Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:8]([NH:14][C:15](=[O:19])[CH:16](Cl)[CH3:17])([CH2:12][OH:13])[CH:9]([F:11])[F:10])[CH:7]=1.[OH-].[K+]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:8]2([CH:9]([F:11])[F:10])[NH:14][C:15](=[O:19])[CH:16]([CH3:17])[O:13][CH2:12]2)[CH:7]=1
Reactant: CC(Cl)C(=O)NC(CO)(c1cc(Br)ccc1F)C(F)F
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CC1OCC(c2cc(Br)ccc2F)(C(F)F)NC1=O

Procedure:
A solution of N-[1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-2-chloro-propionamide first eluting diastereomer (442 mg, 1.180 mmol) in 4.4 mL acetonitrile was treated with potassium hydroxide (86 mg, 1.298 mmol) and stirred over night. Additional potassium hydroxide (26 mg, 0.472 mmol) was added and the reaction mixture was stirred for another night. Eventually, the reaction mixture was partitioned between 1N HCl and EtOAc. The layers were separated, washed with brine and EtOAc. The combined organic layers were dried over MgSO4.H2O and evaporated. The crude product was crystallized from TBME to give 251 mg of the title compound as white crystals.
Reaction SMILES: [OH-].[K+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([OH:14])=[O:13])[CH:10]=2)[CH:5]=[CH:4]1.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CO>[CH2:15]([N:22]1[CH2:23][CH:24]=[C:25]([C:5]2[C:6]3[C:11](=[CH:10][C:9]([C:12]([OH:14])=[O:13])=[CH:8][CH:7]=3)[NH:3][CH:4]=2)[CH2:26][CH2:27]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2c(C3=CCN(Cc4ccccc4)CC3)c[nH]c2c1
Reaction time: 15 h
Yield: 240.5 %

Procedure:
2.6 g potassium hydroxide are suspended in 25 ml of methanol and 2.5 g 1H-indole-6-carboxylic acid and 5.5 g 1-benzyl-piperidin-4-one are added. The reaction mixture is stirred for 15 hours at reflux temperature and then evaporated to dryness. The residue is combined with hydrochloric acid (1 M) and evaporated to dryness. The residue is treated with methanol and diethyl ether and the solid is suction filtered. 12.4 g product are obtained as a solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:8][C:9](=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH2:16]Cl)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([N:8]2[CH2:16][C:11]3[C:10](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:9]2=[O:18])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Br)cccc1NC(=O)c1ccccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Br)cccc1N1Cc2ccccc2C1=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
A solution of 3-bromo-2-methylaniline (10 g, 53.7 mmol) in DCM (200 mL) at 0° C. was treated with TEA (14.98 mL, 107 mmol), followed by dropwise addition of 2-(chloromethyl)benzoyl chloride (10.16 g, 53.7 mmol) in DCM (50 mL) over 1 h. The mixture was diluted with DCM (ca. 1 L), washed with NaHCO3 (aq) and water, and concentrated to remove most of the solvent. The precipitate was collected by filtration and washed with DCM (2×10 mL) to provide N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide as a white solid (8.0 g). The filtrate was concentrated further, resulting in additional precipitate which was collected by filtration and washed with DCM (2×10 mL) to provide additional N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide as a white solid (3.06 g), for a combined yield of 61%. Mass spectrum 338, 340, 342 The filtrate was concentrated and purified by column chromatography (hexane-EtOAc) to provide 2-(3-bromo-2-methylphenyl)isoindolin-1-one as a yellow solid (2.0 g, 12%). A solution of the N-(3-bromo-2-methylphenyl)-2-(chloromethyl)benzamide (11.06 g, 32.7 mmol) in DMF (50 mL) was cooled to 0° C. and treated with a mixture of sodium hydride (60% oil dispersion, pre-washed with hexane, 1.70 g, 42.5 mmol) and DMF (10 mL). The mixture was stirred at 0° C. for 1.5 h, then was treated with water. The precipitate was collected by filtration, dried and combined with the material purified by column chromatography (see above) to provide 2-(3-bromo-2-methylphenyl)isoindolin-1-one as a yellow solid (9.41 g, 95%). 1H NMR (400 MHz, chloroform-d) δ 7.96 (1 H, d, J=7.5 Hz), 7.58-7.67 (2 H, m), 7.49-7.57 (2 H, m), 7.20-7.25 (1 H, m), 7.15 (1 H, t, J=7.9 Hz), 4.72 (2 H, s), 2.31 (3 H, s). Mass spectrum m/z 302, 304 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][NH2:10].F[C:12]1[N:19]=[CH:18][CH:17]=[C:16]([I:20])[C:13]=1[CH:14]=O>CN1C(=O)CCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:12]2=[N:19][CH:18]=[CH:17][C:16]([I:20])=[C:13]2[CH:14]=[N:10]1
Reactant: O=Cc1c(I)ccnc1F
Reactant: NNc1c(F)cccc1F
Solvent: CN1CCCC1=O
Product: Fc1cccc(F)c1-n1ncc2c(I)ccnc21
Temperature: 185 °C
Yield: 111.5 %

