Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]1([C@@H:17]2[C@@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:20][C:19]3([CH2:31][CH2:30][C@H:29]([CH2:32]S(C4N(C5C=CC=CC=5)N=NN=4)(=O)=O)[CH2:28]3)[O:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH:47]1([C:50]2[CH:51]=[CH:52][C:53]([C:58]([C:60]3[CH:65]=[CH:64][C:63]([CH2:66][CH3:67])=[CH:62][CH:61]=3)=O)=[N:54][C:55]=2[O:56][CH3:57])[CH2:49][CH2:48]1.[Cl-].[NH4+]>O1CCCC1>[CH:47]1([C:50]2[C:55]([O:56][CH3:57])=[N:54][C:53](/[C:58](/[C:60]3[CH:61]=[CH:62][C:63]([CH2:66][CH3:67])=[CH:64][CH:65]=3)=[CH:32]/[C@H:29]3[CH2:30][CH2:31][C:19]4([O:20][C@H:21]([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=5)[C@@H:17]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=5)[O:18]4)[CH2:28]3)=[CH:52][CH:51]=2)[CH2:48][CH2:49]1
Reactant: CCc1ccc(C(=O)c2ccc(C3CC3)c(OC)n2)cc1
Reactant: O=S(=O)(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1nnnn1-c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCc1ccc(/C(=C\[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c2ccc(C3CC3)c(OC)n2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 1 M solution of lithium hexamethyldisilazide in tetrahydrofuran (4.0 mL) was added to a solution of 5-({[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]methyl}sulfonyl)-1-phenyl-1H-tetrazole obtained in Reference Example 3-1 (2.01 g) in tetrahydrofuran (20 mL) in a nitrogen gas stream at −78° C., and the mixture was stirred at −78° C. for one hour. A solution of (5-cyclopropyl-6-methoxypyridin-2-yl)(4-ethylphenyl)methanone obtained in Reference Example 1-53 (700 mg) in tetrahydrofuran (10 mL) was added, and the mixture was stirred at −78° C. to 0° C. for one hour. The reaction solution was poured into a saturated ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:chloroform=1:1) to give 3-cyclopropyl-6-[(E)-2-[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]-1-(4-ethylphenyl)ethenyl]-2-methoxypyridine as a colorless amorphous (270 mg, 24%).
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][NH2:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23]>>[F:1][C:2]1[C:10]2[S:9][C:8]([C:11]3[N:31]([C:28]4[CH:27]=[CH:26][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:30][CH:29]=4)[N:32]=[C:13]([C:14]([F:17])([F:16])[F:15])[CH:12]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: O=C(CC(=O)C(F)(F)F)c1nc2cccc(F)c2s1
Agent: Cl
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2nc3cccc(F)c3s2)cc1
Yield: 38 %

Procedure:
The procedure of Example 9 was repeated using 1-(7-fluorobenzothiazol-2-yl)-4,4,4-trifluorobutane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 7-fluoro-2-[1-(4-methylsulfonylphenyl)-3-trifluoromethyl-1H-pyrazol-5-yl]benzothiazole (yield, 38%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11]O)=[CH:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]C(Br)(Br)Br>ClCCl>[Br:32][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCc1c[nH]c2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.4 %

Procedure:
2-(indol-3-yl)ethanol (623 mg, 3.86 mmol) was dissolved in dichloromethane (20 mL) and the solution was cooled to 0° C. Triphenylphosphine (1.12 g, 4.25 mmol) and tetra-bromomethane (1.41 g, 4.25 mmol) were then added thereto, followed by stirring for 1 hour. After the reaction was completed, the reaction mixture was concentrated under reduced pressure to remove the solvent. The resulting residue was purified by column chromatography to afford the title compound (765 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][C:28]([O:30]CC)=[O:29])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH:14]=[CH:13][C:12]=1[Cl:26])=[O:10].O>C(O)(=O)C.Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:27][C:28]([OH:30])=[O:29])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([C:11]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH:14]=[CH:13][C:12]=1[Cl:26])=[O:10]
Reactant: CCOC(=O)Cc1ccc(NC(=O)c2cc(OCc3cccc(Cl)c3)ccc2Cl)c(Cl)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)Cc1ccc(NC(=O)c2cc(OCc3cccc(Cl)c3)ccc2Cl)c(Cl)c1
Yield: 45.9 %

