Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:27]COC)=[C:7]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:12]=3[N:13]=2)[CH:8]=1.BrCC1C2N=[C:40](C3C=C(OC)C(OC)=CC=3OCOC)[O:41]C=2C=CC=1>>[CH3:40][O:41][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:12]=3[N:13]=2)=[C:6]([OH:27])[CH:5]=1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CNCc3ccccn3)cccc2o1
Reactant: COCOc1cc(OC)c(OC)cc1-c1nc2c(CBr)cccc2o1
Product: COc1cc(O)c(-c2nc3c(CNCc4ccccn4)cccc3o2)cc1OC

Procedure:
2-(4,5-dimethoxy-2-hydroxyphenyl)-4-(2-pyridylmethyl)aminomethyl-benzoxazole (F19) was prepared in a similar manner for the preparation of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-(2-pyridylmethyl)aminomethylbenzoxazole (F16) using 4-bromomethyl-2-(4,5-dimethoxy-2-methoxymethoxyphenyl)benzoxazole (F13) (612 mg, 1.59 mmol) instead of 4-bromomethyl-2-(5-methoxy-2-methoxymethoxyphenyl)benzoxazole (F12) in 17% (112 mg); 1H-NMR (500 MHz, CDCl3) δ3.56 (s, 3H), 3.95 (s, 3H), 3.97 (s, 3H), 4.02 (s, 2H), 4.30 (s, 2H), 5.27 (s, 2H), 6.85 (s, 1H), 7.15 (dd, 1H, J=7.5, 5.0 Hz), 7.28 (t, 1H, J=7.5 Hz), 7.33 (d, 1H, J=7.5 Hz), 7.42 (d, 1H, J=7.5 Hz), 7.47 (d, 1H, J=7.5 Hz), 7.64 (m, 2H), 8.55 (d, 1H, J=5.0 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[N:11]1.[CH2:18](Br)[CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:20][CH:19]=[CH2:18])=[CH:4][C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([CH3:16])[C:12]([CH3:17])=[N:11]1
Reactant: C=CCBr
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(C)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCOc1cc(-n2nc(C)c(C)c2C)c(F)cc1Cl
Reaction time: 3 h
Yield: 97.3 %

Procedure:
A mixture of 1-(2-fluoro-4-chloro-5-hydroxyphenyl)-3,4,5-trimethylpyrazole (25.5 g), allyl bromide (13.3 g), anhydrous potassium carbonate (14.5 g) and acetonitrile (150 ml) was heated under reflux, with stirring for 3 hours. After cooling, the reaction mixture was filtered through a filter to remove the inorganic salts therefrom and the filtrate was concentrated to a small volume under reduced pressure, affording the titled compound (28.7 g) as a pale brown crystalline solid. Recrystallization of this solid from cyclohexane yielded a white crystalline solid. m.p. 97°-99° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]=[C:5]([CH3:8])[CH:6]=O)[CH3:2].[CH3:9][N:10]([CH3:12])[NH2:11].C(O)(=O)C>C(OCC)C>[CH3:9][N:10]([CH3:12])[N:11]=[CH:6][C:5]([CH3:8])=[CH:4][O:3][CH2:1][CH3:2]
Reactant: CN(C)N
Reactant: CCOC=C(C)C=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC=C(C)C=NN(C)C

Procedure:
A mixture of 3-ethoxy-2-methyl-2-propenal, (E)-- and (Z)-- (4.0 g, 35 mmol), 1,1-dimethylhydrazine (2.73 g, 46 mmol) and acetic acid (0.04 g, 0.7 mmol) in diethyl ether is refluxed for one hour, cooled, washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:13]1[CH:14]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=2)[CH:10]=[CH:11][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [O-][n+]1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Product: FC(F)(F)c1ccc(-c2ccnc(Cl)c2)cc1

Procedure:
To 4-(4-trifluoromethyl-phenyl)-pyridine 1-oxide (2.4 g, 10 mmol) was added phosphorous oxychloride (12 mL) at room temperature. The reaction mixture was heated at reflux for 5 h. POCl3 was removed under reduced pressure, and the residue was partitioned between EtOAc and aqueous ammonium hydroxide. The aqueous layer was extracted with EtOAc and the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by chromatography on a Biotage 40 M column (8:1 hexanes: EtOAc) to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 258.5 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[CH2:3]1.C(N(CC)CC)C.[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>C(Cl)Cl>[F:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][CH:2]1[CH2:9][CH2:8][CH2:7][NH:6][C:4](=[O:5])[CH2:3]1)=[O:21]
Reactant: O=C(Cl)c1ccccc1F
Reactant: NC1CCCNC(=O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC(NC(=O)c2ccccc2F)CCCN1

