Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.O.[NH2:14][NH2:15]>C1COCC1.O>[Cl:1][C:2]1[C:3]([C:10]([NH:14][NH2:15])=[O:12])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1
Reactant: NN
Reactant: CSc1ncc(Cl)c(C(=O)O)n1
Solvent: C1CCOC1
Solvent: O
Product: CSc1ncc(Cl)c(C(=O)NN)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
5-Chloro-2-(methylthio)pyrimidine-4-carboxylic acid (4.0 g, 19.6 mmol) and 1,1-carbonyl diimidazole (6.35 g, 39.2 mmol) were dissolved in 80 mL THF and stirred at room temperature. After 3 h, the solution was cooled in an ice bath and hydrazine hydrate (1.90 mL, 39.2 mmol) was added in one quick portion. The solution was allowed to stir for 5 h, gradually warming to room temperature. The reaction mixture was diluted with excess H2O and extracted with EtOAc several times. These organics were combined and washed with 2 N HCl. The combined aqueous layers were then basified carefully with 5 N NaOH, and extracted once again with EtOAc. This second set of organic layers was combined, dried over magnesium sulfate and concentrated under vacuum to give 2.46 g (58% yield) of product as a white solid. MS (M+H)+ 219.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O)([O-:3])=[O:2].CO.[NH2:16][NH:17][C:18]([NH2:20])=[S:19]>CC(O)=O>[N+:1]([CH2:4][CH2:5][C:6](=[N:16][NH:17][C:18]([NH2:20])=[S:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(CC[N+](=O)[O-])c1ccccc1
Reactant: NNC(N)=S
Solvent: CC(=O)O
Solvent: CO
Product: NC(=S)NN=C(CC[N+](=O)[O-])c1ccccc1
Yield: 60.4 %

Procedure:
Into a round bottom flask containing 3-nitropropiophenone (1.02 g, 5.53 mmol), 30 mL of anhydrous methanol were added and the solution was refluxed for about 15 minutes. To the warm ketone solution, thiosemicarbazide (0.485 g, 5.33 mmol) and 1% solution of HOAc (0.4 mL) were added. The reaction mixture was refluxed under nitrogen atmosphere for 30 h, at which point, the solvent was evaporated and, the crude reaction mixture was purified by flash chromatography (50% EtOAc/50% hex) to obtain 0.8119 g (3.22 mmol) of the product in a 58% yield.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:37])[CH2:32][CH2:33][C:34](O)=[O:35])=[CH:27][CH:26]=1>>[CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][N:21]([C:34](=[O:35])[CH2:33][CH2:32][C:31]([C:28]3[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=3)=[O:37])[CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Product: O=C(CCC(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1)c1ccc(F)cc1

Procedure:
N-Cyclopropyl-N-{1-[4-(4-fluorophenyl)-4-oxobutanoyl]-piperidin-4-yl}-3-trifluoromethylbenzenesulfonamide was prepared from N-cyclopropyl-N-(piperidin-4-yl)-3-trifluoromethylbenzenesulfonamide and 4-(4-fluorophenyl)-4-oxo-butanoic acid. LC: 100%. MS: m/z=527 (M+H+). 1H NMR (CDCl3): δ 8.14 (1H, s), 8.04 (3H, m), 7.87 (1H, d), 7.70 (1H, t), 7.12 (2H, t), 4.68 (1H, d), 4.09 (2H, m), 3.30 (2H, m), 3.09 (1H, t), 2.77 (2H, m), 2.53 (1H, t), 1.85 (5H, m), 0.92 (2H, m), 0.75 (2H, m);
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35]([NH2:38])(=[O:37])=[O:36].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[S:21][CH:22]=[C:23]([C:25](=[O:26])[NH:38][S:35]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[CH3:28])(=[O:36])=[O:37])[N:24]=4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)c1csc(-c2cc3cc(Cc4nc(C(=O)O)cs4)ccc3o2)n1
Reactant: Cc1ccccc1S(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1csc(Cc2ccc3oc(-c4nc(C(C)(C)C)cs4)cc3c2)n1
Temperature: 0 °C
Yield: 65 %