Procedure:
A solution of ethyl (3-chloro-4-{[(2-chloro-5-{[(3-chlorophenyl)methyl]oxy}phenyl)carbonyl]amino}phenyl)acetate (72 mg, 0.15 mmol) in acetic acid (3 ml) and 2M HCl (3 ml) was heated at 90° C. for 2 hours. On cooling water was added and the mixture filtered. The resulting solid was dried in vac oven, then triturated with ether to afford the title compound as an off-white solid (32 mg). MS (ES+) m/z 464 [M+H]+ (C24H2035Cl3NO4). 1H-NMR (400 MHz, d6-DMSO) δ 3.63 (2H, s), 5.20 (2H, s), 7.17 (1H, dd, J 8.8, J 2.8), 7.25-7.60 (10H, m), 10.18 (1H, s), 12.5 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])O.[Na+].[N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[S:27](Cl)(=[O:29])=[O:28])[CH:20]=[CH:19][CH:18]=1>O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][S:27]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:26]=2[N:17]=[CH:18][CH:19]=[CH:20]3)(=[O:28])=[O:29])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O)c1cc(F)ccc1NS(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A reaction mixture of 10.0 g (64 mmol) of 5-fluoro-2-aminobenzoic acid, 16.3 g (193 mmol) of sodium hydrogencarbonate and 16.3 g of 8-quinoline-sulfonyl chloride in 325 ml of water and 325 ml of ethyl acetate was stirred overnight at RT. The aqueous phase was separated off and extracted once with 50 ml of ethyl acetate. The aqueous phase was then rendered acidic using conc. hydrochloric acid and stirred for 2 h. The precipitate deposited was filtered off with suction, dried in vacuo and 19.5 g of 5-fluoro-2-(quinoline-8-sulfonylamino)benzoic acid were obtained.
Reaction SMILES: O.[Na].[SH:3][C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1.[Cl-].[CH3:11][NH+:12]1[CH:16]=[CH:15][N:14]([CH3:17])[CH:13]1[S:18][CH2:19][C:20](=[O:23])[CH2:21][Cl:22]>C(O)C>[Cl-:22].[CH3:17][NH+:14]1[CH:15]=[CH:16][N:12]([CH3:11])[CH:13]1[S:18][CH2:19][C:20](=[O:23])[CH2:21][S:3][C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1
Reactant: Cn1nnnc1S
Reactant: CN1C=C[NH+](C)C1SCC(=O)CCl
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CN1C=C[NH+](C)C1SCC(=O)CSc1nnnn1C