Procedure:
3-Amino-ε-caprolactam (11.0 g) and triethylamine (15.7 ml) were added to 200 ml of methylenechloride. Then a solution of 2-fluorobenzoyl chloride (15.0 g) in methylenechloride (30 ml) was added dropwise to the mixture under ice-cooling and stirring. Thereafter, the mixture was stirred for 1.5 hrs. at room temperature, and the resultant precipitate was collected by filtration to give 3-(2-fluorobenzoyl)amino-ε-caprolactam as crude crystals. This crystals and phosphorus pentasulfide (16.5 g) were added to 200 ml of pyridine, and the whole was refluxed for 12 hrs. After cooling, the pyridine was removed by distillation, and to the residue was added a saturated sodium hydrogen carbonate solution and extracted with chloroform. The extract was washed with water, dried, and the solvent was distilled off under reduced pressure. The residue was purified by a column chromatography on silica gel, and then recrystallized from ethyl ether to give the title compound (4.55 g, 24.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:12][O:13][CH2:14][CH2:15][OH:16])[CH3:11])=[CH:6][N:5]=1)[CH3:2].O[C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:12][O:13][CH2:14][CH2:15][O:16][C:18]2[CH:50]=[CH:49][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]3=[O:48])=[CH:20][CH:19]=2)[CH3:11])=[CH:6][N:5]=1)[CH3:2]
Reactant: CCOc1ccc(C(C)=NOCCO)cn1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOc1ccc(C(C)=NOCCOc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cn1
Yield: 80.7 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 410 mg of 2-[1-(2-ethoxy-5-pyridyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 19), 655 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 480 mg of triphenylphosphine and 319 mg of diethyl azodicarboxylate, 763 mg of the title compound were obtained as a foam-like solid.
Reaction SMILES: C(#N)C.[O:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH:22]=2)=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:23](Br)[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(N(CC)CC)C>[O:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][N:20]([CH2:23]/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:19][CH:18]=2)=[CH:13][CH:12]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: BrCC=Cc1ccccc1
Reactant: C1=C(c2ccc(Oc3ccccc3)cc2)CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C1=C(c2ccc(Oc3ccccc3)cc2)CCN(C/C=C/c2ccccc2)C1
Temperature: 0 °C
Yield: 73 %

Procedure:
To an 8 ml acetonitrile solution of 300 mg of the compound (8) synthesized in Example 1 were added 234 mg cinnamyl bromide and 0.5 ml of triethylamine. This was then heated and refluxed for 3 hours. To the reaction mixture was added 10 ml of ice water. This was then extracted with ethyl acetate. The extract was dried, filtered, then concentrated under reduced pressure to obtain a residue which was then purified by silica gel column chromatography (methylene chloride:methanol=25:1) to obtain the above-referenced compound (18) in an amount of 320 mg (yield 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([C:35]([F:38])([F:37])[F:36])[C:33]=1[OH:34])[CH2:5][C@@H:6]([CH2:10][C:11](=[O:30])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[NH:20][C:19]2=[O:29])[CH2:14][CH2:13]1)[C:7]([OH:9])=O.[O:39]1[CH2:44][CH2:43][CH:42]([N:45]2[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]2)[CH2:41][CH2:40]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[C:32]([C:35]([F:36])([F:37])[F:38])[C:33]=1[OH:34])[CH2:5][C@@H:6]([CH2:10][C:11]([N:12]1[CH2:13][CH2:14][CH:15]([N:18]2[CH2:24][CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[NH:20][C:19]2=[O:29])[CH2:16][CH2:17]1)=[O:30])[C:7]([N:48]1[CH2:47][CH2:46][N:45]([CH:42]2[CH2:43][CH2:44][O:39][CH2:40][CH2:41]2)[CH2:50][CH2:49]1)=[O:9]
Reactant: C1CN(C2CCOCC2)CCN1
Reactant: O=C(O)[C@H](CC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)Cc1cc(Cl)c(O)c(C(F)(F)F)c1
Product: O=C(C[C@H](Cc1cc(Cl)c(O)c(C(F)(F)F)c1)C(=O)N1CCN(C2CCOCC2)CC1)N1CCC(N2CCc3ccccc3NC2=O)CC1

