Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([CH:10]([F:12])[F:11])[N:7]=[C:6]([NH:13][CH:14]([CH2:16][CH3:17])[CH3:15])[CH:5]=1.[OH-].[Li+].Cl>CO.C1COCC1>[C@@H:14]([NH:13][C:6]1[CH:5]=[C:4]([CH:9]=[C:8]([CH:10]([F:12])[F:11])[N:7]=1)[C:3]([OH:18])=[O:2])([CH2:16][CH3:17])[CH3:15]
Reactant: CCC(C)Nc1cc(C(=O)OC)cc(C(F)F)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC[C@H](C)Nc1cc(C(=O)O)cc(C(F)F)n1

Procedure:
Dissolve 2-sec-butylamino-6-difluoromethyl-isonicotinic acid methyl ester (140 mg, 0.54 mmol) in methanol (2 mL) and THF (10 mL). Slowly add 1 N aqueous lithium hydroxide (0.7 mL) and stir overnight at room temperature. Acidify the mixture to about pH=6 by 5 N HCl and concentrate to near dryness. Dilute with ethyl acetate (20 mL) and wash the organic layer with saturated aqueous sodium chloride. Dry (magnesium sulfate) and concentrate to give the title compound as a solid.
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[C@@H:14]1[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:17]([NH:23][C:24](=[O:36])[C@H:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[NH2:26])[C@H:15]1[OH:16].[C:37]([O:41][C:42]([NH:44][C@@H:45]([C:53](O)=[O:54])[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:43])([CH3:40])([CH3:39])[CH3:38]>>[NH2:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[C@@H:14]1[O:19][C@H:18]([C:20]([OH:22])=[O:21])[C@@H:17]([NH:23][C:24](=[O:36])[C@H:25]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)[NH:26][C:53](=[O:54])[C@@H:45]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[NH:44][C:42]([O:41][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:43])[C@H:15]1[OH:16]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: COc1ccc(C[C@H](N)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Agent: Cl
Solvent: O
Product: COc1ccc(C[C@H](NC(=O)[C@@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N[C@H]2[C@@H](O)[C@H](n3cnc4c(N)ncnc43)O[C@@H]2C(=O)O)cc1
Yield: 89.6 %

Procedure:
1-(6-Amino-9H-purin-9-yl)-3-[N-(N-tert-butoxycarbonyl-β-phenyl-D-alanyl)-O-methyl-L-tyrosylamino]-1,3-dideoxy-β-D-ribofuranuronic acid (488 mg) was prepared by reacting 1-(6-amino-9H-purin-9-yl)-1,3-dideoxy-3-(O-methyl-L-tyrosylamino)-β-D-ribofuranuronic acid dihydrochloride monohydrate (424 mg) prepared in Example 4 with N-hydroxysuccinimide ester of N-tert-butoxycarbonyl-β-phenyl-D-alanine (290 mg) according to a similar manner to that of Example 5, mp. 164°-168° C. (dec.).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:8])=[C:5]([Br:7])[N:6]=1.[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]1[CH2:22][CH:23]([CH3:25])[CH3:24])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:7][C:5]1[N:6]=[C:2]([N:19]2[CH2:20][CH2:21][N:16]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C@@H:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:18]2)[S:3][C:4]=1[CH3:8]
Reactant: CC(C)C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: Cc1sc(Br)nc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1sc(N2CCN(C(=O)OC(C)(C)C)[C@@H](CC(C)C)C2)nc1Br
Temperature: 25 °C

