Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C@H:11]([CH3:15])[C:12](O)=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:16][NH:17][C:18]([NH:20][NH2:21])=[S:19].CS(O)(=O)=O.C(=O)(O)[O-].[Na+]>C1S(=O)(=O)CCC1.O>[SH:19][C:18]1[N:20]([NH2:21])[C:12]([C@H:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:1]=[CH:2][CH:3]=[CH:4]3)[CH3:15])=[N:16][N:17]=1
Reactant: NNC(=S)NN
Reactant: C[C@H](C(=O)O)c1ccc2ncccc2c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: C[C@@H](c1ccc2ncccc2c1)c1nnc(S)n1N
Temperature: 90 °C
Yield: 63.8 %

Procedure:
As shown in step v of Scheme 1, (S)-2-(quinolin-6-yl)propanoic acid (50 g, 248.5 mmol) and 1,3-diaminothiourea (29.02 g, 273.4 mmol) were suspended in a mixture of tetramethylene sulfone (sulfolane, 38 mL) and water (57 mL). Methane sulfonic acid (35.5 ml, 546.7 mmol) was added to the mixture, whereupon all solids dissolved. The reaction temperature was slowly increased to 90° C. and the reaction was heated at 90° C. for 40 hours, at which time a 68% conversion of starting material to product was observed by HPLC analysis. The reaction mixture was cooled in an ice bath and water (75 mL) was added, followed by the careful addition of saturated sodium bicarbonate (500 mL) until a pH 8 was achieved. The resulting fine purple precipitate was collected by vacuum filtration, washed with water, saturated sodium bicarbonate, water, and methyl t-butyl ether, respectively. The product was dried in a vacuum oven at 55° C. for 2 days to afford 6-((S)-1-(5-mercapto-4-amino-4H-1,2,4-triazol-3-yl)ethyl)quinoline (compound 1005, 43 g): ESMS (M+1), 272.09; 1H NMR (300.0 MHz, DMSO-d6) δ 13.65 (1H, br s), 8.86 (1H, dd, J=1.8, 8.4 Hz), 8.34 (1H, d, J=7.5 Hz), 7.98 (1H, d, J=8.7 Hz), 7.84 (1H, dd, J=1.7, 13.7 Hz), 7.82 (1H, d, J=1.5 Hz), 7.70 (1H, dd, J=1.8, 8.7 Hz), 7.50 (1H, dd, J=1.8, 8.7 Hz), 5.44 (2H, s), 4.57 (1H, q, J=7.2 Hz), 1.65 (3H, d, J=7.2 Hz). The product was 92% pure by 1H NMR analysis, with the major impurities being compound 1004 and sulfolane. Chiral HPLC analysis showed 92% ee (ChiralPak® AD-H, 70% i-propanol/hexanes; retention time: 4.98 min for S-enantiomer, 12.33 min for R-enantiomer). The product was used as is in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][CH2:21][C:22]1[O:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH2:21][O:20][CH3:19])[O:23][C:24]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:28])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: COCc1nc(C(=O)O)c(-c2ccccc2)o1
Product: COCc1nc(C(=O)Nc2cnn(Cc3ccc(C(C)=O)o3)c2)c(-c2ccccc2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methoxymethyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.96 min; [M+H]+=421.6.
Reaction SMILES: CCN(CC)CC.[F:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1.Cl.FC1C=CC(N2[C:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:28]=3[C:27]([CH2:35][OH:36])=N2)=CC=1>CCO>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:27]([CH2:35][OH:36])=[C:28]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:29]3=[N:16]2)=[CH:11][CH:10]=1
Reactant: NNc1ccc(F)cc1
Reactant: OCc1nn(-c2ccc(F)cc2)c2c1CCCCC2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: OCc1c2c(nn1-c1ccc(F)cc1)CCCCC2
Reaction time: 8 h

