Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([OH:26])=O)=[CH:9][N:8]=1)[CH2:2]2.[CH3:27][C:28]1[N:29]=[CH:30][C:31]([CH2:34][NH2:35])=[N:32][CH:33]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:35][CH2:34][C:31]3[CH:30]=[N:29][C:28]([CH3:27])=[CH:33][N:32]=3)=[O:26])=[CH:9][N:8]=1)[CH2:2]2
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Reactant: Cc1cnc(CN)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCc2cnc(C)cn2)cc1Cl
Reaction time: 18 h
Yield: 40.5 %

Procedure:
In THF (50 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)pyrimidine-5-carboxylic acid (202 mg, 0.54 mmol), (5-methylpyrazine-2-yl)methylamine (79 mg, 0.64 mmol) and triethylamine (0.2 mL). The solution was cooled in an ice bath and HATU (266 mg, 0.70 mmol) was then added. The reaction was conducted at ambient temperature for 18 h. The reaction mixture was concentrated, followed by addition of water and extraction with ethyl acetate. The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM/methanol=50/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-((5-methylpyrazine-2-yl)methyl)pyrimidine-5-formamide (105 mg, 40% yield).
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].[CH2:15]([C:17]([C:28]1[CH:33]=[CH:32][C:31]([C:34]#[C:35][C:36]2([OH:42])[CH2:41][CH2:40][S:39][CH2:38][CH2:37]2)=[C:30]([CH3:43])[CH:29]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:18][CH3:19])[CH3:16]>O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C>[CH2:15]([C:17]([C:28]1[CH:33]=[CH:32][C:31](/[CH:34]=[CH:35]/[C:36]2([OH:42])[CH2:41][CH2:40][S:39][CH2:38][CH2:37]2)=[C:30]([CH3:43])[CH:29]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:18][CH3:19])[CH3:16]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCSCC2)c(C)c1
Agent: COCCO[Al+]OCCOC
Agent: [Cl-]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(/C=C/C2(O)CCSCC2)c(C)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.7 %

Procedure:
Sodium bis(2-methoxyethoxy)aluminum hydride (65 wt % solution in toluene, 1.2 mL, 4 mmol) was added to a solution of 4-{4-[1-ethyl-1-(4-hydroxy-3-methyl-phenyl)-propyl]-2-methyl-phenylethynyl}-tetrahydro-thiopyran-4-ol (Example 136-(1); 0.54 g, 1.3 mmol) in tetrahydrofuran (6 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred at 0° C. for five hours. Then, ethyl acetate and brine were added to the reaction mixture, which was further diluted with ethyl acetate. Thereafter, celite was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 25:75) to give the target compound as a colorless oil (0.5 g, 92%).
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]([S:35]([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:9][CH2:10][N:11]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH2:12][CH2:13][NH:14][S:15]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)(=[O:17])=[O:16])=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][OH:55].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:5][C:6]([N:8]([S:35]([C:38]1[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=1)(=[O:37])=[O:36])[CH2:9][CH2:10][N:11]([S:25]([C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)(=[O:26])=[O:27])[CH2:12][CH2:13][N:14]([S:15]([C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)(=[O:16])=[O:17])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][OH:55])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: OCCCCCCCCCBr
Reactant: CCCCOC(=O)N(CCN(CCNS(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCOC(=O)N(CCN(CCN(CCCCCCCCCO)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1)S(=O)(=O)c1ccc(C)cc1
Temperature: 65 °C
Reaction time: 24 h
Yield: 46.8 %