Procedure:
To a solution of 0.271 g (0.00196 mol) of 5-mercapto-1-methyltetrazole sodium salt hydrate in 30 mL of absolute ethanol was added 0.50 g (0.0020 mol) of 1,3-dimethyl-2-[(3-chloro-2-oxopropyl)thio]- 1H-imidazolium chloride whereupon a white precipitate formed immediately. The precipitate was removed by filtration and was recrystallized from ethanol to obtain the desired 1,3-dimethyl-2-({3-[(1-methyl-1H-tetrazol-5-yl)thio]-2-oxopropyl}thio)-1H-imidazolium chloride, m.p. 196-197° C.
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][O:18][CH2:19][C:20]1[N:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=1>ClCCl>[N:26]([C:22]1[CH:21]=[C:20]([CH2:19][O:18][CH3:17])[N:25]=[CH:24][N:23]=1)=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COCc1cc(N)ncn1
Solvent: ClCCl
Product: COCc1cc(N=C=S)ncn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
To a bright orange solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.84 g, 3.59 mmol) was in dichloromethane at ambient temperature was added 6-(methoxymethyl)pyrimidin-4-amine (0.5 g, 3.59 mmol). The orange solution was stirred at ambient temperature for 18 h. The solution was purified by column chromatography (0-40% ethyl acetate/hexanes) to afford 4-isothiocyanato-6-(methoxymethyl)pyrimidine (0.32 g, 1.77 mmol, 49% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.91 (1H, d, J=1.26 Hz), 7.19 (1H, d, J=1.01 Hz), 4.52 (2H, s), 3.49 (3H, s). MS (LC/MS) R.T.=1.39; [M+H]+=182.10.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=[C:4]([F:17])[N:3]=1.[C@H:18]1([NH2:25])[CH2:23][CH2:22][C@H:21]([NH2:24])[CH2:20][CH2:19]1>C(O)C>[F:17][C:4]1[N:3]=[C:2]([NH:24][C@H:21]2[CH2:22][CH2:23][C@H:18]([NH2:25])[CH2:19][CH2:20]2)[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[CH:5]=1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: Fc1cc(-c2c[nH]c3ncccc23)cc(F)n1
Solvent: CCO
Product: N[C@H]1CC[C@H](Nc2cc(-c3c[nH]c4ncccc34)cc(F)n2)CC1

Procedure:
A mixture of EXAMPLE 56B (0.60 g, 2.60 mmol) and trans-cyclohexane-1,4-diamine (1.04 g, 9.08 mmol) in ethanol (10 mL) was heated at in a Biotage Initiator microwave reactor at 170° C. for 80 minutes. After concentration, the residue was treated with 20% brine and extracted twice with ethyl acetate. The combined organic layers were concentrated and purified on a 110 g silica column (KP-NH from Biotage) eluting with ethyl acetate/methanol (97:3 to 90:10) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20](S(C)(=O)=O)[C:15]=3[CH:14]=2)=[CH:4][CH:3]=1.CC1([N:34]2C(C3SC4N=CN=C(S(C)(=O)=O)C=4C=3)=CN=C2)C=CC=CC1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]([CH3:26])[C:12]=2[C:13]2[S:25][C:16]3[N:17]=[CH:18][N:19]=[C:20]([NH2:34])[C:15]=3[CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC1(n2cncc2-c2cc3c(S(C)(=O)=O)ncnc3s2)C=CC=CC1
Reactant: Cn1cnc(-c2ccc(Br)cc2)c1-c1cc2c(S(C)(=O)=O)ncnc2s1
Product: Cn1cnc(-c2ccc(Br)cc2)c1-c1cc2c(N)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Example 8 but using 6-[4-(4-Bromophenyl)-1-methyl-1H-imidazol-5-yl]-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (Intermediate 68) in place of 6-(1-Methyl-4-phenyl-1H-imidazol-5-yl)-4-(methylsulfonyl)thieno[2,3-d]pyrimidine (intermediate 17); Solid (568 mg, 95%);
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[N:14][C:15]=1[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1>>[C:20]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:1]2[CH:2]([C:10]3[C:11]([O:18][CH3:19])=[N:12][CH:13]=[N:14][C:15]=3[O:16][CH3:17])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:21]=1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Reactant: COC(=O)CCCC(N)c1c(OC)ncnc1OC
Product: COc1ncnc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(4,6-dimethoxypyrimidin-5-yl)pentanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.86 min.; [M+H]+: 403.96 g/mol.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([CH:27]([C:36]([NH:38][CH2:39][C:40]([O:42]CC)=[O:41])=[O:37])[CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[CH:23][CH:22]=2)=[O:19])[CH:15]=[CH:16][CH:17]=1.C(O)(C(F)(F)F)=O.[OH-].[Li+]>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:18]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([CH:27]([C:36]([NH:38][CH2:39][C:40]([OH:42])=[O:41])=[O:37])[CH2:28][C:29]([OH:31])=[O:30])=[CH:25][CH:26]=2)=[O:19])[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CNC(=O)C(CC(=O)OC(C)(C)C)c1ccc(NC(=O)c2cccc(NC=NN)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NN=CNc1cccc(C(=O)Nc2ccc(C(CC(=O)O)C(=O)NCC(=O)O)cc2)c1
Temperature: 25 °C
Yield: 104 %