Procedure:
The crude diketone was dissolved in 60 mL of absolute EtOH and combined with 3.07 mL (22 mmol, 2.23 g) of Et3N and 3.45 g (21.1 mmol) of 4-fluorophenylhydrazine.HCl. The resulting solution was stirred under N2 overnight and refluxed for 4 h. A 30 mL portion of 1N aqueous HCl was added and the mixture was refluxed for an additional hour. The mixture was cooled and extracted with 200 mL of Et2O. The organic phase was washed with water, saturated aqueous NaHCO3, and brine and dried over Na2SO4. The solution was concentrated to give 5.50 g of a 1.2:1 mixture of 1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydrocycloheptapyrazole-3-methanol and the title compound as a brown oil. The crude product was crystallized from EtOAc:Et2O to afford 0.97 g (18%) of the title compound as an off-white solid, m.p. 177°-178° C.; 1H NMR (CDCl3, 300 MHz) 1.72 (m, 4), 1.85 (m, 2), 2.60 (m, 2), 2.80 (m, 2), 4.51 (d, 2, J=5 Hz), 7.15 (m, 2), 7.60 (m, 2); IR (KBr) 3240 (broad), 1513, 1223 cm-1 ; MS (DCI) m/z 261 (base). Anal. Calcd. for C15H17FN2O: C, 69.21; H, 6.58; N, 10.76. Found: C, 69.15; H, 6.77; N, 10.63.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11].CN(C)C=O.C(N(CC)CC)C.[N+](C1C=CC([O:44][C:45]([N:47]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:50][CH2:49][CH2:48]2)=O)=CC=1)([O-])=O>>[F:21][C:19]([F:22])([F:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2][C:45]([N:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH2:50][CH2:49][CH2:48]1)=[O:44])(=[O:12])=[O:11]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Reactant: NCCCCCCNS(=O)(=O)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCCCCCCNS(=O)(=O)c1ccccc1C(F)(F)F)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
To a solution of N-(6-Aminohexyl) -2-trifluoromethylbenzene sulfonamide Hydrochloride( 0.1 g, 0.27 mmol) dimethyl formamide (3 mL) and triethylamine (0.1 g, 1 mmol) was added 3, 4-Dihydro-2H-quinoline-1-carboxylic acid 4-nitrophenyl ester (0.09 g, 0.3 mmol) and the reaction mixture was stirred at room temperature for 4 h. Solvent was evaporated and purification by preparative TLC afford the titled compound as an oil (0.08 g, 61%).
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[CH2:9](O)[CH2:10][CH2:11][CH3:12]>Cl>[ClH:1].[CH2:9]([O:7][C:6](=[O:8])[C@H:3]([CH2:4][SH:5])[NH2:2])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCO
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Product: CCCCOC(=O)[C@@H](N)CS
Yield: 30 %

Procedure:
L-Cysteine hydrochloride (100 g) is dissolved in 250 ml of butanol saturated with dry HCl. The solution is heated under reflux for 4 hours. Excess solvent is evaporated and ethyl acetate (150 ml) is added to the residue. The crystals which form are recrystallized from ethyl acetate, mp 91° C., yield 30%, IR (KBr)1745 cm-1 ; NMR (CDCl3) δ9.2-3.4 (b, 3, NH3⊕), 4.7 (t, 1, --CH), 4.3 (t, 2, --OCH2 --), 3.3 (b, 2, CH2S), 1.0 (5, 3, --CH3), 1.0-3.0 (m, 4, --CH2CH2).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:49]1[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([C:58]3[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=3)[CH:56]=2)[CH:51]=[CH:50]1>CN(C=O)C>[NH:49]1[C:57]2[C:52](=[CH:53][CH:54]=[C:55]([C:58]3[CH:59]=[C:60]([NH:64][C:22]([C:17]4[C:18](=[O:21])[O:19][C:20]5[C:15]([CH:16]=4)=[CH:14][CH:13]=[CH:12][C:11]=5[OH:10])=[O:24])[CH:61]=[CH:62][CH:63]=3)[CH:56]=2)[CH:51]=[CH:50]1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: Nc1cccc(-c2ccc3cc[nH]c3c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(-c2ccc3cc[nH]c3c2)c1)c1cc2cccc(O)c2oc1=O
Temperature: 25 °C
Yield: 58.2 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.013 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(1H-indol-6-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.015 g of product in 58% yield: LCMS (ESI) m/z 397 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].[C:17]([O:23][CH2:24][CH3:25])(=[O:22])[CH2:18][C:19]([CH3:21])=O.Cl[Sn](Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH2:24]([O:23][C:17]([C:18]1[C:19]([CH3:21])=[N:1][C:2]2[C:3]([C:4]=1[NH2:5])=[C:6]([O:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:7]=[CH:8][CH:9]=2)=[O:22])[CH3:25]
Reactant: N#Cc1c(N)cccc1OCC1CCCC1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCC3)c2c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
To a solution of 2-amino-6-(cyclopentylmethoxy)benzonitrile (Tachdjian, C. et al. PCT Int. Appl. 2008, WO 2008154221) (21.63 g, 100.0 mmol) and ethyl acetoacetate (12.6 mL, 100.0 mmol) in anhydrous toluene (300 mL) was added SnCl4 (23.1 mL, 200.0 mmol) over a period of 25 minutes at room temperature under nitrogen. The stirred reaction mixture was then refluxed for 5 h under nitrogen. After it was cooled down to room temperature, the reaction solution was concentrated to remove most of the solvent under reduced pressure. The residue was re-dissolved in EtOAc (3.5 L) and carefully neutralized to pH 8 with aqueous NaOH solution (6.0 N, ˜130 mL) at 0° C. The resultant mixture was stirred at room temperature overnight. The precipitate was filtered off, and the organic layer was separated and washed with brine (400 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with 30% EtOAc in hexanes to give the title compound as a pale yellow solid (24.6 g, 75%). 1H NMR (400 MHz, DMSO-d6) δ 1.30-1.36 (m, 5H), 1.53-1.65 (m, 4H), 1.81-1.86 (m, 2H), 2.42-2.45 (m, 1H), 2.54 (s, 3H), 4.05 (d, J=7.2 Hz, 2H), 4.31 (q, J=7.2 Hz, 2H), 6.89 (d, J=7.6 Hz, 1H), 7.21-7.23 (m, 1H), 7.50 (t, J=8.0 Hz, 1H), 8.08 (s, 2H). MS 329 (MH+).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:2][CH2:3][CH2:4][N:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:7][Cl:8]
Reactant: BrCc1ccccc1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: ClCCN(CCCl)Cc1ccccc1
Reaction time: 8 h