Procedure:
2,4-dibromo-5-methyl-thiazole (1.189 g, 3.563 mmol), (S)—N-Boc-2-isobutylpiperazine (863.5 mg, 3.563 mmol) and potassium carbonate (1.477 g, 10.69 mmol) in DMF (15 mL) were heated at 95° C. for 18 h. Cooled to rt, diluted with EtOAc, washed with water, brine, dried (MgSO4), filtered and concentrated in vacuo. Crude product purified by flash chromatography (40 g SiO2, 0 to 5% EtOAc/petrol) to leave impure product as a very pale orange sticky oil (930 mg, 49% based on 78.9% purity); 1H NMR DMSO-d6 δ 0.90 (t, 6H), 1.36-1.31 (br m, 2H), 1.42 (s, 9H), 1.46-1.42 (masked signal, 1H), 2.18 (s, 3H), 3.02-2.91 (m, 2H), 3.14 (dd, 1H), 3.60 (d, 1H), 3.78-3.68 (m, 1H), 3.86 (d, 1H), 4.19 (br s, 1H); ES+ 420.11.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26]([OH:28])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[N:33]1[CH:38]=[C:37]([C:39]2([NH2:42])[CH2:41][CH2:40]2)[CH:36]=[N:35][CH:34]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:28])[NH:42][C:39]5([C:37]6[CH:38]=[N:33][CH:34]=[N:35][CH:36]=6)[CH2:41][CH2:40]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2cncnc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cncnc5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.2 g, 0.46 mmol, 1 eq), 1-(pyrimidin-5-yl)cyclopropanamine (0.074 g, 0.55 mmol, 1.2 eq), EDCI.HCl (0.076 g, 0.4 mmol, 1.2 eq), HOBT (0.054 g, 0.4 mmol, 2 eq) and TEA (0.14 ml, 1.02 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water. The Organic layer was separated, washed with water, concentrated and the crude product was purified by Prep. TLC (20 mm thickness) using 5% methanol/DCM as an eluent. Yield: 50 mg (20%) 1H NMR (400 MHz, DMSO-d6): δ 1.33-1.36 (m, 2H), δ 1.42-1.45 (m, 2H), 2.29 (s, 3H), 2.81-2.82 (d, J=4.4 Hz, 3H), 3.96 (s, 3H), 7.14 (s, 1H), 7.33 (dd, J=1.6, 8.4 Hz, 1H), 7.40 (t, J=8.8, 2H), 7.50 (d, J=1.2 Hz, 1H), 7.52 (s, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.97-8.01 (m, 2H), 8.47 (q, J=4.4 Hz, 1H), 8.67 (s, 2H), 8.91 (s, 1H), 9.00 (s, 1H) LCMS: (ES+) m/z=551.2 (M+H)+
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][CH2:27][O:28][C:21]=3[CH:20]=2)[C:10]2[CH:15]=[C:14]([Cl:16])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][CH2:27][O:28][C:21]=4[CH:20]=3)[C:10]3[CH:15]=[C:14]([Cl:16])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Clc1nc(NCc2ccc3c(c2)OCCO3)c2cc(Cl)sc2n1
Reactant: c1c[nH]cn1
Product: Clc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2,6-dichloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-chloro-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:15]([O:17]CC2C=CC=CC=2)=[O:16])[CH2:4]1)=O.[C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[CH:35][CH:34]=1)#[N:32]>>[C:31]([C:33]1[CH:34]=[CH:35][C:36]([CH2:39][CH2:40][CH2:41][CH:42]2[CH2:47][CH2:46][N:45]([CH2:1][C@@H:3]3[C@@H:7]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:6][N:5]([C@H:14]([CH:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[C:15]([OH:17])=[O:16])[CH2:4]3)[CH2:44][CH2:43]2)=[CH:37][CH:38]=1)#[N:32]
Reactant: O=C[C@H]1CN([C@@H](C(=O)OCc2ccccc2)C2CCCCC2)C[C@@H]1c1ccccc1
Reactant: N#Cc1ccc(CCCC2CCNCC2)cc1
Product: N#Cc1ccc(CCCC2CCN(C[C@H]3CN([C@@H](C(=O)O)C4CCCCC4)C[C@@H]3c3ccccc3)CC2)cc1

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, benzyl ester (from EXAMPLE 1, Step 1) and 4-(3-(4-cyanophenyl)propyl)piperidine×HCl (from EXAMPLE 116, Step A) using procedures analogous to those described in EXAMPLE 1, Steps J and K. For the title compound: HPLC (Zorbax SB-C8 4.6 mm×7.5 cm column, gradient elution using 10:90 v/v CH3CN/H2O+0.1% TFA to 100% CH3CN over 7.5 min, hold for 45 sec, 2.25 mL/min, 220 nm): Retention Time: 4.13 min; ESI-MS 528 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2.[N:24]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[CH:10]([NH:12][C:13]1[O:14][CH2:15][C:16]3[CH:22]=[C:21]([NH:23][S:30]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)(=[O:32])=[O:31])[CH:20]=[CH:19][C:17]=3[N:18]=1)[CH2:9][CH2:8]2
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CC2
Product: COc1cccc2c1C(NC1=Nc3ccc(NS(=O)(=O)N4CCCCC4)cc3CO1)CC2
Yield: 74.6 %