Procedure:
A solution of 4-tert-butyl-2-{5-[(4-carboxythiazol-2-yl)methyl]benzofuran-2-yl}thiazole (0.20 g), 2-methylbenzenesulfonamide (0.10 g), 4-dimethylaminopyridine (0.12 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.19 g) in N,N-dimethylformamide (6 ml) was stirred at ambient temperature for 2 days. The resulting mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in reduced pressure. The residue was subjected to column chromatography on silica gel and eluted with ethyl acetate. The fractions containing object compound were combined and concentrated under reduced pressure. The residue was crystallized from diethyl ether and filtered to give 4-tert-butyl-2-{5-{{4-[N-(2-methylphenylsulfonyl)carbamoyl]thiazol-2-yl}methyl}-benzofuran-2-yl}thiazole (0.18 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]#[N:13])[C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9]=2[CH:10]=1.C([Sn](CCCC)=O)CCC.C[Si]([N:28]=[N+:29]=[N-:30])(C)C.[OH-].[Na+]>C1(C)C=CC=CC=1.CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH3:11])=[C:4]([C:12]2[NH:30][N:29]=[N:28][N:13]=2)[CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cn1ncc2c(C#N)cc(Br)cc21
Agent: CCCC[Sn](=O)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cn1ncc2c(-c3nnn[nH]3)cc(Br)cc21
Temperature: 110 °C
Reaction time: 28 h
Yield: 99.4 %

Procedure:
6-Bromo-1-methyl-1H-indazole-4-carbonitrile (514 mg, 2.177 mmol) was dissolved in toluene (20 mL) and dibutyl(oxo)stannane (108 mg, 0.435 mmol) and trimethylsilyl azide (0.573 mL, 4.35 mmol) were added over 2 mins. The mixture was then stirred at 110° C. under nitrogen for 28 h. Further trimethylsilyl azide (0.03 mL, 0.228 mmol) was added and the mixture continued stirring at 110° C. under nitrogen for 44 h. The solvent was removed in vacuo to give a white solid. 2M sodium hydroxide in methanol was added and the mixture heated to 50° C. and then filtered whilst hot to remove insoluble impurities. The filtrate was cooled and then acidified via dropwise addition of 2M hydrochloric acid. The resultant precipitate was filtered and dried in a vacuum oven to give the title compound as a white solid (604 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([CH:14]([CH2:20][S:21](Cl)(=[O:23])=[O:22])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C(Cl)Cl>[O:4]1[CH2:5][CH2:6][N:1]([S:21]([CH2:20][CH:14]([CH2:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:23])=[O:22])[CH2:2][CH2:3]1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Reactant: C1COCCN1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)N1CCOCC1
Reaction time: 1 h
Yield: 92.8 %

Procedure:
6.6 g (75.8 mmol) of morpholine are added dropwise at -10° to a solution of 6.23 g (21.4 mmol) of ethyl 2-benzyl-3-chlorosulphonyl-propionate (EPA 0236734) in 150 ml of methylene chloride. The solution is stirred at -10° for 1 hour and at 0° for 1 hour and subsequently acidified with 1N hydrochloric acid. The organic phase is then extracted with 50 ml of water, dried over sodium sulphate and evaporated. For purification, the residue (7.64 g) is chromatographed on 300 g of silica gel using methylene chloride as the eluent. There are obtained 6.78 g of ethyl (RS)-α-[(morpholinosulphonyl)methyl]-hydrocinnamate as a colourless oil; MS: 341 (M)+. This is converted into (S)-α-[(morpholinosulphonyl)methyl]hydrocinnamic acid by enzymatic hydrolysis using α-chymotrypsin in an analogous manner to that described in Example 1(d).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[O:41])[CH:7]=[C:8]([CH2:11][NH:12][C:13]([CH:15]2[CH2:20][N:19]([S:21]([C:24]3[NH:25][C:26]4[C:31]([CH:32]=3)=[CH:30][C:29]([Cl:33])=[CH:28][CH:27]=4)(=[O:23])=[O:22])[CH2:18][CH2:17][N:16]2C(OC(C)(C)C)=O)=[O:14])[O:9][CH:10]=1)(=[O:3])[CH3:2].[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(Cl)Cl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[C:1]([O:4][C:5]1[C:6](=[O:41])[CH:7]=[C:8]([CH2:11][NH:12][C:13]([CH:15]2[NH:16][CH2:17][CH2:18][N:19]([S:21]([C:24]3[NH:25][C:26]4[C:31]([CH:32]=3)=[CH:30][C:29]([Cl:33])=[CH:28][CH:27]=4)(=[O:23])=[O:22])[CH2:20]2)=[O:14])[O:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1coc(CNC(=O)C2CN(S(=O)(=O)c3cc4cc(Cl)ccc4[nH]3)CCN2C(=O)OC(C)(C)C)cc1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Oc1coc(CNC(=O)C2CN(S(=O)(=O)c3cc4cc(Cl)ccc4[nH]3)CCN2)cc1=O

