Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][C:16]1=[O:21])([CH3:14])[C:12](=[O:22])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.C([O-])(O)=O.[Na+].[CH2:28]([OH:30])[CH3:29]>OS(O)(=O)=O>[CH2:28]([O:30][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C:16](=[O:21])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C:12]2=[O:22])[CH2:4][C@@H:3]1[OH:1])[CH3:29]
Reactant: CCO
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCO[C@H]1C[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2C(=O)C[C@]2(C)C(=O)CC[C@@H]32)C[C@@H]1O

Procedure:
A solution of 2α,3α-epoxy-5α-androstane-11,17-dione (5.0 g) in absolute ethanol (250 ml) was treated with eight drops of fuming H2SO4 at room temperature. After 45 minutes the reaction mixture was treated with aqueous NaHCO3 and evaporated to low volume. Water was added to the mixture which was then refrigerated overnight. The precipitate was collected by filtration, washed with water and dried. Recrystallisation from water-ethanol afforded the title compound (2.1 g), m.p. 164°-167°, [α]D +114°.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([S:16](=[O:21])(=[O:20])[N:17]([CH3:19])[CH3:18])=[CH:12][C:11]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[Cl:30]>Cl.CO.C(O)C>[Cl:30][C:24]1[CH:25]=[C:26]([I:29])[CH:27]=[CH:28][C:23]=1[NH:22][C:11]1[CH:12]=[C:13]([S:16](=[O:21])(=[O:20])[N:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:9]([NH:8][OH:7])=[O:31]
Reactant: CN(C)S(=O)(=O)c1ccc(C(=O)NOC2CCCCO2)c(Nc2ccc(I)cc2Cl)c1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: CN(C)S(=O)(=O)c1ccc(C(=O)NO)c(Nc2ccc(I)cc2Cl)c1

Procedure:
The compound 2-(2-chloro-4-iodo-phenylamino)-4-dimethylsulfamoyl-benzoic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide is dissolved in an appropriate hydrogen chloride-saturated solvent like methanol or ethanol. Once homogeneous, the solution is concentrated in vacuo to give the desired product. The product may be triturated with an appropriate solvent like chloroform or dichloromethane if further purification is necessary.
Reaction SMILES: [NH2:1][NH2:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:13]=[CH:14][C:15]3[NH:21][C:20](=S)[CH2:19][N:18]=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[C:16]=3[CH:30]=2)=[O:11])=[CH:6][CH:5]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[CH:13]=[CH:14][C:15]3[N:21]=[C:20]([NH:1][NH2:2])[CH2:19][N:18]=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=4)[C:16]=3[CH:30]=2)=[O:11])=[CH:6][CH:5]=1
Reactant: NN
Reactant: O=C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)=NCC(=S)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: NNC1=Nc2ccc(C(=O)c3ccc(Cl)cc3)cc2C(c2cccc(Cl)c2)=NC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Hydrazine (1.5 ml) was added to a mixture of intermediate (13) (0.00353 mol) in THF (20 ml). The mixture was stirred at room temperature for 15 min. K2CO3 10% was added and the mixture was extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 1.5 g (100%) of (4-chlorophenyl)[5-(3-chlorophenyl)-2-hydrazino-3H-1,4-benzodiazepin-7-yl]-methanone (intermediate 14).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]([CH3:20])([CH3:19])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([OH:23])=[O:22])[CH:15]=3)[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>N1C=CC=CC=1>[F:8][C:7]1[CH:6]=[CH:5][C:4]([CH:9]2[C:18]([CH3:19])([CH3:20])[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:21]([OH:23])=[O:22])[CH:15]=3)[NH:10]2)=[CH:3][C:2]=1[NH:1][S:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=1)(=[O:33])=[O:32]
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(N)c1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: c1ccncc1
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1ccc(F)c(NS(=O)(=O)c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To an ice-cold mixture of 2-(3-amino-4-fluorophenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid (0.19 mmol, 1.0 eq.) in pyridine (5 mL) was added 3-fluorobenzene-1-sulfonyl chloride (0.29 mmol, 1.5 eq.) under nitrogen. Then the reaction mixture was stirred at room temperature for two hours. Thin layer chromatography and LC-MS indicated that the starting material was consumed completely. The reaction was quenched with 20 mL water extracted with ethyl acetate (20 mL×2). The combined organic layers were concentrated and the residue was purified by column chromatography (petroleum ether/ethyl acetate=1:1) to afford 2-(4-fluoro-3-(3-fluorophenylsulfonamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a pale yellow solid; Yield: 65%; MS (ESI+APCI) M+1=473.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.O1CCOCC1>O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:31]3[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCOCC3)nc(Cl)nc21
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCOCC4)c23)cn1
Temperature: 110 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a degassed mixture of 2-chloro-5-iodo-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.1 equiv) and potassium phosphate tribasic trihydrate (3 equiv) in a 10:1 mixture of 1,4-dioxane and water (0.09 M)) was added palladium 1,1-bis(diphenylphosphion)ferrocene dichloride (0.2 equiv). The mixture was stirred at 110° C. for 2 h. The suspension was cooled to room temperature and filtered. The filtrate was concentrated and the residue obtained was purified by silica gel chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (88% yield). MS (ESI) m/z=464.1 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.[Li]CCCC.[CH3:15][Si:16]([CH3:26])([CH3:25])[O:17][C:18]([CH3:24])([CH3:23])[C:19](OC)=[O:20]>C1COCC1.CCCCCC>[CH3:15][Si:16]([CH3:26])([CH3:25])[O:17][C:18]([CH3:24])([CH3:23])[C:19]([C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1)=[O:20]
Reactant: CSc1ccc(Br)cc1
Reactant: COC(=O)C(C)(C)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)C(C)(C)O[Si](C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 33.6 %

