Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.[N:39]1([C:47](=O)[CH2:48]Cl)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[N:39]1([CH2:47][CH2:48][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]3[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=3[CH:20]3[CH2:29][CH2:28][C:27]4[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=4[CH2:21]3)=[CH:37][CH:38]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Reactant: O=C(CCl)N1CCCCCCC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCCCc2ccc(OCCN3CCCCCCC3)cc2)c1
Yield: 64.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and 1-azocan-1-yl-2-chloroethanone (22 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (21 mg) was obtained.
Reaction SMILES: C([C:3]([N:10]1[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)=[CH:4][C:5]1[S:6][CH:7]=[CH:8][N:9]=1)#N.[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O>[S:6]1[CH:7]=[CH:8][N:9]=[C:5]1[C:4]1[NH:25][N:24]=[N:23][C:3]=1[N:10]1[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C#N)=Cc2nccs2)CC1
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nn[nH]c2-c2nccs2)CC1
Temperature: 110 °C

Procedure:
To a stirred solution of tert-butyl 4-(1-cyano-2-(thiazol-2-yl)vinyl)piperazine-1-carboxylate (2.25 g), sodium azide (0.4 g) were taken in dry DMSO (4 ml) and heated to 110° C. overnight. The reaction mixture was carefully quenched with water (10 ml) and the reaction mixture was extracted with dichloromethane (3×10 ml). The combined organic layer was washed with brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using methanol:chloroform (1:9) as an eluent to afford tert-butyl 4-(5-(thiazol-2-yl)-1H-1,2,3-triazol-4-yl)piperazine-1-carboxylate as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:12]=[C:13]([N:20]3[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl>ClCCl.C(OCC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11]2[CH:12]=[C:13]([N:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(Nc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-])c1cccc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC(Nc1cc(N2CCNCC2)ccc1[N+](=O)[O-])c1cccc(Cl)c1
Reaction time: 4 h
Yield: 139 %

Procedure:
To a solution of t-butyl 4-(3-(1-(3-chlorophenyl)ethylamino)-4-nitrophenyl)piperazine-1-carboxylate (97 mg, 0.21 mmol) in dry dichloromethane (2.0 mL) was added a saturated solution of HCl in diethyl ether (15 mL). The reaction mixture was stirred for 4 hours. The product was collected by filtration and dried in vacuo to afford the title compound (58.0 mg, 70% yield). 1H NMR (400 MHz, CD3OD): δ 8.06 (d, 1H), 7.43 (s, 1H), 7.33 (m, 2H), 7.26 (m, 1H), 6.38 (d, 1H), 5.88 (s, 1H), 4.80 (m, 1H), 3.54-3.43 (m, 4H), 3.22 (m, 4H), 1.62 (d, 3H); MS (ESI) m/z: Calculated for C18H22ClN4O2: 360.14; Observed: 361.5 (M++1) [corresponding to the free base].