Procedure:
A mixture of 14 g of 1-butoxycarbonyl-1,4,7-tri-(p-toluenesulfonyl)-1,4,7-triazaheptane, 7.04 g of 9-bromo-1-nonanol, and 34.25 g of Cs2CO3 in 700 ml of DMF was stirred at 65° C. for 24 hours. The mixture was cooled and concentrated under reduced pressure. CH2Cl2 was added and the remaining solid was filtered and discarded. The solvent was evaporated to give 22.17 g of crude product which was purified on silica gel and eluted with CH2Cl2/ethyl acetate (50/1-20/1 v/v). 7.95 g of pure product was obtained. The preparation scheme is shown below:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13](=[NH:15])[NH2:14])=[N:6]1.[CH3:20][O:21][CH:22]([C:25]#[N:26])[C:23]#[N:24].O>CN(C=O)C>[F:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:14]=[C:25]([NH2:26])[C:22]([O:21][CH3:20])=[C:23]([NH2:24])[N:15]=2)=[N:6]1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2c1CCC2
Reactant: COC(C#N)C#N
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(N)nc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1N
Temperature: 100 °C

Procedure:
100 mg of 1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carboximidamide 1-2-4 (0.39 mmol, 1.0 eq.) and 37 mg methoxymalononitrile (0.39 mmol, 1.0 eq.; for preparation see: US2003/144538 A1, 2003) were dissolved in 1 mL DMF. The mixture was heated for 30 min in a microwave oven at 100° C. After addition of 10 mL water, the precipitated, crude product was filtered off and was purified by flash chromatography yielding 66 mg (0.19 mmol, 48%) of analytically pure target compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]([C@@H:9]([NH2:11])[CH3:10])=[N:7][CH:8]=1.[Br:12][C:13]1[C:14]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH3:27])[NH:23][N:22]=2)=[N:15][C:16](Cl)=[N:17][CH:18]=1.CCN(C(C)C)C(C)C>CCCCO>[Br:12][C:13]1[C:14]([NH:20][C:21]2[CH:25]=[C:24]([O:26][CH3:27])[NH:23][N:22]=2)=[N:15][C:16]([NH:11][C@H:9]([C:6]2[N:7]=[CH:8][C:3]([F:2])=[CH:4][N:5]=2)[CH3:10])=[N:17][CH:18]=1
Reactant: COc1cc(Nc2nc(Cl)ncc2Br)n[nH]1
Reactant: C[C@H](N)c1ncc(F)cn1
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ncc2Br)n[nH]1
Temperature: 165 °C
Yield: 33.1 %

Procedure:
To a microwave vial was added (S)-1-(5-fluoropyrimidin-2-yl)ethanamine hydrochloride (Method 7, 155 mg, 0.77 mmol), 5-bromo-2-chloro-N-(5-methoxy-1H-pyrazol-3-yl)pyrimidin-4-amine (Method 39, 180 mg, 0.59 mmol), and DIEA (181 mg, 1.48 mmol). Anhydrous n-BuOH (2.5 mL) was added, and the vial was heated in microwave oven at 165° C. for 5 hours. The reaction mixture was concentrated. The resulting residue was separated by silica gel column to afford desired product (80 mg, 33%). LC-MS, 409 (M+1). 1H NMR δ 12.03 (s, 1H), 9.38 (s, 1H), 8.82 (s, 2H), 7.97-8.12 (m, 2H), 5.60 (s, 1H), 5.13 (s, 1H), 3.75 (m, 3H), 1.49 (m, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([C@@H:18]([CH2:22][CH3:23])[CH:19](N)[OH:20])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C([N:26](CC)CC)C.P([O-])(O)(O)=O.[Na+]>C(Cl)Cl>[C:11]([C@:18]([NH2:26])([CH2:22][CH3:23])[CH:19]=[O:20])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: CC[C@H](C(=O)OC(C)(C)C)C(N)O
Reactant: CCN(CC)CC
Agent: O=C(Cl)C(=O)Cl
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC[C@](N)(C=O)C(=O)OC(C)(C)C
Temperature: -60 °C
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
A solution of oxalyl chloride (40.39 g, 265 mmol) in MeCl2 (700 mL) was stirred and cooled to −60° C. Dimethylsulfoxide (51.7 g, 663 mmol) in MeCl2 (100 mL) was added dropwise. After 10 min., a solution of 2(S)-Boc-amino-1-butanol (50 g, 265 mmol) in MeCl2 (100 mL) was added dropwise at −70° C. The reaction mixture was allowed to warm to −40° C. for 10 min. and then cooled to −70° C. again. A solution of triethylamine (74.9 g, 742 mmol) in MeCl2 (100 mL) was added. The reaction mixture was allowed to warm to room temperature over 2 h. Saturated sodium dihydrogen phosphate (100 mL) was added, and then the organic layer was washed with brine and dried over MgSO4. The solvent was removed to yield 45 g of 2(S)-Boc-aminobutyraldehyde.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[N:11]/[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].B(F)(F)F.CCOCC.[CH2:28]=[C:29]([CH3:31])[CH3:30]>C(#N)C>[CH3:28][C:29]1([CH3:31])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[NH:11][CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:30]1
Reactant: Cc1ccc(/N=C/c2cccc([N+](=O)[O-])c2)cc1
Reactant: C=C(C)C
Agent: FB(F)F
Solvent: CC#N
Solvent: CCOCC
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc([N+](=O)[O-])c1)N2

