Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:25][CH2:24][N:23]([CH:26]=S)[CH2:22][CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].S(C1C=CC(C)=CC=1)(OC)(=O)=O.[NH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Cl>C(Cl)(Cl)Cl>[CH2:1]([N:3]([CH2:28][CH3:29])[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:20]3[CH2:25][CH2:24][N:23]([CH:26]=[N:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[CH2:22][CH2:21]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CCN(C=S)CC1
Reactant: Nc1ccccc1
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CCN(C=Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A sample of compound 11b (0.1 g, 0.25 mmol) in 1 mL of chloroform was placed in a pressure tube and treated with methyl tosylate (0.037 mL, 0.25 mmol). The reaction was heated for 1 h on a steam bath. At that time the reaction was cooled to room temperature and aniline (0.023 mL, 0.25 mmol) was added, and the reaction was heated again on a steam bath for another 2 h. After 2 h, the reaction was cooled, washed with 1 N NaOH, and evaporated. Flash chromatography on silica gel was used to purify the crude material, eluting the product with 5% methanol/CH2Cl2, followed by conversion to its hydrochloride salt with ethereal hydrogen chloride (0.004 g, 0.009 mmol). MS m/z (MH+) 466.3. 1H NMR 300 MHz (CDCl3) δ 1.2 (br s, 6H), 3.1 (m, 4H), 3.3 (d, 2H) 3.4-3.8 (m, 4H), 4.3 (s, 2H),) 7.1-7.4 (m, 10H), 7.7 (s, 2H), 8.0 (s, 1H), 13.6 (s, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:5])C.[CH2:30]([NH2:32])[CH3:31]>CO>[CH2:30]([NH:32][C:4]([C:6]1[S:10][C:9]([N:11]2[C:15]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:14]=3[N:13]=[CH:12]2)=[N:8][C:7]=1[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:5])[CH3:31]
Reactant: CCOC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1
Reactant: CCN
Solvent: CO
Product: CCNC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1-c1ccccc1

Procedure:
2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid ethylamide was prepared from 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carboxylic acid ethyl ester (30 mg, 0.07 mmol) and ethylamine in methanol (2 molar) as described above in the general amide formation procedure. Product was isolated by preparative HPLC: 16 mg, 56%. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.81 (s, 1H); 8.53 (t, 1H); 7.88-7.69 (m, 3H); 7.55-7.44 (m, 3H); 7.40 (s, 1H); 3.88 (s, 3H); 3.85 (s, 3H); 3.25 (q, 2H); 1.08 (t, 3H). MS M/z 409 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[NH:9][CH2:10][C:11]3([CH2:13][CH2:12]3)[C:5]2=[N:4][N:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:9]2[CH2:10][C:11]3([CH2:12][CH2:13]3)[C:5]3=[N:4][N:3]=[C:2]([CH3:1])[N:6]3[C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]2=3)=[CH:21][CH:20]=1
Reactant: Clc1ccc(I)cc1
Reactant: Cc1nnc2n1-c1ccccc1NCC21CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nnc2n1-c1ccccc1N(c1ccc(Cl)cc1)CC21CC1
Yield: 4.8 %

Procedure:
A solution of 1-methyl-5,6-dihydrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine-4,1′-cyclopropane] (111 mg, 0.49 mmol), 1-chloro-4-iodobenzene (468 mg, 2.0 mmol), tris(dibenzylideneacetone)dipalladium(0) (35 mg, 0.049 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (40 mg, 0.098 mmol) and cesium carbonate anhydrous (320 mg, 0.98 mmol) in toluene (10 mL) was heated to 110° C., and maintained at the same temperature for 12 hours. The reaction mixture was concentrated, added with water (20 mL), extracted with ethyl acetate (20 mL). The organic phase was separated, and concentrated to give a crude product, which was purified by preparative-TLC (silica-gel, dichloromethane/methanol=30:1) to afford 6-(4-chlorophenyl)-1-methyl-5,6-dihydrospiro[benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine-4,1′-cyclopropane] (8 mg, 4.8%).