Procedure:
To a dry 15 mL ChemGlass pressure bottle under N2 was added (2,6-difluorophenyl)hydrazine (431 mg, 2.99 mmol), 2-fluoro-4-iodonicotinaldehyde (750 mg, 2.99 mmol) and anhydrous NMP (4.5 mL). The reaction mixture was flushed with argon, securely capped and heated to 185° C. for 1.5 h. The reaction mixture was worked up according to the general procedure described in Intermediate 69A to give 1.19 g (quantitative yield) of the title compound (contains approximately 50% of the hydrazone intermediate) as thick, dark oil. LC/MS (Condition B): ret. T=3.5 min, (M+H)+ 357.91.
Reaction SMILES: [Na].CC(C)=O.Cl.[C:7]([NH2:15])(=[NH:14])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:16][S:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1>C1C=CC=CC=1.CCCCC>[CH3:16][S:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][C:25]([NH:14][C:7](=[NH:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[S:26])=[CH:22][CH:23]=1
Reactant: CCCCCCC(=N)N
Reactant: CSc1ccc(N=C=S)cc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Solvent: c1ccccc1
Solvent: CCCCC
Product: CCCCCCC(=N)NC(=S)Nc1ccc(SC)cc1

Procedure:
Following a procedure similar to that described in Example 42 but using 3.4 g. sodium in 500 ml. dry acetone, 24.7 g. heptanamidine hydrochloride, and 27.2 g. 4-(methylthio)phenyl isothiocyanate (m.p. 60°-61°C.; prepared from 4-methylthioaniline) in 120 ml. dry acetone there was obtained 1-[4-(methylthio)phenyl]-3-(heptanimidoyl)-2-thiourea, m.p. 100°-101°C. (from benzene-n-pentane); hydrochloride (43.5 g.), m.p. 181°-182°C.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C@@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([CH3:14])([CH3:13])[CH3:12])=[N:9][CH:10]=2)[C@@H:3]1[C:15]([O:17]CC)=[O:16].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1([CH3:20])[C@@H:4]([C:5]2[CH:6]=[N:7][C:8]([C:11]([CH3:12])([CH3:13])[CH3:14])=[N:9][CH:10]=2)[C@@H:3]1[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)[C@H]1[C@H](c2cnc(C(C)(C)C)nc2)C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ncc([C@H]2[C@H](C(=O)O)C2(C)C)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.9 %

Procedure:
A solution of ethyl trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl)pyrimidin-5-yl]cyclopropane carboxylate (2.6 g) in ethanol (50 cm3) was mixed with a solution of sodium hydroxide (1.0 g) in water (50 cm3) and the mixture stirred at the ambient temperature for 5 hours. After removal of the bulk of the ethanol by evaporation under reduced pressure the pH of the residual mixture was adjusted to 3 with dilute hydrochloric acid. The mixture was extracted with diethyl ether (2×200 cm3), and the combined extracts washed with water and dried over anhydrous magnesium sulphate. Evaporation of the ether under reduced pressure yielded trans-2,2-dimethyl-3-[2-(2-methylprop-2-yl)pyrimidin-5-yl]cyclopropane carboxylic acid (2.1 g), melting point 168°-9° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][CH:13]=[N:14][C:15]([NH:16][C@@H:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:18]O)=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)Cl>C(Cl)Cl>[C:1]1([N:7]2[C:11]3[N:12]=[CH:13][N:14]4[CH2:18][C@H:17]([CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:16]=[C:15]4[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC[C@H](Cc1ccccc1)Nc1ncnc2c1cnn2-c1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: C1=Nc2c(cnn2-c2ccccc2)C2=N[C@@H](Cc3ccccc3)CN12

