Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH3:14])=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:26][CH2:27][CH:28]=[C:29]1[C:35]2=[CH:36][CH:37]=[CH:38][NH:39][C:34]2=[CH:33][O:32][C:31]2[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:26][CH2:27][CH:28]=[C:29]3[C:35]4[CH:36]=[CH:37][CH:38]=[N:39][C:34]=4[CH2:33][O:32][C:31]4[CH:40]=[CH:41][C:42]([C:44]([OH:47])([CH3:46])[CH3:45])=[CH:43][C:30]3=4)[CH2:10][C@H:9]2[CH3:14])=[CH:6][CH:7]=1
Reactant: C[C@@H]1CNCCN1c1ccc(Cl)cc1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)C1=CC=CNC1=CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: C[C@@H]1CN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CCN1c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 20 h

Procedure:
To a solution of 4-(4-chloro-phenyl)-3-(R)-methyl-piperazine (0.2 g, 0.95 mmol) in isopropanol (20 mL) was added 2,6-lutidine (0.11 mL, 0.94 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and then treated with 2-[5-(3-bromo-propylidene)-5,1-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.24 g, 0.63 mmol), added in portions over 2 h. The solution was then stirred at 80° C. for an additional 20 h. The reaction was concentrated in vacuo and purified by flash chromatography (100% dichloromethane to 2% methanol/dichloromethane) to yield the title compound.
Reaction SMILES: OS(O)(=O)=O.[C:6]1([CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:22])=[O:21])=[CH:16][C:15]=2[C:23]([OH:25])=[O:24])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:26]OC(C1C=CC(OCC2C=CC=CC=2)=C(C=1)C(O)=O)=O>CO>[CH3:26][O:24][C:23]([C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:14]=1[O:13][CH2:12][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:20]([OH:22])=[O:21])=[O:25]
Reactant: COC(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: O=C(O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(C(=O)O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
H2SO4 (0.8 ml, 11.02 mmol) was added dropwise to a solution of 4-[(phenylmethyl)oxy]-1,3-benzenedicarboxylic acid (may be prepared as described in Description 48; 3 g, 11.02 mmol) in methanol (40 ml). The mixture was stirred at room temperature for 3 h before being poured into ice-water (40 ml). The precipitate was collected and added to a saturated NaHCO3 solution. The mixture was filtered to remove the insoluble residue and the pH of the filtrate was adjusted to pH=4.8 by HCl (6 mol/L). The precipitate was collected to afford crude product. The crude product was added to a silica gel column (300 g), and was eluted with dichloromethane/methanol=100:1 (3 L) to afford a mixture of 5-[(methyloxy)carbonyl]-2-[(phenylmethyl)oxy]benzoic acid and the title compound as a white solid. 1 g.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]([CH3:24])([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH:16]2[CH2:20][NH:19][C:18](=[O:21])[N:17]2[CH3:22])=[CH:9][C:8]=1[CH3:23])[CH3:5].[C:26]1([C:32]2[CH:39]=[CH:38][C:35]([CH2:36]Cl)=[CH:34][CH:33]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:32]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:39]=[CH:38][C:35]([CH2:36][N:19]2[CH2:20][CH:16]([CH2:15][CH2:14][CH2:13][C:10]3[CH:11]=[CH:12][C:7]([O:6][C:4]([CH3:24])([CH3:5])[C:3]([OH:25])=[O:2])=[C:8]([CH3:23])[CH:9]=3)[N:17]([CH3:22])[C:18]2=[O:21])=[CH:34][CH:33]=1
Reactant: COC(=O)C(C)(C)Oc1ccc(CCCC2CNC(=O)N2C)cc1C
Reactant: ClCc1ccc(-c2ccccc2)cc1
Product: Cc1cc(CCCC2CN(Cc3ccc(-c4ccccc4)cc3)C(=O)N2C)ccc1OC(C)(C)C(=O)O

Procedure:
The titled compound was prepared using 2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionic acid methyl Ester (0.112 g, 0.322 mmole) and 4-phenyl benzyl chloride (0.078 g, 0.186 mmole) to produce an oil (0.054 g, 34%). Mass [EI+] 501 (M+H)+, [EI−] 499 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[NH:8][N:9]=[CH:10][CH:11]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:15]>>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[N:8][C:7]=1[Cl:15])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1ccn[nH]c1=O
Product: CCOC(=O)c1ccnnc1Cl
Temperature: 100 °C

