Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:19])/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH:16]2[CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1>O.O1CCOCC1.[OH-].[Na+]>[CH:16]1([C:14]([C:11]2[CH:12]=[CH:13][C:8](/[CH:7]=[CH:6]/[C:5]([OH:19])=[O:4])=[CH:9][CH:10]=2)=[O:15])[CH2:17][CH2:18]1
Reactant: COC(=O)/C=C/c1ccc(C(=O)C2CC2)cc1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C=C/c1ccc(C(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
A solution of lithium hydroxide (27 mg, 1.1 mmol) in water (2.00 ml) was added to a solution of (E)-3-(4-(cyclopropanecarbonyl)phenyl)acrylic acid methyl ester (217 mg, 0.94 mmol) in 1,4-dioxane (2.00 ml). 1,4-Dioxane was added until a clear solution was obtained. The reaction mixture was stirred for 16 h at room temperature. It was diluted with an 1 N aqueous solution of sodium hydroxide (50 ml) and washed with tert-butyl methyl ether (2×40 ml). The aqueous solution was acidified with a 10% aqueous solution of sodium hydrogensulphate until pH 3 was obtained. It was extracted with ethyl acetate (3×100 ml) The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo to give 170 mg of crude (E)-3-(4-(cyclopropanecarbonyl)phenyl)acrylic acid which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH:7]=[C:6]3[C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=[C:5]3[C:4]=2[CH:3]=1.C(OC(C1C=NC2C(C=1[Cl:37])=CC(F)=C(Cl)C=2)=O)C>>[Cl:37][C:11]1[C:2]([F:1])=[CH:3][C:4]2[C:5]3[C:6]([C:12](=[O:21])[N:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)=[CH:7][NH:8][C:9]=2[CH:10]=1
Reactant: CCOC(=O)c1cnc2cc(Cl)c(F)cc2c1Cl
Reactant: O=c1c2c[nH]c3ccc(F)cc3c-2nn1-c1ccccc1
Product: O=c1c2c[nH]c3cc(Cl)c(F)cc3c-2nn1-c1ccccc1

Procedure:
The title compound was prepared following procedure for 23a using ethyl-4,7-dichloro-6-fluoro-quinoline-3-carboxylate. 1H-NMR (DMSO-d6) δ (ppm): 7.20 (1H, t, J=7.41 Hz), 7.48 (3H, m), 8.19 (2H, m), 8.43 (1H, dd, J=8.79, 2.46 Hz), 8.54 (1H, d, J=2.20 Hz), 8.92 (1H, s). m/z 314.7 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C@@H:13]2[CH2:18][N:17]([CH3:19])[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[O:14]2)[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:24][C:25]1[CH:26]=[C:27]([C:32]([CH3:38])([CH3:37])[C:33]([O:35][CH3:36])=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31].N1C=CC=CC=1.O>ClCCl>[Cl:31][C:30]1[CH:29]=[CH:28][C:27]([C:32]([CH3:37])([CH3:38])[C:33]([O:35][CH3:36])=[O:34])=[CH:26][C:25]=1[NH:24][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH2:12][C@@H:13]2[CH2:18][N:17]([CH3:19])[C:16]3[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=3[O:14]2)=[CH:10][C:2]=1[Cl:1]
Reactant: COC(=O)C(C)(C)c1ccc(Cl)c(N)c1
Reactant: CN1C[C@@H](COc2ccc(C(=O)Cl)c(Cl)c2)Oc2ccccc21
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)C(C)(C)c1ccc(Cl)c(NC(=O)c2ccc(OC[C@@H]3CN(C)c4ccccc4O3)cc2Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the compound prepared in Example 17 in dichloromethane (1.8 mL) was dropped to a solution of the compound (100 mg) prepared in Example 16 in dichloromethane (1.8 mL). Pyridine (0.057 mL) was added to the reaction mixture, which was stirred for 1 hour at room temperature. The reaction mixture dissolved to water was extracted with ethyl acetate. The organic layer was sequentially washed with diluted hydrochloric acid, saturated sodium hydrogencarbonate solution, and saturated brine solution and was dried by anhydrous magnesium sulphate. The title compound (164 mg) having the following physical data was obtained by purifying the residue obtained by removing the solvent by silica gel column chromatography (n-hexane:ethyl acetate=4:1). TLC: Rf 0.41 (n-hexane:ethyl acetate=2:1).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12](O)=[O:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.ON1C2C=CC=CC=2N=N1.[CH2:31]([C@H:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.C1COCC1>[CH2:31]([C@H:33]([NH:40][C:12]([C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]=1[OH:1])=[O:13])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH3:32]
Reactant: O=C(O)c1c(O)c(-c2ccccc2)nc2ccccc12
Reactant: CC[C@H](N)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1c(O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
2.49 g (9.4 mmol) of 3-hydroxy-2-phenylquinoline-4-carboxylic acid (CAS [485-89-2]) were suspended in 150 ml of a 7/3 mixture of THF/CH3CH; 1.40 g (10.3 mmol) of 1-hydroxybenzotriazole (HOBT) and 1.27 g (9.4 mmol) of (S)-α-ethylbenzylamine dissolved in 20 ml of CH2Cl2 were added and the reaction mixture was stirred at room temperature for 30 minutes. 2.13 g (10.3 mmol) of dicyclohexylcarbodiimide (DCC) dissolved in 20 ml of CH2Cl2 were added dropwise. The reaction was left at room temperature overnight, quenched with 20 ml of H2O, evaporated in-vacuo to dryness and dissolved in EtOAc. The precipitated dicyclohexylurea was filtered off and the organic layer was washed with H2O, 20% citric acid, sat. sol. NaHCO3, sat. sol. NaCl. The organic layer was separated, dried over Na2SO4 and evaporated in-vacuo to dryness; the residue was purified by gradient column chromatography on 60-240 mesh silica gel using a mixture of hexane/EtOAc 9:1 as starting eluent and a mixture of hexane/EtOAc 7:3 as final eluent. The crude product was recrystallized from i-PrOH to yield 1.75 g of the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([OH:12])=O)=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH:20]=1>>[C:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][C:10]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[O:12])=[C:6]([CH2:15][CH2:16][CH3:17])[C:5]=1[OH:18])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCC(=O)O)ccc(C(C)=O)c1O
Reactant: NCCCCc1cccnc1
Product: CCCc1c(OCC(=O)NCCCCc2cccnc2)ccc(C(C)=O)c1O