Procedure:
A 2000 mL of autoclave was charged with [1-(3-nitro-phenyl)-meth-(E)-ylidene]-p-tolyl-amine (44.5 g, 0.185 mmol), acetonitrile (500 mL), boron trifluoride etherate (30 mL). The mixture was cooled with liquid nitrogen, and then isobutene was added quickly. The resultant mixture was stirred at room temperature for 60 h. The reaction mixture was washed with brine, water, dried over magnesium sulfate, concentrated. The residue was washed with ethyl acetate and the desired 4,4,6-trimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline was obtained by filtration (53 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8](C)[CH2:9][CH2:10][C:11]([O:13]C)=O)[CH:5]=[CH:6][CH:7]=1.[CH3:16][NH:17][CH3:18].Cl>O>[CH3:16][N:17]([CH3:18])[C:11](=[O:13])[CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=1
Reactant: CNC
Reactant: COC(=O)CCC(C)c1cccc(O)c1
Agent: Cl
Solvent: O
Product: CN(C)C(=O)CCCc1cccc(O)c1
Reaction time: 25 h
Yield: 41 %

Procedure:
A mixture of 3.7 g of methyl 4-(3-hydroxyphenyl)pentanoate and 40 mL of 40% dimethylamine in water was stirred for 25 hours. The mixture was acidified with 5N hydrochloric acid and extracted with dichloromethane. The organic phase was washed with a saturated sodium chloride solution, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl ether/methanol to provide 1.62 g (41%) of the title intermediate. NMR
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][C:15](N(OC)C)=[O:16])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:23])#[N:2].[H-].C([Al+]CC(C)C)C(C)C>C1COCC1.C(Cl)Cl>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][CH:15]=[O:16])=[CH:11][N:10]=[CH:9]2)=[CH:5][C:4]=1[F:23])#[N:2]
Reactant: CON(C)C(=O)CCc1cncn1Cc1ccc(C#N)c(F)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#Cc1ccc(Cn2cncc2CCC=O)cc1F
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[1-(4-cyano-3-fluorobenzyl)-1H-imidazol-5-yl]-N-methoxy-N-methylpropionamide, as described above in Step A, (505 mg, 1.60 mmol) in dry THF (30 mL) at −78° C., under argon, was added diisobutylaluminum hydride (3.5 mL of a 1.0 M solution in CH2Cl2, 3.5 mmol), dropwise. The reaction mixture was stirred at −78° C. for 2 hours, then quenched with MeOH (1 mL) followed by saturated aqueous sodium potassium tartrate (20 mL). The mixture was allowed to warm to ambient temperature, then extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column chromatography, eluting with a gradient of CH2Cl2—1% to 6% MeOH—0.1% to 0.6% NH4OH to give a mixture of the desired aldehyde and its methyl hemiacetal. Treatment of this mixture with dilute HCl in MeOH/H2O followed by concentration from toluene afforded the desired aldehyde.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[N:18]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[Cl:42][C:43]1[CH:44]=[C:45]([CH2:49][C:50](O)=[O:51])[CH:46]=[CH:47][CH:48]=1.CO>C1COCC1>[Cl:42][C:43]1[CH:44]=[C:45]([CH2:49][C:50]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([C:8]3[C:16]([C:17]4[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[N:18]=4)=[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][N:10]4[N:9]=3)[CH:3]=2)=[O:51])[CH:46]=[CH:47][CH:48]=1
Reactant: Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Reactant: O=C(O)Cc1cccc(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Cc1cccc(Cl)c1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 58.9 %

