Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CO>C1COCC1.CCOC(C)=O>[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:21][C:19]2[CH:18]=[CH:17][C:15]3[NH:16][C:12]([C:8]4[C:7]([NH:6][C:4](=[O:5])[C:3]5[C:2]([F:1])=[CH:26][CH:25]=[CH:24][C:23]=5[F:27])=[CH:11][NH:10][N:9]=4)=[N:13][C:14]=3[CH:20]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:29])[CH3:30]
Reactant: O=Cc1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc3[nH]c(-c4n[nH]cc4NC(=O)c4c(F)cccc4F)nc3c2)CC1
Temperature: 25 °C
Yield: 111.6 %

Procedure:
To a mixture of 2,6-difluoro-N-[3-(5-formyl-1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-benzamide (50 mg, 0.14 mmol) in anhydrous THF (1.5 mL) stirring at ambient temperature was successively added 3 Å molecular sieves, piperazine-1-carboxylic acid tert-butyl ester (52 mg, 0.28 mmol) and sodium triacetoxy borohydride (90 mg, 0.42 mmol). The mixture was stirred for 4 h, MeOH (3 ml) added and then the mixture was reduced in vacuo. The residue was taken up in EtOAc, washed with brine, dried (MgSO4), reduced in vacuo and then purified through preparative LC/MS to give the title compound (84 mg) as a yellow oil. (LC/MS: Rt 2.22, [M+H]+ 538.15).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=1[NH2:16]>>[F:12][C:13]([F:25])([F:26])[C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][C:15]=1[NH:16][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[OH:11]
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: Cc1ccc(O)c(C(=O)O)c1
Product: Cc1ccc(O)c(C(=O)Nc2cc(C(F)(F)F)ccc2C(F)(F)F)c1
Yield: 1.5 %

Procedure:
Using 5-methylsalicylic acid and 2,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [O:1]=[C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)[CH2:3][C:4]([O-:6])=O.[Li+].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(C(C)C)C(C)C)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[O:6]=[C:4]([N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH2:3][C:2]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)=[O:1]
Reactant: O=C([O-])CC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: C1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCCC1)Nc1cccc(C(F)(F)F)c1

Procedure:
A solution of Example 35A (200 mg, 0.79 mmol), pyrrolidine (62 mg, 0.869 mmol), ethyldiisopropylamine (224 mg, 1.7 mmol), 1-hydroxy-1H-benzotriazol hydrate (129 mg, 0.95 mmol), 4-N,N-dimethylaminopyridine (1 mg), and 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (197 mg, 1.03 mmol) in dimethyl formamide (8 ml) is stirred at room temperature overnight (18 h). The crude reaction mixture is purified directly by preparative RP-HPLC to afford a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([CH:16]([CH3:22])[C:17]([O:19]CC)=[O:18])[CH2:15][O:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH:16]([CH3:22])[C:17]([OH:19])=[O:18])[CH2:13][O:14][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)C1(NC(=O)OCc2ccccc2)COC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)O)C1(NC(=O)OCc2ccccc2)COC1

Procedure:
Ethyl 2-(3-{[(benzyloxy)carbonyl]amino}oxetan-3-yl)propanoate (Preparation 29, 43 g, 140 mmol) was stirred in methanol (200 mL) and a 1M aqueous solution of sodium hydroxide (200 mL) for 18 hours at room temperature. The reaction was concentrated in vacuo and partitioned between diethyl ether and water. The pH of the aqueous layer was adjusted to pH3 with potassium hydrogen sulphate and extracted with dichloromethane. The organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound that was used without purification in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:56][C:57]([CH2:62][OH:63])([CH2:60][OH:61])[CH2:58][OH:59]>CN(C=O)C>[OH:59][CH2:58][C:57]([NH:56][C:30]([C:26]1[C:25]([CH3:33])=[C:24](/[CH:23]=[C:16]2\[C:17](=[O:22])[NH:18][C:19]3[C:15]\2=[CH:14][C:13]([S:10]([CH2:9][C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])(=[O:11])=[O:12])=[CH:21][CH:20]=3)[NH:28][C:27]=1[CH3:29])=[O:32])([CH2:62][OH:63])[CH2:60][OH:61]
Reactant: NC(CO)(CO)CO
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)NC(CO)(CO)CO
Temperature: 25 °C
Reaction time: 216 h