Procedure:
(4-Acetyl-3-hydroxy-2-propylphenoxy)acetic acid was allowed to react with 3-pyridine butanamine according to procedure A and the product was purified by chromatography on silica gel to give (4-acetyl-3-hydroxy-2-propylphenoxy)-N-[4-(3-pyridinyl)butyl]acetamide, the title compound, mp 95°-97° (from methylene chloride-ether) in 57% yield.
Reaction SMILES: C([O:7][C:8]1[CH:21]=[C:20]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])[C:11]2[C:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:13][S:14][C:10]=2[CH:9]=1)(=O)C(C)(C)C.CO.C([O-])([O-])=O.[K+].[K+]>O>[CH3:19][O:18][C:16](=[O:17])[CH2:15][C:12]1[C:11]2[C:20]([C:22](=[O:26])[N:23]([CH3:25])[CH3:24])=[CH:21][C:8]([OH:7])=[CH:9][C:10]=2[S:14][CH:13]=1
Reactant: COC(=O)Cc1csc2cc(OC(=O)C(C)(C)C)cc(C(=O)N(C)C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)Cc1csc2cc(O)cc(C(=O)N(C)C)c12
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.4 %

Procedure:
To a mixture of 4-(dimethylcarbamoyl)-3-(2-methoxy-2-oxoethyl)-1-benzothiophen-6-yl pivalate (128 mg) and MeOH (3 mL) was added K2CO3 (46.9 mg) at room temperature. The mixture was stirred at room temperature for 12 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (75 mg).
Reaction SMILES: [CH2:1]([NH:8][S:9]([N:12]1[CH2:16][CH2:15]O[C:13]1=O)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CC[CH:21]([N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]2=[O:33])[CH2:20]C1.C(N(CC)CC)C>C(#N)C>[CH2:1]([NH:8][S:9]([N:12]1[CH2:13][CH2:20][CH:21]([N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]2=[O:33])[CH2:15][CH2:16]1)(=[O:10])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCN1S(=O)(=O)NCc1ccccc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccccc2n1C1CCN(S(=O)(=O)NCc2ccccc2)CC1
Temperature: 80 °C
Yield: 11.3 %

