Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:9]2[CH:4]3[CH:5]([CH2:10][C:11](=[O:12])[N:3]3[C:2]1=[O:13])[CH2:6][CH2:7][CH2:8]2.Cl.C([OH:22])C1C=CC=CC=1>C(OCC)C>[O:12]=[C:11]1[CH2:10][CH:5]2[CH:4]([CH:9]([CH2:1][C:2]([OH:13])=[O:22])[CH2:8][CH2:7][CH2:6]2)[NH:3]1
Reactant: O=C1CC2CCCC3CC(=O)N1C23
Reactant: OCc1ccccc1
Agent: Cl
Solvent: CCOCC
Product: O=C(O)CC1CCCC2CC(=O)NC12
Temperature: 100 °C

Procedure:
A solution of 9.5 grams (0.053 mol) hexahydropyrrolo [3,2,1-hi]-indole-2,4(1H, 5H)-dione (5aα, 8aα, 8bα) in 50 ml of benzyl alcohol is treated with four drops of drops of concentrated hydrochloric acid. The solution is heated to 100° C. for 72 hours, cooled, and diluted with 250 ml of anhydrous diethyl ether. A white crystalline precipitate of octahydro-2-oxo-1H-indole-7-acetic acid (3aα, 7β, 7aα) is isolated by filtration with a melting point of 238°-240° C. The filtrate is cooled and octahydro-2-oxo-1H-indole-7acetic acid benzyl ester (3aα, 7β, 7aα). This is purified by chromatography over silica gel using methylene chloride for elution. The eluate is concentrated at reduced pressure. The resulting solid is triturated with anhydrous diethyl ether and filtered. The filtrate is concentrated at reduced pressure to yield octahydro-2-oxo-1H-indole-7-acetic acid benzyl ester (3aα, 7β, 7aα) with a melting point of 89°-90° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:12])[C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH2:6].C(N(CC)CC)C.S=[C:21]1[CH2:25][S:24][C:23](=[O:26])[NH:22]1>C(O)C>[CH3:12][N:3]([CH3:2])[C:4](=[O:11])[C@H:5]([C@H:7]([CH2:9][CH3:10])[CH3:8])[NH:6][C:21]1[CH2:25][S:24][C:23](=[O:26])[N:22]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)N(C)C
Reactant: O=C1NC(=S)CS1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC[C@H](C)[C@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the crude product (19.4 g) containing N,N-dimethyl-L-isoleucinamide hydrochloride obtained in B) and triethylamine (49.5 g) in ethanol (150 mL) was added 4-thioxothiazolidin-2-one (16.3 g) at room temperature. The reaction mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, the obtained solid was suspended in THF, and the suspension was filtered through celite pad and silica gel pad. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/petroleum ether) to give the title compound (6.2 g).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5]C)=[O:4].Cl[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]2[CH:16]=[C:17]([C:22]3[S:26][C:25]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[N:24][CH:23]=3)[CH:18]=[C:19]([CH3:21])[CH:20]=2)[N:9]=1.C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)C(O)=O>>[CH3:21][C:19]1[CH:20]=[C:15]([NH:14][C:10]2[N:9]=[C:8]([O:1][CH2:2][C:3]([OH:5])=[O:4])[CH:13]=[CH:12][N:11]=2)[CH:16]=[C:17]([C:22]2[S:26][C:25]([C:27]([OH:33])([CH3:32])[C:28]([F:31])([F:30])[F:29])=[N:24][CH:23]=2)[CH:18]=1
Reactant: COC(=O)CO
Reactant: Cc1cc(Nc2nccc(Cl)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(Nc2nccc(OCC(=O)O)n2)cc(-c2cnc(C(C)(O)C(F)(F)F)s2)c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 15 %