Reaction SMILES: [CH:1]1([NH:4][C:5]([CH:7]([NH:12][C:13]([CH:15]([C:20](=[CH2:24])[C:21]([OH:23])=[O:22])[CH2:16][CH:17]([CH3:19])[CH3:18])=[O:14])[C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH2:3][CH2:2]1.[SH:25][C:26]1[S:27][CH:28]=[CH:29][CH:30]=1.C(OCC)C>CO>[CH:1]1([NH:4][C:5]([CH:7]([NH:12][C:13]([CH:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH:20]([CH2:24][S:25][C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)[C:21]([OH:23])=[O:22])=[O:14])[C:8]([CH3:10])([CH3:9])[CH3:11])=[O:6])[CH2:3][CH2:2]1
Reactant: C=C(C(=O)O)C(CC(C)C)C(=O)NC(C(=O)NC1CC1)C(C)(C)C
Reactant: Sc1cccs1
Solvent: CCOCC
Solvent: CO
Product: CC(C)CC(C(=O)NC(C(=O)NC1CC1)C(C)(C)C)C(CSc1cccs1)C(=O)O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2-[1-(1 -Cyclopropylcarbamoyl-2,2-dimethyl-propylcarbamoyl)-3-methyl-butyl]-acrylic acid (4.40 g, 12.4 mmol) was dissolved in methanol (10 ml) and placed under a blanket of argon prior to addition of 2-mercaptothiophene (4.5 ml). The mixture was stirred overnight at 60° C. under argon with the exclusion of light. The solvent was removed under reduced pressure to leave an oil to which was added cold diethyl ether (200 ml). The product precipitated on standing in an ice bath and was removed by filtration and washing with thoroughly with cold diethyl ether. The product was further purified by trituration with hot ethyl acetate and column chromatography (silica gel, gradient elution, 0-20% methanol in dichloromethane). Fractions were combined and evaporated to yield the title compound as an pale yellow solid (6.95 g, including minor impurities). 1H-NMR (CDCl3, partial deuterium exchange); δ 8.10 (1H, m), 7.85 (1H, d, J=9.2 Hz), 7.35 (1H, m), 7.03 (1H, m), 6.88 (1H, m), 4.06 (1H, d, J=9.2 Hz), 2.85 (1H, m), 2.67 (2H, m), 2.51 (1H, m), 1.53 (1H, m), 1.25 (1H, m), 1.02 (1H, m), 0.87 (9H, s), 0.76 (3H, d, J=6.4 Hz), 0.71 (3 H, d,J=6.5 Hz), 0.61 (2H, m) and 0.32 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][OH:19])[C:11]=2[CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:29]([N:31]=C=O)=[O:30]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH:15]([CH3:17])[CH3:16])[N:13]=[C:12]([CH2:18][O:19][C:29](=[O:30])[NH2:31])[C:11]=2[CH2:20][C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)n1nc(CO)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)n1nc(COC(N)=O)c(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution containing 100 mg of 5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazole-3-methanol in 3 ml of anhydrous dichloromethane was stirred under nitrogen at 0° C. while 35 μl of trichloroacetyl isocyanate was added dropwise. The mixture was stirred at 0° C. for 2 h. The mixture was evaporated under reduced pressure and then the residue was treated with 2 ml of methanol, 1 ml water and 100 mg of potassium carbonate under nitrogen at 0° C. The mixture was then stirred at room temperature for 1 h. The mixture was partitioned between ethyl acetate and water then extracted with ethyl acetate three times. The combined extracts were washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using methanol/dichloromethane (1:49) for the elution to give 67 mg of carbamic acid [5-(3,5-dichlorophenylthio)-1-isopropyl-4-[(4-pyridyl)methyl]-1H-pyrazol-3-yl]methyl ester as a white solid. Mass spectrum (ESI) m/z 451 [M+H]+. 1H NMR (DMSO) 1.30 (d, 6H), 3.91 (s, 2H), 4.77 (m, 1H), 5.05 (s, 2H), 6.55 (br s, 1H), 6.78 (br s, 1H), 6.79 (s, 2H), 7.08 (d, 2H), 7.39 (s, 1H), 8.30 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21](OCC)=[O:22])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:27][CH2:28][C@@H:29]([OH:32])[CH2:30][OH:31]>>[OH:32][C@@H:29]([CH2:30][OH:31])[CH2:28][NH:27][C:21]([C:14]1[C:15](=[O:20])[N:16]([CH3:19])[C:17]2[C:12]([C:13]=1[OH:26])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:22]