Procedure:
2-Oxo-oxazolidine-3-sulfonic acid benzylamide (0.059 g; 0.23 mmol; 1 equiv) was added to a solution of 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.050 mg; 0.23 mmol) in acetonitrile (2 mL). Triethylamine (32 μL; 0.23 mmol) was added and the reaction mixture was heated at 80° C. for 48 h. The reaction mixture was evaporated under reduced pressure and the crude product was purified by preparative liquid chromatography to provide 4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-sulfonic acid benzylamide (0.010 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH:12]=[CH:13][C:14]([O:16][CH3:17])=[O:15])=[CH:5]2.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O.C([O-])(=O)C.[K+].BrC1C=CC2C(=CC=CC=2)N=1>C(O)C.O>[C:19]1([CH3:18])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([CH:12]=[CH:13][C:14]([O:16][CH3:17])=[O:15])=[CH:5]2
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)C=Cc1cnc2ccc(Br)cc2c1
Agent: Brc1ccc2ccccc2n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COC(=O)C=Cc1cnc2ccc(-c3ccccc3C)cc2c1

Procedure:
5-Bromo-2-nitrobenzaldehyde 1 (6.03 g, 26.2 mmol) was dissolved in MeOH (200 mL) and treated with 5N HCl (10 mL). The mixture was heated to 70° C. and iron powder (7.32 g, 131 mmol) was added in five portions every 5 min. Upon completion (by TLC) the reaction was cooled and DCM (200 mL) was added before filtering through a pad of celite. The filtrate was concentrated under reduced pressure to 150 mL. To this material, a solution of 1,1,3,3-tetramethoxypropane (9.52 ml, 57.7 mmol) in 5N HCl (10 mL) pre-mixed for 45 min was added. The reaction mixture was stirred at 80° C. for 60 min. Toluene (100 mL) and acetic acid (40 mL) were added and the solution was heated to 110° C. for 3 h, then cooled and evaporated to dryness under reduced pressure. The crude material was purified using silica chromatography (20-60% ethyl acetate in hexane gradient) to give 6-bromoquinoline-3-carbaldehyde 2. Step 2 6-Bromoquinoline-3-carbaldehyde 2 (2.8 g, 12.0 mmol) and methyl(triphenylphosphoranylidene)acetate (4.0 g, 12.0 mmol) were dissolved in dry THF (50 mL) and heated to 50° C. After 40 min the solution was evaporated to dryness under reduced pressure. Purification using silica chromatography (hexane to 60% ethyl acetate in hexane gradient) gave methyl 3-(6-bromoquinolin-3-yl)acrylate 3 as a mixture of E and Z isomers. Step 3 Methyl 3-(6-bromoquinolin-3-yl)acrylate 3 (0.91 g, 3.1 mmol), 2-methylphenyl boronic acid (R1 substituted ring A in 4 above; 0.61 g), potassium acetate (1.0 g) and bis(4-(di-tert-butylphosphino)-N,N-dimethylbenzenamine)dichloropalladium (II) (0.19 g) were suspended in ethanol (70 mL) and water (5 mL) and heated to reflux for 90 min. LC/MS showed the bromoquinoline had been consumed the reaction was evaporated to dryness under reduced pressure. The crude was partitioned between ethyl acetate and water. The organic layer was separated and dried with magnesium sulfate, evaporated to dryness under reduced pressure and purified using silica chromatography (hexane to ethyl acetate gradient) to give methyl 3-(6-o-tolylquinolin-3-yl)acrylate 4 (representative compound 4 wherein ring A is ortho-toluene).
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]1[N:4]([C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=1)[C:5](=O)[NH:6]2.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>P(Cl)(Cl)(Cl)=O>[Cl:20][C:5]1[N:4]2[C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=[C:3]2[C:2]2[C:7](=[CH:8][CH:9]=[CH:10][CH:1]=2)[N:6]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1[nH]c2ccccc2c2nc3ccccc3n12
Solvent: O=P(Cl)(Cl)Cl
Product: Clc1nc2ccccc2c2nc3ccccc3n12