Procedure:
A solution of 204 mg (1.0 mmol) of 4-bromothioanisole in 2.5 mL of THF was cooled to -78° C. and treated with 0.42 mL of 2.5M n-BuLi solution in hexane. After stirring at -78° C. for 1 h, a solution of 380 mg (2.0 mmol) of methyl 2-trimethylsilyloxyisobutyrate in 2 mL of THF was added. The mixture was stirred at -78° C. for 2 h and then quenched with NH4OAc buffer. The product was extracted with EtOAc, dried over MgSO4 and concentrated. The residue was purified by flash chromatography, eluting with 19:1 hexane/EtOAc to give 95 mg of the title product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15]Br)[CH:5]=1.CC([O-])=[O:20].[K+].CO.C[O-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[N:11]=[CH:12][S:13][C:14]=2[CH2:15][OH:20])[CH:5]=1
Reactant: CC(=O)[O-]
Reactant: COC(=O)c1cccc(-c2ncsc2CBr)c1
Agent: C[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(-c2ncsc2CO)c1
Reaction time: 0.5 h

Procedure:
3-(5-Bromomethyl-thiazol-4-yl)-benzoic acid methyl ester was stirred in DMF (10 mL) together with KOAc (1.52 g) at 20° C. for 30 min. MeOH (20 mL) and NaOMe (0.84 g) were added and stirring was continued at 50° C. for 30 min. The mixture was partitioned between AcOEt and brine and the organic layer was dried and evaporated. The residual oil was chromatographed on silica gel using AcOEt/hexane (1:2) as eluent to give 3-(5-hydroxymethyl-thiazol-4-yl)-benzoic acid methyl ester (1.43 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:44])[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[N:37]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=5)[N:36]=[N:35][N:34]=4)[CH2:29][CH2:28]3)=[O:26])[C:4]=12.[C:45](Cl)(=[O:50])[O:46][CH:47]([CH3:49])[CH3:48]>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:16][CH2:17][N:18]([C:45]([O:46][CH:47]([CH3:49])[CH3:48])=[O:50])[CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[C:5]2[NH:21][CH:22]=[C:23]([C:24](=[O:44])[C:25](=[O:26])[N:27]3[CH2:32][CH2:31][N:30]([C:33]4[N:37]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=5)[N:36]=[N:35][N:34]=4)[CH2:29][CH2:28]3)[C:4]=12
Reactant: CC(C)OC(=O)Cl
Reactant: COc1cnc(-c2ccc(N3CCNCC3)cc2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cnc(-c2ccc(N3CCN(C(=O)OC(C)C)CC3)cc2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Reaction time: 3 h
Yield: 35 %