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[Cl:7][C:8]1[CH:9]=[C:10]([C:16]2([C:40]([F:43])([F:42])[F:41])[O:20][N:19]=[C:18]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[C:26]3([CH2:32][N:31]([C:33]([CH:35]5[CH2:38]S(=O)[CH2:36]5)=[O:34])[CH2:30]3)[O:25][CH2:24]4)[CH2:17]2)[CH:11]=[C:12]([Cl:15])[C:13]=1[F:14]>O.CO>[Cl:15][C:12]1[CH:11]=[C:10]([C:16]2([C:40]([F:41])([F:43])[F:42])[O:20][N:19]=[C:18]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[C:26]3([CH2:32][N:31]([C:33]([CH:35]5[CH2:38][S:3](=[O:5])(=[O:2])[CH2:36]5)=[O:34])[CH2:30]3)[O:25][CH2:24]4)[CH2:17]2)[CH:9]=[C:8]([Cl:7])[C:13]=1[F:14]
Reactant: O=S([O-])OO
Reactant: O=C(C1CS(=O)C1)N1CC2(C1)OCc1cc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(C1CS(=O)(=O)C1)N1CC2(C1)OCc1cc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 0 °C
Yield: 15.9 %

Procedure:
To a 20 mL vial containing a solution of oxone (320 mg, 0.52 mmol) in water (2 mL) at 0° C. was added (5′-(5-(3,5-dichloro-4-fluorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-3′H-spiro[azetidine-3,1′-isobenzofuran]-1-yl)(1-oxidothietan-3-yl)methanone from Example 4 (100 mg, 0.17 mmol) as a solution in methanol (4 mL). The reaction was stirred at 0° C. and allowed to warm to room temperature while stirring over 2 hours. Next, the reaction mixture was concentrated to remove excess MeOH and diluted with water. The crude product was extracted with CH2Cl2 (75 mL) and the organic phase was dried (Na2SO4) and concentrated under vacuum. The residue was purified by preparative HPLC to afford the final product (16 mg, 16%) as a solid. 1HNMR (CDCl3) δ ppm: 7.69 (1H), 7.63-7.60 (3H), 7.49 (1H), 5.19 (2H), 4.61-4.45 (4H), 4.36 (2H), 4.24-4.09 (3H), 3.72 (1H), 3.30 (1H); m/z (CI) 593 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:42]#[N:43])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:39][CH3:40])[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[N:30](C(OC(C)(C)C)=O)[NH:29][C:28](=[O:38])[CH:27]=4)=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:41])[CH:9]=2)[CH:7]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:42]#[N:43])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:39][CH3:40])[C:17]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[NH:30][NH:29][C:28](=[O:38])[CH:27]=4)=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:41])[CH:9]=2)[CH:7]=1
Reactant: CCC(C(=O)Nc1ccc(-c2cc(=O)[nH]n2C(=O)OC(C)(C)C)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O
Solvent: O=C(O)C(F)(F)F
Product: CCC(C(=O)Nc1ccc(-c2cc(=O)[nH][nH]2)cc1)n1cc(OC)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
17 mg (purity 70%, 0.02 mmol) of tert-butyl 5-[4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]butanoyl}amino)phenyl]-3-oxo-2,3-dihydro-1H-pyrazole-1-carboxylate (racemate) were hydrolysed with TFA according to General Method 2. Yield: 8 mg (78% of theory)
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH2:16])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].[CH:17]([C:20]1[CH:21]=[CH:22][C:23]([S:26](Cl)(=[O:28])=[O:27])=[N:24][CH:25]=1)([CH3:19])[CH3:18].Cl>N1C=CC=CC=1>[N+:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]=[C:13]([NH:16][S:26]([C:23]3[CH:22]=[CH:21][C:20]([CH:17]([CH3:19])[CH3:18])=[CH:25][N:24]=3)(=[O:27])=[O:28])[S:14][CH:15]=2)[CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)nc1
Reactant: Nc1nc(-c2cccc([N+](=O)[O-])c2)cs1
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1ccc(S(=O)(=O)Nc2nc(-c3cccc([N+](=O)[O-])c3)cs2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.5 %

Procedure:
A mixture of 0.5 g of 4-(3-nitro-phenyl)-thiazol-2-ylamine hydrochloride with 0.46 g of 5-isopropyl-pyridine-2-sulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 25 ml of 1N hydrochloric acid and the solid which thereby separated was filtered off and dissolved in a mixture of 30 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 40 ml of ethanol and 20 ml of ethyl acetate yielded 0.31 g of 5-isopropyl-pyridine-2-sulfonic acid [4-(3-nitro-phenyl)-thiazol-2-yl]-amide as yellowish crystals.