Procedure:
In methylene chloride (5 ml), 2-[N-[(5-acetoxy-4-oxo-4H-pyran-2-yl)methyl]carbamoyl]-1-(tert-butoxycarbonyl)-4-[(5-chloroindol-2-yl)sulfonyl]piperazine was treated with trifluoroacetic acid (5 ml), followed by concentration to dryness under reduced pressure, whereby the title compound (224 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]([NH:29]C(=O)C)[CH:11]=[C:12]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:13]=1.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[C:10]([NH:29][S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH:11]=[C:12]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=4)=[CH:22][C:17]=3[N:16]=[CH:15]2)[CH:13]=1
Reactant: CC(=O)Nc1cc(-c2ccncc2F)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)Nc1cc(-c2ccncc2F)cc(-n2cnc3cc(-c4cnn(C)c4)ccc32)c1
Yield: 15.13 %

Procedure:
The compound was prepared from the compound of Example 277 (0.9 g, 2.11 mmol, 1 eq.) using the procedure of Example 2 and ethanesulfonyl chloride (60 mg, 0.46 mmol, 1.2 eq.) to give the product in 15.13% yield (28 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.69-8.68 (d, 1H), 8.58 (s, 1H), 8.54-8.52 (d, 1H), 8.18 (s, 1H), 7.97 (s, 1H), 7.93 (s, 1H), 7.74-7.71 (t, 1H), 7.67-7.64 (d, 1H), 7.58-7.56 (d, 1H), 7.44-7.43 (t, 1H), 7.36-7.33 (d, 2H), 3.87 (s, 3H), 3.07-3.02 (quartet, 2H), 1.22-1.18 (t, 3H); LC-MS (ESI): Calculated mass: 476.14; Observed mass: 476.9 [M+H]+ (rt: 0.36 min).
Reaction SMILES: [CH:1]1([O:7][C:8](=[O:14])/[CH:9]=[CH:10]\[C:11]([OH:13])=[O:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20]>C(N(CC)CC)C>[CH2:4]1[CH2:3][CH2:2][CH:1]([O:7][C:8](=[O:14])[C@H:9]([CH2:10][C:11]([OH:13])=[O:12])[NH:20][CH2:19][CH2:18][CH2:17][N:16]([CH3:21])[CH3:15])[CH2:6][CH2:5]1
Reactant: O=C(O)/C=C\C(=O)OC1CCCCC1
Reactant: CN(C)CCCN
Solvent: CCN(CC)CC
Product: CN(C)CCCN[C@@H](CC(=O)O)C(=O)OC1CCCCC1
Yield: 73.2 %

Procedure:
In a manner analogous to that described in Example 1, 100 ml of triethylamine are added dropwise, with cooling, to 99.1 g (0.5 mol) of maleic acid-monocyclohexyl ester, and the mixture is reacted with 61.3 g (0.5 mol+20% excess) of 3-dimethylaminopropylamine for 1 hour at 80°-93° C. The reaction product is purified as described in Example 1 to yield 109.9 g (73.2% of theory) of the desired aspartic acid derivative having a melting point of 150°-152.5° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[C:19](C)[CH:20]=[CH:21][CH:22]=3)[C:3]=12.[F:25]C1C=CC=CC=1C=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:24])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[F:25])[C:3]=12
Reactant: Cc1cccc(-c2nn(C)c3nnc(-c4ccccc4)c(Cl)c23)c1
Reactant: O=Cc1ccccc1F
Product: Cn1nc(-c2ccccc2F)c2c(Cl)c(-c3ccccc3)nnc21