Procedure:
Prepared analogously to Example 7i from 70 mg (0.13 mmol) (S)-2-(3-chloro-4-hydroxy-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid and 22 mg (0.13 mmol) 1-(tetrahydropyran-4-yl)-piperazine.
Reaction SMILES: [O:1]1CCOCC1.[CH2:7]([C:10]([CH2:17][CH2:18][CH3:19])([CH2:14][CH2:15][CH3:16])[C:11](N)=[O:12])[CH2:8][CH3:9].Cl>[OH-].[K+]>[CH2:7]([C:10]([CH2:17][CH2:18][CH3:19])([CH2:14][CH2:15][CH3:16])[C:11]([OH:1])=[O:12])[CH2:8][CH3:9]
Reactant: C1COCCO1
Reactant: CCCC(CCC)(CCC)C(N)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCCC(CCC)(CCC)C(=O)O
Yield: 75.8 %

Procedure:
In a flask equipped with a dropping-funnel were placed 480 g of distilled dioxan followed by 80 g (0.432 mol) of tri-n-propylacetamide which was dissolved by stirring. For a period of 20 minutes a current of dry hydrochloric acid gas was passed through the dioxan solution at room-temperature, which represented a total of 100 g of hydrochloric acid gas. At the end of this operation, 88 g (0.86 mol) of freshly distilled butyl nitrile was slowly added over a period of 2 hours through the dropping-funnel. The temperature of the reaction medium rose from 31 to 43° C which necessitated cooling in a water-bath. The solution was then maintained for 2 hours at 85°-90° C. The dioxan was distilled off under a reduced pressure of 20 mm. Hg and a pasty residue obtained at room-temperature. This residue was dissolved in 290 g of a 10% aqueous solution of potassium hydroxide. The aqueous layer was decanted out and extracted twice with 75 g of ethyl ether. The potassium solution was acidified with 118 g of a 36% solution of hydrochloric acid (at 10/20° C) after which the oily phase was decanted out. The aqueous phase was extracted twice with 75 g of ethyl ether after which the oily phase and the ethereal extracts were placed together. The ethereal solution was washed twice with 100 g of water and dried for 24 hours over 100 g of anhydrous sodium sulphate. The sodium sulphate was then centrifuged out. The ethyl ether was distilled off under atmospheric pressure and the residue recuperated under 7 mm Hg. The fraction obtained boiled at 126° to 128° C and crystallized rapidly. In this way, 61 g of crude tri-n-propylacetic acid were obtained, which represents a yield of 76%. The crude product was then dissolved by heating in 75 g of ethyl ether. The ethereal solution was filtered while hot and the filtrate left at a temperature of -30° C for 4 hours. The precipitate which formed was centrifuged out and dried in a desiccator under a reduced pressure of 20 mm Hg for 6 hours. By this means, 46 g of pure tri-n-propylacetic acid were obtained which represents a yield in pure product of 75.4% and a total yield of 57.3%. M.P. 67° C.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1.O.NN.[Cl-].[Na+]>C(O)COCCO>[CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[N:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2-c2ncccc21
Agent: NN
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCOCCO
Solvent: O
Product: c1ccc2c(c1)Cc1cccnc1-2
Temperature: 168 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
Subsequently, in a stream of argon, 500 mL of diethylene glycol was added to 16.8 g (92.6 mmol) of 4-azafluorene-9-one and 25 mL (370 mmol) of hydrazine monohydrate, and was heated and stirred at 168° C. for 3 hours. After the reaction liquid was cooled to room temperature, an aqueous solution of sodium chloride was added to the reaction liquid, and then, was extracted with ethyl acetate. The organic phase was washed with water, dried over sodium sulfate and concentrated, to thereby obtain 15.3 g of 4-azafluorene (99% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([N+:20]([O-])=O)[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH:6]=[CH:7][CH:8]=1.C([O-])=O.[NH4+]>[Pd].CO>[NH2:20][CH:10]([CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:11][CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: COc1cccc(CC(CCC(=O)OC(C)(C)C)[N+](=O)[O-])c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: COc1cccc(CC(N)CCC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.5 %