Procedure:
Next, 300 mg of the above product (S)-β-[(1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzenepropanol was dissolved in 15 ml CH2Cl2 followed by addition of 0.44 ml SOCl2. The reaction was heated to reflux for 3.5 hours. The solvent was then removed under a stream of nitrogen. The white solid was recrystallized from about 30% isopropyl alcohol/hexane followed by a second recrystallization from about 5% MeOH/butanone to yield 45 mg of (S)-2,7-dihydro-7-phenyl-2-(phenylmethyl)-3H-imidazo[1,2-c]pyrazolo[4,3-e]pyrimidine after drying under vacuum at 39° C. for 5 days (m.p. 255° C.).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][NH:26][CH2:25]2>CN(C=O)C>[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[CH2:27][N:26]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=1[F:16])[CH2:25]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: Fc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4ccc(F)cc4C3)c(F)cc2c1=O
Yield: 45.4 %

Procedure:
170 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid, 247 mg of 5- fluoroisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 109 mg of the target compound.
Reaction SMILES: [CH2:1]1[C:6](=[O:7])[O:5][CH2:4][C:2]1=[O:3].C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.[CH2:27]([C:34]1[CH:49]=[CH:48][C:37]([O:38][CH:39](C)[CH2:40][CH2:41][CH2:42][CH2:43][C:44](O)=[O:45])=[CH:36][CH:35]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:27]([C:34]1[CH:49]=[CH:48][C:37]([O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][C:44]([C:1]2[C:6](=[O:7])[O:5][CH2:4][C:2]=2[OH:3])=[O:45])=[CH:36][CH:35]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: O=C1COC(=O)C1
Reactant: CCCCCCCc1ccc(OC(C)CCCCC(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCc1ccc(OCCCCCC(=O)C2=C(O)COC2=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 49.2 %

Procedure:
To a stirring solution of 1.1 g (10.98 mmol) of tetronic acid in 25 mL of dimethylformamide is added 1.53 mL (10.98 mmol) of triethylamine and 400 mg of 4-dimethylaminopyridine at 0° C. Next, 2.28 g (11.98 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 3.38 g (10.98 mmol) of 6-(4-heptylphenoxy)heptanoic acid are added and the reaction mixture is stirred for 3 days at room temperature. The reaction mixture is acidified with 1.0N HCl and extracted with three 200 mL portions of ether. The combined organic layers are dried over MgSO4 and concentrated in vacuo. Trituration of the crude product in ethyl acetate/hexane affords 2.1 g (50%) of 3-[6-(4-heptylphenoxy)-1-oxohexyl]-4-hydroxy-2(5H)-furanone.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:32]([N:35]1[CH:39]([C:40]2[CH:41]=[CH:42][C:43]([O:51][CH3:52])=[C:44]([CH:50]=2)[O:45][CH2:46][C:47](O)=[O:48])[CH2:38][C:37]([C:53]2[CH:58]=[C:57]([O:59][CH3:60])[C:56]([O:61][CH3:62])=[C:55]([O:63][CH3:64])[CH:54]=2)=[N:36]1)(=[O:34])[CH3:33]>ClCCl.O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:47](=[O:48])[CH2:46][O:45][C:44]1[CH:50]=[C:40]([CH:39]2[N:35]([C:32](=[O:34])[CH3:33])[N:36]=[C:37]([C:53]3[CH:58]=[C:57]([O:59][CH3:60])[C:56]([O:61][CH3:62])=[C:55]([O:63][CH3:64])[CH:54]=3)[CH2:38]2)[CH:41]=[CH:42][C:43]=1[O:51][CH3:52]
Reactant: Nc1nc2ccccc2s1
Reactant: COc1ccc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NN2C(C)=O)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NN2C(C)=O)cc1OCC(=O)Nc1nc2ccccc2s1
Yield: 799.1 %

Procedure:
To a solution of 2-aminobenzothiazole (359.37 ma, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 ma, 0.1 mmol). Then added 2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetic acid (3) (458 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (10a) (472 mg, 80% yield)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:22])[C:6]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)=[CH:7][CH:8]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:6]2[C:5]([NH:22][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[O:21])=[CH:12][CH:13]=1)([CH3:18])([CH3:19])[CH3:20]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(NC(=O)c2ccc(C(C)(C)C)cc2)c(N)c1
Product: COc1ccc(C(=O)Nc2cc(OC)ccc2NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 99 %

