Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([CH3:5])[CH3:4].S(=O)(=O)(O)O>O>[CH2:1]([O:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)CCOCCC(C)C

Procedure:
The cock was opened to pass water into the cooling pipe 29, and the flask 30 charged with 600 ml of isoamyl alcohol and 60 g of concentrated sulfuric acid was heated. In a short time, the content of the flask was boiled and a suspended distillate was stored in the flask 31. When the filter medium A was covered with this distillate, the liquid feed pump 32 was operated, whereby a transparent liquid (isoamyl alcohol having a boiling point of 130° C.) was flowed into the reaction flask 30, and the volume of water left in the bottom of the flask 31 was increased. Occasionally, the glass pipe 33 was taken up so that the lower half of the filter medium A located near the top end of the glass pipe 33 was immersed in the surface portion of the distillate. When the reaction was advanced in this state, no fresh distillate was obtained any more in about 5 hours. Accordingly, the heating was stopped, and steam was blown into the reaction flask 30. The obtained distillate was distilled to obtain 275 g of isoamyl ether (having a boiling point of 172° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([C:10]([OH:12])=O)[CH:3]=1.Br.[Br:14][CH2:15][CH2:16][NH2:17]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:8][CH:9]=1)[C:6](=[O:7])[N:17]([CH2:16][CH2:15][Br:14])[CH:10]2[OH:12]
Reactant: NCCBr
Reactant: O=Cc1ccc(Cl)cc1C(=O)O
Agent: Br
Product: O=C1c2ccc(Cl)cc2C(O)N1CCBr
Yield: 27.8 %

Procedure:
The compound was prepared as described in example 1A, starting from 2.5 g (0.013 mole) of 4-chloro-2-carboxybenzaldehyde (I1 farmaco, Ed. Sci 31, 691, 1976) and 2.76 g (0.013 mole) of 2-bromoethylamine hydrobromide. 1.05 g of the title product were obtained; mp=164°-168 ° C. (n-hexane).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][CH:9]([CH2:12][NH2:13])[CH2:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:17]([CH3:23])([CH:19]([N:21]=[O:22])[CH3:20])[CH3:18]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]([CH2:10][NH:11][C:17]([CH3:23])([CH3:18])[C:19](=[N:21][OH:22])[CH3:20])[CH2:12][NH:13][C:17]([CH3:23])([CH3:18])[C:19](=[N:21][OH:22])[CH3:20])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: CC(N=O)C(C)(C)Cl
Reactant: NCC(CN)Cc1ccc([N+](=O)[O-])cc1
Solvent: CO
Product: CC(=NO)C(C)(C)NCC(CNC(C)(C)C(C)=NO)Cc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3.9 g of diamine [10] was dissolved in 90 ml methanol and cooled to 0° C., after which 6.5 g of 2-chloro-2-methyl-3-nitrosobutane were added with agitation. After heating to room temperature the mixture was agitated for two hours, boiled with reflux for a further two hours, the solvent was removed and the remaining solid was dissolved in water. The mixture was neutralised with sodium hydrogen carbonate and concentrated and the remaining precipitate was re-crystallised from ethanol.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH2:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH3:22])[C:3]([O:5][CH2:6]C)=[O:4].C1C=C(Cl)C=C(C(OO)=O)C=1.ClC(Cl)(Cl)C([N:39]=C=O)=O>C[O-].[Na+]>[NH2:39][C:13]1[C:12]2[N:11]=[C:10]([CH3:22])[N:9]([CH2:8][C:2]([CH3:1])([CH3:23])[C:3]([O:5][CH3:6])=[O:4])[C:21]=2[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N:14]=1
Reactant: CCOC(=O)C(C)(C)Cn1c(C)nc2cnc3ccccc3c21
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Agent: C[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Product: COC(=O)C(C)(C)Cn1c(C)nc2c(N)nc3ccccc3c21
Yield: 33.5 %

