Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][CH:36]=2)[CH2:34][CH2:33]1)=[O:31])[CH3:28]>Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH2:27]([O:29][C:30]([C:32]1([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:26])[CH2:16][CH2:17][C:18]4[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=4[Cl:25])=[CH:4][CH:3]=3)=[CH:37][CH:36]=2)[CH2:33][CH2:34]1)=[O:31])[CH3:28]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1c(F)cccc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)CCc4c(F)cccc4Cl)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) as the catalyst and using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[3-(2-chloro-6-fluoro-phenyl)-1-methyl-propyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C[Mg]Cl.CON(C)[C:7]([CH:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:8].[C:25](O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.O>[C:7]([CH:9]1[CH2:13][S:12][C:11](=[O:14])[N:10]1[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=1)(=[O:8])[CH3:25]
Reactant: COc1ccc(CN2C(=O)SCC2C(=O)N(C)OC)cc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2C(=O)SCC2C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A dry three-necked round bottom flask fitted with an internal temperature probe and a mechanical stirrer was charged with 0.805 L of a 3 M solution of methylmagnesium chloride in THF. The solution was purged with nitrogen and cooled to 0° C. In a separate flask, 3-(4-methoxy-benzyl)-2-oxo-thiazolidine-4-carboxylic acid methoxy-methyl-amide (250.0 g, 0.805 mol) was dissolved in 1.00 L of dry THF. The resulting solution was added to the solution of methyl magnesium chloride at a rate that maintained an internal reaction temperature less than 5° C. The reaction was monitored by HPLC and was considered complete upon the disappearance of starting material. The reaction mixture was slowly added to 1.00 L of a 10% citric acid solution at a rate that maintained a temperature of less than 25° C. The mixture was diluted with 0.90 L of water. The THF was removed by distillation at atmospheric pressure. The product was extracted with 2.5 L of ethyl acetate. The organic phase was separated, concentrated to a final volume of ˜800 mL and cooled to room temperature. A suspension was formed by the addition of 16 L of n-heptane. The suspension was stirred for 30 minutes. The resulting solid was isolated by filtration and was dried in a vacuum oven at 40° C. for 12 hours. Approximately 170 g of 4-acetyl-3-(4-methoxy-benzyl)-thiazolidin-2-one was obtained (80% yield). 1H NMR (300 MHz, DMSO) δ 7.14 (d, 8.9 Hz, 2H), 6.88 (d, 8.9 Hz, 2H), 4.48 (dd, J=9.4, 2.6 Hz, 1H), 4.27 (AB, JAB=15.2 Hz, ΔvAB=267.3 Hz, 2H), 3.72 (s, 3H), 3.62 (dd, J=11.9, 10.0 Hz, 1H), 3.37 (dd, J=11.8, 2.6 Hz, 1H), 2.19 (s, 3H). 13C NMR (75 MHz, DMSO) δ 26.9, 27.9, 47.2, 55.8, 66.0, 114.7, 129.1, 130.0, 159.4, 171.7, 205.1; [α]26.5D-56.00 (c=1.39, EtOH).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[I:13])[C:7]([OH:9])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:7]([N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[O:9])[CH:10]=[CH:11][C:12]=1[I:13])[CH3:2]
Reactant: CCOc1cc(C(=O)O)ccc1I
Reactant: C1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOc1cc(C(=O)N2CCCCC2)ccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
3-Ethoxy-4-iodo-benzoic acid (2.73 grams, 9.36 mmol) was suspended in methylene chloride (25 mL), and oxalyl chloride (5.15 mL, 2.0 M in methylene chloride, 10.3 mmol) was added by pipette. Three drops of dimethylformamide was added and this mixture was stirred overnight at room temperature. The volatiles from the now homogeneous reaction were removed under vacuum and the residue reconstituted in methylene chloride. One half of this was treated with piperidine (2.0 mL, 20 mmol). The mixture was stirred at room temperature for 2 h. The reaction was diluted with methylene chloride, washed with 1.0 M hydrochloric acid, water, saturated sodium bicarbonate solution and brine. The organic layers was dried (magnesium sulfate), filtered and concentrated to give (3-ethoxy-4-iodo-phenyl)-piperidin-1-yl-methanone (1.69 g, 100%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.CN(C=O)C.[OH-].[K+]>O>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH2:2][C:3]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:4])=[CH:18][CH:17]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNc1ccc(F)cc1)Nc1ccccc1C(=O)O
Yield: 89.3 %