Reaction SMILES: CN([CH:4]=[O:5])C.O=P(Cl)(Cl)Cl.[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH2:16][C:17](=[O:23])[C:18]1[CH:22]=[CH:21][NH:20][CH:19]=1)[CH3:12]>ClCCCl>[CH2:11]([O:13][C:14](=[O:24])[CH2:15][CH2:16][C:17](=[O:23])[C:18]1[CH:22]=[C:21]([CH:4]=[O:5])[NH:20][CH:19]=1)[CH3:12]
Reactant: CCOC(=O)CCC(=O)c1cc[nH]c1
Reactant: CN(C)C=O
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CCC(=O)c1c[nH]c(C=O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of DMF (1.2 mL) in 1,2-dichloroethane (25 mL) at 0° C. was treated with POCl3 (1.5 mL). The resulting solution was warmed to ambient temperature and then treated with a solution of γ-oxo-1-H-pyrrole-3-butanoic acid ethyl ester (2.06 g) in 1,2-dichloroethane (10 mL). The reaction mixture was heated to 55° C. After 3.5 hours, the reaction was quenched with the addition of 1N NaOH (16 mL), and then stirred overnight at ambient temperature. The reaction mixture was extracted with ethyl acetate (150 mL), and the organic layer was dried (MgSO4) and concentrated. The resulting oil was chromatographed on SiO2 (100 g) using 4:1 hexane/ethyl actetate to afford 5-formyl-γ-oxo-1-H-pyrrole-3-butanoic acid ethyl ester (0.54 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:17][NH:18][CH3:19]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([N:18]([CH3:19])[CH3:17])=[O:10])[CH2:6]1
Reactant: CNC
Reactant: Cc1cccc(Cl)c1OC1CN(C(=O)Cl)C1
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc(Cl)c1OC1CN(C(=O)N(C)C)C1
Reaction time: 72 h

Procedure:
A stirred solution of 3.9 g (0.015 mole) of 3-(2-chloro-6-methylphenoxy)-1-azetidinecarbonyl chloride in 20 mL of tetrahydrofuran was treated all at once with 5.1 mL (0.045 mole) of 40% aqueous dimethylamine. After stirring for 72 h the raction mixture was diluted with 200 mL of water and the oil which separated was extracted into methylene chloride (3×30 mL). The combined extracts were dried by filtering through Whatman PS paper and concentrated in vacuo (3.6 g). The crude oil solidified when cooled in a dry ice/acetone bath and was recrystallized from ethyl ether in a dry ice-acetone bath yielding, after filtering cold, 2.6 g (64.5%) of coarse white crystals, mp 46°-47° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][C:3]1=[O:8].[C:9]([O:13][C:14]([N:16]1[CH2:19][C:18](=O)[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:9]([O:13][C:14]([N:16]1[CH2:19][CH:18]([N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:8])[CH2:4]2)[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CN1CCNCC1=O
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCN(C2CN(C(=O)OC(C)(C)C)C2)CC1=O
Yield: 69.9 %

Procedure:
A mixture of 1-methylpiperazin-2-one (128 mg, 1.12 mmol), 3-oxoazetidine-1-carboxylic acid tert-butyl ester (231 mg, 1.35 mmol) and 4 Å powdered molecular sieves (150 mg) in DCE (4 mL) was stirred at room temperature for 1.5 h before the addition of sodium triacetoxyborohydride (475 mg, 2.24 mmol). The reaction mixture was filtered through celite, washing with DCM. The filtrate was concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-10%) affording 3-(4-Methyl-3-oxopiperazin-1-yl)azetidine-1-carboxylic acid tert-butyl ester as an oil (211 mg, 70%). 1H NMR (CDCl3, 300 MHz): δ 3.99-3.92 (m, 2 H); 3.81 (dd, J=8.8, 5.1 Hz, 2 H); 3.36 (t, J=5.5 Hz, 2 H); 3.20-3.14 (m, 1 H); 3.08 (t, J=5.5 Hz, 2 H); 2.97 (s, 3 H); 2.70-2.56 (m, 2 H); 1.44 (s, 9 H).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[C:13]([C:19]([CH3:22])([CH3:21])[OH:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[NH3:23]>>[NH2:23][C:2]1[C:11]2[N:12]=[C:13]([C:19]([CH3:22])([CH3:21])[OH:20])[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: N
