Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([C:26]([OH:28])=[O:27])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].I[CH2:32][CH2:33][CH3:34].O>CS(C)=O.C(OCC)(=O)C>[CH2:32]([O:27][C:26]([C:24]1[N:25]=[C:21]([NH:20][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:22][CH:23]=1)=[O:28])[CH2:33][CH3:34]
Reactant: CCCI
Reactant: O=C(O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCOC(=O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 60 °C
Yield: 73.6 %

Procedure:
To a solution of 2-(trityl-amino)-thiazole-4-carboxylic acid (400 mg, 1.03 mmol) in DMSO (1 ml) was added KOH (215 mg, 1.55 mmol) followed by addition of 1-iodo-propane (263 mg, 1.55 mmol). The reaction was heated at 60° C. for 1 hour. It was taken into water and ethyl acetate. After separation, the organic layer was washed, dried and evaporated. The obtained crude product was purified via flash column (silica gel, 10% ethyl acetate in hexane) to yield 2-(trityl-amino)-thiazole-4-carboxylic acid propyl ester as a white solid (325 mg, 76%). LC/MS (m/z 429.14 (M+H)+); HPLC Rt: 4.182 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH:9]1[C:21]2[NH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>CN(C)C(=O)C.[Cu-]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:20]2[C:21]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]3[C:19]2=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: Brc1ccc(I)cc1
Agent: O=[Cu-]
Solvent: CC(=O)N(C)C
Product: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 25 °C

Procedure:
9-(4-bromophenyl) carbazole was prepared through the Ullmann Reaction following the procedures reported in the literature (Macromolecules 2004, 37, 5531-5537). Briefly, a mixture of 1-bromo-4-iodobenzene (2.83 g, 10 mmol), copper (I) oxide (2.86 g, 20 mmol) and carbazole (0.84 g, 5 mmol) in 10 ml N,N-dimethylacetamide (DMAC) was heated to reflux in an oil bath for 24 h under N2 atmosphere. The reaction mixture was cooled to room temperature and then filtered to remove excess copper complex. The filtrate was evaporated to dryness and went through silica gel column to give product, yielding 1.22 g (76%). 1H NMR (400 MHz, CDCl3): δ(ppm) 8.132-8.122 (d, J=8.0 Hz, 2H), 7.715-7.695 (t, J=8.0 Hz, 2H), 7.476-7.247 (m, 8H).
Reaction SMILES: [Cl:1]C(OCC)=O.[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=O.C(N(CC)CC)C>ClCCl>[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:15][CH2:16][O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([Cl:1])=[O:26]
Reactant: CCOC(=O)Cl
Reactant: O=C(O)CCCCCCOCCc1cccc(F)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cl)CCCCCCOCCc1cccc(F)c1F
Yield: 95.4 %

Procedure:
Ethyl chloroformate (414 mg, 3.82 mmol) was added at 0° C. to a solution of 7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptanoic acid (800 mg, 2.94 mmol) and triethylamine (387 mg, 3.82 mmol) in dichloromethane (15 mL), then after 2 h volatile material was removed by distillation, producing 7-[2-(2,3-difluoro-phenyl)-ethoxy]-heptanoyl chloride (855 mg). This was redissolved in acetone (2 mL) and treated at 0° C. with a solution of sodium azide (268 mg, 4.12 mmol) in water (4 mL) under vigorous stirring. The reaction mixture was stirred for 1 h at 10° C., then partitioned between toluene and brine. The organic layer was separated and heated at 65° C. for 90 min, then concentrated in vacuo, affording [6-(2,3-difluoro-benzyloxy)-hexyl]-isocyanate (486 mg, 61%) as a yellow oil.
Reaction SMILES: B.C1COCC1.[O:7]1[CH2:12][CH2:11][O:10][C:9]2[CH:13]=[C:14]([CH2:17][C:18](O)=[O:19])[CH:15]=[CH:16][C:8]1=2.O>C1COCC1>[O:7]1[CH2:12][CH2:11][O:10][C:9]2[CH:13]=[C:14]([CH2:17][CH2:18][OH:19])[CH:15]=[CH:16][C:8]1=2
Reactant: O=C(O)Cc1ccc2c(c1)OCCO2
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccc2c(c1)OCCO2
Temperature: 25 °C
Yield: 96.5 %

