90 %

Procedure:
To a suspension of [6-chloro-5-(3,6-dihydro-2H-pyridin-1-yl)-pyridazin-3-yl]hydrazine (1.0 g) in 0.1 M HCl (40 ml) at room temperature was added benzaldehyde (1.05 eq.). The mixture was heated at 50° C. for 2 hours then allowed to cool, diluted with water (100 ml) and filtered. The resulting solid was dried in vacuo, and isolated as a yellow solid (1.25 g, 90%). 1H NMR (250 MHz, CDCl3) 11.65 (1H, br s), 8.31 (1H, s), 7.73 (2H, m), 7.38 (2H, m), 7.04 (1H, s), 5.97 (1H, m), 5.83 (1H, m), 3.80 (2H, m), 3.54 (2H, m), 2.40 (2H, m). MS (ES+) 314 [MH]+, 316 [MH]+.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:8][C:9](O)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:23])=O>C1C=CC=CC=1>[C:1]1([C:7]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:8][C:9]([Cl:23])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of 22 g. of 3-phenyl-3-(4-nitrophenyl)propenoic acid, 11.7 g. of thionyl chloride and 150 ml. of benzene was heated under reflux for 1 hour. The solvent was removed by evaporation in vacuo, and the residual solid was recrystallized from carbon tetrachloride. This afforded 20 g. of the title compound, m.p. 117°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][CH2:18][NH:19]C(OC(C)(C)C)=O)[N:13]=[C:12]([NH2:27])[N:11]=2)[C:7]([CH3:28])=[CH:6][C:5]=1[O:29][CH3:30].FC(F)(F)C(O)=O.[C:39]([O:43][C:44]([NH:46][CH2:47][CH2:48][CH2:49][C:50]([OH:52])=O)=[O:45])([CH3:42])([CH3:41])[CH3:40].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>ClCCl>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][CH2:17][CH2:18][NH:19][C:50](=[O:52])[CH2:49][CH2:48][CH2:47][NH:46][C:44]([O:43][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:45])[N:13]=[C:12]([NH2:27])[N:11]=2)[C:7]([CH3:28])=[CH:6][C:5]=1[O:29][CH3:30]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: COC(=O)c1cc(-c2cc(SCCNC(=O)OC(C)(C)C)nc(N)n2)c(C)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(-c2cc(SCCNC(=O)CCCNC(=O)OC(C)(C)C)nc(N)n2)c(C)cc1OC
Reaction time: 4 h
Yield: 83.5 %

Procedure:
5-[2-Amino-6-(2-tert-butoxycarbonylaminoethylsulfanyl)pyrimidin-4-yl]-2-methoxy-4-methylbenzoic acid methyl ester (52 mg, 0.11 mmol) obtained in Step 1 above was dissolved with dichloromethane (2.5 ml) in a reaction vessel. Trifluoroacetic acid (0.7 ml) was added to the solution and stirred for 4 hours while gradually warming from 0° C. to room temperature. The reaction solution was concentrated under reduced pressure, and then benzene (1.5 ml) was added to the resulting residue. The solution was concentrated under reduced pressure. This treatment was repeated three times. The obtained pale yellow oily material was dissolved in N,N-dimethylformamide (1.5 ml). 4-tert-Butoxycarbonylaminobutanoic acid (35 mg, 0.17 mmol), N-hydroxybenzotriazole (31 mg, 0.23 mmol), and diisopropylethylamine (0.5 ml, 2.8 mmol) were added to the solution, and then 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (66 mg, 0.34 mmol) was added thereto. The resulting mixture was stirred at room temperature for 2.5 hours. A saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml). The ethyl acetate solution was sequentially washed with 1N hydrochloric acid (50 ml), water (50 ml), a saturated aqueous sodium bicarbonate solution (50 ml), water (50 ml), and a saturated aqueous sodium chloride solution (50 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate (10 g). After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate to ethyl acetate:methanol=25:1) to yield 5-{2-amino-6-[2-(4-tert-butoxycarbonylaminobutyrylamino)ethylsulfanyl]pyrimidin-4-yl}-2-methoxy-4-methylbenzoic acid methyl ester (49 mg) as a colorless syrup-like material.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH:11]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C(O)c1cccc(S(=O)(=O)c2ccccc2)c1
Product: COc1ccc(NC(=O)c2cccc(S(=O)(=O)c3ccccc3)c2)cc1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(phenylsulfonyl)benzoic acid and 4-methoxyaniline as the starting materials.
Reaction SMILES: C([O:5][PH:6]([CH2:8][C:9]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:12]([OH:19])=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=1)=[O:7])CCC.Cl>[OH-].[Na+].C(O)(C)C>[C:15]([C:13]1[CH:14]=[C:9]([CH:10]=[C:11]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:12]=1[OH:19])[CH2:8][PH:6](=[O:5])[OH:7])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCCCO[PH](=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(C)(C)c1cc(C[PH](=O)O)cc(C(C)(C)C)c1O
Temperature: 100 °C