Reactant: CC(C)Cn1c(C(C)(C)O)nc2c(Cl)nc3ccccc3c21
Product: CC(C)Cn1c(C(C)(C)O)nc2c(N)nc3ccccc3c21

Procedure:
4-Chloro-α,α-dimethyl-1-(2-methylpropyl)-1H-imidazo-[4,5-c]quinoline-2-methanol (Example 22) was aminated in a Parr bomb at 150° C. using 15% methanolic ammonia. The product was purified by silica gel column chromatography (5% methanol in ethyl acetate as eluent). The product was then recrystallized from ethyl acetate/hexane to give a solid, m.p. 214-217° C. Analysis: Calculated: C, 68.4; H, 7.4; N, 18.8. Found: C, 68.2; H, 7.4; N, 18.7.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.Cl.[NH2:19][C:20]([C:23]1[N:27]=[C:26]([NH2:28])[O:25][N:24]=1)([CH3:22])[CH3:21]>>[NH2:28][C:26]1[O:25][N:24]=[C:23]([C:20]([NH:19][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])([CH3:22])[CH3:21])[N:27]=1
Reactant: CC(C)(N)c1noc(N)n1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Agent: Cl
Product: CC(C)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1noc(N)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and 3-(1-amino-1-methyl-ethyl)-[1,2,4]oxadiazol-5-ylamine hydrochloride (1:1) (Example 296b) as starting materials, LC-MS (UV peak area/ESI) 98%, 358.1879 (M+H)+.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CC=CC=1.C([O:23][C:24](=[O:42])[C@H:25]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34]CC2C=CC=CC=2)=[CH:30][CH:29]=1)[NH2:26])C1C=CC=CC=1>CO.O1CCCC1.[Pd]>[CH:1]1([C:7]([NH:26][C@H:25]([C:24]([OH:42])=[O:23])[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(N[C@@H](Cc1ccc(O)cc1)C(=O)O)C1CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.8 %

Procedure:
Cyclohexanoyl chloride (7 mL, 47 mmole) was added dropwise to a stirred solution of dry pyridine (400 mL) and O-benzyltyrosine benzyl ester (25 g, 46.8 mmole). The reaction temperature was maintained at 0° C. throughout the addition. The reaction mixture was stirred for an additional 2 hours after the addition was complete. The reaction mixture was concentrated to dryness in vacuo to provide a solid material. The solid was washed with aqueous hydrochloric acid (1N, 4×400 mL). The residue was dissolved in ethyl acetate (300 mL), washed with aqueous hydrochloric acid (1N, 2×500 mL), aqueous sodium bicarbonate (2×300 mL), and dried over magnesium sulfate. Filtration, followed by concentration in vacuo, provided an oil which was dissolved in methanol/tetrahydrofuran (400 mL/70 mL) and was hydrogenated at atmospheric pressure and room temperature over 10% palladium on carbon (600 mg). The reaction mixture was filtered through Celite and concentrated in vacuo to provide a solid which was recrystallized from ethyl acetate/hexane. The crystals were collected to-provide the N-cyclohexanoyl-(L)-tyrosine (8.7 g, 64%) as a white solid.