Procedure:
The compound of Example 72 (500 mg) was added to methylene chloride (5 mL) followed by the addition of TFA (2 mL). The reaction was monitored by HPLC. After the reaction was complete the product was freeze dried. The product was added to water/aceonitrile 1:1 (50 mL), followed by the addition of lithium hydroxide (100 mg, 0.4 mmol). The reaction was stirred at 25° C., and monitored by HPLC. After complete hydrolysis the product was extracted with ethyl acetate and dried over Na2SO4 to give a yellow oil (450 mg). NMR and MS were consistent with the proposed structure.
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6][C@@H:7]([C:11]([OH:13])=[O:12])[C@H:8]([CH3:10])[OH:9].Cl[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:16]>C1COCC1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:9][C@@H:8]([CH3:10])[C@@H:7]([NH:6][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:16])[C:11]([OH:13])=[O:12]
Reactant: CCCCCOC(=O)Cl
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCOC(=O)N[C@@H](C(=O)O)[C@H](C)O
Yield: 90.5 %

Procedure:
In a round bottom flask NaHCO3 (13.0 g, 155.3 mmol) was suspended in THF (35 mL) and water (70 mL), then D-threonine (7.33 g, 61.6 mmol) and tetrabutylamonium bromide (0.733 g) were added. Amyl chloroformate (10 mL, 68.4 mmol) was added dropwise and the reaction vigorously stirred 18 h at rt. The mixture was diluted with water, washed twice with Et2O and pH adjusted to 2 with 2M HCl solution. The aqueous phase was extracted with AcOEt, the collected organic phases were dried over Na2SO4, filtered and the solvent removed under vacuum to yield the tile compound (13.0 g, 90%) as pale yellow oil, which was used in the next step without further purification. Rf=0.26 (Cy/AcOEt 2:8+1% CH3COOH; detection: ninhydrin, bromocresol green). FTIR (cm−1): 3344, 2959, 2932, 2873, 1724, 1529, 1468, 1415 1378, 1258, 1075.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][CH:15]=O)[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Mg+2].[C:29](OC1C=CC([N+]([O-])=O)=CC=1)(=[O:31])[CH3:30]>C1COCC1.O.C(OCC)(=O)C>[C:29]([NH:1][CH2:2][CH2:3][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([NH:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1)(=[O:31])[CH3:30]
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCC1CCCc2ccc(NC=O)cc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1ccc2c(c1)C(CCNC(C)=O)CCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.8 %

Procedure:
To a solution of 1-(2-aminoethyl)-7-formylamino1,2,3,4-tetrahydronaphthalene (1.80 g, 8.25 mmol) in THF (20 ml) was added added, under ice-cooling, lithium aluminum hydride (0.63 g, 16.5 mmol). The mixture was heated for 4 hours under reflux under argon atmosphere. The reaction mixture was cooled with ice, to which was added water (0.9 ml), followed by further addition of ethyl acetate, anhydrous magnesium sulfate and celite, successively. The mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in DMF (20 ml). To the solution was added 4-nitrophenyl acetate (1.33 g, 7.34 mmol), and the mixture was stirred for 20 minutes at room temperature. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate. The extract solution was washed with brine, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (methanol/ethyl acetate, 97:3-96:5) to give 1.10 g (yield 54%) of the above-titled compound as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Br[C:24]1[C:33]2[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[C:28]=2[CH:27]=[N:26][CH:25]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][C:3]=1[C:24]1[C:33]2[CH2:32][CH2:31][CH2:30][CH:29]([NH:34][S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[C:28]=2[CH:27]=[N:26][CH:25]=1
Reactant: CCS(=O)(=O)NC1CCCc2c(Br)cncc21
Reactant: CN1C(=O)CCc2cc(B3OC(C)(C)C(C)(C)O3)c(Cl)cc21
Product: CCS(=O)(=O)NC1CCCc2c(-c3cc4c(cc3Cl)N(C)C(=O)CC4)cncc21
Yield: 40 %