Procedure:
To a mixture of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.19 mmol), HOBt (31 mg, 1.2 eq.), EDAC.HCl (44 mg, 1.2 eq.) and 2-amino-2-hydroxymethyl-propane-1,3-diol (58 mg, 1.1 eq.) in DMF (2 mL) was added TEA (0.066 mL, 2.5 eq.). After stirring at rt for 9 days, the reaction was concentrated, diluted with DCM and then added solid sodium bicarbonate. After stirring at rt for 15 mins, the resulted suspension was loaded onto a silica gel column to give the titled compound as an orange solid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[S:12][C:13]([CH:17]=[O:18])=[C:14]([Cl:16])[N:15]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:16][C:14]1[N:15]=[C:11]([NH:10][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:12][C:13]=1[CH:17]=[O:18]
Reactant: Nc1nc(Cl)c(C=O)s1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=Cc1sc(NC(=O)c2ccccc2)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
Benzoyl chloride (1.25 mL, 10.70 mmol) was added to a solution of 2-amino-4-chlorothiazole-5-carbaldehyde (1.63 g, 10.00 mmol), pyridine (79.10, 12.30 mmol) and 4-dimethylaminopyridine (10 mg) in tetrahydrofuran (100 mL) at 0° C. The reaction mixture was stirred at ambient temperature overnight and then concentrated. Purification of the residue by column chromatography afforded N-(4-chloro-5-formylthiazol-2-yl)benzamide in 19% yield (0.52 g); 1H NMR (CDCl3, 300 MHz) δ 10.0 (s, 1H), 8.28-7.45 (m, 5H); MS (ES+) m/z 267.1 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([CH2:14][OH:15])[CH2:9]1)(C)(C)C.[ClH:17]>CCOC(C)=O>[ClH:17].[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][OH:15])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H](CO)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H]1CCC[C@H](CO)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl[cis-3-(hydroxymethyl)cyclohexyl]carbamate (311 mg) in EtOAc (3.1 ml) was added 4M HCl in EtOAc which was stirred at ambient temperature for 1 hour. Resulting precipitates were collected by filtration and washed with diisopropyl ether to give [cis-3-aminocyclohexyl]methanol hydrochloride (236 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]([N:15]=[CH:16][N:17]([CH3:19])[CH3:18])=[CH:13][C:12](=[O:20])[NH:11][C:10]1=[O:21].N12CCCN=C1CCCCC2.[CH3:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1.C(O)(C)C>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]([N:15]=[CH:16][N:17]([CH3:18])[CH3:19])=[CH:13][C:12](=[O:20])[N:11]([CH2:39][C:38]2[CH:41]=[CH:42][C:35]([O:34][CH3:33])=[CH:36][CH:37]=2)[C:10]1=[O:21]
Reactant: CN(C)C=Nc1cc(=O)[nH]c(=O)n1-c1ccc(I)cc1F
Reactant: COc1ccc(CCl)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)cc(N=CN(C)C)n(-c3ccc(I)cc3F)c2=O)cc1
Temperature: 75 °C
Yield: 77.8 %

Procedure:
To a solution of N′-[3-(2-fluoro-4-iodophenyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformamidine 81 (20.0 g) in N,N-dimethylformamide (150 ml) was added 1,8-diazabicyclo[5.4.0]undec-7-en (14.9 ml) and 4-methoxybenzyl chloride 82 (10.1 ml) at room temperature. The mixture was stirred with heating at 75° C. for 2.5 hrs, 1,8-diazabicyclo[5.4.0]undec-7-en (7.50 ml) and 4-methoxybenzyl chloride (4.00 ml) were added, and the mixture was stirred with heating at the same temperature for 2.5 hrs. After allowing to cool to room temperature, isopropyl alcohol (150 ml) and water (300 ml) were successively added dropwise. The mixture was stirred overnight at room temperature, and the precipitated crystals were collected by filtration and dried to give N′-[3-(2-fluoro-4-iodophenyl)-1-(4-methoxybenzyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl]-N,N-dimethylformamidine 83 (20.2 g, yield 77.8%) as yellow crystals.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]([CH3:14])[N:12]=2)[CH:7]=[CH:6][C:5]1=[O:16].[CH3:17][N:18]=[C:19]=[S:20]>O>[CH3:17][NH:18][C:19]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[C:9]([CH3:15])[CH:10]=[C:11]([CH3:14])[N:12]=2)[CH:7]=[CH:6][C:5]1=[O:16])=[S:20]
Reactant: Cc1cc(C)c2ccc(=O)n(CCN)c2n1
Reactant: CN=C=S
Solvent: O
Product: CNC(=S)NCCn1c(=O)ccc2c(C)cc(C)nc21