Procedure:
To a solution of 4-[2-(3-aminophenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-phenyl-2-pyrimidine (30 mg, 0.08 mmol) (see Example 3, Step H) in THF (3 mL) was added CDI (14 mg, 0.09 mmol). The resultant mixture was stirred at rt for 1 hour. To the mixture was added (3-chlorophenyl)acetic acid (15 mg, 0.09 mmol) and then stirred at rt for 15 h. Methanol (2 mL) was added and the mixture was concentrated in vacuo. The residue was purified by chromatography on silica gel (hexanes/EtOAc) to give the title compound (25 mg, 60% yield). 1H NMR (400 MHz, DMSO-d6): δ 3.68 (s, 2H), 6.53 (d, 1H, J=5.3 Hz), 6.92 (m, 1H), 6.92 (m, 1H), 7.12 (m, 1H), 7.21-7.50 (m, 9H), 7.68-7.76 (m, 3H), 7.89 (m, 1H), 8.26 (d, 1H, J=5.3 Hz), 8.47 (m, 1H), 8.83 (d, 1H, J=6.8 Hz), 9.56 (s, 1H), 10.35 (s, 1H). ES-LC/MS m/z=531 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7](I)[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[F:11][C:12]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:13]=1[CH2:14][C:15]1[O:19][N:18]=[C:17]([C:20]([NH:22][CH2:23][CH2:24][C:25]#[C:26][Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])=[O:21])[CH:16]=1.[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.[Cl-].[Na+].O.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:8]=[C:7]2[C:5](=[C:4]([F:10])[CH:3]=1)[NH:6][C:26]([Si:27]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:28][CH3:29])=[C:25]2[CH2:24][CH2:23][NH:22][C:20]([C:17]1[CH:16]=[C:15]([CH2:14][C:13]2[CH:34]=[C:35]([F:38])[CH:36]=[CH:37][C:12]=2[F:11])[O:19][N:18]=1)=[O:21]
Reactant: Nc1c(F)cc(Cl)cc1I
Reactant: CC[Si](C#CCCNC(=O)c1cc(Cc2cc(F)ccc2F)on1)(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[Si](CC)(CC)c1[nH]c2c(F)cc(Cl)cc2c1CCNC(=O)c1cc(Cc2cc(F)ccc2F)on1
Temperature: 100 °C
Reaction time: 8 h
Yield: 26.3 %

Procedure:
A mixture of 4-chloro-2-fluoro-6-iodoaniline (0.100 g; 0.368 mmol), 5-(2,5-difluorobenzyl)-N-(4-(triethylsilyl)but-3-ynyl)isoxazole-3-carboxamide (0.150 g; 0.347 mmol), Bis(diphenylphosphino)ferrocene]palladium(II) chloride (0.015 g; 0.018 mmol), lithium chloride (0.016 mg; 0.368 mmol), sodium carbonate (0.078 g; 0.737 mmol) in DMF (5 mL) was stirred at 100° C. overnight. The solution was reparted between ethyl acetate and brine, washed with sodium thiosulphate, dried and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica (eluent 2 to 60% ethyl acetate in heptane) to yield 0.05 g (25%) of N-(2-(5-chloro-7-fluoro-2-(triethylsilyl)-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)isoxazole-3-carboxamide as a yellow oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1>>[Cl:19][C:20]1[CH:25]=[C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[CH:22][N:21]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccnc(Cl)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, off-white solid (50 mg, 59%), MS (ISP) m/z=335.4 [(M+H)+], mp 281° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 2-chloro-pyridin-4-ylboronic acid (51.1 mg, 0.325 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][OH:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:8][C:5]1[N:4]=[CH:3][C:2]([O:1][CH2:10][CH2:11][OH:12])=[CH:7][CH:6]=1
Reactant: Cc1ccc(O)cn1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCCO)cn1
Reaction time: 8 h