Reactant: NC[C@@H](O)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Product: Cn1c(=O)c(C(=O)NC[C@@H](O)CO)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Yield: 69.4 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (50 mg, 0.140 mmol) and (2R)-3-amino-1,2-propanediol (0.03 mL, 0.42 mmol) was prepared N-[(2R)-2,3-dihydroxypropyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (39 mg, 68% yield) as a white solid. 1H NMR (DMSO-d 6)δ 10.44 (br s, 1 H), 8.53 (s, 1 H), 8.01 (s, 1 H), 7.40-7.36 (m, 2 H), 7.15-7.10 (m, 2 H), 5.06 (m, 1 H), 4.77 (m, 1 H), 4.16 (s, 2 H), 3.61-3.55 (m, 4 H), 3.39 (m, 1 H), 3.24 (m, 1 H); MS m/z 402 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][S:10][C:9]2=[S:14])=[CH:4][CH:3]=1.[C:15]([O:18][C:19](=O)[CH3:20])(=O)[CH3:16]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:15]([O:18][CH2:19][CH3:20])[CH2:16][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[S:10][C:9]2=[S:14])=[CH:6][CH:7]=1
Reactant: O=C1CSC(=S)N1c1ccc(Cl)cc1
Reactant: CC(=O)OC(C)=O
Product: CCOC(Cc1ccccc1)=C1SC(=S)N(c2ccc(Cl)cc2)C1=O

Procedure:
As described in Example 1, triethylorthophenylacetate is reacted with 3-(4'-chlorophenyl)-rhodanine in acetic anhydride for 12 hours to yield 3-(4'-chlorophenyl)-5-(1'-ethoxy-2'-phenylethylidene)-rhodanine. To a suspension of the latter (15 g., 0.0385 m.) in 100 ml. of dioxane and 100 ml. of water is added 22 ml. of 10% sodium hydroxide solution. The mixture is stirred at room temperature for 3 hours, concentrated in vacuo at 40°-40°C. and the remaining solution is washed with ether, then decolorized. The aqueous layer is acidified with dilute hydrochloric acid and the precipitate is taken up in methylene chloride. The latter solution (after being washed with water and dried) is evaporated in vacuo. The residue is dissolved in 10% sodium hydroxide and water, washed with ether and acidified with dilute hydrochloric acid to give 3-(4'-chlorophenyl)-5-(1'-hydroxy-2'-phenylethylidene)-rhodanine, m.p. 134°-137°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:17][CH3:18])=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13]C(=O)C)[CH2:9][CH2:8]2.N1C=CC=CC=1.P(Cl)(Cl)(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:17][CH3:18])=[C:7]2[C:12]=1[CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2
Reactant: COc1ccc(SC)c2c1CC(NC(C)=O)CC2
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc(SC)c2c1CC(N)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1.0 g. (3.8 mmole) of N-[1,2,3,4-tetrahydro-8-methoxy-5-(methylthio)-2-naphthalenyl]acetamide in 100 ml. of toluene containing 0.474 g. (6 mmole) of pyridine was heated to 65°. Phosphorous pentachloride (1.25 g., 6 mmol.) was added and heating continued for two hours. The toluene was removed under reduced pressure, 200 ml. of methanol was added and the solution stirred overnight at room temperature. The methanol was evaporated and 100 ml. of 1:1 tetrahydrofuran-H2O was added. After 30 minutes the tetrahydrofuran was removed and the aqueous layer was washed with ether. It was made alkaline with ammonium hydroxide and extracted with three portions of methylene chloride. The combined extracts were dried and evaporated to yield as an oil the free base, 1,2,3,4-tetrahydro-8-methoxy-5-(methylthio)-2-naphthalenamine. This was dissolved in ether and treated with excess ethereal hydrogen chloride. The resulting precipitate was removed by filtration and recrystallized from methanol-ethyl acetate-ether to give 0.45 g. of 1,2,3,4-tetrahydro-8-methoxy- 5-(methylthio)-2-naphthalenamine hydrochloride as a white solid, m.p. 290° (dec.).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:8]([CH2:22][CH3:23])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2[NH:17][CH:18]=[C:19]([CH3:20])[C:13]=2[C:12]1=[O:21])[CH3:7].O.[OH-].[Na+].CN(C)[CH:29]=[O:30]>>[CH2:22]([N:8]([CH2:6][CH3:7])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2[NH:17][C:18]([CH:29]=[O:30])=[C:19]([CH3:20])[C:13]=2[C:12]1=[O:21])[CH3:23]