Procedure:
Methyl hydroxyacetate (22 mg, 0.24 mmol) and 2-(5-(3-[(4-chloropyrimidin-2-yl)amino]-5-methylphenyl)-1,3-thiazol-2-yl)-1,1,1-trifluoropropan-2-ol (Example 98, 50 mg, 0.12 mmol) were taken up in N,N′-dimethylacetamide (1.2 mL). Cesium carbonate (118 mg, 0.36 mmol) was added and the mixture was stirred for 24 h at 70° C. The reaction was cooled to room temperature, quenched with saturated aqueous ammonium chloride, and extracted with ethyl acetate (2×). The combined organics were concentrated under reduced pressure and purified by reverse phase HPLC (10-80% acetonitrile/water+0.05% TFA modifier). Desired fractions were combined and lyophilized to afford {[2-({3-methyl-5-[2-(1,1,1-trifluoro-2-hydroxypropan-2-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}acetic acid (10 mg, 0.018 mmol, 15%) as the trifluoroacetic acid salt as a white solid. MS ESI: [M+H]+ m/z 455.1.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[O:4][N:3]=1.[H][H]>[Pt](=O)=O.C(O)C>[NH2:3][C:2]([CH3:1])=[CH:6][C:5]([C:7]1[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=1)=[O:4]
Reactant: [H][H]
Reactant: Cc1cc(-c2ccc(F)cc2)on1
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(N)=CC(=O)c1ccc(F)cc1

Procedure:
3-Methyl-5-(4-fluorophenyl)isoxazole (620 mg, 3.49 mmol) is introduced into 16 ml of ethanol, platinum(IV) oxide catalyst (62 mg) is added, and the mixture is then hydrogenated under atmospheric pressure hydrogen for 12 h. The catalyst is filtered off and the filtrate is concentrated. 573 mg (91% of theory) of the title compound are obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:3]=1[NH:4][C:5]1[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[C:6]=1[C:14](OCC)=O.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1(OC)C=CC=CC=1>[Ti](Cl)(Cl)(Cl)Cl>[Br:23][C:20]1[CH:21]=[CH:22][C:2]2[N:1]=[C:14]([N:28]3[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]3)[C:6]3[C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[S:9][C:5]=3[NH:4][C:3]=2[CH:19]=1
Reactant: CCOC(=O)c1c(Nc2cc(Br)ccc2N)sc2ccccc12
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: COc1ccccc1
Product: CN1CCN(C2=Nc3ccc(Br)cc3Nc3sc4ccccc4c32)CC1

Procedure:
In the same manner as in Example 1 and using ethyl 2-(2-amino-5-bromoanilino)benzo[b]thiophene-3-carboxylate, 1-methylpiperazine, anisole and titanium tetrachloride, 8-bromo-12-(4-methylpiperazin-1-yl)-6H-[1]benzothieno[2,3-b][1,5]benzodiazepine is obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.C[N+](C)(C)C.[NH2:33][C:34]1[CH:46]=[C:45]([CH:47]2[CH2:52][CH2:51][N:50]([CH3:53])[CH2:49][CH2:48]2)[CH:44]=[CH:43][C:35]=1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>ClCCl>[CH3:53][N:50]1[CH2:51][CH2:52][CH:47]([C:45]2[CH:44]=[CH:43][C:35]([C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])=[C:34]([NH:33][CH:11]3[CH2:12][CH2:13][O:8][CH2:9][CH2:10]3)[CH:46]=2)[CH2:48][CH2:49]1
Reactant: CN1CCC(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C[N+](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(c2ccc(C(=O)OC(C)(C)C)c(NC3CCOCC3)c2)CC1
Yield: 87.6 %

Procedure:
7.18 mL of 2,2,2-trifluoroacetic acid (93 mmol), 4.11 mg of dihydro-2H-pyran-4(3H)-one (44.5 mmol) and then 14.5 g of tetramethylammonium triacetoxyborohydride (53.8 mmol) are successively added to a solution of 15 g of tert-butyl 2-amino-4-(1-methylpiperidin-4-yl)benzoate in 200 mL of dichloromethane under stirring. The reaction medium is stirred at room temperature for 2 h and then taklen up with a 1N soda solution. The organic phase is isolated, dried on magnesium sulfate and then dried concentrated. The residue contained always HI. It is thus taken up in dichloromethane and washed with 100 mL of a 1H soda solution. The organic phase is decanted, dried on magnesium sulfate and dry concentrated to yield 14.6 g of a yellow solid (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([O:16]C)=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:5][CH:6]1[C:13]2[CH:12]=[C:11]([C:14]([OH:16])=[O:15])[NH:10][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2Cc1ccc(F)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2c([nH]1)CCC2Cc1ccc(F)c(Cl)c1