Procedure:
17 grams (50 mmol) of (3,5-di-tert-butyl-4-hydroxy-benzyl)-phosphinic acid butyl ester in a mixture of 100 mL of 2.5 N sodium hydroxide solution and 10 mL of isopropanol is heated at 100° C. for 1 hour. The cooled reaction mixture is poured into a mixture of 25 mL of concentrated hydrochloric acid and 200 mL of ice. The product is extracted into 400 mL of chloroform and the chloroform layer is washed with 200 mL of water and then dried over sodium sulfate.
Reaction SMILES: O[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[Cl:16][C:17]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19]>>[Cl:16][C:17]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1cnc2ccnn2c1O
Reactant: Nc1cccc(Cl)c1Cl
Product: CCOC(=O)c1cnc2ccnn2c1Nc1cccc(Cl)c1Cl
Yield: 79.1 %

Procedure:
Using ethyl 7-hydroxypyrazolo[1,5-a]pyrimidine-6-carboxylate (5.0 g, 24.1 mmol) and 2,3-dichloroaniline (3.13 g, 19.3 mmol) instead of 4-fluoro-2-methylaniline, and in the same manner as in Example 1 step 1, the title compound (5.36 g, 63%) was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.C(Cl)Cl.Cl.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([S:38](Cl)(=[O:40])=[O:39])[CH:33]=1>CN(C)C1C=CN=CC=1.CN(C)C=O>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH:14]=[CH:15][C:16]([C:17]#[N:18])=[CH:19][CH:20]=3)=[CH:9][N:10]2[S:38]([C:34]2[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=2)(=[O:40])=[O:39])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#Cc1ccc(-c2c[nH]c3cc([N+](=O)[O-])ccc23)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1ccc(-c2cn(S(=O)(=O)c3cccnc3)c3cc([N+](=O)[O-])ccc23)cc1
Reaction time: 8 h
Yield: 56 %

Procedure:
Method N Combine 4-(6-nitro-1H-indol-3-yl)-benzonitrile, 9, (290 mg, 1.1 mmol), 4-dimethylaminopyridine (14 mg, 0.11 mmol), triethyl amine (740 μL, 5.3 mmol), methylene chloride (7.0 mL) and dimethylformamide (2.5 mL) in a 25 mL flask. Add 3-pyridine sulfonyl chloride hydrochloride (283 mg, 1.32 mmol). Let the solution stir overnight. Isolate the precipitate by filtration and wash the precipitate 3× with methylene chloride to yield 251 mg, 0.62 mmol, 56% of the title compound. LRMS (API ES+)=405.0 (M+H).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[NH:21][C:20]([C:23]([O:25]CC)=[O:24])=[CH:19]2)(=[O:12])=[O:11])=[O:4].CO.[OH-].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([NH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:22]=1[NH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19]2)(=[O:12])=[O:11])([OH:4])=[O:2]
Reactant: CCOC(=O)c1cc2cccc(NS(=O)(=O)c3ccsc3C(=O)OC)c2[nH]1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2cccc(NS(=O)(=O)c3ccsc3C(=O)O)c2[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.5 %