Reactant: CN(C)C=O
Reactant: CCN(CC)CCN1CCc2[nH]cc(C)c2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38 %

Procedure:
A stirred solution of N,N-dimethylformamide (2 ml) was added slowly with 104 μl of phosphorus oxychloride under an argon atmosphere while maintaining the temperature at 0° C. Upon completion of the addition, the mixture was stirred for 15 minutes at room temperature, and cooled down to 0˜5° C. in an ice-water bath. A mixture of 5-(2-diethylamino-ethyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (249 mg, 1 mmol) in 2 ml of N,N-dimethylformamide was added dropwise to the above solution. Upon completion of the addition, the mixture was stirred for 2 hours at 0° C., added with cold water (15 ml), stirred for 5 minutes. The resulting mixture was adjusted to pH 12 with 10% aqueous sodium hydroxide solution and extracted with dichloromethane (15 ml×6). The combined organic extracts were washed with brine (15 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with triethylamine:methanol:dichloromethane (1:20:500) as eluents to give 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (105 mg, 38%) as a pink oil which was used as such.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)O>C1C=CC=CC=1.N1C=CC=CC=1>[CH3:5][CH:6]([Cl:3])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: CC(O)c1ccc(C2CCCCC2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(Cl)c1ccc(C2CCCCC2)cc1

Procedure:
25 ml of thionyl chloride are added dropwise to a solution of 20.4 g of methyl-(para-cyclohexylphenyl)-carbinol in 100 ml of benzene and 3 ml of pyridine, and the mixture then refluxed for 5 hours. It is then poured on to ice, the aqueous mixture is extracted with ether, and the ethereal solution washed with sodium bicarbonate solution and water. When the solution is dried and the ether evaporated, α-methyl-para-cyclohexyl-benzyl chloride is obtained in the form of a dark viscous liquid which is processed directly.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18]C)[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1>Br.C(O)(=O)C>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([OH:18])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(-c2cc3ccc(O)cc3s2)cc1
Yield: 75.1 %

Procedure:
2-(4-Methoxyphenyl)-6-methoxybenzo[b]thiophene (10 g, 35.5 mmol) was suspended in 50 mL of 48% aqueous hydrobromic acid and 100 mL of glacial acetic acid. The reaction was heated to reflux under a nitrogen atmosphere for 120 hours. The reaction was allowed to cool and filtered. The solid product was washed with water and dried to yield 6.46 g of the title compound. 1H NMR: (CDCl3-d6DMSO): δ 7.54 (d, 1H), 7.48 (d, 2H), 7.27 (s, 1H), 7.24 (m, 1H), 6.92 (d, 1H), 6.85 (d, 2H). MS(FD): m/e=242 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[CH:7][C:6]([N+:13]([O-:15])=[O:14])=[C:5]2[C:16]([F:19])([F:18])[F:17].P(Br)(Br)([Br:22])=O>>[Br:22][C:7]1[C:6]([N+:13]([O-:15])=[O:14])=[C:5]([C:16]([F:19])([F:18])[F:17])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=1
Reactant: O=[N+]([O-])c1c[n+]([O-])c2ccc(Cl)cc2c1C(F)(F)F
Reactant: O=P(Br)(Br)Br