Procedure:
Prepared from rac-N2-(7-methoxy-indan-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 10) (100 mg, 0.323 mmol) and piperidine-1-sulfonyl chloride (65 mg, 0.353 mmol) according to the procedure described for Example 27. Obtained the title compound as a light yellow foam (110 mg, 75%), MS (ISP) m/e=457.4 [(M+H)+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:17][OH:18].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:17][OH:18]
Reactant: COC(=O)CCCC#CCN1C(=O)CCCC1CO
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCN1C(=O)CCCC1CO
Reaction time: 23 h
Yield: 101.2 %

Procedure:
Palladium on carbon (10 wt.%, 20 mg) was added to a solution of 7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (180 mg, 0.67 mmol) in MeOH (6.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 23 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 184 mg (quant.) of 7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11]NC(=O)CCC(N)=O>C(Cl)(Cl)Cl>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: Clc1ncnc2[nH]ccc12
Reactant: NC(=O)CCC(=O)NBr
Solvent: ClC(Cl)Cl
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Yield: 88.2 %

Procedure:
To a stirred solution of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (30 g/0.02 mol) dissolved in 75 mL of chloroform was added 3.5 g (0.02 mol) of N-bromosuccinamide and the resulting mixture refluxed for 1 h. After cooling to room temperature, the precipitate was removed by filtration and dried under reduced pressure affording 4.1 g (89%) of the title compound. 1H NMR (400 MHz) (CDCl3) δ: 7.93 (d, 1H, J=2.8 Hz), 8.60 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:17])=[C:4]([CH3:8])[CH:3]=1
Reactant: Cc1cc(Br)ccn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(Br)cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-bromo-2-methylpyridine (5 g, 29 mmol) in DCM (20 mL) is cooled to 0° C. and m-CPBA (7.55 g, 43.87 mmol, 1.5 equiv.) is added portionwise over 30 min. The ice bath is then removed and the mixture is allowed to stir at room temperature for 3 hours. The resulting solution is diluted with sodium bicarbonate (sat. aq.) and extracted with DCM. The organic layers are combined, washed with sodium bicarbonate (sat. aq.), dried over Na2SO4, and concentrated under vacuum to afford the title compound as a pale orange oil which is without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:13]([CH3:14])[CH:12]=[CH:11][C:5]2=[N:6][C:7]=1[C@@H:8]([NH2:10])[CH3:9].[NH:15]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]1.CC([O-])(C)C.[K+]>O1CCOCC1>[NH2:10][C@H:8]([C:7]1[N:6]=[C:5]2[CH:11]=[CH:12][N:13]([CH3:14])[C:4]2=[CH:3][C:2]=1[N:15]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16]1)[CH3:9]
Reactant: OC1CCNC1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2ccn(C)c2cc1N1CCC(O)C1
Temperature: 150 °C

Procedure:
A mixture of (S)-1-(6-bromo-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (510 mg, 2.0 mmol), pyrrolidin-3-ol (870 mg, 10 mmol) and potassium 2-methylpropan-2-olate (1.56 g, 14.0 mmol) in dioxane (15 mL) was heated to 150° C. for 2 hours in a microwave reactor. The solvent was evaporated in vacuo to give the title compound as a yellow oil which was used without further purification (1.5 g). ESI-MS m/z [M+H]+ calc'd for C14H20N4O, 261. found 261.
Reaction SMILES: [CH:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3](=[O:18])[N:4]1[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:5]1=[N:6]2.[CH2:19](Br)[CH3:20]>>[CH2:19]([N:11]1[C:5]2=[N:6][C:7]3[C:2]([C:3](=[O:18])[N:4]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]1=2)=[CH:1][CH:10]=[CH:9][CH:8]=3)[CH3:20]
Reactant: CCBr
Reactant: O=c1c2ccccc2nc2[nH]c3ccccc3n12
Product: CCn1c2ccccc2n2c(=O)c3ccccc3nc12

Procedure:
6-Ethylbenzimidazo[2,1-b]quinazolin-12(6H)one is prepared with benzimidazo[2,1-b]quinazolin-12(6H)one and ethyl bromide.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:16])=O>>[C:1]([O:9][CH2:10][C:11]([Cl:16])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)COC(=O)c1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)COC(=O)c1ccccc1