Procedure:
The title compound was synthesized from methyl 4-(3-chloro-4-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.034 g, 0.11 mmol) and lithium hydroxide (0.023 g, 0.55 mmol), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-100% EtOAc/heptane to afford the title compound. 17 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.97-2.16 (m, 1H) 2.44-2.67 (m, 3H) 2.67-2.85 (m, 2H) 3.19-3.29 (m, 1H) 6.31 (s, 1H) 7.10-7.15 (m, 2H) 7.28 (d, J=7.52 Hz, 1H) 19F NMR δ ppm −122.88 (q, J=7.1 Hz); LCMS-MS (ESI−) 292.0 (M−H); HPLC (UV=98.1%), (ELSD=100%).
Reaction SMILES: CN(C)[CH:3]=[O:4].N1C=CN=C1.[F:11][C:12]([F:48])([F:47])[C:13]1[CH:14]=[C:15]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:16][N:17]([CH3:39])[C:18](=[O:38])[C:19]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[CH:23][C:22]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[N:21][CH:20]=1>>[F:48][C:12]([F:47])([F:11])[C:13]1[CH:14]=[C:15]([CH:40]=[C:41]([C:43]([F:45])([F:46])[F:44])[CH:42]=1)[CH2:16][N:17]([CH3:39])[C:18](=[O:38])[C:19]1[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])=[CH:23][C:22]([N:32]2[CH2:33][CH2:34][N:35]([CH:3]=[O:4])[CH2:36][CH2:37]2)=[N:21][CH:20]=1
Reactant: Cc1ccccc1-c1cc(N2CCNCC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN(C)C=O
Agent: c1c[nH]cn1
Product: Cc1ccccc1-c1cc(N2CCN(C=O)CC2)ncc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Yield: 75.5 %

Procedure:
To a mixture of 0.089 ml (1.1 mmol) N,N-dimethylformamide and 38 mg (0.56 mmol) imidazole 0.071 ml (0.56 mmol) trimethylchlorosilane were added dropwise at room temperature. The reaction mixture was cooled to 0° C., and 0.10 g (0.19 mmol) N-(3,5-bis-trifluoromethyl-benzyl)-N-methyl-6-piperazin-1-yl-4-o-tolyl-nicotinamide (Example 53) were added. The ice-water bath was removed and the mixture stirred over night. The reaction was quenched with a mixture of 2 ml 1 N aqueous hydrochloric acid solution and 4 ml water, and the mixture was extracted with ethyl acetate. The combined extracts were dried with sodium sulfate and concentrated. Flash column chromatography afforded 81 mg (82%) of the title compound as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]([C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:15][N:14](COCC[Si](C)(C)C)[C:11]3=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH:39]1[CH3:44])=O)(C)(C)C>>[CH3:20][C:18]([CH3:21])([CH3:19])[C:17]([C:16]1[C:10]2[C:11](=[N:12][CH:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([N:41]4[CH2:42][CH2:43][NH:38][CH:39]([CH3:44])[CH2:40]4)[CH:3]=3)[N:9]=2)[NH:14][CH:15]=1)=[O:22]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(I)c3)nc12
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Product: CC1CN(c2cccc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c2)CCN1