Procedure:
The methods described in Part B of Example 60 were used to treat ethyl 2,2-dimethyl-3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate (7.2 g, 22 mmol) with mCPBA (9.6 g of 77% pure material), followed by trichloroacetyl isocyanate (3.1 mL, 26 mmol), followed by sodium methoxide (20 mL of 25% in methanol). After the collection of the precipitate, the filtrate was concentrated under reduced pressure, and the residue was mixed with methanol (50 mL). The resulting solid was isolated by filtration, and the isolated solids were combined to provide 2.3 g of methyl 3-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropanoate.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:13]=1.Cl.Cl.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][CH:2]1[CH2:6][O:5][CH2:4][CH:3]1[O:7][C:8]1[CH:9]=[C:10]([C:21]([NH:35][C@@H:33]([C:30]2[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=2)[CH3:34])=[O:22])[CH:11]=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[CH:13]=1
Reactant: Cc1ccc([C@@H](C)N)cn1
Reactant: Cc1ccc(-c2cc(OC3COCC3O)cc(C(=O)O)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(OC3COCC3O)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(4-hydroxytetrahydrofuran-3-yloxy)-4′-methylbiphenyl-3-carboxylic acid (35 mg, 0.11 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (100 mg, 0.26 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:7]=1.C([O-])([O-])=O.[K+].[K+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:14][CH3:15])=[C:6]([C:8]#[CH:9])[CH:7]=1
Reactant: COc1ccc(Cl)cc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1cc(Cl)ccc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
((5-chloro-2-methoxyphenyl)ethynyl)trimethylsilane (0.4 g, 1.7 mmol) was dissolved in MeOH (1 mL), K2CO3 (0.69 g, 5 mol) was added to it. Then the mixture was stirred at 25° C. for 1 hour, and added to H2O (50 mL). The mixture was extracted with ethyl acetate and washed with brine, dried over Na2SO4. After the combined organic layers were concentrated, the resulting residue was purified using prep-TLC (petroleum ether:EtOAc=10:1) to provide the product of 4-chloro-2-ethynyl-1-methoxybenzene (0.25 g, yield: 80%). 1H-NMR (CDCl3, 400 MHz) δ 7.43 (s, 1H), 7.28˜7.29 (m, 1H), 6.81˜6.85 (m, 1H), 3.89 (s, 3H), 3.34 (s, 1H). MS (M+H)+: 167/169.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([S:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[NH2:29])=[CH:17][CH:16]=1>>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([S:21][C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:23]=2[NH:29][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(Sc2ccc(C)cc2N)cc1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Product: COc1ccc(Sc2ccc(C)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (167 mg, 0.94 mmol) was reacted with the product from Example 50b (245 mg, 0.94 mmol) for 48 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (325 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 2.35 (s, 3H) 2.77 (s, 3H) 3.73 (s, 3H) 6.26 (d, J=6.99 Hz, 1H) 6.85 (d, J=8.82 Hz, 2H) 7.11 (d, J=7.72 Hz, 1H) 7.26 (d, J=8.82 Hz, 2H) 7.31 (s, 1H) 7.80 (d, J=8.46 Hz, 1H) 8.41 (d, J=6.99 Hz, 1H) 8.99 (d, J=8.82 Hz, 1H) 11.04 (br. s., 1H) 14.32 (br. s., 1H); MS ESI+ m/z 388 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:5]([C:6](O)=[O:7])[CH:4]=1.[NH2:16][C:17]1[NH:21][N:20]=[N:19][N:18]=1>CN(C)C=O>[CH3:1][O:2][C:3]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:5]([C:6]([NH:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[O:7])[CH:4]=1
Reactant: COc1cc(C(=O)O)nc2ccccc12
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Methoxyquinaldic acid (7.25 g) was dissolved in dry dimethylformamide (20 ml). N,N'-carbonyldiimidazole (5.8 g) was added, and the solution was stirred for 6 hours at room temperature. 5-Aminotetrazole (3.69 g) was added and the mixture was stirred overnight at room temperature. The solid was filtered off, washed with methanol and dissolved in dimethylformamide (500 ml) with the minimum addition of dimethylaminoethanol to effect dissolution. Water (50 ml) was added, and the solution was adjusted to pH 2 by the addition of aqueous hydrochloric acid. The solid was filtered off to give 4-methoxy-N(1H-tetrazol-5-yl)quinaldamide, m.p. 289° (d).
Reaction SMILES: [CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]1[CH2:13][CH:12]([C:14](O)=[O:15])[CH:11]([CH3:17])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:28])=O.CN(C=O)C>C(Cl)Cl>[CH2:1]([N:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:9]1[CH2:13][CH:12]([C:14]([Cl:28])=[O:15])[CH:11]([CH3:17])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1CC(N(Cc2ccccc2)Cc2ccccc2)CC1C(=O)Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 4-(dibenzylamino)-2-methylcyclopentanecarboxylic acid (7.34 g, 22.7 mmol, Preparation #TT.1) in DCM (100 mL), oxalyl chloride (4.37 mL, 49.9 mmol) was slowly added followed by a dropwise addition of DMF (0.26 mL, 3.4 mmol). The mixture was stirred at ambient temperature for about 14 h and the solvent was removed under reduced pressure to yield 4-(dibenzylamino)-2-methylcyclopentanecarbonyl chloride as a beige solid. The solid was dissolved in THF and MeCN (1:1, 100 mL) and added to a solution of trimethylsilyldiazomethane (2 M in Et2O, 39.7 mL, 79.4 mmol) in 1:1 mixture of THF and MeCN (100 mL) at about 0° C. The resulting mixture was stirred at about 0° C. for about 3 h and then was quenched by dropwise addition of 48% aqueous HBr (25 mL, 221 mmol). The resulting mixture was neutralized by dropwise addition of saturated aqueous NaHCO3 (300 mL) and the layers were separated. The organic layer was dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The residue was purified by silica gel flash chromatography eluting with a gradient of 5-45% EtOAc in heptane to yield 2-bromo-1-(4-(dibenzylamino)-2-methylcyclopentyl)ethanone (6.3 g, 69%) as a yellow oil: LC/MS (Table 1, Method a) Rt=2.90 min; MS m/z 400, 402 (1:1) (M+H)+.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:35])[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:9]=[CH:8][C:7]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:29]1([CH2:28][O:27][C:7]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:11][C:6]=2[C:5]([OH:35])=[O:4])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)O)c1
Yield: 94 %