Procedure:
BH3.THF (44 mL, 44 mmol, 1 M/THF) was added to a 0° C. solution of 2-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acetic acid (3.419 g, 17.6 mmol) in THF (8.8 mL). The reaction was allowed to warm to room temperature and after 2 h, 20 mL H2O was added slowly by syringe. The resulting mixture was extracted with ethyl acetate, the organic portion was washed with brine, and then was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (ethyl acetate/hexanes) gave the title compound (3.059 g, 99%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][CH:7]=[CH:8][CH:9]=1)([O-])=O.[CH3:17]O.[NH2:19][C:20]1[N:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>CS(C)=O.ClCCl>[C:14]1([CH3:17])[CH:15]=[CH:16][C:11]([N:10]2[C:5]3=[N:6][CH:7]=[CH:8][CH:9]=[C:4]3[N:1]=[C:22]2[C:21]2[C:20]([NH2:19])=[N:27][CH:26]=[CH:25][CH:24]=2)=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1cccnc1Nc1ccccc1
Reactant: CO
Reactant: Nc1ncccc1C=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1ccc(-n2c(-c3cccnc3N)nc3cccnc32)cc1
Temperature: 100 °C

Procedure:
3-nitro-N-phenylpyridin-2-amine was dissolved in dimethylsulfoxide (4 mL) and methanol (2 mL) in a round bottom flask. 2-aminonicotinaldehyde 4 (77 mg, 1.1 eq.) was added and Na2S2O4 (274 mg). The reaction mixture was heated to 100° C. for 18 hours. After cooling to room temperature the reaction mixture was diluted with dichloromethane (50 mL) and washed with water and brine. The organic phase was separated and dried over Na2SO4. After filtration the solvent was removed under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate/hexanes) to afford 20 mg of desired product. 400 M Hz 1H NMR (DMSO-d6) δ: 8.29 (dd, J=1.6 Hz and 5.0 Hz, 1H), 8.17 (dd, J=1.1 Hz and 7.8 Hz, 1H), 7.96 (dd, J=1.6 Hz and 4.7 Hz, 1H), 7.35 (dd, J=5.09 Hz and 8.21 Hz, 1H), 7.31-7.26 (m, 4H), 7.18 (dd, J=1.9 Hz and 7.8 Hz, 1H), 6.96 (s, 2H), 6.37 (dd, J=4.6 Hz and 7.8 Hz, 1H), 2.36 (s, 3H); LCMS [M+H]: 302.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:12])([F:11])[C@@H:4]([CH3:10])[C@H:5]([NH:8]N)[CH2:6][OH:7]>CO.Cl.O=[Pt]=O>[ClH:1].[NH2:8][C@@H:5]([C@H:4]([CH3:10])[C:3]([F:12])([F:11])[F:2])[CH2:6][OH:7]
Reactant: C[C@@H]([C@@H](CO)NN)C(F)(F)F
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: C[C@@H]([C@H](N)CO)C(F)(F)F
Reaction time: 1 h