Procedure:
A solution of 2-(N-bromoacetylamino)benzoic acid from Example 79 (8.00 g, 31.0 mmol), para-fluoroaniline (7.34 mL, 77.5 mmol) and DMF (80 mL) was heated to 75° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature and filtered. The filter cake was rinsed with water (60 mL) and dried under high vacuum at 45° C. to yield 7.98 g (89%) of the title compound as an off-white solid; 1H NMR (DMSO-d6) δ 13.45 (broad s, 1H), 12.00 (s, 1H), 8.72 (d, J=8, 1H), 7.94 (dd, J=8, J=1.2, 1H), 7.59 (td, J=7.2, J=1.6, 1H), 7.13 (td, J=7.2, J=0.8, 1H), 6.95 (m, 2H), 6.58 (m, 2H), 6.47 (s, 1H), 3.82 (s, 2H); 13C NMR (DMSO-d6) δ 170.73, 169.04, 154.95 (J=232.0), 144.78, 140.54, 134.15, 131.13, 122.69, 119.43, 116.00, 115.38 (J=21.9), 113.22 (J=7.6), 49.31.
Reaction SMILES: [N:1]#[C:2]Cl.[S:4]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:5]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(#N)C>[C:2]([C:11]1[N:10]([CH2:9][C:6]2[CH:7]=[CH:8][S:4][CH:5]=2)[CH:14]=[CH:13][N:12]=1)#[N:1]
Reactant: N#CCl
Reactant: c1cn(Cc2ccsc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N#Cc1nccn1Cc1ccsc1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
In a 250 ml, 4-neck flask equipped with a nitrogen bubbler, gas inlet tube, thermometer and septum, add 100 ml acetonitrile and bubble cyanogen chloride (15 g, 0.24 mol) into the acetonitrile. Cool the solution in an ice bath and add 8.2 (0.05 mol) 1-(3-thienylmethyl)-1H-imidazole. After the colorless solution turns yellow-orange and about 1 hour after an orange precipitate forms, cool the slurry to -20° C., slowly add 42 ml (0.3 mol) of triethylamine, holding the temperature below 0° C. After 1 hour at room temperature, pour the reaction onto 600 ml saturated NaHCO3 and extract with ether (3×150 ml). Dry and combine organic layers to obtain tan oil. The oil is purified via Kugelrohr distillation to obtain a colorless oil.
Reaction SMILES: [OH:1][C@H:2]([CH2:26][OH:27])[CH2:3][NH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([F:25])([F:24])[F:23])[NH:11][C:12]2=[O:15])=[CH:7][CH:6]=1.[CH3:28][O-:29].[Na+].CO>C(=O)(OCC)OCC>[OH:27][CH2:26][C@H:2]1[O:1][C:28](=[O:29])[N:4]([C:5]2[CH:14]=[C:13]3[C:8]([CH:9]=[C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:22]([F:25])([F:23])[F:24])[NH:11][C:12]3=[O:15])=[CH:7][CH:6]=2)[CH2:3]1
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NC[C@H](O)CO)cc12
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(=O)OCC
Solvent: CO
Product: O=C1O[C@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 105 °C
Reaction time: 13 h
Yield: 78 %