Procedure:
A mixture of 23.5 g (100 mmol) of benzimidazo[1,2-c]quinazolin-6(5H)-one [16367-99-0], 22.9 g (110 mmol) of phosphorus pentachloride and 250 ml of phosphoryl chloride is heated under reflux for 24 h. The excess phosphoryl chloride is removed in vacuo, 1000 ml of dichloromethane are added to the residue, the mixture is hydrolysed by addition of 1000 g of ice, rendered weakly alkaline by addition of 10% by weight sodium hydroxide solution, the organic phase is separated off, dried over sodium sulfate, and the dichloromethane is then removed in vacuo. Yield: 24.1 g (94 mmol), 94%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [C:1]1([C@@H:7]([CH3:13])[CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:15]([CH2:19][CH3:20])[C:16](O)=[O:17]>>[CH2:19]([C@@H:15]1[S:11][C:10]([NH:9][CH2:8][C@@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:13])=[N:12][C:16]1=[O:17])[CH3:20]
Reactant: CCC(Br)C(=O)O
Reactant: C[C@@H](CNC(N)=S)c1ccccc1
Product: CC[C@@H]1SC(NC[C@H](C)c2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-[(2R)-2-phenylpropyl]thiourea and 2-bromo-butyric acid according to Method D3.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][C:9]12[CH:20]3[CH2:21][C:16]([CH:28]=[O:29])([C:17]1([C:25]([O-:27])=[O:26])[C:18]([CH:22]([CH3:24])[CH3:23])=[CH:19]3)[CH:15]1[CH:11]([CH:12]([CH3:30])[CH2:13][CH2:14]1)[CH2:10]2)=[O:6])=[N+]=[N-].[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][C:5]([O:7][CH2:8][C:9]12[CH:20]3[CH2:21][C:16]([CH:28]=[O:29])([C:17]1([C:25]([OH:27])=[O:26])[C:18]([CH:22]([CH3:24])[CH3:23])=[CH:19]3)[CH:15]1[CH:11]([CH:12]([CH3:30])[CH2:13][CH2:14]1)[CH2:10]2)=[O:6]
Reactant: [H][H]
Reactant: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC(=O)CN=[N+]=[N-])C13C(=O)[O-]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)C1=CC2CC3(C=O)C4CCC(C)C4CC2(COC(=O)CN)C13C(=O)O

Procedure:
The azide obtained above was dissolved in methanol and palladium hydroxide on carbon was added. The reaction was stirred under one atmosphere of hydrogen for a time sufficient to remove the benzyl ester group and reduce the azide. Concentration under reduced pressure gave the title compound. 1H NMR (CD3OD): δ0.77 (3H, d, J=6.4), 0.93 (3H, d, J=6.7), 0.94 (3H, d, J=6.6), 1.50-2.30 (11H, m), 2.36 (1H, m), 2.51 (1H, m), 3.60-4.60 (4H, m), 5.90 (1H, s), 9.81 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]([OH:13])=[O:12])[CH2:6][CH2:5]2.COC1C=C2[C@@]34[C@@H]5C[C@H]6C(CN5CC3)=CCO[C@H]3CC(=O)N([C@H]4[C@@H]63)C2=CC=1OC.Cl>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([C:11]([OH:13])=[O:12])[CH2:6][CH2:5]2
Reactant: O=C(O)C1CCc2cc(F)ccc21
Agent: COc1cc2c(cc1OC)[C@@]13CCN4CC5=CCO[C@H]6CC(=O)N2[C@H]1[C@H]6[C@H]5C[C@H]43
Agent: Cl
Solvent: CC(C)=O
Product: O=C(O)[C@@H]1CCc2cc(F)ccc21
Yield: 10.5 %

Procedure:
The combined mother liquors from the resolution of Intermediate T3 were concentrated under reduced pressure until no acetone remained and acidified to pH 3 with 0 EC 5N HCl. This solution was extracted 3 times with Et2O (200 ml portions) and the combined Et2O portions were washed successively with 1N HCl, H2O and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give a yellow solid (71 g). This residue was recrystallized from hexane to give pure 5-fluoro-indan-1-carboxylic acid (Intermediate 2a, 58.6 g, 325.5 mmol) which was enriched in the R enantiomer. To Intermediate 2a in refluxing acetone (1 L) was added pulverized brucine (128.4 g, 325.5 mmol). After most solids had dissolved the solution was hot filtered and reheated to reflux as H2O (1 L) was added gradually. Excess acetone was boiled off until the solution became hazy. The solution was allowed to stand in a recrystallization dish for 1 month before solids appeared. The resultant solids were broken up, filtered off and recrystallized four more times in similar manner from acetone and H2O to give a buff colored solid which was taken up in 0 EC 1N HCl (150 ml). This solution was extracted 3 times with Et2O (75 ml portions) and the combined Et2O portions were washed successively with 1N HCl, H2O and brine, dried (MgSO4), filtered and concentrated under reduced pressure to give 6.13 g of (R)-5-fluoro-indan-1-carboxylic acid (Intermediate T4) as a pale solid which rotates sodium light at 20 EC with [α]20D +31.8 (c=4.49, benzene).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([O:7][CH:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:3][CH:2]=1.[CH3:26][O:27][CH2:28][N:29]=[C:30]=[O:31].C(N(CC)CC)C.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC>O1CCCC1>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([O:7][CH:8]([N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH:9]([O:14][C:30](=[O:31])[NH:29][CH2:28][O:27][CH3:26])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:3][CH:2]=1
Reactant: COCN=C=O
Reactant: CC(C)(C)C(O)C(Oc1ccc(-c2ccccc2)cc1)n1cncn1
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCNC(=O)OC(C(Oc1ccc(-c2ccccc2)cc1)n1cncn1)C(C)(C)C
Yield: 82.9 %