Procedure:
(2S,3S)-4,4,4-Trifluoro-2-hydrazino-3-methyl-butan-1-ol HCl (130 g, 0.623 mole) was dissolved in 1.4 L MeOH with 60 mL concentrated HCl. The solution was hydrogenated with 10 g PtO2 at 50 psig for 12 hours. The mixture was filtered and the filter washed with 1 L MeOH. The MeOH was removed to dryness under vacuum at 30-40° C. The solid was chased with two portions of 1 L MeOH. The solid was stirred with 0.5 L MeOH for 1 hour and the NH4Cl was removed by filtration. To remove more NH4Cl, the filtrate can be concentrated to ⅔ volume and crystallized NH4Cl removed by filtration. The filtrate was concentrated to dryness and dried at 35° C. at <10 mm Hg. The hydrochloride can be purified by stirring with 20% v/v CH3CN: EtOAc removing a green coloring and removing essentially all the Pt to the 10 ppm level.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].Br.C([N:9]1[CH2:14][CH2:13][C:12](=O)[CH:11](Br)[CH2:10]1)(=O)C.Cl.[OH2:18]>>[NH:3]1[C:12]2[CH2:13][CH2:14][NH:9][CH2:10][C:11]=2[S:1][C:2]1=[O:18]
Reactant: N#C[S-]
Reactant: O
Reactant: CC(=O)N1CCC(=O)C(Br)C1
Agent: Br
Agent: Cl
Agent: [NH4+]
Product: O=c1[nH]c2c(s1)CNCC2
Yield: 6 %

Procedure:
Ammonium thiocyanate (5.54 g, 72.8 mmol) was mixed with water (450 ml) and heated to 80°. A solution of N-acetyl-3-bromo-4piperidone hydrobromide (20.0 g, 66.2 mmol) in water (200 ml) was added dropwise over 3 hours. The reaction was then allowed to stir at 80° for sixteen hours. The reaction solution (containing the crude N-acetyl-3-thiocyanate-4-piperidone) was treated with concentrated hydrochloric acid (6 ml of a 12M solution, 93 mmol) and heated to reflux for 2 hours. The reaction mixture was then freeze-dried, and the residue dissolved in methanol and filtered. The precipitate was purified by column chromatography (eluant: 89:10:1 chloroform:methanol: concentrated ammonium hydroxide) to provide the title product as a white solid, m.p. 208° (decomp.) (0.60 g, 3.8 mmol, 6% yield).
Reaction SMILES: C[N:2]1[C:6]([N:7]=[CH:8]OCC)=[C:5]([C:12]#[N:13])[CH:4]=[N:3]1.O.[NH2:15][NH2:16].[CH2:17](O)C>>[CH3:17][N:15]1[C:12]2[N:13]=[CH:8][NH:7][C:6](=[N:2][NH2:3])[C:5]=2[CH:4]=[N:16]1
Reactant: CCO
Reactant: CCOC=Nc1c(C#N)cnn1C
Reactant: NN
Solvent: O
Product: Cn1ncc2c(=NN)[nH]cnc21

Procedure:
160 g. of 1-methyl-4-cyano-5-ethoxymethyleneaminopyrazole are dissolved in 1 liter of absolute ethanol and 76.0 g. of hydrazine hydrate are added dropwise with stirring. This mixture is refluxed for 8 hours. After cooling, the product, 1,5-dihydro-1-methyl-4H-pyrazolo-[3,4-d]pyrimidin-4-one hydrazone, is filtered under suction and crystallized from dimethylformamide, yield 135 g., m.p. 231°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[S:12][C:13]=1[CH:14]=[O:15].[BH4-].[Na+].O>O1CCCC1.C(O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:23])[F:24])[CH:17]=2)[S:12][C:13]=1[CH2:14][OH:15]
Reactant: O=Cc1sc(-c2cccc(C(F)(F)F)c2)nc1COC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: OCc1sc(-c2cccc(C(F)(F)F)c2)nc1COC1CCCCO1
Temperature: 0 °C
Reaction time: 5 h
Yield: 90.8 %

Procedure:
To a mixed solution of the compound (2.2 g, 5.9 mmol) obtained in Example 89b in tetrahydrofuran/ethanol (v/v=1/1, 10 mL) was added sodium tetrahydroborate (340 mg, 8.9 mmol), and the mixture was stirred at 0° C. for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=50/50) to give the title compound (2.0 g, 92%) as a colorless oil.
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][NH:11][C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH2:34]1[O:36][CH2:35]1>C1C=CC=CC=1>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:34][CH2:35][OH:36])[C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(CC2(C)CN(C(c3ccccc3)c3ccccc3)CCN2)cc1OC
Reactant: C1CO1
Solvent: c1ccccc1
Solvent: CO
Product: COc1ccc(CC2(C)CN(C(c3ccccc3)c3ccccc3)CCN2CCO)cc1OC
Yield: 97.7 %