Procedure:
Compound 22 was synthesised following similar procedures outlined in Example 24 (Compound 19), using 2-fluorobenzaldehyde instead of 3-methylbenzaldehyde in Step 1.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH:15]1[CH:20]=[C:19]2[C:21]([C:23](O)([OH:26])[C:24](=[O:25])[C:18]2=[CH:17][CH:16]=1)=[O:22]>S(=O)(=O)(O)O>[OH:26][C:23]1([C:5]2[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=2[NH:9][C:10](=[O:14])[CH:11]([CH3:12])[CH3:13])[C:24](=[O:25])[C:18]2[C:19](=[CH:20][CH:15]=[CH:16][CH:17]=2)[C:21]1=[O:22]
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C
Reactant: O=C1c2ccccc2C(=O)C1(O)O
Agent: O=S(=O)(O)O
Product: Cc1cc(NC(=O)C(C)C)c(C2(O)C(=O)c3ccccc3C2=O)cc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 93.8 %

Procedure:
N-(3,4-dimethylphenyl)isobutyramide (1.00 mg, 5.61 mmol) and ninhydrin (1.07 mg, 5.61 mmol) were dissolved in conc. sulfuric acid (15 mL) and stirred at room temperature for 5 hrs. The reaction was stopped by slowing pouring the solution to 200 g of ice and stirring. The reaction mixture was extracted with ethylacetate and water, washed with brine. The washed organic layer was dried over sodium sulfate, concentrated in a vacuum, and purified through silica gel column chromatography (30% ethylacetate in hexane) to afford the title compound (yellow solid, 1.85 g, 94%).
Reaction SMILES: Cl.C[O:3][C:4](=[O:15])[C@H:5]([NH2:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N:16]1[S:20][N:19]=[C:18]2[C:21]([S:25]([NH:28][C:29]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:30]=3[C:31](O)=[O:32])(=[O:27])=[O:26])=[CH:22][CH:23]=[CH:24][C:17]=12>>[N:16]1[S:20][N:19]=[C:18]2[C:21]([S:25]([NH:28][C:29]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:30]=3[C:31]([NH:14][C@H:5]([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=3)[C:4]([OH:3])=[O:15])=[O:32])(=[O:27])=[O:26])=[CH:22][CH:23]=[CH:24][C:17]=12
Reactant: O=C(O)c1cc(Cl)ccc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@H](N)Cc1ccc(Cl)cc1
Agent: Cl
Product: O=C(N[C@H](Cc1ccc(Cl)cc1)C(=O)O)c1cc(Cl)ccc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
(R)-2-(tert-Butoxycarbonylamino)-3-(4-chloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (R)-2-amino-3-(4-chloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled with 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-5-chloro-benzoic acid as in EXAMPLE 1, Part C. The resulting methyl ester was hydrolyzed as in EXAMPLE 2, Part E, to afford the title compound. HPLC: RT=10.28 min. MS (ESI−): mass calcd. for C22H16Cl2N4O5S2, 549.99; m/z found, 549/551 [M−H]−. 1H NMR (500 MHz, CDCl3): 10.92 (s, 1H), 8.30 (d, J=7.0, 1H), 8.19 (d, J=8.8, 1H), 7.70-7.66 (m, 1H), 7.64 (d, J=9.0, 1H), 7.31-7.26 (m, 3H), 7.14 (d, J=2.3, 1H), 7.08 (d, J=8.3, 2H), 6.38 (d, J=7.3, 1H), 5.00-4.96 (m, 1H), 3.29 (dd, J=14.3, 5.7, 1H), 3.20 (dd, J=14.2, 5.8, 1H).
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=3)[N:10]=[CH:9]2)C=CC=CC=1>C(O)(=O)C>[NH:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: N#Cc1ccnc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1
Solvent: CC(=O)O
Product: N#Cc1ccnc(-c2c[nH]cn2)c1
Yield: 63.7 %