Procedure:
In analogy to the procedure described for the preparation of example 28, 7-chloro-1-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-1H-quinolin-2-one (intermediate A-10) and (rac)-ethanesulfonic acid (4-bromo-5,6,7,8-tetrahydro-isoquinolin-8-yl)-amide (intermediate B-4) were used to give the title compound as a white solid in 40% yield. MS: 434.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.Cl[CH2:15][C:16]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[O:18][N:17]=1>>[Cl:1][C:2]1[C:10]([C:11]#[N:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[N:6]2[CH2:15][C:16]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[CH:22]=2)[O:18][N:17]=1
Reactant: FC(F)(F)c1cccc(-c2nc(CCl)no2)c1
Reactant: Cc1cc2c(Cl)c(C#N)ccc2[nH]1
Product: Cc1cc2c(Cl)c(C#N)ccc2n1Cc1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 4 from 4-chloro-2-methyl-1H-indole-5-carbonitrile and 3-(chloromethyl)-5-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazole: 1H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J=7.9 Hz, 1 H), 8.24 (s, 1 H), 8.06 (d, J=7.6 Hz, 1 H), 7.94 (d, J=1.1 Hz, 1 H), 7.87-7.79 (m, 2 H), 7.59 (dd, J=8.5, 1.5 Hz, 1 H), 5.85 (s, 2 H), 2.47 (s, 3 H); MS (ES) m/z 417 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:4][CH2:3]1.O.NN>C(O)C.C(Cl)Cl>[NH2:9][O:8][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: CN1CCC(ON2C(=O)c3ccccc3C2=O)CC1
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CN1CCC(ON)CC1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 25.4 %

Procedure:
To a solution of 2-[(1-methylpiperidin-4-yl)oxy]-1H-isoindole-1,3(2H)-dione 49 (1.18 g, 4.53 mmol) in a mixture of ethanol (3 mL) and DCM (18 mL) was added hydrazine hydrate (0.268 g, 4.53 mmol). The reaction mixture was stirred at room temperature for 4.5 h. Precipitate was filtered off. The filtrate was evaporated and sonicated in ethyl acetate (20 mL). Solid was filtered off and filtrate was evaporated to give the residue which was subjected to chromatography to give 50 (0.15 g, 25%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Cl)=[CH:6][CH:5]=[CH:4][N:3]=1.[C-:10]#[N:11].[Na+]>CS(C)=O>[Cl:1][C:2]1[C:7]([CH2:8][C:10]#[N:11])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: [C-]#N
Reactant: ClCc1cccnc1Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCc1cccnc1Cl
Temperature: 50 °C
Reaction time: 4 h
Yield: 60.6 %

Procedure:
To a solution of the compound (20.5 g) obtained in step 2 in DMSO (100 mL) was added sodium cyanide (12.4 g), and the mixture was stirred at 50° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was poured into a mixture of water and ethyl acetate. The organic layer was washed with brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 10→25% ethyl acetate/hexane) to give (2-chloropyridin-3-yl)acetonitrile (11.7 g, 61%) as a white powder.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[N:8][CH:9]=[C:10]([CH:15]=2)[C:11]([O:13]C)=[O:12])[CH:5]=[N:4][N:3]=[N:2]1.[OH-].[Li+]>C1COCC1.O>[N:1]1([C:6]2[CH:7]=[N:8][CH:9]=[C:10]([CH:15]=2)[C:11]([OH:13])=[O:12])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: COC(=O)c1cncc(-n2cnnn2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cncc(-n2cnnn2)c1
Reaction time: 1 h