Procedure:
A mixture of 3-oxo-2,3-dihydro-pyridazine-4-carboxylic acid ethyl ester (355 mg, 2.11 mmol) and POCl3 (6 ml) was heated to 100° C. for 1 h. The volatiles were then removed and the remaining residue was neutralized with sat. NaHCO3-solution. This mixture was extracted three times with Et2O and the combined extracts were dried (Na2SO4) and evaporated to obtain the crude title compound. The remaining brown solid (364 mg, 1.95 mmol, 92%) was used in the next reaction step without further purification. MS: m/e=187.1 [M+H+].
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:35])[CH2:15][N:16]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:19][C:18]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[N:17]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(=O)C>ClCCl>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:18]2[N:19]=[C:20]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[N:16]([CH2:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:35])[N:17]=2)=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cn2nc(-c3ccc(F)cc3)nc2-c2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Cn1nc(-c2ccc(F)cc2)nc1-c1ccc(F)cc1)N1CCNCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 93.6 %

Procedure:
3.1 g 4-(2-(3,5-bis-(4-fluoro-phenyl)-(1,2,4)triazol-1-yl)-acetyl)-piperazine-1-carboxylic acid tert-butyl ester was dissolved in 20 ml dichlormethane and 20 mL trifluor acetic acid was added. The reaction was stirred 24 h at RT and the solvent was evaporated. 10% potassiumcarbonate solution was added to the residue. The precipate was filtered and crystallized with a mixture of acetonitrile and isopropylether to give 2.3 g of the desired compound. (M+H)+: 384
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]([C:14](=O)[NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[NH2:23])[CH:12]2[CH2:25][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH:13]([C:14]2[NH:23][C:17]3[CH:18]=[C:19]([Br:22])[CH:20]=[CH:21][C:16]=3[N:15]=2)[CH:12]2[CH2:25][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1C(=O)Nc1ccc(Br)cc1N
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1nc2ccc(Br)cc2[nH]1
Temperature: 130 °C

Procedure:
The above mixture of regioisomer 3-(2-Amino-4-bromo-phenylcarbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester was dissolved in ethanol and heated to 130° C. in sealed tube overnight and continue heating at 170° C. for 3 days. LC-MS showed desired product and Boc cleaved product (about 1:1 ratio). The mixture was concentrated down and dissolved DCM. Di-tert-butyl dicarbonate (0.6 eq.) was added and reaction was stirred overnight at room temperature. The reaction mixture was concentrated down and purified by flash column chromatography (silica gel, 20 to 80% ethyl acetate/hexane) to give 3-(6-Bromo-1H-benzoimidazol-2-yl)-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.383 g, 72%) as an orange foam.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[C:11](OCC)=O.Cl.[C:20]1(=[N:29][NH2:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21]1>O1CCCC1.CCCCCC>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:11]2[C:21]3[CH2:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]=3[NH:29][N:30]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)c1cccc(OC)c1
Reactant: NN=C1CCc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1