Procedure:
50 g of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-piperazine (cf. Example 2) are dissolved in 200 ml of benzene and 400 ml of methanol and heated for 48 hours in a pressure vessel at 60° C. with addition of 22 g of ethylene oxide. Subsequently, the solution is evaporated to dryness. The residue is dissolved in 500 ml of diethylether, combined with 60 ml of 2N HCl, and vigorously stirred. The organic phase is separated and washed halide-free with water. The aqueous acid extract is alkalized with ammonium hydroxice solution and extracted with diethyl ether. The extract is dried, filtered, and the solvent is removed by distillation. 54 g (98 percent of theory) of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-4-hydroxyethyl-piperazine are obtained as a colorless resin.
Reaction SMILES: [OH-].[Na+].[S:3]1[C:7]([NH2:8])=[N:6][CH:5]=[N:4]1.[C:9]([C:11]1[CH:12]=[C:13]([S:18](Cl)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17])#[N:10].Cl>O.O1CCOCC1>[C:9]([C:11]1[CH:12]=[C:13]([S:18]([NH:8][C:7]2[S:3][N:4]=[CH:5][N:6]=2)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17])#[N:10]
Reactant: Nc1ncns1
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Reaction time: 0.08 h
Yield: 120.3 %

Procedure:
Sodium hydroxide (5.08 g, 130 mmol) was dissolved in water (60 mL) and 1,4-dioxane (300 mL). 1,2,4-Thiadiazol-5-amine (10 g, 100 mmol) was added and the reaction mixture was stirred for 5 minutes. 3-Cyano-4-fluorobenzene-1-sulfonyl chloride (8.25 g, 38 mmol) was added and the reaction mixture was allowed to stir for 3 hours at 20° C. After this time, the reaction mixture was poured into 1N aqueous hydrogen chloride solution (150 mL). This solution was extracted with ethyl acetate (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a brown solid (13 g, 69%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[CH:10][CH:11]1[CH2:15][CH:14](O)[CH:13](O)[O:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:27][CH2:28][OH:29]>N1C=CC=CC=1>[CH2:1]([O:3][P:4]([CH:9]=[CH:10][CH:11]1[CH2:15][CH:14]([C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]([C:28](=[O:29])[C:27]2[CH:14]=[CH:15][CH:11]=[CH:10][CH:9]=2)[O:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(C=CC1CC(O)C(O)O1)OCC
Reactant: CCO
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CCOP(=O)(C=CC1CC(C(=O)c2ccccc2)C(C(=O)c2ccccc2)O1)OCC
Temperature: 45 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Compound 9.7 (3.1 g, 11.8 mmol) in pyridine (15 mL) was treated with benzoyl chloride (4.0 mL, 35 mmol) dropwise and the mixture was stirred at 45° C. for 1 h (significant exotherm upon BzCl addition). The mixture was cooled to 0° C. and EtOH (2 mL) was added dropwise and stirred for 10 minutes. The solution was concentrated in vacuo and the residue was dissolved in EtOAc (100 mL) and washed with 1 N HCl (10 mL) and brine (10 mL). The solution was dried over MgSO4, filtered, and concentrated in vacuo. The residue was treated to silica gel column chromatography (SiO2, 4×20 cm, 50-100% EtOAc-hexanes gradient) to afford compound 9.8 (4.2 g, 75% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:24]C)[C:10](=[O:23])[N:11]3[CH2:19][CH:18]([CH2:20][OH:21])[O:17][C:16](=[O:22])[C:12]3=2)[C:7]1=[O:26].Br.[C:32](O)(=[O:34])[CH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[F:30])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:24])[C:10](=[O:23])[N:11]3[CH2:19][CH:18]([CH2:20][O:21][C:32](=[O:34])[CH3:33])[O:17][C:16](=[O:22])[C:12]3=2)[C:7]1=[O:26]
Reactant: COc1c2c(c3n(c1=O)CC(CO)OC3=O)CCN(Cc1ccc(F)c(Cl)c1)C2=O
Reactant: CC(=O)O
Agent: Br
Product: CC(=O)OCC1Cn2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C(=O)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 9-(3-chloro-4-fluorobenzyl)-3-(hydroxymethyl)-7-methoxy-3,4,10,11-tetrahydro[1,4]oxazino[3,4-a]-2,6-naphthyridine-1,6,8(9H)-trione (50 mg, 0.11 mmol) and 33% hydrogen bromide in acetic acid (0.1 g) in acetic acid (1 mL) was stirred at room temperature for 30 minutes. The product mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to reverse phase column chromatography on C-18 stationary phase eluted with a 95-5% water-acetonitrile gradient. Collection and lyophilization of appropriate fractions afforded the title compound.
Reaction SMILES: NCCCC(NC1C=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[CH:13][N:12]=[C:11]2NC1C=CC(OCC2C=CC=C(F)C=2)=C([Cl:34])C=1)=O.[N:35]1[CH:40]=CC=C[CH:36]=1>>[ClH:34].[CH3:36][N:35]([CH3:40])[CH2:17][CH2:16][CH2:15][N:14]=[C:13]=[N:12][CH2:11][CH3:10]
Reactant: NCCCC(=O)Nc1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: c1ccncc1
Product: CCN=C=NCCCN(C)C
Product: Cl