Procedure:
The 7-((S)-2,3-dihydroxypropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (281.9 mg, 0.745 mmol) obtained in step A was suspended in diethyl carbonate (2.93 ml), and thereafter, a 28% sodium methoxide-methanol solution (117 μl) was added thereto. The obtained mixture was stirred at 105° C. for 13 hours. Thereafter, diethyl carbonate was distilled away under reduced pressure. The obtained residue was dissolved in methanol (15 ml), and the obtained solution was stirred under heating to reflux for 10 minutes. Thereafter, the reaction solution was concentrated, and a saturated ammonium chloride aqueous solution was then added to the residue, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and was then concentrated. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=40:1 to 20:1), so as to obtain 7-((S)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (233.8 mg; yield: 78%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[Cl:14][C:15]1[CH:27]=[C:26]([O:28][CH2:29][CH:30]=[C:31]([Cl:33])[Cl:32])[CH:25]=[C:24]([Cl:34])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][NH2:23].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>N1C=CC=CC=1>[Cl:14][C:15]1[CH:27]=[C:26]([O:28][CH2:29][CH:30]=[C:31]([Cl:33])[Cl:32])[CH:25]=[C:24]([Cl:34])[C:16]=1[O:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][N:23]=[CH:7][C:6]1[CH:9]=[CH:10][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=1
Reactant: NOCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: c1ccncc1
Product: FC(F)(F)c1ccc(C=NOCCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a mixture of 0.14 g of 4-(trifluoromethyl)benzaldehyde and 10 ml of pyridine was added 0.30 g of O-(4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyl)hydroxylamine hydrochloride. After stirring at room temperature for 1 hour, the reaction mixture was poured into 5% aqueous citric acid solution, and extracted twice with ethyl acetate. The ethyl acetate layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.37 g (yield, 95.6%) of 4-(trifluoromethyl)benzaldehyde O-(4-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyl)oxime, nD21.0 1.5387.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:33])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28]C(C)(C)C)=[O:27])=[CH:22][CH:21]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[N+](C)([O-])=O.Cl>CCOCC>[C:1]([NH:7][C:8]1[N:9]=[C:10]([OH:33])[C:11]2[CH:17]=[C:16]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([OH:28])=[O:27])=[CH:24][CH:25]=3)[CH:15]=[N:14][C:12]=2[N:13]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(C#Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)cc1
Agent: Cl
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1nc(O)c2cc(C#Cc3ccc(C(=O)O)cc3)cnc2n1
Temperature: 0 °C
Yield: 92.6 %

Procedure:
One gram of 2-pivaloylamino-4-hydroxy-6-(4-tert.-butoxycarbonylphenylethynyl)pyrido[2,3-d]pyrimidine is added to 25 ml of nitromethane saturated with hydrogen chloride gas at 0° C. After stirring at 0° C., the reaction mixture is allowed to reach room temperature and stirred for an additional hour. The suspension is diluted with anhydrous ether and suction filtered. The collected solid is washed with ether, methanol, and ether again, and then dried under reduced pressure to give 0.81 g of 2-pivaloylamino-4-hydroxy-6-(4-carboxyphenylethynyl)pyrido[2,3-d]pyrimidine as a yellowish powder: m.p. >250° C.; NMR (CDCl3, 300 MHz) delta 1.25 (s, 9H), 7.72 (d, 2H, J=8.02 Hz), 7.98 (d, 2H, J=8.02 Hz), 8.52 (d, 1H, J=2.01 Hz), 9.01 (d, 1H, J=2.01 Hz); IR (KBr) 3420, 3000, 1725, 1680, 1425, 1405, 1360, 1250, 1130, 1020, and 800 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][S:9]([C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)(=[O:11])=[O:10].[Cl:21][C:22]([C:28]1[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([S:34](Cl)(=[O:36])=[O:35])[CH:33]=1)([Cl:27])[C:23]([F:26])([F:25])[F:24]>C(Cl)Cl.N1C=CC=CC=1>[Cl:21][C:22]([C:28]1[CH:29]=[CH:30][C:31]([O:38][CH3:39])=[C:32]([S:34]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=3[CH:13]=2)(=[O:11])=[O:10])(=[O:36])=[O:35])[CH:33]=1)([Cl:27])[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccc(C(Cl)(Cl)C(F)(F)F)cc1S(=O)(=O)Cl
Reactant: Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(Cl)(Cl)C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid (2-aminophenyl)-amide (1 mmol, prepared as in Example 1) in DCM (2 mL) and pyridine (2 mL), 5-(1,1-dichloro-2,2,2-trifluoroethyl)-2-methoxybenzenesulfonyl chloride (1.1 mmol) was added at RT and the reaction mixture was then allowed to stir at RT overnight. The reaction mixture was then diluted with DCM (20 mL). The organic phase was washed with 10% aqueous HCl (20 mL), water (20 mL) and brine (20 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to afford 374 mg of benzo[b]thiophene-2-sulfonic acid [2-(5-(1,1-dichloro-2,2,2-trifluoroethyl)-2-methoxy-benzenesulfonylamino)phenyl]-amide. LC: Tr 1.40 min; MS: 625.8 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:36])(C[Si](OC(C)C)(C)C)[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:18][CH:17]=2)[C:12]1=[O:27])[CH3:10].[C:37](=O)(O)[O-:38].[Na+]>CO.O1CCCC1.OO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:8]([OH:36])([CH2:37][OH:38])[C@H:9]([N:11]1[CH:15]=[CH:14][N:13]([C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH:26]=[N:25][N:24]=[N:23]3)=[CH:20][CH:21]=2)[C:12]1=[O:27])[CH3:10]
Reactant: CC(C)O[Si](C)(C)C[C@](O)(c1ccccc1F)[C@@H](C)n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](n1ccn(-c2ccc(-n3cnnn3)cc2)c1=O)[C@](O)(CO)c1ccccc1F
Temperature: 50 °C
Yield: 57.4 %