Procedure:
A mixture of tert-butyl 5-(3-methoxyphenyl)-4-nitrovalerate (0.31 g), 10% palladium on carbon (0.31 g), and ammonium formate (0.63 g) in methanol (3.1 ml) was stirred at ambient temperature for 0.5 hour. After the insoluble material was removed by filtration, the filtrate was evaporated in vacuo. To the residue, ethyl acetate and water were added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give tert-butyl 4-amino-5-(3-methoxyphenyl)valerate (245 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12]Br)=[CH:4][CH:3]=1.[CH3:14][O:15][P:16]([O:19]C)[O:17][CH3:18]>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][P:16](=[O:19])([O:17][CH3:18])[O:15][CH3:14])=[CH:4][CH:3]=1
Reactant: Clc1ccc(CBr)c2ccccc12
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccc(Cl)c2ccccc12)OC

Procedure:
Following the procedure of Compound 11, 4-chloro-1-bromomethylnaphthalene is reacted with trimethylphosphite.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[O:34])[CH2:32][CH3:33])[CH:25]=4)[CH2:20][CH2:19]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CC3)CC2)c1

Procedure:
Example 63 was prepared from 1-(4-chlorophenyl)cyclopropanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 468.3 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[CH3:17][S:18][C:19](SC)=[N:20][C:21]#[N:22]>N1C=CC=CC=1.C(OCC)(=O)C>[C:21]([N:20]=[C:19]([S:18][CH3:17])[NH:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]1[OH:16])#[N:22]
Reactant: CSC(=NC#N)SC
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CSC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 63.6 %

Procedure:
A mixture of trans-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (2.18 g) and dimethyl N-cyanoimidodithiocarbonate [(CH3S)2C=N--CN] (1.54 g) in dry pyridine (11 ml) was stirred at 80° C. for 2.5 hours, and under reflux for 2.5 hours. The reaction mixture was diluted with ethyl acetate (40 ml) and washed with 5% hydrochloric acid (30 ml×2). The organic layer was washed successively with water (30 ml), saturated aqueous sodium bicarbonate (30 ml) and brine (30 ml), dried over magnesium sulfate, and evaporated in vacuo. The residue was subjected to column chromatography on silica gel (70 g) and eluted with chloroform and a mixture of chloroform and methanol (50:1 and then 20:1). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was triturated with diisopropyl ether. The crystals were recrystallized from ethanol to give trans-4-(3-cyano-2-methyl-1-isothioureido)-3,4-dihydro- 3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (2.01 g).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9](S(C)(=O)=O)[N:8]=1.[NH2:20][CH2:21][CH2:22][CH2:23][OH:24].[H-].[Na+]>C(O)(C)(C)C>[F:1][C:2]([F:19])([F:18])[CH2:3][N:4]=[C:5]([NH2:17])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:24][CH2:23][CH2:22][CH2:21][NH2:20])[N:8]=1
Reactant: CS(=O)(=O)c1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: NCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: NCCCOc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
4-[2-(2,2,2-Trifluoroethyl)guanidino]-2-methylsulphonylpyrimidine (0.15 g.) was added to a mixture of 3-aminopropanol (0.075 g.), t-butanol (5 ml.) and a 50% w/w dispersion of sodium hydride in mineral oil (0.05 g.) which was stirred under an argon atmosphere. The mixture was stirred at room temperature for 2 hours, heated under reflux for 4 hours and then evaporated to dryness. The residue was partitioned between 2N aqueous acetic acid and ether, and the aqueous phase basified with 17N NaOH and extracted three times with ether. The combined ether extracts were dried and evaporated to dryness to give 4-[2-(2,2,2-trifluoroethyl)guanidino]-2-(3-aminopropyloxy)pyrimidine (0.07 g.) which was used without further purification.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][CH:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[CH3:27])[N:20]([CH3:28])[CH2:19]2)[C:9]1=[O:29])[CH3:7]>O1CCOCC1.O>[CH3:28][N:20]1[C:21]2[C:26](=[C:25]([CH3:27])[CH:24]=[CH:23][CH:22]=2)[C:18]([CH2:17][N:10]2[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:8]([CH:6]([CH3:7])[CH2:5][CH2:4][C:3]([OH:30])=[O:2])[C:9]2=[O:29])=[CH:19]1
Reactant: COC(=O)CCC(C)n1c(=O)n(CC2CN(C)c3cccc(C)c32)c2ccccc21
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc2c1c(Cn1c(=O)n(C(C)CCC(=O)O)c3ccccc31)cn2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 14.5 %