Procedure:
505 g (1.5 moles) of 1-(4-biphenylyloxy)-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol (A form) and 140 g (1.6 moles) of methoxymethyl isocyanate were heated under reflux in 2.5 liters of tetrahydrofuran in the presence of 40 ml of triethylamine and 1 ml of dibutyl-tin dilaurate for 48 hours. Thereafter, the solvent was stripped off in vacuo and 3 liters of petroleum ether were added to the residue. The crystalline precipitate formed was extracted by stirring with 1.5 liters of diisopropyl ether. 528 g (82.5% of theory) of 1-(4-biphenylyloxy)-3,3-dimethyl-2-methoxymethylcarbamoyloxy-1-(1,2,4-triazol-1-yl)-butane (A form) of melting point 95°-98° C. were obtained.
Reaction SMILES: [CH:1]1(N(O)C(N)=O)[CH2:5][O:4][C:3]2[CH:6]=[CH:7][C:8]3[C:13]([C:2]1=2)=[CH:12][CH:11]=[CH:10][CH:9]=3.C[Si](N=C=[O:25])(C)C>C1COCC1>[C:1]1(=[O:25])[CH2:5][O:4][C:3]2[CH:6]=[CH:7][C:8]3[C:13]([C:2]1=2)=[CH:12][CH:11]=[CH:10][CH:9]=3
Reactant: C[Si](C)(C)N=C=O
Reactant: NC(=O)N(O)C1COc2ccc3ccccc3c21
Solvent: C1CCOC1
Product: O=C1COc2ccc3ccccc3c21
Temperature: 60 °C
Yield: 11 %

Procedure:
N-{1-(1,2-Dihydronaphtho[2,1-b]furyl}-N-hydroxyurea. To a solution of N-{1-(1,2-dihydronaphtho[2,1-b]furyl}-N-hydroxyamine (698 mg, 3.5 mmol) in THF (10 mL) was added trimethylsilylisocyanate (0.94 mL, 7.0 mmol). The resulting solution was heated at 60° C. for 1 h, then allowed to cool and concentrated under reduced pressure. The residue was dissolved in EtOAc and washed successively with H2O and saturated aqueous NaCl. The solvent was removed in vacuo. The residue was triturated with Et2O and recrystallized from MeOH/CH2Cl2 /hexanes to provide the title compound (93 mg, 11%). m.p. 194.5°-195.5° C.
Reaction SMILES: [CH:1]([Si:4]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[O:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[O:15][CH3:16])([CH3:3])[CH3:2].[H][H]>CCO.[Pd]>[CH3:16][O:15][C:7]1[CH:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:6]=1[O:5][Si:4]([CH:17]([CH3:19])[CH3:18])([CH:20]([CH3:22])[CH3:21])[CH:1]([CH3:3])[CH3:2]
Reactant: COc1cc([N+](=O)[O-])ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Yield: 77.6 %