Procedure:
2,2-Dimethyl-1-{2-[3-(3-methyl-piperazin-1-yl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-propan-1-one was prepared starting from 1-[2-(3-iodo-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one and 2-methyl-piperazine-1-carboxylic acid tert-butyl ester following general procedures as described in these Examples. M+H=378.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:14]([C:15](=[O:17])[CH3:16])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:18]=1)(=O)C.[OH-].[Na+].Cl>C(O)C.O>[C:15]([N:14]1[C:8]2[CH:7]=[CH:6][C:5]([OH:4])=[CH:18][C:9]=2[CH2:10][CH2:11][CH2:12][CH2:13]1)(=[O:17])[CH3:16]
Reactant: CC(=O)Oc1ccc2c(c1)CCCCN2C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)N1CCCCc2cc(O)ccc21
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
7-Acetoxy-1-acetyl-2,3,4,5-tetrahydro-1H-benzazepine (D23, 3.88 g, 16 mmol) was stirred in ethanol (40 ml) as NaOH (1.26 g, 32 mmol) was added in water (5 ml). After stirring for 30 min, the mixture was diluted with water (500 ml), and acidified with 5M HCl. The tan precipitate was filtered off and dried, yielding 2.02 g (63%) of the title compound. A further 0.80 g (25%) of this material was isolated by dichloromethane extraction of the filtrate.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[C:7]([NH:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:8]=1.Cl[C:17]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1.O>CS(C)=O>[Br:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[CH:6]=[C:7]([NH:9][CH2:10][C:11]([F:13])([F:14])[F:12])[CH:8]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Nc1cc(Br)cc(NCC(F)(F)F)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)CNc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
Aqueous HCl (1.0 M, 1.5 mL, 1.5 mmol) was added to a stirred mixture of the product of Step 2 (0.80 g, 2.97 mmol) and 2-chloro-4-trifluoromethylpyrimidine (8.0 mL, 66.2 mmol) in DMSO and the mixture was stirred at 100° C. for 2 h. The mixture was cooled, water was added and the mixture was extracted with Et2O (3×). The combined organic fractions were washed with HCl, water, aqueous copper sulfate and brine, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (0-60% ethyl acetate in hexanes) to give 5-bromo-N-(2,2,2-trifluoroethyl)-N′-[4-(trifluoromethyl)-pyrimidin-2-yl]benzene-1,3-diamine (622 mg, 1.50 mmol, 50% yield) as a off-white solid. MS ESI: [M+H]+ m/z 416.9.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>CC(O)C>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][N:14]=[C:13]2[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:3]1[CH2:2][OH:1]
Reactant: OCC1Cc2ccccc2N1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3c4ccccc4CC3CO)c2cc1OC
Yield: 57 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 57% yield from 2-hydroxymethyl-indoline (1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 145.5°-147° C.; LC-MS: 338 (MH+); anal. RP18-HPLC RT: 4.03 min.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[C:20]3[CH:19]=[C:18]([C:21](=[O:23])[CH3:22])[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[C:20]3[CH:19]=[C:18]([CH:21]([OH:23])[CH3:22])[CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:3][CH:2]=1
Reactant: CC(=O)c1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc2c(c1)C(Cc1ccncc1)(Cc1ccncc1)c1ccccc1-2
Temperature: 25 °C

Procedure:
To 300 mg of 9,9-bis(4-pyridinylmethyl)-2-acetylfluorene was dissolved in 5ml of ethanol cooled to 0° was added 100 mg of sodium borohydride. The reaction mixture was warmed to room temperature overnight, quenched with water and methanol and the solvents evaporated. The residue was partitioned between ethyl acetate and 1N NaOH, washed with water, brine, dried (MgSO4) and evaporated. Recrystallization from ethanol yielded product. NMR (CDCl3, 200 MHz) δ: 1.50(d,J=6.5Hz,3H), 3.39(s,4H), 4.92(q,J=6.4Hz,1H), 6.43(2d,4H), 7.08-7.58(m,arom.), 7.87(D,2H), 7.97(d,2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.[CH3:12][O:13][C:14]([C:16]1[N:20]([CH:21]2C3C(=CC=CC=3)C=[CH:23][C:22]2([CH3:32])[CH3:31])[CH:19]=[N:18][CH:17]=1)=[O:15]>C(Cl)Cl>[CH3:12][O:13][C:14]([C:16]1[N:20]([CH:21]2[C:3]3[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=3)[CH:8]3[O:10][CH:23]3[C:22]2([CH3:32])[CH3:31])[CH:19]=[N:18][CH:17]=1)=[O:15]
Reactant: COC(=O)c1cncn1C1c2ccccc2C=CC1(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)c1cncn1C1c2ccccc2C2OC2C1(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 18.9 %