Procedure:
Using the procedure described in Example 68, Part A, 4-methoxy-N1-(4-tert-butylbenzoyl)-1,2-benzenediamine (3.35 g, 10.1 mmol) was reacted with 4-methoxybenzoyl chloride to yield 1.45 g (99%) of the title compound as a white solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([C:28]#[C:29][Si](C)(C)C)[CH:26]=[CH:27][C:21]=2[N:20]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]>CO>[C:7]([O:11][C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[C:19]1[NH:23][C:22]2[CH:24]=[C:25]([C:28]#[CH:29])[CH:26]=[CH:27][C:21]=2[N:20]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(C#C[Si](C)(C)C)cc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc2nc(C3CCCN3C(=O)OC(C)(C)C)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.7 %

Procedure:
Potassium carbonate (144 mg) was added to 2-(6-trimethylsilanylethynyl-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (200 mg, 0.52 mmol) in 6 ml methanol. The reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, 20 to 100% ethyl acetate/hexane) to give 2-(6-ethynyl-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (121 mg, yield 75%). LCMS-ESI−: calc'd for C18H21N3O2: 311.38. Found: 311.8 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH2:17][NH:18][CH:19]3[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:37]=2[S:38][C:39]=1[C:40](Cl)=[O:41]>>[Cl:34][C:35]1[C:36]2[C:46]([F:47])=[CH:45][CH:44]=[C:43]([F:48])[C:37]=2[S:38][C:39]=1[C:40]([N:18]([CH2:17][C:11]1[CH:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)[CH:14]=[CH:13][C:12]=1[O:15][CH3:16])[CH:19]1[CH2:24][CH2:23][CH:22]([N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:21][CH2:20]1)=[O:41]
Reactant: O=C(Cl)c1sc2c(F)ccc(F)c2c1Cl
Reactant: COc1ccc(-c2cccc(C#N)c2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2cccc(C#N)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Biaryl amine 22 (475 mg, 1.06 mmol) is treated with acid chloride 8 (338 mg, 1.27 mmol) using Method D to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[OH-].[K+].CCOCC.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>O>[CH2:21]([O:20][C:18]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(S)[C@H](N)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CC(C)(S)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 0 °C
Yield: 71 %

Procedure:
To L-penicillamine (15.75 g; 105.8 mmol) was added a solution of KOH (12.4 g; 222.2 mmol) in water (250 ml). When the solution was complete, Et2O (100 ml) was added and the solution cooled to 0° C. Benzyl chloroformate (14.9 ml; 105.8 mmol) was added dropwise and the stirred reaction mixture allowed to warm to RT. The layers were separated, the aqueous layer acidified to pH 1-1.5 with 1N hydrochloric acid, extracted with CH2Cl2 (×3) and dried (MgSO4). The solvent was removed in vacuo to yield N-benzyloxycarbonyl-L-penicillamine (21.27 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C@H:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][NH:13][C:12]1=[O:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24](I)[CH3:25]>[Ag]=O.CN(C)C=O>[CH2:24]([N:13]1[CH2:14][C@@H:15]([C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[N:11]([C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])[C:12]1=[O:23])[CH3:25]
Reactant: CC(C)(C)OC(=O)[C@@H]1CNC(=O)N1C(=O)OCc1ccccc1
Reactant: CCI
Agent: O=[Ag]
Solvent: CN(C)C=O
Product: CCN1C[C@@H](C(=O)OC(C)(C)C)N(C(=O)OCc2ccccc2)C1=O
Yield: 59.4 %

Procedure:
9.6 g of tert.-butyl (4S)-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate, 14.0 g of silver oxide, 46.8 g of ethyl iodide and 200 ml of dimethylformamide are treated in the same manner as described in Example 1-(2). 6.2 g of tert.-butyl (4S)-1-ethyl-3-benzyloxycarbonyl-2-oxo-imidazolidine-4-carboxylate are obtained as colorless crystals.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1)#[N:3].C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26]>ClCCl>[C:2]([C:4]1[CH:5]=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:25]([O:27][CH2:28][C:29]([Cl:32])([Cl:31])[Cl:30])=[O:26])[CH2:13][CH2:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1)#[N:3]
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: N#Cc1cc(F)cc(N2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(F)cc(N2CCN(C(=O)OCC(Cl)(Cl)Cl)CC2)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In 30 ml of dichloromethane was suspended 2.54 g of 1-(3-cyano-5-fluorophenyl)piperazine hydrochloride, and the suspension was cooled to 0° C. To the suspension were added 7.3 ml of triethylamine and 3 ml of 2,2,2-trichloroethyl chloroformate, followed by stirring at room temperature for 2 hours. The reaction mixture was washed with water and then with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column chromatography using chloroform as a developing solvent. The fraction containing the desired compound was concentrated to give 4.79 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].C(N(C(C)C)CC)(C)C.Cl[C:20]([O:22][CH3:23])=[O:21]>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[N:4]([CH3:5])[C:20](=[O:21])[O:22][CH3:23]
Reactant: COC(=O)Cl
Reactant: CNc1ccccc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N(C)c1ccccc1Br
Reaction time: 8 h