Procedure:
In a similar manner to Example 1, indan-1-one hydrazone (3.55 g) was dissolved in tetrahydrofuran (80 ml) at 0° C. under nitrogen with stirring. n-Butyllithium (28.8 ml of a 2.5M solution in hexane) was added to the solution and the mixture was stirred at 0° C. for 0.5 h. Ethyl 3-methoxybenzoate (2.16 g) was added, followed by 3M hydrochloric acid (80 ml) and the mixture was worked up as described in Example 1 to give 3-(3-methoxyphenyl)-1,4-dihydroindeno[1,2-c]pyrazole, m.p. 172-174° C.
Reaction SMILES: [NH2:1][C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:29]([C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48])[C@H:30]([C:32]([NH:34][C@H:35]([C:37](ON1C(=O)CCC1=O)=[O:38])[CH3:36])=[O:33])[CH3:31]>CN(C=O)C.C(OCC)(=O)C>[NH:29]([C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:48])[C@H:30]([C:32]([NH:34][C@H:35]([C:37]([NH:1][C@H:2]([C:26]([OH:28])=[O:27])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:38])[CH3:36])=[O:33])[CH3:31]
Reactant: N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The tripeptide Z-Ala-Ala-Asn(Trt)-OH (2) was prepared according to the following procedure: To a stirred solution of H-Asn(Trt)-OH (4.97 g, 13.28 mmol, obtained from Bachem) in dry DMF (25 ml) a solution of Z-Ala-Ala-OSu (5.2 g, 13.28 mmol) in dry DMF (20 ml) was added and stirred for 14 h at room temperature. The solvent was evaporated in vacuo by using an oil pump. The obtained crude compound was dissolved in ethyl acetate (100 ml), washed with 1 N HCl (2×30 ml) and water (30 ml). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to give the tripeptide as a white solid (7.95 g, 92%) of m.p. 196° C. The peptide was used without further purification.—1H NMR (500 MHz, DMSO-d6): δ=1.18 (d, 3 H, J=7.1 Hz, CH3), 1.22 (d, 3 H, J=7.0 Hz, CH3), 2.62-2.88 (m, 2 H, CHCH2), 4.06-4.12 (m, 1 H, CH), 4.31-4.37 (m, 1 H, CH), 4.46-4.50 (m, 1 H, CH), 4.98-5.04 (m, 2 H, CH2O), 7.15-7.35 (m, 20 H, aryl-H). —MS(EI) m/z (%): 651 [M+H+], 673 [M+Na+], 689 [M+K+].
Reaction SMILES: [F:1][C:2]1[C:31]([N:32]2[CH2:38][CH2:37][CH2:36][N:35]([CH3:39])[CH2:34][CH2:33]2)=[CH:30][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH:14][C:15](=[O:23])[N:16]([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])=[CH:12][N:11](C4CCCCO4)[N:10]=3)=[N:8][C:4]=2[CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[C:31]([N:32]2[CH2:38][CH2:37][CH2:36][N:35]([CH3:39])[CH2:34][CH2:33]2)=[CH:30][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH:14][C:15](=[O:23])[N:16]([CH:17]([CH3:18])[CH3:19])[CH:20]([CH3:22])[CH3:21])=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)N(C(=O)Nc1cn(C2CCCCO2)nc1-c1nc2cc(F)c(N3CCCN(C)CC3)cc2[nH]1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)N(C(=O)Nc1c[nH]nc1-c1nc2cc(F)c(N3CCCN(C)CC3)cc2[nH]1)C(C)C
Yield: 6.5 %

Procedure:
A solution of 278.5 mg of 3-[3-[5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-1-(tetrahydropyran-2-yl)-1H-pyrazol-4-yl]-1,1-diisopropylurea in solution in 5.1 mL of a 4N solution of hydrochloric acid in dioxane is stirred at 22° C. for 4 hours. After evaporation, the reaction crude is purified by preparative HPLC with, as eluent, a gradient of water/acetonitrile containing respectively 0.07% of trifluoroacetic acid. 15.2 mg of 3-{3-[5-fluoro-6-(4-methylperhydro-1,4-diazepin-1-yl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-1,1-diisopropylurea are isolated in the form of a trifluoroacetate salt. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.26 (d, J=7.0 Hz, 12H); 2.21 (broad m, 2H); 2.90 (s, 3H); from 3.14 to 3.68 (m, 8H); 3.90 (m, 2H); 7.16 (d, J=8.0 Hz, 1H); 7.48 (d, J=12.0 Hz, 1H); 7.98 (s, 1H). ES mass spectrum: m/z=457: MH+(base peak)—m/z=330 (MH−C7H13NO)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[C:11]([CH3:16])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].Cl.[CH3:19]O>CO>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]1[CH2:19][NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:17])[CH2:6][C:7]2=1
Reactant: CO
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2c(C)cccc12
Agent: Cl
Product: COC(=O)[C@@H]1Cc2c([nH]c3c(C)cccc23)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
3.02 g of 7-methyl-L-tryptophan methyl ester are dissolved in 20 ml of methanol, and 4 ml of 15% HCl-methanol are added thereto. The mixture is evaporated to remove the solvent. The residue is dissolved in 30 ml of methanol, and 2.86 g of 35% formalin are added thereto. The mixture is stirred at room temperature overnight. The mixture is evaporated to remove the solvent, and water is added to the residue. The aqueous solution is adjusted to pH 10 with 10% aqueous ammonia, and extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent. The residue is recrystallized from chloroform. 2.0 g of methyl (3S)-8-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate are obtained as pale yellow prisms. Yield: 63%
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(OCC)(=O)C.[Pd]>[NH2:22][C:19]1[CH:18]=[CH:17][C:16]([CH:7]([CH2:6][CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])=[CH:21][CH:20]=1
Reactant: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 22, 345 mg, 1.0 mmol) in ethyl acetate (100 mL) was treated with 10% palladium on activated carbon (34.5 mg). The reaction mixture was stirred under hydrogen gas at 60 psi at 25° C. for 6 h. The catalyst was then filtered off through a pad of celite, which was washed well with ethyl acetate. The resulting filtrate was concentrated in vacuo to give 2-(4-amino-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (288.3 mg, 91.4%) as a yellow solid: mp 102-107° C.; EI-HRMS m/e calcd for C17H21N3OS (M+) 315.1405, found 315.1401.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][C@@:11]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]([C:22]3[C:26]4[S:27][CH:28]=[CH:29][C:25]=4[O:24][N:23]=3)[CH:19]=[CH:20][CH:21]=2)[CH2:13][O:12]1.ClC(Cl)C>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:10][C@:11]([CH3:13])([OH:12])[CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[C:26]4[S:27][CH:28]=[CH:29][C:25]=4[O:24][N:23]=3)[CH:17]=2)=[CH:4][CH:3]=1
Reactant: C[C@@]1(COc2cccc(-c3noc4ccsc34)c2)CO1
Reactant: NCc1ccc(F)cc1
Solvent: CC(Cl)Cl
Solvent: CCO
Product: C[C@](O)(CNCc1ccc(F)cc1)COc1cccc(-c2noc3ccsc23)c1