Procedure:
Sodium hydroxide hydrolysis of 2-(phenylmethoxy)-5-(tetradecyloxy)benzoic acid methyl ester under conditions described in Example 60 gave 2-(phenylmethoxy)-5-(tetradecyloxy)benzoic acid (94% yield, mp 73°-74°).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:3]=1[CH3:19].O.CC[O:23]C(C)=O>CN1C(=O)CCC1>[F:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([OH:23])=[C:3]([CH3:19])[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Reactant: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1O

Procedure:
4-Chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (200 mg, 0.73 mmol) in NMP (2 mL) and water (0.26 mL, 14.7 mmol) was heated in the microwave at 150° C. for 4 h. After this EtOAc (10 mL) was added. The resulting precipitate was filtered to give 7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ol. Mass Spectrum (ESI) m/e=255.2 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1.[C:20]12([CH2:30][CH:31]=O)[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>C(Cl)Cl>[C:20]12([CH2:30][CH:31]3[C:12]4[NH:13][C:14]5[C:19]([C:11]=4[CH2:10][CH2:9][NH:8]3)=[CH:18][CH:17]=[CH:16][CH:15]=5)[CH2:21][CH:22]3[CH2:28][CH:26]([CH2:25][CH:24]([CH2:23]3)[CH2:29]1)[CH2:27]2
Reactant: O=CCC12CC3CC(CC(C3)C1)C2
Reactant: NCCc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2c3c([nH]c2c1)C(CC12CC4CC(CC(C4)C1)C2)NCC3
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (443 μl, 5.8 mmol) was added to a solution of tryptamine (5.76 g, 36 mmol) and 1-adamantylacetaldehyde (6.52 g, 36.6 mmol) in dry DCM (450 ml) wth 3A molecular sieves (46.5 g) at 0° C. The reaction mixture was stirred at 0° C. for 2 hours, followed by the addition of trifluoroacetic acid (5.76 ml, 74.8 mmol) then allowed to warm to room temperature and stirring continued for a further 16 hours. The resultant suspension was concentrated in vacuo, taken up in ethyl acetate (200 ml), filtered, washed successively with saturated NaHCO3 solution (200 ml), brine (2×200 ml) and dried (MgSO4). Filtration and evaporation of the solvent gave the crude product as an orange foam which was used without further purification. (10.95 g, 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[N:8]([CH2:13][CH2:14][N:15]([CH3:25])[C:16](=[O:24])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:6][CH2:5]2.I.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1[C:32](SC)=[NH:33]>C(O)C.O.C(=O)([O-])[O-].[Na+].[Na+]>[F:12][C:10]1[CH:11]=[C:2]([NH:1][C:32]([C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)=[NH:33])[CH:3]=[C:4]2[C:9]=1[N:8]([CH2:13][CH2:14][N:15]([CH3:25])[C:16](=[O:24])[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: CN(CCN1CCCc2cc(N)cc(F)c21)C(=O)Oc1ccccc1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CN(CCN1CCCc2cc(NC(=N)c3cccs3)cc(F)c21)C(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.2 %