Procedure:
Dissolve triisopropyl-(2-methoxy-4-nitro-phenoxy)-silane (95.7 g, 294.0 mmol) in EtOH (1800 mL) and add 5% Pd/C (10.0 g). Hydrogenate the slurry at RT under 50 psi hydrogen for 8 h. Filter the slurry through a pad of Celite® and rinse with EtOH. Concentrate the filtrate in vacuo to give a brown oil. Purify the oil by flash chromatography, using a gradient from 100% hexanes to 20% EtOAc/hexanes, to provide 67.4 g (77.6%) of the title compound as a brown solid. MS/ES m/z 296.2 [M+H]+.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=O)[CH2:2]1.C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:24]>C(Cl)Cl.CN(C=O)C>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([NH2:24])=[O:16])[CH2:2]1
Reactant: [NH4+]
Reactant: O=C(O)C1CCc2[nH]c3ccccc3c2C1
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)C1CCc2[nH]c3ccccc3c2C1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
2,3,4,9-tetrahydro-1H-carbazole-3-carboxylic acid (30.4 g, 141 mmol), was suspended in 450 ml of methylene chloride and cooled to 0° C. Oxalyl chloride (14.8 mL, 169 mmol) was added dropwise, followed by two drops of DMF. The resulting mixture was allowed to warm to room temperature and was stirred for 24 h. After re-cooling to 0° C., 450 mL of conc. aqueous ammonium hydroxide were added dropwise. The yellow precipitate that formed was collected by vacuum filtration. After drying, the title compound weighed 17.4 g (58%).
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][CH2:7][C:8]1[O:12][C:11]([C:13]2[N:14]=[C:15]([NH:18][C:19]([NH:21]C(=O)C3C=CC=CC=3)=[S:20])[S:16][CH:17]=2)=[CH:10][CH:9]=1)(=[O:5])[CH3:4]>O.CO>[C:3]([NH:6][CH2:7][C:8]1[O:12][C:11]([C:13]2[N:14]=[C:15]([NH:18][C:19]([NH2:21])=[S:20])[S:16][CH:17]=2)=[CH:10][CH:9]=1)(=[O:5])[CH3:4]
Reactant: CC(=O)NCc1ccc(-c2csc(NC(=S)NC(=O)c3ccccc3)n2)o1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)NCc1ccc(-c2csc(NC(N)=S)n2)o1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
A solution of sodium hydroxide (0.55 g) in water (5 ml) was added to a suspension of 4-(5-acetylaminomethylfuran-2-yl)-2-(3-benzoylthioureido)thiazole (5.40 g) in methanol (50 ml) and the mixture was stirred at 60° C. for two hours. Following evaporation in vacuo, the residue was mixed with water (50 ml) and ethyl acetate (15 ml) and stirred for several minutes. The resulting precipitate was collected by filtration and washed with water and ethyl acetate to afford 4-(5-acetylaminomethylfuran-2-yl)-2-thioureidothiazole (2.95 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([O:11][CH2:12][O:13][CH3:14])=[CH:9][C:8]([O:15][CH3:16])=[C:7]([O:17][CH2:18][O:19][CH3:20])[C:4]=1[CH:5]=O.[CH3:21][C:22]1([CH3:30])[O:29][C:27](=[O:28])[CH2:26][C:24](=[O:25])[O:23]1.C(N(CC)CC)C.C(OCC)(=O)C>C1C=CC=CC=1>[CH3:21][C:22]1([CH3:30])[O:29][C:27](=[O:28])[C:26](=[CH:5][C:4]2[C:7]([O:17][CH2:18][O:19][CH3:20])=[C:8]([O:15][CH3:16])[CH:9]=[C:10]([O:11][CH2:12][O:13][CH3:14])[C:3]=2[O:2][CH3:1])[C:24](=[O:25])[O:23]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COCOc1cc(OC)c(OCOC)c(C=O)c1OC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COCOc1cc(OC)c(OCOC)c(C=C2C(=O)OC(C)(C)OC2=O)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3 Grams (10.48 mM) of 2,5-dimethoxy-3,6-bis(methoxymethoxy)benzaldehyde was dissolved in 100 ml of benzene, next 1.82 g (1.2 times the equivalent) of Meldrum's acid and 3 ml of triethylamine were added thereto, and the reaction mixture was stirred at room temperature for 5 hours. 200 milliliters of ethyl acetate was added to the reaction mixture, and the organic layer was washed twice with 50 ml of water, then washed three times with a saturated sodium chloride aqueous solution. The organic layer was then dehydrated on anhydrous sodium sulfate and concentrated to yield 4.39 g of 1-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)-1-[2,5-dimethoxy-3,6-bis(methoxymethoxy)phenyl]methane. Yellow powdery substance.
Reaction SMILES: C(OC(=O)[N:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:24])[CH2:8][CH2:9][O:10][CH3:11])(C)(C)C>CCCCCCC.CCOC(C)=O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[NH:7][CH2:8][CH2:9][O:10][CH3:11]
Reactant: COCCN(C(=O)OC(C)(C)C)c1cnccc1-c1ccccc1Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COCCNc1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 85, intermediate a, from [4-(2-chloro-phenyl)-pyridin-3-yl]-(2-methoxy-ethyl)-carbamic acid tert-butyl ester and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Colorless oil (72%). MS (ESI): m/z=263.094 [M+H]+.