Procedure:
5.00 g (45.82 mmol) of 3-hydroxy-6-methylpyridine are dissolved in 65 ml of dry DMF, 6.87 g (54.98 mmol) of 2-bromoethanol and 25.33 g (183.27 mmol) of potassium carbonate are added and the mixture is stirred at +150° C. for 8 h. The mixture is then filtered, and the filtrate is concentrated on a rotary evaporator. After addition of 100 ml of ethyl acetate and 30 ml of saturated aqueous sodium bicarbonate solution, the phases are separated and the aqueous phase is extracted two more times with in each case 30 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate, and the solvent is removed on a rotary evaporator. Without further purification, the residue is used for the subsequent reaction.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:34]([CH3:35])[C@@H:33]2[C@@:5]([CH3:37])([CH2:6][CH2:7][C@@:8]3([CH3:36])[C@:14]4([CH3:32])[CH2:15][CH2:16][C@H:17]5[C@:22]([C:24]([OH:26])=[O:25])([CH3:23])[C@H:21]([O:27][C:28]([CH3:30])=[O:29])[CH2:20][CH2:19][C@:18]5([CH3:31])[C@H:13]4[C:11](=[O:12])[CH:10]=[C:9]32)[CH2:4][CH2:3]1.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][C@H:2]1[C@H:34]([CH3:35])[C@@H:33]2[C@@:5]([CH3:37])([CH2:6][CH2:7][C@@:8]3([CH3:36])[C@:14]4([CH3:32])[CH2:15][CH2:16][CH:17]5[C@:22]([C:24]([OH:26])=[O:25])([CH3:23])[C@H:21]([O:27][C:28]([CH3:30])=[O:29])[CH2:20][CH2:19][C@:18]5([CH3:31])[C@H:13]4[C:11](=[O:12])[CH:10]=[C:9]32)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@]3(C)[C@@H]2C(=O)C=C2[C@@H]4[C@@H](C)[C@H](C)CC[C@]4(C)CC[C@]23C)[C@@]1(C)C(=O)O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(=O)O[C@@H]1CC[C@@]2(C)C(CC[C@]3(C)[C@@H]2C(=O)C=C2[C@@H]4[C@@H](C)[C@H](C)CC[C@]4(C)CC[C@]23C)[C@@]1(C)C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 39.2 %

Procedure:
A mixture of 3-O-acetyl-11-keto-β-boswellic acid (5 g, 0.0097 mol), 3 mL of chloroform taken in a round bottom flask. Then phosphorous pentachloride (16 g; 0.078 mol) was added to reaction mixture (RM) at Room temperature. RM was stirred at 50° C. for 1 hr, then stirred at RT for 4 hours. Then RM was poured in ice cold water, extracted with Ethyl acetate (EtOAc), organic layer was washed with brine, dried over sodium sulphate and concentrated. The crude was subjected to column chromatography, hexane/acetone as an eluent. Compound eluted in 15% acetone in hexane. [Yield 2 g; Percentage of yield is 39.2%].
Reaction SMILES: [CH:1]1([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1.O>N1C=CC=CC=1>[C:21]([O:19][C:16]1[CH:15]=[CH:14][C:13]([CH:1]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:18][CH:17]=1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[N:24][CH:23]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Oc1ccc(C2CCCCCCCCCCC2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(Oc1ccc(C2CCCCCCCCCCC2)cc1)c1cccnc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
8 g (30.8 mmol) of p-cyclododecylphenol and 5.9 g (33.2 mmol) of nicotinic acid chloride hydrochloride was mixed with 140 ml of dry pyridine and kept at 30° C. for 15 hours. Subsequently, 42 ml of water was added slowly drop by drop, and the mixture cooled to 0° C. The crystallized precipitate was sucked off, freed from pyridine by washing with water and dried.
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[C:10](Br)=[C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:7]=1)=[O:5])[CH3:2].[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>>[CH2:1]([NH:3][C:4]([C:6]1[C:10]([C:40]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:35])[CH:41]=2)=[C:9]([C:12]2[CH:17]=[C:16]([Cl:18])[C:15]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:14][C:13]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1Br
Product: CCNC(=O)c1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1cccc(Cl)c1
Yield: 55 %