Procedure:
A mixture of the free base of 1-(2-aminoethyl)-5,7-dimethyl-1,8-naphthyridin-2(1H)-one (700 mg., 0.0032 mole) as prepared in Example 12 and methyl isothiocyanate (180 mg., 0.004 mole) in 5 ml. of water is heated at reflux for 30 minutes. On cooling the reaction, the product is collected by filtration. After recrystallization from methanol, 1-{2-[(N-methylthiocarbamoyl)amino]ethyl}-5,7-dimethyl-1,8-naphthyridin-2(1H)-one m.p. 216.5-218° C. is obtained.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH:7]=O)[CH:4]=[N:3][CH:2]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([BH3-])#N.[Na+]>C(O)C.C(O)(=O)C>[N:3]1[CH:4]=[C:5]([CH2:7][N:19]2[CH2:18][CH2:17][N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:15])[CH2:21][CH2:20]2)[CH:6]=[N:1][CH:2]=1
Reactant: O=Cc1cncnc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cncnc2)CC1
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
A solution of pyrimidine 5-carboxaldehyde (100 mg, 0.92 mmol) in ethanol (2 mL) and acetic acid (0.2 mL) at room temperature was treated with tert-butyl-1-piperazine carboxylate (2.5 eq, 2.31 mmol, 430 mg) and stirred for 5 minutes. Sodium cyanoborohydride (0.95 eq, 0.88 mmol, 55 mg) was added portionwise and the reaction then stirred for 16 h. Concentration in vacuo and preparative tlc purification (EtOAc) gave the product (141 mg, 55%) as a pale yellow oil; δH (500 MHz, CDCl3) 1.47 (s, 9H, C(CH3)3), 1.95 (br, 2H, piperazine NCH2), 2.42 (t, J=4.7 Hz, 2H, piperazine NCH2), 3.45 (t, J=4.9 Hz, 4H, piperazine N(CH2)2), 3.54 (s, 2H, CH2), 8.78 (s, 2H, pyrimidine H-4 & H-6), 9.15 (s, 1H, pyrimidine H-2);
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)=[O:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1>C(OCC)(=O)C>[ClH:1].[Br:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)=[O:19])[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)N2CCN(S(=O)(=O)c3ccc(Br)cc3)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(N1CCNCC1)N1CCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Reaction time: 8 h

Procedure:
A solution (200 ml) of ethyl acetate saturated with hydrogen chloride was added to a mixture of 1-(4-bromophenylsulphonyl)-4-[1-(t-butoxycarbonyl)piperazin-4-ylcarbonyl]piperazine and ethyl acetate (200 ml) . The mixture was stirred overnight. The solvent was removed by evaporation to give 1-(4-bromophenylsulphonyl)-4-(1-piperazinylcarbonyl)piperazine hydrochloride (16.30 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)[CH2:6][N+:7]([O-:9])=[O:8].[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].Cl>C(O)(C)(C)C.C(OCC)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][CH:5]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=1)[CH:6]([N+:7]([O-:9])=[O:8])[CH2:21][CH2:20][C:19]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc(OC)cc1
Reactant: C=CC(=O)OC
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)(C)O
Product: COC(=O)CCC(C(CC(=O)OC)c1ccc(OC)cc1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 94 h

Procedure:
A solution of 200 g of 4-nitro-3-(4-methoxyphenyl)butanoic acid methyl ester, 68 g of methyl acrylate, and 25 ml of Triton B in 500 ml of t-butanol is allowed to stir at room temperature for 94 hours. Excess aqueous hydrochloric acid (1 N) is added and the solution is diluted with diethyl ether. The organic layer is separated, dried over anhydrous magnesium sulfate, and evaporated to give 4-nitro-3-(4-methoxyphenyl)heptanedioic acid dimethyl ester.
Reaction SMILES: [CH3:1][C:2]1[N:3]([S:13]([C:16]2[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[BH4-].[Na+]>CO>[CH3:1][C:2]1[N:3]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([CH3:20])=[CH:21][CH:22]=2)(=[O:14])=[O:15])[C:4]2[C:9]([C:10]=1[CH2:11][OH:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1ccc(S(=O)(=O)n2c(C)c(C=O)c3ccccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2c(C)c(CO)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
To a stirred solution of 2-methyl-1-tosyl-1H-indole-3-carbaldehyde [104142-15-6] (1.2 g, 3.83 mmol) in methanol (40 mL), NaBH4 (145 mg, 3.83 mmol) was added at 0° C. and stirred for 10 min. Then the mixture was allowed to warm to rt and stirred for 4 h. The mixture was concentrated under reduced pressure at 45° C., saturated aqueous NH4Cl solution was added and extracted with ethyl acetate (2×). The combined organic layers were washed with water, brine and dried over anhydrous Na2SO4. The organic layer was filtered and concentrated under reduced pressure to yield the title compound as a pale yellow liquid (1.0 g, 83%). [TLC Rf=0.16 (ethyl acetate/hexane 30:70)].
Reaction SMILES: O.[OH-].[Li+].[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:18][CH2:19][CH3:20])[NH:11][C:12]=1[C:13]([O:15]CC)=[O:14])([CH3:7])[CH3:6].Cl>O.CO>[OH:4][C:5]([C:8]1[N:9]=[C:10]([CH2:18][CH2:19][CH3:20])[NH:11][C:12]=1[C:13]([OH:15])=[O:14])([CH3:7])[CH3:6]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.2 %