Procedure:
9.4 g of 55% 3-chloroperbenzoic acid are added to a solution of 8.5 g of 1-(1,2-dihydro-2,2-dimethylnaphthalen-1-yl)-5-imidazolecarboxylic acid methyl ester in 150 ml of methylene chloride and the mixture is stirred at room temperature for 2 hours. The precipitate is separated off and the filtrate is washed twice using 50 ml of sodium hydrogen carbonate solution (5%) each time, dried over magnesium sulfate and concentrated by evaporation. Chromatography of the residue on silica gel [eluant: ether/hexane (3:1)] yields 1.7 g of a mixture of 1,4-cis-1-(3,4-epoxy-2,2-dimethyltetralin-1-yl)-5-imidazolecarboxylic acid methyl ester and 1,4-trans-1-(3,4-epoxy-2,2-dimethyltetralin-1-yl)-5-imidazolecarboxylic acid methyl ester in a ratio of 1:1 (m.p. 60°-68° C.).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:3].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[CH:16][N:15]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=3[O:29][CH3:30])[C:14]=2[CH:31]=1>>[CH2:5]([O:4][C:2]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[CH:16][N:15]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][C:20]=3[O:29][CH3:30])[C:14]=2[CH:31]=1)=[O:3])[CH2:6][CH2:7][CH3:8]
Reactant: CCCCOC(=O)Cl
Reactant: COC(=O)c1ccc(Cn2cnc3ccc(N)cc32)c(OC)c1
Product: CCCCOC(=O)Nc1ccc2ncn(Cc3ccc(C(=O)OC)cc3OC)c2c1
Yield: 34 %

Procedure:
Using a similar procedure to that described in Example 35, but using butyl chloroformate and (J), the title compound was obtained as a solid in 34% yield; partial NMR: 0.9(t,3H, CH3CH2), 1.4(m,2H, CH3CH2), 1.6(m,2H, CH2CH2O), 4.1(t,2H, CH2O).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:22]([C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](O)=[O:19])[CH:8]=1)=[O:5].C(OC(=O)[NH:38][CH2:39][CH2:40][NH2:41])(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:38][CH2:39][CH2:40][NH:41][C:18]([C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]2[CH:21]=[C:22]([C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][N:26]=3)[CH:23]=[CH:24][C:2]=2[Cl:1])[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1)=[O:19]
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCNC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The title compound was prepared according to the method described for Example 3 using 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 105) and tert-butyl(2-aminoethyl)carbamate. The residue was dissolved in DCM (10 mL) and treated with 4M HCl in dioxane (5 mL) with stirring at room temperature for 4 hours. The reaction was concentrated in vacuo and eluted through an SCX-2 column using MeOH followed by 7N NH3 in MeOH; followed by reverse phase chromatography eluting with 5-95% MeCN (with 0.1% NH3) in water (with 0.1% NH3); followed by silica gel column chromatography eluting with 1-5% 7N NH3/MeOH in DCM and finally trituration with TBME.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[CH:11]=1)([CH3:9])[CH3:8])C.C(O)C.[OH-].[K+]>O>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:7]([CH3:8])([CH3:9])[CH2:6][CH2:5][C:4]([OH:19])=[O:3])=[CH:11][C:12]=1[CH3:18]
Reactant: CCOC(=O)CCC(C)(C)c1ccc(OC)c(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(C)(C)CCC(=O)O)cc1C
Temperature: 60 °C
Yield: 96.8 %