Procedure:
5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-bromo-isoxazole-3-carboxylic acid ethylamide (60 mg, 0.11 mmol), and 3-chlorobenzene boronic acid (23 mg, 1.3 equiv.) were coupled together using the suzuki method previously described to provide 35 mg (55% yield) of the crude as a brown powder which was taken on to the next step.
Reaction SMILES: CO.[OH-].[K+].Cl.C[O:7][C:8]([CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[C:25]3[S:29][C:28](=[O:30])[NH:27][C:26]3=[O:31])=[CH:20][CH:19]=2)[CH2:12][CH2:11]1)=[O:9]>O>[O:30]=[C:28]1[NH:27][C:26](=[O:31])/[C:25](=[CH:24]/[C:21]2[CH:22]=[CH:23][C:18]([O:17][CH2:16][CH:13]3[CH2:12][CH2:11][CH:10]([C:8]([OH:9])=[O:7])[CH2:15][CH2:14]3)=[CH:19][CH:20]=2)/[S:29]1
Reactant: COC(=O)C1CCC(COc2ccc(C=C3SC(=O)NC3=O)cc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C1NC(=O)/C(=C/c2ccc(OCC3CCC(C(=O)O)CC3)cc2)S1

Procedure:
To 30 ml of methanol in which methyl-4-((4-((2,4-dioxothiazolidine-5-ylidene)methyl)phenoxy)methyl)cyclohexane carboxylate prepared in Example 66 was dissolved, 2N KOH (30 ml) was added while stirring. The mixture was stirred for 1 hour under reflux, then diluted with water and acidified by HCl. Subsequently, the precipitate thus formed was washed with water and dried to afford 4-({4-[(Z)-(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]phenoxy}methyl)cyclohexane carboxylic acid (Derivative 111 having the above formula) as white solid (0.74 g, yield: 77.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.Cl[CH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>C1COCC1>[NH:30]1[C:29]([CH2:28][C@@H:10]2[CH2:9][C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C@@H:13]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)[NH:12][C:11]2=[O:21])=[N:33][N:32]=[N:31]1
Reactant: ClCc1nnn[nH]1
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C1N[C@H](c2ccc(Cl)cc2)[C@@H](c2cccc(Cl)c2)C[C@H]1Cc1nnn[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 100 mL round-bottomed flask was placed under vacuum and heated with a heat gun to ensure dryness. The flask was allowed to cool to room temperature and a solution of 500 mg (1.56 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1, Step E) in THF (12 mL) under argon was added and cooled to 0° C. Butyllithium (1.6M in hexanes, 2440 μL, 3.90 mmol) was added followed by 5-chloromethyl-1H-tetrazole (185 mg, 1.561 mmol) and the reaction mixture was stirred for 15 minutes at 0° C. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The aqueous layer was acidified with 1M HCl. The aqueous layer was extracted with ethyl acetate (2×30 mL) and the combined organic layers were washed with sat. aq. NaCl solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by reversed phase preparatory HPLC (column: Gemini-NX C18 5 μm column; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA, over 25 minutes) to afford the title compound.