Procedure:
A solution of 0.28 g of lithium hydroxide monohydrate in 5 ml of water was added to a solution of 0.48 g of ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate (prepared as described in Preparation 9) in 5 ml of methanol, and the resulting mixture was stirred at room temperature for 18 hours. At the end of this time, the pH of the reaction mixture was adjusted to a value of 2.3 by adding 6.67 ml of 1N aqueous hydrochloric acid, and the mixture was concentrated by evaporation under reduced pressure to a volume of about 2 ml. The crystals which precipitated were collected by filtration to give 0.20 g of the title compound, melting at 232° C. (with decomposition).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@@H:2]1[C:3]([OH:5])=[O:4].O=[CH:10][C:11]([Cl:14])([Cl:13])[Cl:12]>C(#N)C>[Cl:12][C:11]([Cl:14])([Cl:13])[CH:10]1[N:1]2[CH2:8][CH2:7][CH2:6][CH:2]2[C:3](=[O:5])[O:4]1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: O=C(O)[C@H]1CCCN1
Solvent: CC#N
Product: O=C1OC(C(Cl)(Cl)Cl)N2CCCC12
Reaction time: 18 h

Procedure:
To a solution of D-proline (100.0 g) in acetonitrile (400 ml) was added dropwise chloral (169 ml) at room temperature, and the mixture was stirred for 18 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. To the resulting residue was added water, and the mixture was extracted with chloroform. The separated organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was slurry-washed with n-hexane/ethyl acetate (20/1, 900 ml) to give the titled compound (159.7 g).
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[CH2:12].[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Cl.O>CS(C)=O>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][O:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]([N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)=[CH2:12]
Reactant: C=C(c1cc(F)ccc1O)n1ccnc1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C=C(c1cc(F)ccc1OCc1ccc(Cl)cc1Cl)n1ccnc1
Temperature: 55 °C
Reaction time: 0.83 h
Yield: 68 %

Procedure:
85% Potassium hydroxide powder (36.0 g, 0.545 mole) was suspended in dimethyl sulfoxide (500 g) and stirred at 55° C. for 50 minutes. After cooling to 25° C., 1-[1-(2-hydroxy-5-fluorophenyl)vinyl]-1H-imidazole (90.0 g, 0.441 mole) was added and the mixture was stirred at room temperature for 1 hour. Then, 2,4-dichlorobenzyl chloride (94.5 g, 0.483 mole) was added dropwise over 1 hour and the mixture was stirred for 2 hours. Water (680 ml) was added dropwise over 25 minutes to the reaction mixture with stirring and then stirring was continued for additional 1 hour. The precipitated crystals were filtered off and washed with water (135 ml×5) and n-hexane (135 ml×3). The resulting crude crystals were recrystallized from n-hexane/ethyl acetate to obtain the title compound (109 g, 68.1%), m.p. 118°-120° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH:11]=O)[O:9][CH:10]=1)=[O:5])[CH3:2].[NH2:13]O>CO>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]#[N:13])[O:9][CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1coc(C=O)n1
Reactant: NO
Solvent: CO
Product: CCOC(=O)c1coc(C#N)n1
Reaction time: 2 h
Yield: 30.4 %