Procedure:
To a mixed solution of ethyl 7-({[2-(methoxycarbonyl)-3-thienyl]sulfonyl}amino)-1H-indole-2-carboxylate (0.35 g) in tetrahydrofuran (10 mL)-methanol (10 mL) was added aqueous solution (5 mL) of 85% potassium hydroxide (350 mg), and the mixture was stirred at room temperature for 18 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were washed with ethyl acetate-hexane to give the title compound (193 mg, yield 62%) as pale-yellow crystals. melting point 272-275° C. (decomposition).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[N:20]=4)=[CH:15][CH:14]=3)=[N:9][CH:10]=[N:11][CH:12]=2)=[CH:3][CH:2]=1.Cl.[C:32](N)(=N)C>>[CH3:32][C:10]1[N:9]=[C:8]([C:13]2[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:15][CH:14]=2)[C:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)=[CH:12][N:11]=1
Reactant: CC(=N)N
Reactant: c1ccc2nc(COc3ccc(-c4ncncc4-c4ccncc4)cc3)ccc2c1
Agent: Cl
Product: Cc1ncc(-c2ccncc2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(5-Pyridin-4-yl-pyrimidin-4-yl)-phenoxymethyl]-quinoline but substituting acetamidine hydrochloride provide the title compound. 1H NMR (400 MHz, CDCl3) δ 9.21 (s, 1H), 8.63 (s, 1H), 8.58 (m, 2H), 8.17 (d, J=8.7 Hz, 1H), 8.04 (d, J=8.7 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.70 (m, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.52 (m, 1H), 7.37 (m, 2H) 7.15 (d, J=6.2, 2H), 6.93 (d, J=9.1 Hz, 2H), 5.35 (s, 2H); MS: (M+H m/z=405.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[N:14][N:13]=[C:12]1[C:16]1[S:29][C:19]2[C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)[C:5]([OH:7])=O.[CH3:30][NH2:31]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[N:14][N:13]=[C:12]1[C:16]1[S:29][C:19]2[C:20]3[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=3[O:22][CH2:23][CH2:24][C:18]=2[CH:17]=1)[C:5]([NH:31][CH3:30])=[O:7]
Reactant: O=C(O)c1ccc(-n2cnnc2-c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1
Reactant: CN
Product: CNC(=O)c1ccc(-n2cnnc2-c2cc3c(s2)-c2ccccc2OCC3)c(Cl)c1

Procedure:
3-Chloro-4-(3-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-4H-1,2,4-triazol-4-yl)benzoic acid and methylamine were reacted by a procedure similar to that to prepare 137 in Example 47 to give 209. MS: (ESI+) 437.1
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH3:13][C@@H:14]1[S:20][C@@H:19]([C:21]([OH:23])=[O:22])[CH2:18][C:17]2[CH:24]=[C:25]3[O:30][CH2:29][O:28][C:26]3=[CH:27][C:16]=2[C:15]1=[O:31].C(OC)(=O)[C@H](C1C=CC=CC=1)O.O>ClCCl.CN(C)C=O.CN(C)C1C=CN=CC=1>[CH3:13][C@H:14]1[S:20][C@H:19]([C:21]([OH:23])=[O:22])[CH2:18][C:17]2[CH:24]=[C:25]3[O:30][CH2:29][O:28][C:26]3=[CH:27][C:16]=2[C:15]1=[O:31]
Reactant: C[C@@H]1S[C@@H](C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: COC(=O)[C@@H](O)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1S[C@H](C(=O)O)Cc2cc3c(cc2C1=O)OCO3
Temperature: 0 °C
Reaction time: 15 h
Yield: 29.8 %

Procedure:
A solution of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.5 g) in dichloromethane (200 ml) was added to a solution of (±)-trans-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (15.34 g) and methyl (S)-(+)-mandelate (18.19 g) in N,N-dimethylformamide (DMF) (200 ml) at 0° C., followed by the addition of 4-dimethylaminopyridine (DMAP) (3.34 g). This mixture was stirred at 0° C. for 1 hour and at room temperature for 15 hours, after which it was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off; the residual crystals were collected by filtration and washed with ether-hexane, followed by recrystallization twice from ethyl acetate-hexane to yield (S)-α-methoxycarbonylbenzyl ester of (2S,4R)-(+)-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxylic acid (4.57 g, 19%). Colorless needles. Melting point 141-142° C. Optical rotation [α]D (23° C.) +239.7° (c=0.50, CHCl3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][NH2:12])[C:7]([F:14])([F:13])[O:6][C:5]2([F:16])[F:15].Cl[C:18](=[CH2:21])[C:19]#[N:20].S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CO.C(N(CC(O)=O)CC(O)=O)CN(CC([O-])=O)CC([O-])=O.[Na+].[Na+]>[NH2:20][C:19]1[N:11]([C:10]2[CH:9]=[C:8]3[C:4](=[CH:3][C:2]=2[Cl:1])[C:5]([F:16])([F:15])[O:6][C:7]3([F:14])[F:13])[N:12]=[CH:21][CH:18]=1
Reactant: C=C(Cl)C#N
Reactant: NNc1cc2c(cc1Cl)C(F)(F)OC2(F)F
Agent: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CO
Product: Nc1ccnn1-c1cc2c(cc1Cl)C(F)(F)OC2(F)F
Reaction time: 4 h
Yield: 37.2 %