Product: O=[N+]([O-])c1c(Br)nc2ccc(Cl)cc2c1C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A mixture of 3 (4.71 g, 16.1 mmol) and POBr3 (9.23 g, 32.2 mmol) were heated to 100° C. After 2 h, the reaction was cooled to rt and partitioned between EtOAc and H2O, adding ice when necessary. The mixture was stirred overnight to break up the solid materials. Et2O (100 mL) was added and the organic phase was removed. The remaining aqueous phase was extracted with EtOAc (3×100 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated to afford 5.5 g (96%) of the desired product which was used without further purification. An analytically pure sample was obtained by recrystallization (EtOH) to provide a fluffy off-white solid, mp 120° C. Rf 0.61 (10% Ethyl acetate-hexane). 1H NMR (CDCl3, 300 MHz) δ8.16 (d, J=9.1 Hz, 1H), 8.16 (m, 1H), 7.92 (dd, J=2.2, 9.1 Hz, 1H); 19F NMR (CDCl3, 300 MHz) δ−57.63; 13C NMR (CDCl3, 75 MHz) δ146.50, 137.35, 134.25, 131.88, 131.32, 124.45, 124.40, 122.44, 121.96, 118.76; IR (KBr) υmax 1606, 1588, 1552, 1492, 1426, 1382, 1361, 1308, 1283, 1219, 1180, 1169, 1157, 1134, 1097, 1023, 960, 846, 823, 792, 693, 661, 632 cm−1.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19](F)=[C:20]([F:25])[CH:21]=2)[N:16]([CH2:27][CH2:28][F:29])[C:15]1=[O:30])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][C:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:20]([F:25])[CH:21]=2)[N:16]([CH2:27][CH2:28][F:29])[C:15]1=[O:30])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C1CCNC1
Reactant: O=c1c2cc(F)c(F)cc2n(CCF)c(=O)n1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1c2cc(F)c(N3CCCC3)cc2n(CCF)c(=O)n1OCc1ccccc1
Yield: 83 %

Procedure:
Pyrrolidine (0.04 mL, 0.52 mmol) was added to a solution of 3-benzyloxy-1-(2-fluoroethyl)-6,7-difluoro-1H-quinazoline-2,4-dione (Example D-4, 0.15 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) in 20 mL of acetonitrile. The solution was warmed to reflux for 17 hours, cooled, and concentrated to a solid. The solid was dissolved in chloroform washed with 1N HCl, saturated NaHCO3, brine and dried over magnesium sulfate. The solution was concentrated to give 0.14 g of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])[C:11]3[CH2:16][N:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:14][C:12]=3[N:13]=2)=[C:4]([F:29])[CH:3]=1.[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31]>>[CH2:20]([O:19][C:17]([N:15]1[CH2:16][C:11]2[C:10]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][C@@H:23]3[CH3:28])=[N:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:33]([NH:32][CH2:30][CH3:31])=[O:34])=[CH:3][C:4]=3[F:29])=[N:13][C:12]=2[CH2:14]1)=[O:18])[CH3:21]
Reactant: CCN=C=O
Reactant: CCOC(=O)N1Cc2nc(-c3ccc(N)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)OCC)C3)c(F)c1
Yield: 34 %

Procedure:
Method as example 85 using (S)-ethyl 2-(4-amino-2-fluorophenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate and ethyl isocyanate as starting materials. The solvent was removed in vacuo and purified by prep HPLC (low pH) yielding the title compound (14.6 mg, 0.03 mmol, 34%).
Reaction SMILES: C([N:8]([CH2:35][CH2:36][CH2:37][CH2:38][C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N:20]3[C:24](=[O:25])[N:23]([CH3:26])[N:22]=[N:21]3)[CH:18]=2)[NH:13][C:12]=1[C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>[OH-].[OH-].[Pd+2].O>[CH3:34][C:29]1[CH:28]=[C:27]([C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH2:10][CH2:9][NH:8][CH2:35][CH2:36][CH2:37][CH2:38][C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)=[CH:18][C:17]([N:20]2[C:24](=[O:25])[N:23]([CH3:26])[N:22]=[N:21]2)=[CH:16][CH:15]=3)[CH:32]=[C:31]([CH3:33])[CH:30]=1