Reaction SMILES: C1([C@H]2[C@H](C3C4C(=CC=CC=4)NC=3)C(=O)NC2=O)C2=C3C(=CC=C2)CCCN3C=1.[NH:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=[CH:30]1.[Br:38][C:39]1[C:40](=[O:52])[N:41]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:42](=[O:45])[C:43]=1Br.C[Mg]Br>>[Br:38][C:39]1[C:40](=[O:52])[N:41]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:42](=[O:45])[C:43]=1[C:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[NH:29][CH:30]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1C(Br)=C(Br)C(=O)N1c1ccccc1
Agent: C[Mg]Br
Agent: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1c[nH]c2ccccc12
Product: O=C1C(Br)=C(c2c[nH]c3ccccc23)C(=O)N1c1ccccc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione may be prepared by reacting 1H-indole and 3,4-dibromo-1-phenyl-pyrrole-2,5-dione in the presence of methyl magnesium bromide to yield 3-bromo-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione. The 3-bromo-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione is subsequently reacted with 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline and LiHMDS (lithium hexamethyldisilane) in toluene or (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-boranediol and Pd(PPh3)4 (tetrakis(triphenylphosphine)palladium) to yield 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione, which is reduced and deprotected by treatment with Mg in methanol, as in Example 2 procedure C, followed by catalytic hydrogenation over palladium on carbon to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione. Bnz is benzyl.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C[N:13](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[OH-]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([NH2:13])=[O:8]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Br)cc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 5-bromo-2-methylbenzoic acid (0.538 g, 2.50 mmol) and HATU (1.289 g, 3.390 mmol) in DMF (8 mL) was added DIPEA (0.800 mL, 4.59 mmol). The mixture was stirred for 10 minutes before addition of NH4OH (0.50 mL) and then left stirring for 16 hours at room temperature. The mixture was poured in to water and cooled at 0° C. for 20 minutes before collecting the resulting precipitate via vacuum filtration to give the title compound (I69) (0.292 g, 55%); 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=2.1 Hz, 1H), 7.45 (dd, J=8.2, 2.1 Hz, 1H), 7.12 (d, J=8.2 Hz, 1H), 5.68 (bs, 2H), 2.44 (s, 3H). LCMS Method C: rt 4.89 min; m/z 214, 216 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][C:6]=1[CH3:7].[Cl:13]N1C(=O)CCC1=O.[OH-].[Na+]>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:13])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)c1cc(Br)c(C)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1[nH]c(C)c(Br)c1Cl
Temperature: 25 °C

Procedure:
Ethyl 4-bromo-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 187, 2.87 g, 12.4 mmol) was dissolved in dry DMF (30 ml), N-chlorosuccinimide (1.66 g, 12.4 mmol) was added and resulting mixture was stirred at room temperature over night, more N-chlorosuccinimide (0.83 g, 6.2 mmol) was added and the reaction temperature was increased to 35° C., stirred for 4 hours. The mixture was poured into cold sodium hydroxide aqueous solution (2M) (50 ml), extracted with diethyl ether (2×50 ml). The organic phase was then washed with water (20 ml) and brine (20 ml), dried over anhydrous sodium sulfate and purified by column chromatography(hexanes/ethyl acetate, gradient) to give the desired product as a white crystal. (1.2 g).