Procedure:
Add a solution of 4-fluorobenzylamine (Aldrich Chemical Company) in ethanol (3 mL, 0.2774 M, 1.77 equivalents) to a reaction tube. Add ethanol (3 mL) to the reaction tube and then add a solution of (S)-3-[3-(2-methyloxiranylmethoxy)phenyl]thieno[2,3-d]isoxazole (example 7, 1.38 mL, 0.337 M) and dichloroethane. Shake the reaction mixture under argon at reflux temperature overnight in a Bohdan apparatus. Cool and concentrate to remove the solvent. Purify the residue by flash chromatography (silica gel) eluting in step gradient fashion sequentially with 1%, 3%, 6%, and 10% methanol in dichloromethane. Combine and concentrate the desired fractions to give the title compound (0.18 g), LC/MS (APCI, condition 6) m/e 413 (MH+), retention time 2.23 min. Preparation of a larger sample and conversion to the hydrochloride salt is described as example 102.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([NH:11]C(OC(C)(C)C)=O)[CH2:6]2.[ClH:19]>C(O)(C)C>[ClH:19].[NH2:11][N:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])[CH2:6]1
Reactant: CC(C)(C)OC(=O)NN1Cc2cccc(F)c2C1
Agent: Cl
Solvent: CC(C)O
Product: NN1Cc2cccc(F)c2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.8 g of 4-fluoro-N-tert.-butoxycarbonylamino-isoindoline are introduced into 30 ml of concentrated hydrochloric acid at room temperature. The mixture is subsequently stirred at room temperature for 1 hour and the solvent is then distuilled off in vacuo. The residue is treated with hot i-propanol; after cooling to 10° C., the precipitate is filtered off with suction. 2.1 g of 2-amino-4-fluoro-isoindoline hydrochloride are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:22])=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[Cl:29][CH2:30]Cl>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:23]([CH3:25])[CH3:24])[C:20]([O:22][CH2:30][Cl:29])=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H](C(=O)O)C(C)C
Solvent: CCO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H](C(=O)OCCl)C(C)C

Procedure:
2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyric acid was esterified by the method described in Example A-I-1, step d. The title compound (2.96 g) was obtained after silica gel column chromatography (0, 1, 2% ethanol in dichloromethane). Rf (2% MeOH/CHCl3) 0.85.
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])/[CH:2]=[CH:3]\[C:4]([O-:6])=[O:5].[Na+].[C:11]1([CH2:17][C:18]#[N:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CN(C)C=O>>[C:18]([CH:17]([CH:2]([CH2:3][C:4]([OH:6])=[O:5])[C:1]([O:8][CH3:9])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)#[N:19]
Reactant: COC(=O)/C=C\C(=O)[O-]
Reactant: N#CCc1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC(=O)O)C(C#N)c1ccccc1
Yield: 87.9 %