Procedure:
To a solution wherein 5-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-6-yl-hydrazine (900 mg, 3.5 mmol) and disodium ethylenediaminetetraacetate (1 mg) are in methanol (6 ml), 2-chloroacrylonitrile (919 mg, 10.5 mmol) was added dropwise at 60° C., and under reflux for 8 hours, subsequently concentrated sulfuric acid (0.5 ml, 9.4 mmol) was added to the solution and was further heated under reflux for 6 hours. After the reaction solution was allowed to cool, anhydrous sodium carbonate (1.17 g, 10.5 mmol) was added to the reaction solution, stirred for 4 hours, and had the solvent distilled off under reduced pressure. Subsequently, water was added to the residue, the solution was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 400 mg of 5-amino-1-(6-chloro-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-pyrazole.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][C:32]([CH:35]([OH:37])[CH3:36])=[CH:33][N:34]=3)[C@H:14]2[CH3:38])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:41][Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1.CI>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][C:32]([CH:35]([O:37][CH3:41])[CH3:36])=[CH:33][N:34]=3)[C@H:14]2[CH3:38])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(O)c1cnc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(C)c1cnc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)s1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a 0° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[5-(1-hydroxyethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 154) (13.2 mg, 0.0221 mmol) in THF (1 mL) was added NaHMDS (26.5 μL of a 1M solution in THF, 0.0265 mmol) followed by MeI (1 drop). After 1.5 hours, additional NaHMDS (15 μL of a 1M solution in THF, 0.015 mmol) and MeI (1 drop) were added to the reaction. The reaction was warmed to room temperature for 20 minutes and then quenched by pouring into saturated NH4Cl (10 mL). The mixture was extracted with EtOAc (35 mL) and the organic layer was washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (15 to 75% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[5-(1-methoxyethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.37 (40% EtOAc/hexanes). LCMS=613.0 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.87 (s, 1H), 7.74-7.82 (m, 5H), 7.67 (d, J=8.0 Hz, 1H), 6.63-5.66 (m, 1H), 5.08-5.14 (m, 1H), 4.83-4.88 (m, 1H), 4.64-4.68 (m, 1H), 4.01-4.08 (m, 1H), 3.34 (m, 3H), 1.60 (d, J=6.4 Hz, 3H), 0.69 (d, J=6.7 Hz, 3H).
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[CH3:20][O:21]C1C=CC(C=O)=CC=1>>[CH3:20][O:21][C:7]1[CH:8]=[CH:3][C:4]([C:9]2[NH:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc(C=O)cc1
Reactant: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1ccc(-c2nc3ccccc3c(=O)[nH]2)cc1
Yield: 96.4 %

Procedure:
According to the preparation of 42, 4-methoxybenzaldehyde (35) (1.0 g, 7.3 mmol) was used to afford 44 (1.8 g, 96.4%) as pale yellow needles.
Reaction SMILES: [CH2:1]([NH:4][C:5]([N:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:8]C(OC(C)(C)C)=O)=[O:6])[CH2:2][CH3:3].[CH3:23][S:24]([OH:27])(=[O:26])=[O:25]>ClCCl>[CH3:23][S:24]([OH:27])(=[O:26])=[O:25].[CH2:1]([NH:4][C:5]([N:7]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:8])=[O:6])[CH2:2][CH3:3]
Reactant: CCCNC(=O)N(Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Solvent: ClCCl
Product: CCCNC(=O)N(N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(Propylaminocarbonyl)-2-(phenylmethyl)hydrazine carboxylic acid, 1,1-dimethylethyl ester (2.33 g, 7.58 mmol) was dissolved in dichloromethane (25 mL). Methanesulfonic acid (615 μL, 9.48 mmol) was added in one portion and the solution was allowed to stir at rt overnight. The solution was heated to reflux for 8 h, then concentrated to afford the title compound as a crude white solid (2.47 g, 107%): mp 78.1-82.9° C.; 1H NMR (DMSO-d6) δ 9.7 (br s, 3H), 7.61 (br s, 1H), 7.38 (t, 1H, J=8 Hz), 7.32 (m, 4H), 4.74 (s, 2H), 3.07 (t, 2H, J=8 Hz), 2.38 (s, 3H), 1.43, (quint, 2H, J=8 Hz), 0.81 (t, 3H, J=8 Hz); 13C NMR (DMSO-d6) δ 157.5, 135.6, 129.3, 128.7, 128.6, 52.8, 42.7, 40.3, 23.3, 11.9; IR (CHCl3) 3009, 1691, 1543, 1196 cm−1; Exact Mass Calcd. For C11H17N3O: 208.1450. Found: 208.1462.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:2]=1.N1C=CC(COC2C=CC(C=O)=CC=2)=C[CH:17]=1>>[N:1]1[CH:2]=[CH:17][C:4]([CH2:3][O:7][C:8]#[C:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1
Reactant: C(#Cc1ccccc1)Oc1cccnc1
Reactant: O=Cc1ccc(OCc2ccncc2)cc1
Product: C(#Cc1ccccc1)OCc1ccncc1