Reactant: [H][H]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(-n4nnn(C)c4=O)cc3c2CCN(CCCCc2cccnc2)Cc2ccccc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(-n4nnn(C)c4=O)cc3c2CCNCCCCc2cccnc2)c1
Temperature: 25 °C
Yield: 94.5 %

Procedure:
To a stirred solution of 1-[3-{2-[benzyl-(4-pyridin-3-yl-butyl)amino]ethyl }-2-(3,5-dimethylphenyl)-1H-indol-5-yl] -4-methyl-1,4-dihydrotetrazol-5-one (20 mg in 4 mL methanol) was added 15 mg of 10% palladium hydroxide on carbon catalyst followed by acetic acid (0.020 mL of a 30% solution in water). The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 30 minutes the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (methylene chloride:methanol:ammonium hydroxide, 90:6.5:1) gave the title compound (16 mg). m/e=496 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][O:7][C@@H:8]2[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23]/[CH:24]=[C:25]1/[C:26]2[CH:39]=[C:38]([C:40]([OH:43])([CH3:42])[CH3:41])[CH:37]=[CH:36][C:27]=2[O:28][CH2:29][C:30]2[N:35]=[CH:34][CH:33]=[CH:32][C:31]/1=2>C(#N)C.O>[Cl:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][O:7][CH:8]2[CH2:12][CH2:11][N:10]([CH2:22][CH2:23][CH:24]=[C:25]3[C:31]4[CH:32]=[CH:33][CH:34]=[N:35][C:30]=4[CH2:29][O:28][C:27]4[CH:36]=[CH:37][C:38]([C:40]([OH:43])([CH3:42])[CH3:41])=[CH:39][C:26]3=4)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(CO[C@@H]2CCNC2)cc1
Reactant: CC(C)(O)c1ccc2c(c1)/C(=C/CCBr)c1cccnc1CO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(OCc3ccc(Cl)cc3)C1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-3-(4-chloro-benzyloxy)-pyrrolidine (0.88 mmol, 2.0 eq) in acetonitrile:water (4:1) was added potassium carbonate (0.88 mmol, 2.0 eqv) and (E)-2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol and the resulting mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo, diluted with ethyl acetate, and dried over sodium sulfate. The crude product was purified by Reverse Phase HPLC. 1H-NMR (CDCl3) δ: 1.40 (6H, s), 1.15-1.35 (1H, m), 1.85-2.05 (1H, m), 2.20-2.40 (1H, m), 2.35-2.65 (8H, m), 3.90-4.10 (1H, m), 4.30-4.50 (2H, d), 5.10-5.30 (2H, br, s), 6.05 (1H, t), 6.50 (1H, dd), 7.10-7.50 (4H, m), 7.70 (1H, dd), 8.50 (1H, dd). ESI-MS m/z: 505 (M+1), UV retention time: 1.52 min.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][O:12][CH3:13])[CH:7]=[C:6]([O:14][CH2:15][O:16][CH3:17])[CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:13][O:12][CH2:11][O:10][C:8]1[CH:9]=[C:4]([CH2:3][OH:2])[CH:5]=[C:6]([O:14][CH2:15][O:16][CH3:17])[CH:7]=1
Reactant: COCOc1cc(OCOC)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCOc1cc(CO)cc(OCOC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of 3,5-bis-methoxymethoxy-benzoic acid methyl ester (220a) (350 g, 1.37 mol) in THF (1.8 L) was added portion wise LiAlH4 (62 g, 1.64 mol) at 0° C. The mixture was stirred at 0° C. for another 1 hr. TLC (EtOAc/petroleum ether=1/2) showed that the reaction was complete. The reaction was quenched with 2 N aqueous NaOH. The mixture was filtered through Celite. The filtrate was dried over Na2SO4 and concentrated to give the title compound (290 g, 76%) as a brown oil. 1H NMR (400 MHz, CDCl3): δ 6.70 (d, 2H), 6.64 (d, 1H), 5.22 (s, 4H), 4.61 (s, 2H), 3.46 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH2:20]([O:22][C:23](Cl)=[O:24])[CH3:21]>ClCCl>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:23](=[O:24])[O:22][CH2:20][CH3:21])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Nc1cccc(C(C)=O)c1
Yield: 91.5 %

Procedure:
A mixture of 27.03 g of m-aminoacetophenone, 27.14 g of diisopropylethylamine, 22.8 g of ethylchloroformate and 300 ml of dichloromethane was reacted as described in Example 1, giving 37.9 g of (3-acetylphenyl)carbamic acid, ethyl ester.