Procedure:
To a stirred solution of phenyl 2-(6-amino-8-fluoro-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate (426 mg, 1.241 mmol) in ethanol (12 ml) was added methyl thiophene-2-carbimidothioate hydroiodide (708 mg, 2.481 mmol). The reaction mixture was stirred at room temperature overnight under argon. The reaction mixture was then diluted with water and sodium carbonate, then extracted with dichloromethane (3×). The combined organics were dried, filtered and concentrated, then chromatographed in 40-100% ethyl acetate in hexanes, giving the desired phenyl 2-(8-fluoro-6-(thiophene-2-carboximidamido)-3,4-dihydroquinolin-1(2H)-yl)ethyl(methyl)carbamate 52 (422 mg, 0.933 mmol, 75% yield). 1H NMR (DMSO-d6) δ 7.74-7.71 (m, 1H); 7.59-7.57 (m, 1H); 7.41-7.36 (m, 2H); 7.23-7.18 (m, 1H); 7.14-7.07 (m, 3H); 6.50-6.42 (m, 3H); 6.37 (s, 1H); 3.62 (t, J=6 Hz, 1H); 3.51 (t, J=6 Hz, 1H); 3.30 (t, J=6 Hz, 1H); 3.23 (t, J=6 Hz, 1H); 3.15-3.09 (m, 2H); 3.09, 2.97 (2s, 3H); 2.69 (t, J=6 Hz, 2H); 1.83-1.75 (m, 2H). EI-MS (m/z, %): 452 (M+, 8); 288 (60); 179 (100).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].OS(O)(=O)=O.[CH3:22]O>>[OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH3:22])=[O:8]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1NCCO
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1NCCO

Procedure:
2-(2-Hydroxyethylamino)-3-nitrobenzoic acid (5.14 g, 22.7 mmol) was dissolved in methanol (200 mL) and concentrated H2SO4 (10 mL) was added. The mixture was heated at reflux for 2.5 h. The solvent was removed at reduced pressure. The residue was treated with water (100 ml) and extracted with ethyl acetate (3×150 mL). The combined organic phase was dried and concentrated. Purification by column chromatography on silica using heptane ethyl acetate 1:1 as an eluent afforded methyl 2-[(2-hydroxyethyl)amino]-3-nitrobenzoate, 3.92 g (72%). MS NISI) m/z 241 [M+H]. 1H NMR (400 MHz, CDCI3) δ ppm 3.12 (t, J=5.10 Hz, 2H), 3.84 (t, J=5.15 Hz, 2H), 3.91 (s, 3H), 6.69 (t, J=7.96 Hz, 1H), 7.95 (dd, J=8.34, 1.52 Hz, 1H), 8.08 (dd, J=7.83, 1.52 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1.BrBr>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[S:17][C:16]([NH2:18])=[N:15][C:5]=2[CH:4]=1
Reactant: COc1cc(NC(N)=S)cc(-c2ccccc2)c1
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2ccccc2)c2sc(N)nc2c1
Temperature: 61 °C
Yield: 86386.6 %

Procedure:
(5-Methoxy-biphenyl-3-yl)-thiourea (109 mg, 0.42 mmol) in chloroform (2 ml) are treated with bromine (22 μl) and the mixture heated to 61° C. for 5 hours. After removal of the volatile components in vacuo, the product (93 g, 86%) is isolated by flash chromatography (silica, eluent ethyl acetate/cyclohexane 2:1 to 5:1) as beige solid. The regiochemistry of the cyclization was checked by transfer-NOE measurements. MS: m/e=256 (M+).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:27])[CH:12]=2)[N:7]=1>CS(C)=O>[CH3:1][NH:2][C:3]([NH:5][C:6]1[N:15]=[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:27])[CH:12]=2)[N:7]=1)=[O:4]
Reactant: CN=C=O
Reactant: Nc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Solvent: CS(C)=O
Product: CNC(=O)Nc1nc(NCc2ccc3c(c2)OCO3)c2cc(Cl)ccc2n1
Temperature: 50 °C
Reaction time: 3 h
Yield: 12.3 %