Procedure:
Into a 200 ml, one-neck flask is placed 35 grams of sodium methyl maleate (0.23 moles), 85 grams (0.73 moles) of phenyl acetonitrile and 80 g(1.1 moles) dimethyl formamide. The reaction mixture is heated to 135°-140° C. for 5 hours and then distilled in vacuo. The residue is extracted three times with 300 ml ether. The solid (56 grams) is then dissolved in water and acidified with 23 grams conc. HCl in 50 mls water. The liquid that separates out is dissolved in ether and washed with water to remove unreacted starting materials. The ether is distilled off to give a residue of 50 grams of product (yield: 88%). The structure is verified by NMR (in CDCl3):
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)=[C:11]([CH3:18])[O:10][N:9]=1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]([C:13]2[N:14]=[CH:15][N:16]([C:20]3[N:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:17]=2)=[C:11]([CH3:18])[O:10][N:9]=1
Reactant: Clc1ncccn1
Reactant: Cc1onc(-c2ccccc2F)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccccc2F)c1-c1cn(-c2ncccn2)cn1
Yield: 65 %

Procedure:
As described for Example 36, 3-(2-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (100 mg, 0.41 mmol) using 2-chloropyrimidine instead of 4-fluoroacetophenone was converted to the title compound (86 mg, 65%) which was obtained as an off-white solid. MS: m/e=322.4 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][N:16]([CH:19]([CH3:21])[CH3:20])[CH2:15][CH2:14]1>CO.[Pd]>[F:22][CH:2]([F:1])[O:3][C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[N:13]1[CH2:18][CH2:17][N:16]([CH:19]([CH3:20])[CH3:21])[CH2:15][CH2:14]1
Reactant: CC(C)N1CCN(c2ccc([N+](=O)[O-])cc2OC(F)F)CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)N1CCN(c2ccc(N)cc2OC(F)F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(2-Difluoromethoxy-4-nitro-phenyl)-4-isopropyl-piperazine (Step B, 0.5 g, 1.9 mmol, 1.0 eq.) was dissolved in MeOH (10 mL). The atmosphere was replaced by argon. A catalytic amount of 10% Pd/C was added and the argon was replaced by a H2 atmosphere. The mixture was stirred for 16 h at RT at balloon pressure. The Pd/C was removed by filtration and the solvent was removed under vacuum to yield 3-difluoromethoxy-4-(4-isopropyl-piperazin-1-yl)-phenylamine. The crude material was used as is in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:40])[C:5]([CH3:39])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:35]C(=O)C)=[C:17]([CH:34]=2)[C:18]([NH:20][C:21]2[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:40])[C:5]([CH3:39])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:35])=[C:17]([CH:34]=2)[C:18]([NH:20][C:21]2[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:23][CH:22]=2)=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(C(=O)OC(C)(C)C)cc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(C(=O)OC(C)(C)C)cc3)c2)=C(C)C1=O
Yield: 51.9 %

Procedure:
tert-Butyl N-[5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoyl]-4-aminobenzoate (0.240 g, 0.437 mmol) was dissolved in methanol (5 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=95:5) and then recrystallized from ether to obtain the titled compound (0.115 g, 0.227 mmol, 52%).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14]([NH:18]C(=O)OC(C)(C)C)=[CH:13][C:12]=2[CH3:26])=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:8]=[C:9]([CH:27]=[CH:28][C:29]=2[O:30][CH3:31])[CH2:10][C:11]2[C:12]([CH3:26])=[CH:13][C:14]([NH2:18])=[CH:15][C:16]=2[CH3:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(Cc2c(C)cc(NC(=O)OC(C)(C)C)cc2C)cc1Cc1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Cc2c(C)cc(N)cc2C)cc1Cc1ccc(F)cc1
Yield: 61.2 %

Procedure:
460 mg (1.02 mmol) of tert-butyl 4-[3-(4-fluorobenzyl)-4-methokybenzyl]-3,5-dimethylphenylcarbarnate (Example IX) are stirred in 10 ml of trifluoroacetic acid/dichloromethane (10% strength solution) at room temperature overnight. After neutralization with NaHCO3 solution, the organic phase is separated, dried over sodium sulphate and concentrated in a rotary evaporator. Chromatography (cyclohexane/ethyl acetate=6:1) affords 218 mg (55%) of 4-[3-(4-fluorobenzyl)-4-methoxybenzyl]-3,5-dimethylaniline.