Procedure:
36 μl of pyridine, 100 mg of the compound obtained in (87-1) of Example 87 and 80 mg of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to 30 μl of acrylic acid dissolved in 2 ml of THF, and reacted at 0° C. for 5 hours. The reacted solution was washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and distilled under a reduced pressure, and the resulting residue was subjected to column chromatography (eluent-chloroform:methanol=15:1) to obtain the title compound (14 mg, 13%).
Reaction SMILES: [H-].[Na+:2].ClC1C=C(C=CC=1)N.[CH3:11][C:12]1[CH2:16][C:15]([CH3:17])=[C:14]([CH3:18])[C:13]=1[CH3:19]>O1CCCC1>[CH3:11][C:12]1[CH:16]([Na:2])[C:15]([CH3:17])=[C:14]([CH3:18])[C:13]=1[CH3:19]
Reactant: [Na+]
Reactant: CC1=C(C)C(C)=C(C)C1
Agent: [H-]
Solvent: C1CCOC1
Solvent: Nc1cccc(Cl)c1
Product: CC1=C(C)C([Na])C(C)=C1C
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Sodium hydride (containing mineral oil; the content of sodium hydride: 60%) (0.80 g) and m-chloroaniline (0.064 g) were added to the solution of tetramethylcyclopentadiene (1.34 g; purity: 91.3%; pure compound: 1.22 g) dissolved in tetrahydrofuran (6.73 g), and stirred at 50° C. for one hour. Thus, tetramethylcyclopentadienylsodium was obtained in the form of a solution in tetrahydrofuran.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:12][O:13]C(Cl)Cl.[Sn](Cl)(Cl)(Cl)Cl.Cl>ClCCCl>[CH3:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: COC(Cl)Cl
Reactant: Cc1ccc2c(c1)OCCO2
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: Cc1cc2c(cc1C=O)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.9 %