Procedure:
4 ml of dimethyl sulfoxide and 260 mg of methyl isocyanate were added to 500 mg of 2-amino-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline. The obtained mixture was stirred at 50° C. for 3 hours and distilled under a reduced pressure to remove excess methyl isocyanate, followed by the addition of chloroform and water. The mixture thus obtained was filtered and the filtrate was extracted with chloroform twice. The organic layers were combined, washed with water twice, dried over magnesium sulfate and distilled under a reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (benzene/acetone) and recrystallized (from benzene/chloroform/ethanol) to give 72 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[C:8]1[NH:9][N:10]=[C:11]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)[C:7]=1[CH2:6]2.C([O:32][CH2:33][C:34](Cl)=[O:35])C1C=CC=CC=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:19][C:15]1[CH:14]=[C:13]([NH:12][C:11]2[C:7]3[CH2:6][C:5]4[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=4)[C:8]=3[N:9]([C:33](=[O:32])[CH2:34][OH:35])[N:10]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc2c(cc1OC)-c1[nH]nc(Nc3cccc(F)c3)c1C2
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(cc1OC)-c1c(c(Nc3cccc(F)c3)nn1C(=O)CO)C2
Yield: 90 %

Procedure:
To a mixture of (6,7-Dimethoxy-1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine (Compound 14) (3.6 g, 10.0 mmol), Benzyloxy-acetyl chloride (Compound 27a) (2.2 g, 12.0 mmole) and DMF (50 mL) was added Diisopropylethylamine (5.2 mL, 30 mmole) at room temperature with stirring. The reaction was stirred at room temperature over night. The reaction was quenched with water and extracted with EtOAc. Dried over sodium sulfate and removed solvent in vacuo. The crude material was then taken up into ethanol and 0.5 g of Pd/C was added. The reaction was shaken on the hydrogenator over night. The reaction was filtered through Celite and removed solvent in vacuo. Triturated in a small amount of EtOAc. 3.2 g of ˜90% pure material was produced. 300 mg of the crude material was prepped on the Gilson and lyophilization gave Compound 432 as a white powder. MS m/z 384 (M+H)+;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:37])[C:10](=[O:36])[CH2:11][NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:37])[CH:10]([OH:36])[CH2:11][NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 93.5 %

Procedure:
To a solution of N-[N-[(S)-3-[[(t-butyloxy)carbonyl]amino]-2-oxobutyl]-L-phenylalanyl]-L-leucine, t-butyl ester (1.50 g, 2.89 mmol) in 15 ml of methanol at 0° C. was added sodium borohydride (109 mg, 2.89 mmol) in six portions over approximately 5 minutes. After 15 minutes, the solvent was evaporated. The residue was taken up into ethyl acetate (100 ml), washed with water until the extracts were neutral, washed with brine and then dried (sodium sulfate) and evaporated to give 1.41 g of the title compound as a mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16](Cl)=[O:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(N([CH2:27][CH3:28])CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([O:14][CH2:15][CH2:16][O:17][C:28]3[CH:27]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=3[Cl:8])=[O:17])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)Cl
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)OCCOc1ccc(Cl)cc1Cl

Procedure:
The 2-[4-(3,5-dichloropyridin-2-yloxy)phenoxy]propanoic acid chloride (3.12 grams; 0.009 mol); triethylamine (5 ml): 2,4-dichlorophenoxyethethanol (1.94 grams; 0.0094 mol) and toluene (100 ml) were stirred in a glass reaction flask until thin layer chromatographic analysis showed completion of the reaction. This mixture was transferred to a separatory funnel and washed three times with water (70 ml). The washed material was dried and stripped to a yellow/brown gum (4.8 grams) that solidified on standing and was recrystallized from a mixture of methylene chloride and hexane. The first crop (1.5 grams) analyzed by elemental analysis as follows:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:18])=[C:4]([C:8](=[O:17])[C:9](=[N+:15]=[N-:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][CH:7]=1.C(P(CCCC)CCCC)CCC>O1CCOCC1>[CH2:13]([O:12][C:10](=[O:11])[C:9](=[N:15][NH2:16])[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[F:18])=[O:17])[CH3:14]
Reactant: CCOC(=O)C(=[N+]=[N-])C(=O)c1cccc(Cl)c1F
Agent: CCCCP(CCCC)CCCC
Solvent: C1COCCO1
Product: CCOC(=O)C(=NN)C(=O)c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of ethyl 3-(3-chloro-2-fluorophenyl)-2-diazo-3-oxopropanoate (1.28 g, 4.73 mmol) in dioxane (12 mL) was added tri-n-butylphosphine (1.23 mL, 4.97 mmol). After stirring for 10 minutes at ambient temperature, the mixture was concentrated in vacuo and the residue was purified by silica gel gradient chromatography (100:0 to 40:60 hexane:ethyl acetate), providing the titled compound.