Procedure:
An ice bath is used to cool a mixture of 150 g of N,N-bis(2-chloroethyl)amine hydrochloride and 100 ml of benzyl bromide in 1000 ml of DMF and then 120 ml of triethylamine are added dropwise and the mixture is left with stirring at AT overnight. The reaction mixture is concentrated under vacuum, the residue is taken up in water and extracted 3 times with ether, the organic phases are dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 113 g of the expected product.
Reaction SMILES: [OH:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:11]([N:18]=[C:19]=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([NH:18][C:19]([O:1][CH:2]([CH3:10])/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)/C=C/C(C)O
Reactant: O=C=NCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/C(C)OC(=O)NCc1ccccc1

Procedure:
Reaction of 21 (rac-Ethyl (2E)-4-hydroxypent-2-enoate) (1.44 g, 10 mmol) with benzyl isocyanate (1.73 g, 13 mmol) in toluene (8 ml) according to Example 1. Purification by flash chromatography (AcOiPr:heptane fraction 25:75) yields 3 (rac-Ethyl (2E)-4-(benzylaminocarbonyloxy)pent-2-enoate) (2.49 g, 90%) as a with solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([F:11])[CH:3]=1.CN.C(Cl)CCl.[CH2:18]([N:20](CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:20][CH3:18])=[O:7])=[C:4]([F:11])[CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: CN
Solvent: ClCCl
Solvent: ClCCCl
Product: CNC(=O)c1ccc(Br)cc1F
Reaction time: 24 h
Yield: 31.4 %

Procedure:
A solution of 4-bromo-2-fluorobenzoic acid (0.8 g, 3.7 mmol), methylamine (3.65 mL, 7.3 mmol), EDC (1.4 g, 7.3 mmol), triethylamine (1.0 mL, 7.3 mmol) dissolved in CH2Cl2 (15 mL) was stirred under N2 for 24 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography (40% EtOAc in hexanes) to give the title compound as a white solid (0.27 g, 32%). 1H NMR (CDCl3): δ 3.03 (d, 3H, J=6.0 Hz), 6.68 (br s, 1H), 7.32 (d, 1H, J=11.3 Hz), 7.42 (d, 1H, J=10.2 Hz), 8.01 (t, 1H, J=8.5 Hz).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[F:20])[CH:8]=[CH:9][C:10]=1[OH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:42]1([CH:45]([C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH2:58]O)[CH:53]=2)[CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44][CH2:43]1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C1(C)C=CC=CC=1>[CH:42]1([CH:45]([C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH2:58][O:11][C:10]3[CH:9]=[CH:8][C:7]([C:12]4[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=4[F:20])=[CH:6][C:5]=3[CH2:4][CH2:3][C:2]([CH3:22])([CH3:21])[CH3:1])[CH:53]=2)[CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:44][CH2:43]1
Reactant: COc1ccc(F)c(-c2ccc(O)c(CCC(C)(C)C)c2)c1
Reactant: CCOC(=O)CC(c1cccc(CO)c1)C1CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)cc2CCC(C)(C)C)c1)C1CC1
Yield: 48.3 %