Procedure:
To a solution of 4-(4-methoxy-3-methylphenyl)-4-methyl-pentanoic acid ethyl ester (Compound 4, 6.8 g, 25.8 mmol) and 20 mL of absolute ethyl alcohol was added aqueous 5M KOH (6 mL). The resulting solution was heated in an 60° C. bath for 24 h. The solution was cooled to room temperature, diluted with water and washed once with 2:1 hexane:ethyl acetate solution, and the layers were separated. The aqueous layer was acidified with HCl 2N to pH=0-1 and the product extracted three times with ethyl acetate. The combined organic extracts were washed with brine, and dried over MgSO4, and filtered. The solvent was removed to give 5.9 g (97%) of the title compound as a dark oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[C:15]1[NH:19][N:18]=[N:17][N:16]=1.C(N(CC)CC)C.Cl.Cl[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1>CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[C:15]1[N:19]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[N:18]=[N:17][N:16]=1
Reactant: COc1cc2ncnc(-c3nnn[nH]3)c2cc1OC
Reactant: ClCc1ccccn1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(-c3nnnn3Cc3ccccn3)c2cc1OC
Temperature: 27.5 °C
Reaction time: 0.29 h
Yield: 28 %

Procedure:
Experimental Procedure: 50.0 ml of N,N-dimethyl acetamide and 5.0 g (0.019 mol) of 6,7-dimethoxy-4-(1H-tetrazol-5-yl)quinazoline were charged into a 250 ml of 4 necked round bottom flask, connected to a mechanical stirrer, thermometer socket, condenser and addition flask under mild nitrogen atmosphere. 3.80 g (0.038 mol) of triethyl amine was added at 25-30° C. Stirred the mass for 15-20 min at 25-30° C. Reaction mass temperature was raised to 50-55° C. Maintained the mass temperature at 50-55° C. for 15-20 min. 2-chloro methylpyridine hydrochloride solution [3.20 g (0.019 mol) 2-chloro methylpyridine hydrochloride was dissolved in 25.0 ml of N,N-dimethyl acetamide] was added slowly at 50-55° C. for 30-45 min. Maintained the mass temperature at 50-55° C. for 15-20 min. Raised the mass temperature to 80-85° C. Maintained the mass temperature at 80-85° C. for 7-8 hours. N,N-dimethyl acetamide was completely distilled off under vacuum. Crude compound was purified by the column chromatography by using hexane and ethyl acetate. Obtained 1.90 g (yield 28.0% by theory) of pure compound weight.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]=[C:18]([CH3:28])[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:15])[CH:10]([CH2:29][C:30]([O:32][CH2:33][C:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(OC(C)(C)C)[NH2:44]>B(F)(F)F.CCOCC.C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[N:17]=[C:18]([CH3:28])[S:19][C:20]=2[C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[O:15])[CH:10]([CH2:29][C:30]2[O:32][CH:33]=[C:34]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)[N:44]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1nc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2CC(=O)OCC(=O)c2ccc(F)cc2)c(-c2ccc(F)cc2)s1
Reactant: CC(C)(C)OC(N)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1C
Product: Cc1nc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2Cc2nc(-c3ccc(F)cc3)co2)c(-c2ccc(F)cc2)s1
Temperature: 140 °C
Reaction time: 48 h

Procedure:
(RS)-4-{1-[5(4-Fluorophenyl)-2-methylthiazol4-yl]-methanoyl}-3-[2-(4-fluoro-phenyl)-2-oxo-ethoxycarbonylmethyl]-piperazine-1-carboxylic acid tert-butyl ester, description 111 (0.385 g), tert-butyl carbamate (0.376 g) and boron trifluoride etherate (4 drops) were dissolved in xylene (5 ml) and heated to 140° C., under argon and with stirring for 48 hours. After cooling, the reaction mixture was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic layer was dried (MgSO4), evaporated and the residue chromatographed over silica gel. Elution with a gradient of 25 to 100% ethyl acetate in hexane provided the title compound as a pale yellow oil (0.130 g), mass spectrum (API+) 581 [MH+], C30H30F2N4O4S requires 580.