Procedure:
A mixture of benzoyloxyacetic acid (5.4 g.) and thionyl chloride (50 ml.) was stirred at 70°-80° C. for an hour and then excess thionyl chloride was distilled off under reduced pressure to give benzoyloxyacetyl chloride. A solution of benzoyloxyacetylchloride obtained above in acetone (10 ml.) was added dropwise to a solution of 3-(N-hydroxyamino)propylphosphonic acid (1.64 g.) in a mixture of water (16 ml.) and acetone (20 ml.) over 30 minutes interval with stirring under ice-cooling and maintaining carefully the pH at around 7-8, together with by adding dropwise a 5% aqueous sodium bicarbonate solution and stirring was continued for additional 30 minutes.
Reaction SMILES: BrC[C:3]1[CH:8]=[C:7](C(C)(C)C)[C:6]([OH:13])=[C:5](C(C)(C)C)[CH:4]=1.[C:18]1([NH:24][C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O1CCCC1>[C:18]1([NH:24][C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:5]3[CH:4]=[CH:3][CH:8]=[CH:7][C:6]=3[OH:13])=[CH:27][CH:26]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1O
Reactant: Nc1ccc(Nc2ccccc2)cc1
Solvent: C1CCOC1
Product: Oc1ccccc1Nc1ccc(Nc2ccccc2)cc1

Procedure:
4-Bromomethyl-2,6-di-tert-butyl-phenol (2.42 g, 0.008 mole) was dissolved in 50 mL of dry tetrahydrofuran . In a separate conical flask N-Phenyl-benzene-1,4-diamine (2.93 g, 0.016 mole) was dissolved in 25 mL of tetrahydrofuran and solution was transferred to a cylindrical funnel with pressure equalizing tube. Three-necked round-bottomed flask containing solution of 4-Bromomethyl-2,6-di-tert-butyl-phenol was kept in oil-bath at 85° C. Solution in the flask was continuously stirred with the help of magnetic stirrer. N-Phenyl-benzene-1,4-diamine solution was added drop-by-drop, from funnel to the flask in acidic medium for a span of 4-5 hours till all the solution was poured out. The reaction was terminated after that and the final reaction mixture was allowed to attain room temperature. Product was separated by solvent evaporation. The product was purified using silica gel column chromatography. Product was identified by 1H-NMR. The yield of 2,6-di-tert-butyl-4-[(4-phenylamino-phenylamino)phenol is 2.044 g (63%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13](O)=[O:14])=[CH:4][C:3]=1[CH3:22].[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)=[N:10][CH:11]=[C:12]([CH:16]=2)[C:13]([NH:31][CH2:30][C:28]2[O:27][N:26]=[C:25]([C:24]([F:33])([F:32])[F:23])[N:29]=2)=[O:14])=[CH:4][C:3]=1[CH3:22]
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: Cc1cc(-c2cc(C(=O)O)cnc2OC2CCC2)ccc1Cl
Product: Cc1cc(-c2cc(C(=O)NCc3nc(C(F)(F)F)no3)cnc2OC2CCC2)ccc1Cl