Procedure:
A solution of 2-[1-(triphenylmethyl)-1H-imidazol-4-yl]pyridine-4-carbonitrile (510 mg, 1.2 mmol) in acetic acid (10 ml) was heated at 90° C. for 18 hr. Reaction mixture was purified by ISCO flash column chromatography (EtOAc/Hexane=0-100%) to get 130 mg of product. Some starting material was recovered and heated in acetic acid again overnight at 90° C. Additional product was obtained to give total 160 mg product as light yellow solid (78%). 1H NMR (400 MHz, DMSO-d6): δ 7.62 (1H, dd, J=1.2 Hz and 4.9 Hz), 7.81 (2H, s), 8.13 (1H, s), 8.73 (1H, d, J=4.8 Hz). [M+H] Calc'd for C9H6N4, 171. Found, 171.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)(O)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:31][C:32]1[CH:51]=[CH:50][C:35]([N:36]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)=[CH:34][CH:33]=1.FC(F)(F)S(O)(=O)=O>ClCCl>[C:1]1([C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]3[C:17]4[C:22]([C:23]([C:47]5[CH:48]=[CH:49][C:44]([N:36]([C:35]6[CH:34]=[CH:33][C:32]([CH3:31])=[CH:51][CH:50]=6)[C:37]6[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=6)=[CH:45][CH:46]=5)([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:8]=23)=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(N(c2ccccc2)c2ccc(C)cc2)cc1
Reactant: OC1(c2ccccc2)c2ccccc2-c2nc3ccccc3c(-c3ccccc3)c21
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(C3(c4ccccc4)c4ccccc4-c4nc5ccccc5c(-c5ccccc5)c43)cc2)cc1
Yield: 89.7 %

Procedure:
In an embodiment, the starting material 10,11-diphenyl-11H-indeno[1,2-b]quinolin-11-ol (385 mg, 1.00 mmol) and 4-methyl-N-phenyl-N-(p-tolyl)aniline (328 mg, 1.20 mmol) are placed in a round bottom flask and then dissolved in 10 ml of dichloromethane. Subsequently, trifluoromethanesulfonic acid (0.13 ml, 1.50 mmol) is slowly dripped into the flask to promote reaction. After 12 hours of reaction at 140° C., the crude product is extracted with 50 ml of Ethyl acetate and sodium bicarbonate for three times. Finally, an organic layer of the crude product is dehydrated with magnesium sulfate and concentrated to be sublimated and purified to obtain 575 mg of 4-(10,11-diphenyl-11H-indeno[1,2-b]quinolin-11-yl)-N,N-di-p-tolylaniline. The percentage yield is 89.7%.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]([CH3:12])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[SH:13][CH2:14][C:15]([OH:17])=[O:16].[OH-].[Na+]>C(O)C>[CH3:12][C:11]1[C:3]([CH2:2][S:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: Cc1cc2c(cc1CCl)OCO2
Reactant: O=C(O)CS
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc2c(cc1CSCC(=O)O)OCO2
Yield: 20.5 %

Procedure:
A suspension of 6.0 g of 5-chloromethyl-6-methyl-1,3-benzodioxole, 6.0 g of mercaptoacetic acid and 6.5 g of sodium hydroxide in 130 ml of 50% aqueous ethanol was heated under reflux for one hour and concentrated, followed by the addition of water. The mixture was washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid and extracted with chloroform. The organic layer was dried over magnesium sulfate and distilled to remove the solvent. The residue was chromatographed over a silica gel column and eluted with chloroform to obtain a crude crystal. This crude crystal was recrystallized from diisopropyl ether to obtain 1.6 g of the title compound as a colorless crystal.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][C:14]=2[CH3:22])=[C:11]([CH3:23])[O:10][N:9]=1.O[N:25]=[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][C:35]([F:38])([F:37])[F:36])[NH2:27].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[C:12]([C:13]2[CH:21]=[CH:20][C:16]([C:17]3[O:19][N:27]=[C:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][C:35]([F:36])([F:37])[F:38])[N:25]=3)=[CH:15][C:14]=2[CH3:22])=[C:11]([CH3:23])[O:10][N:9]=1
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Reactant: Cc1cc(C(=O)O)ccc1-c1c(C)noc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nc(-c3ccccc3OC(F)(F)F)no2)ccc1-c1c(C)noc1C