Procedure:
The methyl 5-(1H-tetrazol-1-yl)nicotinate obtained in step A was dissolved in THF (50 mL) and treated with 1N lithium hydroxide (50 mL) and stirred for 1 hour. The mixture was diluted with water and the resulting solid isolated by filtration and drying under high vacuum to provide 5-(1H-tetrazol-1-yl)nicotinic acid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH3:8].[N+](=[C:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13])=[N-]>CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cu]>[CH2:3]([C:4]1[C:11]([C:16]([O:18][CH3:19])=[O:17])([C:12]([O:14][CH3:15])=[O:13])[C:5]=1[CH2:6][CH2:7][CH3:8])[CH2:2][CH3:1]
Reactant: CCCC#CCCC
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Agent: [Cu]
Solvent: CC(=O)CC(C)=O
Product: CCCC1=C(CCC)C1(C(=O)OC)C(=O)OC

Procedure:
4-Octyne and dimethyl diazomalonate were reacted in the presence of cupric acetylacetonate in a manner similar to that described in Example XCVII Part A to give dimethyl 2,3-di-n-propyl-2-cyclopropene-1,1-dicarboxylate which was saponified to give mono-methyl 2,3-di-n-propyl-2-cyclopropene-1,1-dicarboxylate and worked up by the general procedure of Example XCVII Part B. Reaction of the latter mono-methyl ester in sequence with ethyl chloroformate and 4-bromo-2-methylaniline, in the presence of potassium carbonate and 18-crown-6, in a manner similar to that described in Example XCIX Part B to give methyl 1-(4-bromo-2-methylphenyl-aminocarbonyl)-2,3-di-n-propyl-2-cyclopropenecarboxylate having a melting point of 52° C.-54° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][C:12](=[CH2:14])[CH2:11][CH:10]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[Cl:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1>C1COCC1.CCN(CC)CC>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:13][C:12](=[CH2:14])[CH2:11][CH:10]1[C:15](=[O:17])[NH:45][C:44]1[CH:46]=[CH:47][C:41]([Cl:40])=[CH:42][CH:43]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Cl)cc1
Reactant: C=C1CC(NC(=O)OC(C)(C)C)C(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=C1CC(NC(=O)OC(C)(C)C)C(C(=O)Nc2ccc(Cl)cc2)C1
Reaction time: 16 h
Yield: 64 %

Procedure:
A stirred solution of 1.085 g of 35b in 10 ml of THF was treated subsequently with 1.25 ml of NEt3, 0.69 g hydroxybenzotriazole, 1.21 g of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride and 0.63 g of 4-chloroaniline and stirring was continued at 22° C. for 16 h. The mixture was evaporated and the residue partitioned between CH2Cl2 and 1 N HCl. The separated organic layer consisting of a white suspension was filtered and the residue dried to give 1.01 g (64%) of the title compound 35c. MS: 351.4 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:32])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:31]=[CH:30][C:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][C:20]=3[CH3:29])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1.[OH-].[Na+].Cl>CO>[O:32]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:31]=[CH:30][C:10]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=3[CH3:29])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)O)ccc1N1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)cc2)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 86.2 %

Procedure:
Methyl 4-{4-[4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoyl]piperazin-1-yl}-3-methylbenzoate (1.01 g) described in Example 217 was dissolved in methanol (8 mL), 1N aqueous sodium hydroxide solution (3.3 mL) was added, and the mixture was stirred at 60° C. for 4 hr. The reaction mixture was cooled and neutralized with dilute hydrochloric acid, and the precipitate was collected by filtration to give the title compound (844 mg).