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1(O)[NH:7][N:6]=[C:5]([CH3:8])[CH2:4]1.[Br:11]Br>C(Cl)Cl>[Br:11][C:4]1[C:3]([CH:2]([F:10])[F:1])=[N:7][NH:6][C:5]=1[CH3:8]
Reactant: BrBr
Reactant: CC1=NNC(O)(C(F)F)C1
Solvent: ClCCl
Product: Cc1[nH]nc(C(F)F)c1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(difluoromethyl)-3-methyl-4,5-dihydro-1H-pyrazol-5-ol (1.00 g, 6.66 mmol) in methylene chloride (20 mL) was added bromine (0.43 mL, 8.3 mmol) dropwise. The reaction was stirred at 25° C. for 3 h. and then quenched with a Na2S2O4 solution and neutralized with NaHCO3. The reaction was extracted with dichloromethane and the organic extracts were washed with water, brine, dried (MgSO4), and concentrated in vacuo. 1H NMR (CDCl3): δ 6.56-6.82 (t, 1H), 2.33 (s, 3H). Mass spec(EI) m/z=211&213 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C[N:23]([CH3:26])C=O>CC1C=CC(CN)=CC=1.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][NH:23][CH2:26][C:2]4[CH:21]=[CH:20][C:5]([CH3:6])=[CH:4][CH:3]=4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Agent: Cc1ccc(CN)cc1
Solvent: CCO
Product: Cc1ccc(CNC[C@@H](O)COc2ccc(-c3noc4cc(F)ccc34)cc2)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-methylbenzylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=407.
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:11])[C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:29]=[C:30]([NH:34][C:35](=[O:39])[CH:36]([CH3:38])[CH3:37])[CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1>>[C:35]([NH:34][C:30]1[CH:29]=[C:28]([CH:25]2[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH2:19][NH:18][C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH3:11])[CH2:23][CH2:24]2)[CH:33]=[CH:32][CH:31]=1)(=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: CC(C(=O)O)(c1ccccc1)c1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 30 was prepared from 2,2-diphenylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide according to the procedures described in Scheme 9: 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.42 (s, 1H), 7.39–7.18 (m, 12H), 6.89 (d, 1H, J=7.7 Hz), 6.23 (m, 1H), 3.35 (q, 2H, J=6.4), 2.85 (d, 2H, J=10.8 Hz), 2.5 (quintet, 1H, J=7.4 Hz), 2.45–2.36 (m, 1H), 2.28 (t, 2H, J=6.4 Hz), 1.99 (s, 3H), 1.91–1.82 (m, 2H), 1.75–1.68 (m, 2H), 1.65 (t, 2H, J=6.4 Hz), 1.60–1.47 (m, 2H), 1.23 (d, 6H, J=7.0 Hz); ESMS m/e: 512.4 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13].[OH-].[Na+]>O>[C:3]1([CH3:8])[CH:4]=[CH:5][C:6]([O:7][CH2:10][CH2:11][CH2:12][Cl:13])=[CH:1][CH:2]=1
Reactant: Cc1ccc(O)cc1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(OCCCCl)cc1
Temperature: 0 °C
Yield: 76.7 %

Procedure:
3.0 g of p-cresol and 4.0 g of 3-bromo-1-chloro propane were placed into 20 ml of water and were subjected to reflux for 1 hour under heating, and whereto 20 ml of the aqueous solution of sodium hydroxide containing 1.2 g of sodium hydroxide were fed dropwise. After subjecting the resultant solution prepared as described hereinabove to reflux for another 2 hours, the solution reacted was poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer resulted was washed with dilute aqueous alkaline solution and saturated saline solution in series, and the organic layer resulted was then dried with anhydrous magnesium sulfate, and the solvent used was removed by distillation under reduce pressure, thereby affording 3.6 g of 3-(4-tolyloxy)-1-chloro propane.