Procedure:
To a solution of 3-(3,3-dimethylbutyl)-2′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-ol (200 mg) in THF (5.0 mL) were added triphenylphosphine (260 mg), ethyl 3-cyclopropyl-3-(3-(hydroxymethyl)phenyl)propanoate (246 mg) and a 40% solution of diethyl azodicarboxylate in toluene (400 μL), and the reaction mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (170 mg) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:10][CH3:11])([O:8][CH3:9])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1.[H-].[Na+].I[CH2:22][CH3:23]>CN(C=O)C>[CH2:22]([O:1][CH:2]1[C:7]([O:8][CH3:9])([O:10][CH3:11])[CH2:6][CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3]1)[CH3:23]
Reactant: CCI
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC1CN(C(=O)OC(C)(C)C)CCC1(OC)OC
Yield: 84.7 %

Procedure:
The same operation as in Example (90a) was performed using tert-butyl 3-hydroxy-4,4-dimethoxypiperidine-1-carboxylate (5.2 g, 20 mmol), sodium hydride (55% content, 1.31 g, 30 mmol), 1-iodoethane (6.24 g, 40 mmol) and DMF (50 mL). The residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 4.90 g of the title compound as a colorless oily substance (85%).
Reaction SMILES: O[C:2]1[CH:10]=C(O)C=C[C:3]=1C(N)=O.[OH:12][C:13]1[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(Br)C=C>>[OH:12][C:13]1[CH:22]=[C:21]([O:23][CH2:10][CH:2]=[CH2:3])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: NC(=O)c1ccc(O)cc1O
Solvent: C=CCBr
Product: C=CCOc1ccc(C(=O)OC)c(O)c1

Procedure:
Scheme B shows methods for the preparation of the 2,4-dihydroxybenzamide starting materials. Methyl 2,4-dihydroxybenzoate (X) is reacted with allyl bromide to give methyl 2-hydroxy-4-allyloxybenzoate (XI) which is heated to produce methyl 2,4-dihydroxy-3-(2-propenyl) benzoate (XII). Reaction of XII with an appropriate amine in the presence of ammonium chloride gives the 2,4-dihydroxy-3-(2-propenyl)benzamide (XIII) which can be hydrogenated to the 3-propyl compound (XIV). Alternatively XII may be reacted with methylene iodide and triisobutylaluminum to give methyl 3-(cyclopropylmethyl)-2,4-dihydroxybenzoate (XV) which is then reacted with an appropriate amine in the presence of ammonium chloride to give the 2-(cyclopropylmethyl)-2,4-dihydroxybenzamide (XVI).
Reaction SMILES: S(Cl)([Cl:3])=O.[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1>C(Cl)Cl.CN(C=O)C>[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:3])=[O:11])=[CH:8][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(I)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
Thionyl chloride (36.0 g, 302 mmol) was added to a suspension of 4-iodobenzoic acid (50.0 g, 202 mmol) in anhydrous DCM (300 ml) followed by a few drops of DMF and the reaction mixture was stirred overnight at r.t. Upon completion, reaction flask was concentrated under reduced pressure to yield 51.6 g (96.0% yield) of crude 4-iodobenzoyl chloride that was used in the next step without further purification.
Reaction SMILES: [ClH:1].[NH:2]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:23][O:24]C1C(N)=CC=CC=1>C(O)C>[ClH:1].[CH3:23][O:24][C:4]1[C:3]([NH:2][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]4[N:21]=[CH:20][NH:19][C:17]4=3)[N:12]=[C:11]([CH3:22])[CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Reactant: COc1ccccc1N
Agent: Cl
Solvent: CCO
Product: COc1ccccc1Nc1cc(C)nc2ccc3nc[nH]c3c12

Procedure:
A mixture of 30 g. (0.138 m.) of the compound of Example I, C. 17 g. (15.6 ml. 0.138 m.) of o-anisidine and 200 ml. of ethanol was stirred and heated at reflux overnight. The solution was concentrated in vacuo to give 45 g. m.p. 271°-275°. The crude product was recrystallized from 350 ml. of MeOH. The yield after oven-drying (100°) was 29 g. m.p. 300°-301°.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([NH:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25])[S:20][CH:21]=2)=[C:13]([F:28])[CH:12]=1.Cl[C:30](Cl)([O:32]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:18]=[C:19]([N:22]3[C:23]([CH3:26])([CH3:27])[CH2:24][O:25][C:30]3=[O:32])[S:20][CH:21]=2)=[C:13]([F:28])[CH:12]=1
Reactant: CC(C)(CO)Nc1nc(-c2ccc(Br)cc2F)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)COC(=O)N1c1nc(-c2ccc(Br)cc2F)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 111.5 %