Procedure:
To a solution of 1-(4-methoxy-7-(4-(piperazin-1-yl)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (50 mg, 0.084 mmol) in THF (1 mL) and DMF (1 mL) were added TEA (0.023 mL, 0.168 mmol) and isopropyl carbonochloridate (13.42 mg, 0.109 mmol) at room temperature. The reaction was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. The resulting crude was purified by prep HPLC to give isopropyl 4-(4-(4-methoxy-3-(2-oxo-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)phenyl)piperazine-1-carboxylate (20 mg, 35%) as white solid. LCMS: m/e 680.58 (M+H)+, ret time 2.49 min (method 4). 1H NMR (500 MHz, MeOD) δ ppm 1.30 (d, J=6.10 Hz, 6H) 3.41-3.50 (m, 6H) 3.50-3.58 (m, 2H) 3.65-3.75 (m, 6H) 3.86-3.93 (m, 2H) 4.14 (s, 3H) 4.95-4.99 (m, 1H) 7.28 (d, J=8.85 Hz, 2H) 7.63 (dd, J=7.32, 4.88 Hz, 1H) 7.77 (d, J=8.55 Hz, 2H) 7.89 (d, J=7.93 Hz, 1H) 8.01 (s, 1H) 8.12-8.20 (m, 1H) 8.67 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[NH2:5].C1C(=O)N([Br:20])C(=O)C1>C(Cl)Cl>[Br:20][C:6]1[CH:7]=[C:8]([C:9]([F:10])([F:11])[F:12])[C:2]([F:1])=[CH:3][C:4]=1[NH2:5]
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: Nc1cc(F)c(C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirring mixture of 3-fluoro-4-(trifluoromethyl)aniline (1.5 g) in DCM (12 mL) at room temperature was added dropwise a solution of NBS (1.5 g) in DCM (24 mL) over 15 min. The reaction mixture was stirred at rt for 1.5 h. The product mixture was concentrated under reduced pressure to one half of its original volumn. The white solid was filtered off and the crude product mixture was further purified via column chromatography. Retention time (min)=2.490, method [1], MS (ESI) 257.9 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:14])=[C:4]([CH:7]=[C:8]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.CO>C(Cl)Cl>[CH2:15]([O:14][C:3]1[C:2]([Br:1])=[CH:9][C:8]([C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:7][C:4]=1[CH:5]=[O:6])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)c1cc(Br)c(O)c(C=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1cc(Br)c(OCc2ccccc2)c(C=O)c1

Procedure:
step 1—Benzylation of 3-bromo-5-tert-butyl-2-hydroxy benzaldehyde (36a) with benzyl bromide is accomplished treating 36a with benzyl bromide and tetrabutylammonium hydroxide in a biphasic system comprised of MeOH and DCM to afford 2-benzyloxy-3-bromo-5-tert-butyl-benzaldehyde (36b).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[F:10][C:11]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=1[CH2:13]Br>CN(C)C=O>[F:10][C:11]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:12]=1[CH2:13][O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCO
Reactant: Fc1ccc(Br)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCOCc1cc(Br)ccc1F

Procedure:
In a 100 ml flask, under a nitrogen atmosphere, n-hexanol (1.44 ml, 11.5 mmol) was dissolved in N,N-dimethylformamide (35 ml). To this solution sodium hydride (60%, 521 mg, 13.0 mmol) was added and the resulting mixture was stirred for ten minutes. To the reaction mixture 2-fluoro-5-bromobenzyl bromide (2.054, 7.67 mmol) was added and the resulting mixture was stirred at ambient temperature for six hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was partitioned between 1 M potassium carbonate/brine (1/1) and diethyl ether. The organic fraction was washed with brine six times. The organic fraction was dried over sodium sulfate. The solvents were removed in vacuo. The title intermediate was further purified by liquid chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[O:12]1[CH2:17][CH2:16][CH:15]([NH2:18])[CH2:14][CH2:13]1>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:18][CH:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)[CH:3]=1
Reactant: NC1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Br)cc1NC1CCOCC1
Temperature: 120 °C
Yield: 90.9 %