Procedure:
To a solution of 2-formyl-oxazole-4-carboxylic acid ethyl ester (Panek et al. J. Org. Chem., 6496, (1996)) (171 mg, 1.11 mmol) in MeOH (3 mL) was added NH2OH (50% wt. H2O, 161 μL, 2.4 mmol). The reaction was allowed to stir for 2 h, and then concentrated in vacuo. The crude oxime was treated with acetic anhydride (4 mL) and heated with stirring at 150° C. for 24 h. The acetic anhydride was removed under vacuo, and the crude material was purified by preparative thin layer chromatography (60% ether-hexanes) to afford 56 mg (31%) of the title compound as an off-white solid. 1H-NMR (CDCl3; 400 MHz): δ 8.40 (s, 1H), 4.46 (q, 2H, J=7.1 Hz), 1.43 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[CH:11]1([CH2:16][C@H:17]([CH2:21][NH:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]([OH:20])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[CH:11]1([CH2:16][C@H:17]([CH2:21][N:22]([CH:1]=[O:2])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]([OH:20])=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=CO
Reactant: O=C(O)[C@@H](CNOCc1ccccc1)CC1CCCC1
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 99.8 %

Procedure:
Under a nitrogen atmosphere, formic acid (192 mL, 5 mol) was dissolved in CH2Cl2 (450 mL) and cooled to 0° C. Acetic anhydride (73 mL, 0.77 mol) was then added, and the reaction mixture was stirred for 45 min. After this time, a solution of (2R)-3-cyclopentyl-2-({[(phenylmethyl)oxy]amino}methyl)propanoic acid (22.85 g crude material, assumed 77.1 mmol) in CH2Cl2 (450 mL) was added, and the resulting mixture was stirred for 1.5 h at 0° C. The volatiles were then removed, the crude residue was dissolved in EtOAc (500 mL), and the mixture was washed with brine (4×100 mL). The organics were dried (MgSO4) and concentrated to provide (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (23.5 g, 100%) as a thick syrup. LCMS: (M+H)+: 306.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7](=O)[CH2:8][C:9]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:10]=2[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])=[O:12])[O:5][CH:6]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.CCN(CC)CC>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[F:22])[C:11](=[O:12])[C:10]3[C:9]([CH:8]=2)=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:27])[O:5][CH:6]=1
Reactant: O=C(Cc1cccc(Cl)c1C(=O)NCc1ccc(F)cc1F)c1cc(Br)co1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1c2c(Cl)cccc2cc(-c2cc(Br)co2)n1Cc1ccc(F)cc1F
Temperature: 25 °C
Yield: 82.7 %

Procedure:
To a solution of 2-[2-(4-bromofuran-2-yl)-2-oxoethyl]-6-chloro-N-(2,4-difluorobenzyl)benzamide (2.4 g, 5.1 mmol), prepared in a manner similar to that described above in Paragraph B, in dioxane (30 mL) was added 4-toluenesulfonic acid monohydrate (450 mg, 2.4 mmol). The resulting solution was heated to reflux. After 20 hours at reflux the reaction solution was allowed to cool to ambient temperature, and treated with Et3N (2.0 mL, 14 mmol). The crude product was purified by adsorbing the material onto silica gel from the reaction solution, loading the resulting solid onto the column and eluting with a gradient from 10% to 50% EtOAc in hexane containing 10% CH2Cl2 (to improve the solubility of the product). The broad peak that eluted was collected to afford 3-(4-bromofuran-2-yl)-8-chloro-2-(2,4-difluorobenzyl)-2H-isoquinolin-1-one (1.9 g, 82% yield) as a brown powder. 1H-NMR (400 MHz, CDCl3): δ 7.56-7.51 (2H, m), 7.47 (1H, d, J=0.8 Hz), 7.43 (1H, dd, J=6.3, 2.8 Hz), 7.06-6.99 (1H, m), 6.79-6.73 (2H, m), 6.68 (1H, s), 6.49 (1H, d, J=0.8 Hz), 5.32 (2H, s).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([Br:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[Br:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:26](=[O:27])[C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:29])[C:3]=1[C:8](=[O:9])[NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nn1ccc(Br)c1C(=O)Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1ccc(Br)c1C(=O)Nc1ccccc1
Yield: 51.4 %

Procedure:
The title compound was prepared following the experimental procedure described in Preparation 9a from 810 mg (2.89 mmol) of 1-amino-3-bromo-N-phenyl-1H-pyrrole-2-carboxamide and 656 mg (3.47 mmol) of (S)-2-(tert-butoxycarbonylamino)propanoic acid (purchased from Aldrich). The crude product was purified by flash chromatography in hexane-ethyl acetate to afford 670 mg (49% yield) of the title compound.