Procedure:
To a solution of 4-[3-(1,4-dimethyl-3H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-pentanoic acid methyl ester (120 mg, 0.3 mmol) in dioxane (2.5 ml) was added a solution of LiOH monohydrate (25 mg, 0.6 mmol) in H2O (2.5 mL). The solution was stirred at room temperature for 4 hours. The reaction mixture was quenched with 4M HCl in dioxane (250 □L) and concentrated. The resulting residue was purified by CombiFlash with 10% MeOH in dichloromethane as the eluent to afford the desired 4-{3-[(1,4-dimethyl-1H-indol-3-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}pentanoic acid (17 mg, 15%). LCMS (ESMS): 392.26 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:4]=1[O:5][CH2:6][CH2:7][OH:8].N1C=CC=CC=1.[C:22](Cl)(=[O:24])[CH3:23]>C1COCC1>[C:22]([O:8][CH2:7][CH2:6][O:5][C:4]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=1[O:2][CH3:1])(=[O:24])[CH3:23]
Reactant: COc1cc([N+](=O)[O-])ccc1OCCO
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1OCCOC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.4 %

Procedure:
To a solution of 2-(2-methoxy-4-nitrophenoxy)ethanol (5.5 g, 26 mmol) and pyridine (2.35 g, 30 mmol) in THF (140 mL) at 0° C. was acetyl chloride (2.33 g, 30 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, saturated aqueous CuSO4 solution, brine, dried over MgSO4, and concentrated to give 2-(2-methoxy-4-nitrophenoxy)ethyl acetate as a yellow solid (6 g, 91%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[Cl:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=1[Cl:20].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Cl:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][C:19]=1[Cl:20])[O:21][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCCBr
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCCOc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.8 %

Procedure:
To a solution of tert-butyl 3-bromopropylcarbamate (0.5 g, 2 mmol) and 3,4-dichlorophenol (0.38, 2.3 mmol) in DMF (10.5 mL) was added Cs2CO3 (1.02 g, 3.10 mmol). The reaction mixture was stirred at rt for 72 h. The reaction mixture was diluted with water and extracted with EtOAc (3×). The combined organic extracts were washed with saturated aqueous NaCl and water (1:1), dried over Na2SO4, filtered and evaporated to dryness. The crude product was purified by silica gel chromatography to provide Intermediate 3A (543 mg, 56% yield). HPLC/MS (Method B) RT=3.85 min, [M+H]+ 320.2.
Reaction SMILES: C([O-])=O.[NH4+].C([O:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([O:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28]([CH3:33])=[CH:27]4)=[N:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1)C1C=CC=CC=1>[Pd].CN(C=O)C>[OH:12][C:13]1[CH:22]=[C:21]2[C:16]([C:17]([O:23][C:24]3[CH:25]=[C:26]4[C:30](=[CH:31][CH:32]=3)[NH:29][C:28]([CH3:33])=[CH:27]4)=[N:18][CH:19]=[N:20]2)=[CH:15][CH:14]=1
Reactant: Cc1cc2cc(Oc3ncnc4cc(OCc5ccccc5)ccc34)ccc2[nH]1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Cc1cc2cc(Oc3ncnc4cc(O)ccc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.9 %

Procedure:
10% Palladium on charcoal (200 mg) followed by ammonium formate (4.34 g, 69 mmol) were added to a solution of 7-benzyloxy-4-(2-methylindol-5-yloxy)quinazoline (1.75 g, 4.58 mmol) in DMF (60 ml). After stirring for 1 hour at ambient temperature, the mixture was filtered. The filtrate was evaporated. The residue was triturated with water, filtered, washed with ethyl acetate, and dried under vacuum to give 7-hydroxy-4-(2-methylindol-5yloxy)quinazoline (1.24 g, 93%).