Procedure:
1-[(1R,2S)-2-(2-Fluorophenyl)-2-hydroxy-3-(isopropoxy dimethylsilyl)-1-methylpropyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (1 g) was dissolved in a mixture of methanol and tetrahydrofuran (1:1, 20 ml), to which an 30% aqueous solution of hydrogen peroxide (2 ml) and sodium bicarbonate (157 mg) were added. The mixture was heated at 50° C. for 4 hours, then cooled and extracted with ethyl acetate (100 ml). The extract was washed with water (30 ml), an aqeous solution of Na2S2O3 (30 ml×2) and a saturated aqueous solution of sodium chloride (30 ml) successively, dried over magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=1/4) and recrystallized from diethyl ether (20 ml) to give 1-[(1R,2S)-2-(2-fluorophenyl)-2,3-dihydroxy-1-methyl propyl]-3-[4-(1H-1-tetrazolyl)phenyl]-2(1H,3H)-imidazolone (440 mg) as a colorless crystalline powder.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>>[C:11]([N:5]1[CH2:6][C@H:2]([OH:1])[CH2:3][C@H:4]1[C:7]([OH:9])=[O:8])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Yield: 58 %

Procedure:
According to the literature procedure (J. Am. Chem. Soc. 189 (1957)), trans-4-hydroxy-L-proline (5.12 g, 0.039 mol) was treated with benzyl chloroformate (8.5 mL, 0.06 mol) to provide the title compound (6.0 g) as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:37])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([CH2:23][CH:24](C(OCC)=O)[C:25]([O:27][C:28](C)(C)[CH3:29])=[O:26])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:19]=2)[CH2:7][C:6]([OH:37])=[O:5])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)C(Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)CCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.4 %

Procedure:
A solution of 1-tert-butyl 3-ethyl 2-({5-[(1R)-1-(2-tert-butoxy-2-oxoethyl)-4-cyclohexylbutyl]-1,2,4-oxadiazol-3-yl}methyl)malonate (Preparation 93) (510 mg, 0.79 mmol) in dichloromethane (10 ml) was treated with trifluoroacetic acid (5 ml) and stirred at room temperature for 5 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene. The solid was dissolved in xylene (10 ml) and heated at 140° C. for 7 hours. The solvent was removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 95:5:0 (dichloromethane:isopropyl alcohol:acetic acid) gradually changing to 90:10:1 (dichloromethane:isopropyl alcohol:acetic acid) to afford the title compound as a colourless oil (117 mg).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(OC(=O)C)(=[O:22])C>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:22])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: [O-][n+]1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)OC(C)=O
Product: O=c1cc(OCc2ccc(C(F)(F)F)cc2)cc[nH]1
Temperature: 25 °C

Procedure:
A solution of 4-((4-(trifluoromethyl)benzyl)oxy)pyridine 1-oxide (350 mg) in acetic anhydride (6 ml) was heated under reflux for 4 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with MeOH (10 ml) and 2 M NaOH (10 ml), and heated at reflux for 1 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted with DCM. The DCM layer was concentrated in vacuo and purified by silica gel column chromatography (MeOH/DCM) to give the title compound (110 mg) as an off-white solid.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)(=O)[CH2:2][CH2:3][CH2:4][CH3:5].O.NN.[OH-].[K+]>C(O)COCCO>[CH2:1]([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)c1ccc(Br)cc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CCCCCc1ccc(Br)cc1
Temperature: 130 °C
Yield: 80 %