Procedure:
A mixture of 6-methyl-2,3-dihydrobenzo[b][1,4]dioxine (6.4 g, 42.8 mmol) and 1,2-dichloroethane (250 mL) was cooled to 0° C. and then stirred for 1 h. After this time, dichloromethyl methyl ether (11.5 mL, 128.5 mmol) was then added and the reaction stirred for 1 h then, tin (IV) chloride (7.52 mL, 64.3 mmol) was added portion wise to the reaction over 3 h, and the reaction then allowed to warm to room temperature overnight. After this time, the reaction was poured into 3 N hydrochloric acid (150 mL) and the organic layer extracted three times with dichloromethane (100 mL). The combined organic extracts were then dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 7-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde (4.8 g, 79%) as an off-white solid; 1H NMR(500 MHz, CDCl3) δ 10.07 (s, 1H), 7.33 (s, 1H), 6.72 (s, 1H), 4.28 (m, 4H), 2.55 (s, 3H).
Reaction SMILES: [OH:1][C:2]([CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])([CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9])[C:3](O)=[O:4].Cl.C([O:35][NH2:36])(C)(C)C.CN1CCOCC1>C(Cl)Cl>[OH:35][NH:36][C:3](=[O:4])[C:2]([OH:1])([CH2:18][S:19]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)(=[O:21])=[O:20])[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9]
Reactant: CC(C)(C)ON
Reactant: COc1ccc(C(=O)NCC(O)(CS(=O)(=O)c2ccc(OC)cc2)C(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)NCC(O)(CS(=O)(=O)c2ccc(OC)cc2)C(=O)NO)cc1
Reaction time: 6 h
Yield: 67.5 %

Procedure:
2-Hydroxy-2-[(4-methoxybenzenesulfonyl)methyl]-3-(N-(4-methoxybenzenecarbonyl)amino)-propionic acid (100 mg, 0.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiilnide hydrochloride (68 mg, 0.35 mmol), O-tert-butylhydroxylamine hydrochloride (118 mg, 0.944 mmol), and 4-methylmorpholine (131 mg, 0.354 mmol) are dissolved in 20 mL of methylene chloride. The reaction mixture is stirred under nitrogen for 6 hours. The solvent is removed under reduced pressure, and the residue is dissolved in ethyl acetate. The organic layer is washed with 1N sodium hydrogen sulfate, 5% sodium bicarbonate, and saturated brine and dried over magnesium sulfate. The solvent is removed to yield 71 mg of white solid which is recrystallized from methanol. The tert-butyl protecting group is removed by treatment with 50% trifluoroacetic acid in methylene chloride for 24 hours. The solvents are removed, and the crude product is purified by reverse phase chromatography on a C18 Vydac column using a water-acetonitrile elution system to yield the title compound as a white solid.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](O)=[O:17])=[CH:8]1.[NH2:20][CH2:21][C:22]1[C:23]([OH:30])=[N:24][C:25]([CH3:29])=[CH:26][C:27]=1[CH3:28].Cl.C([N:34]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[OH:30][C:23]1[C:22]([CH2:21][NH:20][C:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:19])[CH:8]=2)=[O:17])=[C:27]([CH3:28])[CH:26]=[C:25]([CH3:29])[N:24]=1.[C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([NH2:34])=[O:17])=[CH:8]1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccccc1-n1cc(C(=O)O)c2ccccc21
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cn(-c3ccccc3C)c3ccccc23)c(O)n1
Product: Cc1ccccc1-n1cc(C(N)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-(o-tolyl)-1H-indole-3-carboxylic acid (100 mg, 0.398 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (60 mg, 0.398 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (114 mg, 0.597 mmol), N-hydroxybenzotriazole (81 mg, 0.597 mmol), triethylamine (81 mg, 0.796 mmol) and dichloromethane (5 mL) was stirred at room temperature for 18 hours. The solvent was removed under reduced pressure and ethyl acetate (10 mL) was added. The resulting mixture was washed with water (10 mL) and brine in turns and then dried over sodium sulfate. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative-TLC(silica gel, dichloromethane:methanol=15:1) to give pure desired product of N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-1-((o-tolyl)-1H-indole-3-carboxamide as an off white solid (100 mg, 65%). LRMS (M+H+) m/z: calcd 385.18. found 385. 1H NMR (300 MHz, CD_OD) δ 8.16 (dd, J=6.1, 2.5 Hz, 1H), 7.87 (s, 1H), 7.44 (d, J=4.9 Hz, 2H), 7.41-7.26 (m, 2H), 7.26-7.12 (m, 2H), 6.93 (dd, J=6.3, 2.4 Hz, 1H), 6.11 (s, 1H), 4.53 (s, 2H), 2.41 (s, 3H), 2.24 (s, 3H), 2.01 (s, 3H).