Procedure:
Prepared as for 4-(pyridine-3-yloxy)ethynylbenzene, using 4-(pyridine-4-ylmethoxy)benzaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15])=[C:12]([CH3:20])[NH:11][C:10]2[CH2:21][O:22][C:23](=[O:24])[C:9]1=2.[OH-].[K+].[CH3:27]I>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16][CH2:17][CH2:18][CH3:19])=[O:15])=[C:12]([CH3:20])[N:11]([CH3:27])[C:10]2[CH2:21][O:22][C:23](=[O:24])[C:9]1=2
Reactant: CCCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1Cl
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCOC(=O)C1=C(C)N(C)C2=C(C(=O)OC2)C1c1ccccc1Cl
Reaction time: 2 h

Procedure:
50 mmol of propyl 4-(2-chlorophenyl)-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro-[3,4-b]pyridine-3-carboxylate are dissolved in 150 ml of dimethyl sulphoxide, and 7 g of potassium hydroxide powder and 50 mmol of methyl iodide are added. After 2 hours at room temperature, the mixture is poured onto ice-water and extracted with CH2Cl2, the extract is dried and evaporated down, and the residue is recrystallized.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]([C:18]2[N:19](C(OCC)=O)[C:20]3[C:25]([C:26]=2[NH:27][C:28](=[O:31])[CH2:29][CH3:30])=[CH:24][CH:23]=[C:22]([Cl:32])[CH:21]=3)=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C.C1COCC1>[Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]([C:18]2[NH:19][C:20]3[C:25]([C:26]=2[NH:27][C:28](=[O:31])[CH2:29][CH3:30])=[CH:24][CH:23]=[C:22]([Cl:32])[CH:21]=3)=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ncccc2CO[Si](C)(C)C(C)(C)C)c(NC(=O)CC)c2ccc(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(=O)Nc1c(C(=O)c2ncccc2CO[Si](C)(C)C(C)(C)C)[nH]c2cc(Cl)ccc12
Reaction time: 1.5 h
Yield: 85.6 %

Procedure:
To a solution of 2-[3-(tert-butyldimethylsilyloxymethyl)pyridine-2-carbonyl]-6-chloro-1-ethoxycarbonyl-3-(propionylamino)indole (step 4, 890 mg, 1.64 mmol) in ethanol-THF (2:1, 30 ml) was added 2N aqueous NaOH (5 ml) at 0° C. After stirring for 1.5 h, the mixture was neutralized with 2N aqueous HCl (5 ml). The mixture was concentrated and the residue was diluted with ethyl acetate (200 ml). The organic solution was washed with water (50 ml×2), dried (MgSO4), and concentrated. The residue was purified by flash column chromatography eluting with ethyl acetate/hexane (1:15) to afford 663 mg (82%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([O:33][CH2:34][CH3:35])[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:37]#[N:38])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([O:33][CH2:34][CH3:35])[C:17]([NH:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:31][CH:32]=3)=[O:18])[C:10](=[O:36])[CH:9]=2)[CH:7]=1
Reactant: CCOC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CCOC(C(=O)Nc1ccc(C(=O)O)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
260 mg (0.48 mmol) of tert-butyl 4-({[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl](ethoxy)acetyl}amino)benzoate (racemate) were hydrolysed with TFA according to General Method 2. Yield: 184 mg (79% of theory)