Procedure:
The title compound was synthesized in analogy to Example 1 using 5-(4-chloro-3-methylphenyl)-6-cyclobutoxy-nicotinic acid (example CC) and 3-trifluoromethyl-[1,2,4]oxadiazol-5-methanamine (example AK) as starting materials; LC-MS (UV peak area/ESI) 93.8%, 467.1 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([N:7]1[C:20]2[CH:19]=[C:18]3[C:21]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:22]4[C:27]([C:17]3=[CH:16][C:15]=2[C:14]([CH3:33])([CH3:32])[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:6].[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[C:34]([C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:5][CH3:6])[C:20]1[CH:19]=[C:18]3[C:21]([CH2:28][CH3:29])([CH2:30][CH3:31])[C:22]4[C:27]([C:17]3=[CH:16][C:15]=1[C:14]2([CH3:33])[CH3:32])=[CH:26][CH:25]=[CH:24][CH:23]=4)(=[O:36])[CH3:35]
Reactant: CCN1c2ccccc2C(C)(C)c2cc3c(cc21)C(CC)(CC)c1ccccc1-3
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCN1c2ccc(C(C)=O)cc2C(C)(C)c2cc3c(cc21)C(CC)(CC)c1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminum chloride (3.43 g, 25.6 mmol) was slowly added into a dichloromethane solution (80 mL) in which were dissolved 11,13,13-triethyl-6,6-dimethyl-11,13-dihydro-6H-11-aza-indeno[2,1-b]anthracene (6.80 g, 20.0 mmol) and acetyl chloride (1.83 mL, 25.7 mmol) at 0° C. under nitrogen atmosphere. After stirring at room temperature overnight, the reaction mixture was poured into ice-water. The product was extracted twice with dichloromethane. The combined organic layer was washed with brine, and dried over MgSO4. Dichloromethane was removed under high vacuum and the product thus obtained was used for the next step without further purification.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33]N)=[CH:29][CH:28]=1.CCN(CC)CC>C(O)C>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)=[CH:29][CH:28]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (337 mg, 1.0 mmol) in ethanol (100 mL) were added 4-chlorophenylhydrazine hydrochloride (269 mg, 1.5 mmol) and Et3N (0.28 mL, 2.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(4-chlorophenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale brown solid (126 mg, 30%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[C:35]([F:37])[CH:36]=1)[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[CH:19][C:18]=1[N+:30]([O-])=O.C1CCCCC=1>[Pd].O1CCOCC1>[NH2:30][C:18]1[CH:19]=[C:20]([N:23]2[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]2)[CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([CH2:5][C:4]3[CH:34]=[C:35]([F:37])[CH:36]=[C:2]([F:1])[CH:3]=3)[CH:7]=2)[NH:11][N:10]=1)=[O:33]
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: C1=CCCCC1
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ccc(Cc5cc(F)cc(F)c5)cc34)c(N)c2)CC1
Temperature: 100 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A mixture of N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-nitro-benzamide (3.21 g, 6.33 mmol), cyclohexene (20 mL), dioxane (200 mL) and 10% Pd/C (0.8 g) was stirred at 100° C. for 2 hours. The reaction mixture was filtered over a celite pad washing thoroughly with THF and MeOH. After evaporation of the organic phase, purification of the crude by chromatography over silica gel (DCM/MeOH 95/5) gave 2.51 g of title compound (83% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH:21][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)COC(=O)[C@H](C)N
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure BB and using 3,4-dichlorophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared as a solid haying a melting point of 811-83° C. The reaction was monitored by tlc on silica gel and purification was by extraction with Et2O followed by washes with aqueous K2CO3 and aqueous HCl.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:11]=2[Cl:17])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:17][C:11]1[C:12]([Cl:16])=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][NH:8][C:6]1[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=[C:2]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NCc1cccc(Cl)c1Cl
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N2CCOCC2)nc1NCc1cccc(Cl)c1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
A mixture of 6-chloro-N-(2,3-dichlorobenzyl)-3-nitropyridin-2-amine (3.37 g, 10.1 mmol), morpholine (2.64 g, 30.3 mmol) and K2CO3 (2.09 g, 15.15 mmol) in DMF (50 mL) was stirred at 80° C. for 1 h. The reaction was cooled to room temperature and poured into water (300 mL). It was extracted with EtOAc (300 mL×2). The combined organic layers were washed with brine (300 mL×3), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluted with EtOAc/Pet Ether=1/1 to afford the desired product as a yellow solid (3.7 g, 96%); LC/MS: MS (ES+) m/e 383 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.54 (s, 4H), 3.56 (s, 4H), 4.81 (d, J=5.7 Hz, 2H), 6.33 (d, J=9.6 Hz, 1H), 7.27-7.34 (m, 2H), 7.53 (dd, J=2.1, 6.9 Hz, 1H), 8.12 (d, J=9.6 Hz, 1H), 9.33 (t, J=6.3 Hz, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:34]=[CH:35][C:36]=1[O:37]C)[CH2:6][C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][C@@H:19]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[C:26]([O:32]C)[CH:25]=1.B(Br)(Br)Br.CO>C(Cl)Cl>[OH:32][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[OH:30])[CH2:23][C@H:19]1[CH2:20][CH2:21][CH2:22][N:18]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:7]1[CH2:6][C:5]1[CH:34]=[CH:35][C:36]([OH:37])=[C:3]([OH:2])[CH:4]=1
Reactant: COc1ccc(C[C@H]2CCCN2CCCCCCN2CCC[C@@H]2Cc2ccc(OC)c(OC)c2)cc1OC
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc(C[C@H]2CCCN2CCCCCCN2CCC[C@@H]2Cc2ccc(O)c(O)c2)cc1O
Temperature: 25 °C

Procedure:
To a solution of (R,R)-1,6-bis-[2-(3,4-dimethoxy-benzyl)pyrrolidin-1-yl]hexane (0.001 mol) in dry CH2Cl2 at -70° C. under an inert atmosphere was added BBr3 (4 mL of a 1M solution, 0.004 mol). The reaction mixture was warmed to room temperature, recooled to -70° C., and CH3OH (4 mL) was added. After warming to room temperature, the solvent was removed in vacuo. The residue was subjected to column chromatography, eluting with CH3OH. The fractions containing the desired product were concentrated in vacuo to provide (R,R)-1,6-bis[2-(3,4-dihydroxybenzyl)pyrrolidin-1-yl]-hexane, [α]D25 =12.86°.