Procedure:
N,N-diisopropylethylamine (1.2 mL, 6.9 mmol) was added to a solution of 2-{[4-(4-bromo-2-fluorophenyl)-1,3-thiazol-2-yl]amino}-2-methylpropan-1-ol (1.0 g, 2.9 mmol), prepared in the previous step, in 50 mL of dry methylene chloride at 0° C. Triphosgene (1.0 g, 3.4 mmol) in 10 mL of dry methylene chloride was added drop-wise over 10 min. The orange solution was stirred at 0° C. for 3 h and then allowed to warm to room temperature. The reaction was washed with 2N HCl and the aqueous layer was extracted with methylene chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 1.2 g of a green residue. The crude product was purified on silica gel using a step-wise gradient of 5-30% ethyl acetate:hexane to give the title compound (0.9 g, 89%). MS (ES) m/z 372 [M+H]+.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[C:3]#[N:4].[H-].[Na+].[C:9]([O:12][C@@H:13]1[C@@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:17][S:16][C@@H:14]1[OH:15])(=[O:11])[CH3:10]>C(Cl)Cl>[Cl:1][C:2]([Cl:6])([Cl:5])[C:3](=[NH:4])[O:15][C@H:14]1[S:16][CH2:17][C@@H:18]([O:24][C:25](=[O:27])[CH3:26])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@H:13]1[O:12][C:9](=[O:11])[CH3:10]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](O)SC[C@H]1OC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](OC(=N)C(Cl)(Cl)Cl)SC[C@H]1OC(C)=O
Reaction time: 4 h
Yield: 53 %

Procedure:
1.5 ml (15.10-3 mol) of trichloroacetonitrile and 70 mg of NaH (2.3.10-3 mol of NaH in 80% dispersion) are added to a solution of 1 g (3.42.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranose in 10 ml of methylene chloride. After 4 h at room temperature, the reaction medium is filtered on silica in methylene chloride and then purified by chromatography on silica gel using a hexane/ethyl acetate mixture (3/1 v/v) as the eluent. 790 mg (yield: 53%) of the expected product are obtained after crystallization from an ethyl acetate/hexane mixture.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[N:14]([CH2:28][C:29]1[CH:46]=[CH:45][C:32]2[N:33]([CH2:43][CH3:44])[C:34](=[O:42])[C:35]([CH3:41])([CH3:40])[C:36](=[O:39])[N:37]([CH3:38])[C:31]=2[CH:30]=1)[CH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH2:21][C:22](=[O:27])[N:23]2[CH3:26])=[CH:18][CH:17]=1)(C)(C)C.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:43]([N:33]1[C:34](=[O:42])[C:35]([CH3:40])([CH3:41])[C:36](=[O:39])[N:37]([CH3:38])[C:31]2[CH:30]=[C:29]([CH2:28][NH:14][CH2:15][C:16]3[CH:25]=[C:24]4[C:19]([CH2:20][CH2:21][C:22](=[O:27])[N:23]4[CH3:26])=[CH:18][CH:17]=3)[CH:46]=[CH:45][C:32]1=2)[CH3:44]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(Cc3ccc4c(c3)N(C)C(=O)CC4)C(=O)OC(C)(C)C)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCc3ccc4c(c3)N(C)C(=O)CC4)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Trifluoroacetic acid (43.2 mg) was added to a dichloromethane solution (5 ml) of N-(1-ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-ylmethyl)carbamic acid tert-butyl ester (208 mg), and the mixture was stirred at room temperature overnight. A saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction using dichloromethane, and condensed under reduced pressure to give the title compound(148 mg) as a white amorphous.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:15]1[CH:16]=[CH:17][C:18]([N+:30]([O-:32])=[O:31])=[C:19]([N:21]([CH3:29])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH:20]=1.[H-].[Na+]>CN(C)C=O>[CH3:29][N:21]([C:19]1[CH:20]=[C:15]([O:13][C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[CH:16]=[CH:17][C:18]=1[N+:30]([O-:32])=[O:31])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26]
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2cccc(-c3ccccc3)c2)ccc1[N+](=O)[O-]
Yield: 91.3 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 3-phenylphenol (4.0 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (6.5 g), sodium hydride (55 wt. %, 1.13 g) and anhydrous N,N-dimethylformamide (35 ml) and the reaction mixture was purified to give the title compound (8.7 g).