Procedure:
2-Bromo-N-methylaniline (1.00 g, 5.37 mmol) and diisopropylethylamine (2.0 ml, 11.50 mmol) were dissolved in dichloromethane (50 mL) and cooled in an ice bath. Methyl chloroformate (1.0 ml, 12.94 mmol) was added dropwise and the reaction stirred overnight. The reaction mixture was partitioned between water (200 mL) and ethyl acetate (200 mL). The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[CH:20]=2)=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([C:20]2[C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[S:23][C:19]=2[C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2sc3ccccc3c2C(=O)c2ccc(Cl)nc2)cc1
Yield: 31 %

Procedure:
By essentially following the procedure detailed in Example 1, Part C, the title compound was prepared from 6-chloronicotinic acid and 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3, Part A) in 31% yield as a yellow solid following flash chromatography (SiO2; CH2Cl2).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][C:11](=[O:26])/[CH:12]=[CH:13]/[C:14]2[S:24][C:23]3[N:25]4[C:16](=[CH:17][N:18]=[C:19]4[CH:20]=[CH:21][CH:22]=3)[CH:15]=2)[CH2:5][CH2:4]1.Br[CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(O)C>[C:31]1([CH2:30][CH2:29][CH2:28][N:3]2[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][C:11](=[O:26])/[CH:12]=[CH:13]/[C:14]3[S:24][C:23]4[N:25]5[C:16](=[CH:17][N:18]=[C:19]5[CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[CH2:5][CH2:4]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(/C=C/C1=Cc2cnc3cccc(n23)S1)CCC1CCNCC1
Reactant: BrCCCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(/C=C/C1=Cc2cnc3cccc(n23)S1)CCC1CCN(CCCc2ccccc2)CC1

Procedure:
A solution of 0.362 g (0.878 mM) of (E)-5-(piperidin-4-yl]-1-(5-thia-1,8b-diazaacenaphthylen-4-yl)-1-penten-3-one dihydrochloride, 0.26 g (1.32 mM) of 1-bromo-3-phenylpropane, and 0.43 ml (3.07 mM) of triethylamine in 30 ml of ethanol was refluxed for 1 day. The reaction mixture was then poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol : 9/1) to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:33]=[CH:32][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH3:22])=[CH:16][C:15]=3[N+:23]([O-:25])=[O:24])=[C:11]([C:27]([O:29]CC)=[O:28])[N:10]=[N:9]2)=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([C:13](=[O:26])[C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([CH3:22])=[CH:16][C:15]=3[N+:23]([O-:25])=[O:24])=[C:11]([C:27]([OH:29])=[O:28])[N:10]=[N:9]2)=[CH:32][CH:33]=1
Reactant: CCOC(=O)c1nnn(Cc2ccc(OC)cc2)c1C(=O)c1cc(OC)c(C)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(Cn2nnc(C(=O)O)c2C(=O)c2cc(OC)c(C)cc2[N+](=O)[O-])cc1

Procedure:
In the same manner as above, a solution of ethyl 1-(4-methoxybenzyl )-5-(5-methoxy-4-methyl-2-nitrobenzoyl)-1,2, 3-triazole-4-carboxylate (b-2) (288 mg, 0.638 mmole) in tetrahydrofuran (7 ml) was hydrolyzed with a 1N aqueous sodium hydroxide solution (1.3 ml) at room temperature for 4.5 hours to give 1-(4-methoxybenzyl)-5-(5-methoxy-4-methyl-2-nitrobenzoyl )-1,2,3-triazole-4-carboxylic acid (c-2': MP) (256 mg, 94%).