Procedure:
A mixture of 2A (77.1 g), hydrazine hydrate (46.4 g) and KOH (590 g) in diethylene glycol (250 ml) is heated at 130° C. for 2 h, the excess of hydrazine hydrate is distilled off and the temperature is raised to 200° C. for 2 h. The cooled mixture is poured into 18% HCl, the product is extracted into ether twice and the combined ethereal extracts are washed with water and dried (MgSO4). The solvent is removed in vacuo and the residue is distilled (bp 145°-148° C. at 20 mm Hg) to yield a colourless liquid (58.1 g, 80%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([C:8]1[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=1[C:10](OC)=[O:11])=O.O.[NH2:19][NH2:20]>C(O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:8]2[C:9](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:11])[NH:20][N:19]=1
Reactant: COC(=O)c1ccccc1C(=O)c1cccs1
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2cccs2)c2ccccc12
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 2-(thiophene-2-carbonyl)benzoate (0.445 g, 1.81 mmol) and hydrazine hydrate (0.40 mL, 7.1 mmol) in ethanol (6 mL) was stirred at 80° C. overnight, concentrated, and azeotroped with toluene to give the title compound, which was used without purification: 1H NMR (300 MHz, DMSO-d6) δ 12.87 (s, 1H), 8.42-8.28 (m, 1H), 8.23-8.09 (m, 1H), 7.95 (dtd, J=19.0, 7.3, 1.5, 2H), 7.82-7.69 (m, 1H), 7.68-7.55 (m, 1H), 7.33-7.19 (m, 1H), 4.12 (s, OH), 1.91 (s, OH), 1.74 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:11][C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]2[O:12][CH:3]12.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH:25]=[CH:24][C:23]([O:26][CH:4]3[C:5]4[CH:6]=[N:7][CH:8]=[CH:9][C:10]=4[O:11][C:2]([CH3:1])([CH3:13])[CH:3]3[OH:12])=[N:22]2)=[CH:19][CH:20]=1
Reactant: O=c1ccn(-c2ccc(Cl)cc2)[nH]1
Reactant: CC1(C)Oc2ccncc2C2OC21
Product: CC1(C)Oc2ccncc2C(Oc2ccn(-c3ccc(Cl)cc3)n2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclopropa[a]naphthalene and 1-(4-chloro-phenyl)-1,2-dihydro-pyrazol-3-one as starting materials, the title compounds were prepared as pale yellow solids.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([OH:19])[CH2:14]1
Reactant: BrCC1COc2ccccc2O1
Reactant: OC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC1CCCN(CC2COc3ccccc3O2)C1
Temperature: 153 °C

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (2.26 g, 9.88 mmol), piperidin-3-ol (1.0 g, 9.88 mmol) and K2CO3 (6.8 g, 49.43 mmol) in DMF (30 ml) was heated under microwaves at 153° C. for 120 min to give the crude title compound after the usual work-up. The product was purified by column chromatography (DCM/MeOH, 98:2).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18](=[O:27])[NH:19][C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:28][N:29]1[CH2:33][CH2:32][N:31]=[C:30]1SC.CCN(CC)CC>N1C=CC=CC=1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:18]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:30]3[N:29]([CH3:28])[CH2:33][CH2:32][N:31]=3)=[CH:8][CH:7]=2)=[O:10])=[O:27])=[N:21][CH:22]=1
Reactant: NCc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: CSC1=NCCN1C
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN1CCN=C1NCc1ccc(C(=O)Nc2ccccc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A mixture of [4-(aminomethyl)phenyl]-N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}carboxamide (74 mg, 0.195 mmol), 1-methyl-2-methylthio-2-imidazoline (25 mg, 0.195 mmol), NEt3 (2 mL) and pyridine (5 mL) was stirred at 80° C. overnight, concentrated and HPLC (C18 reversed phase)eluting with 0.1% TFA in H2O/CH3CN gave N-{2-[N-(5-chloro(2-pyridyl))carbamoyl]phenyl}(4-{[(1-methyl(2-imidazolin-2-yl))amino]methyl}phenyl)carboxamide (52 mg, 65%). MS found for C24H23ClN6O2 (M+H)+: 463.