Procedure:
Oxalyl chloride (132 μL; 1.56 mmol; 3 eq.), Intermediate 30 (120 mg; 0.52 mmol; 1 eq.), Intermediate 2 (114 mg; 0.52 mmol, 1 eq.) and DIEA (268 μL; 1.56 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 80/20) afforded the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH2:24])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:32][C:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][C:39]([C:33]2([CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: COc1ccccc1N1CCN(C[C@H](N)Cc2ccncc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C[C@@H](Cc2ccncc2)NC(=O)C2(C)CCCCC2)CC1
Temperature: 25 °C
Yield: 69.2 %

Procedure:
To a solution of (1R)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1-pyridin-4-ylmethyl-ethylamine (726 mg.; 2.23 mmol, from Example 8) in dichloromethane (30 mL) at 0° C. was added triethylamine (0.62 mL; 4.45 mmol) and 1-methyl-1-cyclohexanecarbonyl chloride (356 mg.; 2.23 mmol). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour, washed sequentially with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (2% methanol/chloroform) to yield the free base of the title compound as a clear oil (695 mg.; 69%). Treatment with an equimolar amount of fumaric acid in ethanol afforded the fumarate salt as a white amorphous solid, m.p. 145° C.; MS EI M+ @ m/z 450; 1H NMR, 400 MHz, DMSO-d6. Analysis for C27H38N4O2C4H4O4.0.5H2O Calculated: C, 64.68; H, 7.53; N, 9.73 Found: C, 64.97; H, 7.53; N, 9.66
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)=[O:8]>O>[N:1]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1)=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)CCc1ccc(C(=O)CCl)cc1
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=NCC(=O)c1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of sodium azide (2.0g.) in water (20ml.) was added to a stirred suspension of 3-[4-(chloroacetyl)phenyl]-propionic acid (5g.) in water (30ml.). After stirring for 16 hours at room temperature, the residual solid was separated, washed with cold water (2 × 10ml.) and dried in vacuo to give 3-[4-(azidoacetyl)phenyl]propionic acid as a white solid, which possessed a characteristic azide absorption in the infra-red spectrum at 2120 cm-1.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[NH:7][C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1.Br[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[C:6]=2[CH:5]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: Cc1nc2c(Br)cc(N3CCOCC3)cc2[nH]1
Reactant: BrCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(Br)cc(N3CCOCC3)cc2n1Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a mixture of 4-(4-bromo-2-methyl-1H-benzo[d]imidazol-6-yl)morpholine (0.5 g, 1.688 mmol), prepared as described in example 1, in N,N-Dimethylformamide (DMF) (10 mL) was added 1-(bromomethyl)naphthalene (0.448 g, 2.026 mmol) and potassium carbonate (0.700 g, 5.06 mmol). The resulting reaction mixture was stirred at 80° C. for 4 h. It was cooled to room temperature and poured into water (100 mL). The aqueous mixture was extracted with DCM (100 mL×2). The combined organic phases were washed with Brine (100 mL) and concentrated. The crude material was purified on silica column (20˜90% EtOAc in Hexane) to give the product as solid (0.53 g, 72%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.57 (s, 3H) 2.97-3.13 (m, 4H) 3.61-3.89 (m, 4H) 5.76 (s, 2H) 6.53 (dd, J=7.07, 1.01 Hz, 1H) 6.56 (d, J=2.02 Hz, 1H) 7.17 (d, J=2.02 Hz, 1H) 7.32 (m, 1H) 7.58-7.73 (m, 2H) 7.83 (m, 1H) 7.98 (m, 1H) 8.08 (d, J=8.06 Hz, 1H); MS (ES+) m/e 436.1 [M+H]+.