Procedure:
To a solution of 4-bromo-2-fluoro-1-nitrobenzene (2 g, 9.137 mmol) in DMF (10 mL) was added tetrahydro-2H-pyran-4-amine (1.108 g, 10.964 mmol) and TEA (2.772 g, 27.410 mmol). The reaction mixture was heated at 120° C. in microwave reactor for 30 mins. The reaction mixture was diluted with H2O then extracted with EA. The combined organic layers were dried over sodium sulfate, filtered and concentrated to yield a crude product (2.5 g) which was used in next step without further purification. LCMS (m/z): 301.0 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][C:7]1([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.[C:20]([C:22]1[CH:35]=[CH:34][C:25]([CH2:26][N:27]2[C:31]([CH2:32]Cl)=[CH:30][N:29]=[CH:28]2)=[CH:24][CH:23]=1)#[N:21].C(N(C(C)C)CC)(C)C>C(#N)C>[C:20]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:27]2[C:31]([CH2:32][N:10]3[CH2:9][CH2:8][C:7]([CH2:6][C:5]4[CH:16]=[CH:17][CH:18]=[C:3]([CH3:2])[CH:4]=4)([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11]3)=[CH:30][N:29]=[CH:28]2)=[CH:34][CH:35]=1)#[N:21]
Reactant: N#Cc1ccc(Cn2cncc2CCl)cc1
Reactant: Cc1cccc(CC2(C(N)=O)CCNCC2)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(CC2(C(N)=O)CCN(Cc3cncn3Cc3ccc(C#N)cc3)CC2)c1

Procedure:
A solution of 4-(3-methylbenzyl)isonipecotamide hydrochloride salt (134 mg, 0.5 mmol), 1-(4-cyanobenzyl)-5-chloromethylimidazole hydrochloride salt (134 mg, 0.5 mmol; Example 52, Step D), and diisopropylethylamine (440 mL, 2.5 mmol) in anhydrous acetonitrile (5 mL) was heated under reflux overnight. The resultant mixture was concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 2% methanol in chloroform saturated with ammonia gas. After collection and concentration of appropriate fractions, the residue was triturated with anhydrous diethyl ether. The white solid precipitated was filtered to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:21][C:22](N(OC)C)=[O:23])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])[CH2:21][C:22]([C:2]2[CH:7]=[N:6][CH:5]=[CH:4][N:3]=2)=[O:23])=[CH:18][CH:19]=1
Reactant: Brc1cnccn1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Agent: [Li]CCCC
Product: Cc1ccccc1C(CC(=O)c1cnccn1)c1ccc(Br)cc1

Procedure:
In analogy to example 151, step 1, 2-bromopyrazine was reacted first with n-butyllithium and later with 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) to give the title compound as a colorless solid, MS (ESI+): m/z=381.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([N+:16]([O-])=O)=[CH:8][N:7]=1)([CH3:5])[CH:3]=[O:4].CC(=O)OCC>[Ni].CO>[NH2:16][C:9]1[CH:10]=[C:11]([C:12]([F:15])([F:13])[F:14])[C:6]([C:2]([CH3:5])([CH3:1])[CH2:3][OH:4])=[N:7][CH:8]=1
Reactant: CC(C)(C=O)c1ncc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Ni]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(CO)c1ncc(N)cc1C(F)(F)F
Yield: 67.2 %

Procedure:
A solution of 2-methyl-2-(5-nitro-3-(trifluoromethyl)pyridin-2-yl)propanal (100 mg, 0.381 mmol) and Raney nickel (22.39 mg, 0.381 mmol) in MeOH (30 mL) was stirred at 25° C. under H2 overnight. After TLC analysis (PE/EA=5/1) showed the starting material was consumed, the mixture was filtered. The filtrate was concentrated to give 2-(5-amino-3-(trifluoro methyl)pyridin-2-yl)-2-methylpropan-1-ol (60 mg, 0.256 mmol, 67% yield): 1H NMR (400 MHz, CD3OD) δ 8.08 (br. s., 1H), 7.36 (d, J=2.8 Hz, 1H), 1.31 (s, 6H); ES-LCMS m/z: 235.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7].[Cl:46][C:47]1[S:51][C:50]([CH2:52]Cl)=[CH:49][CH:48]=1>>[CH3:45][O:44][C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:31]([CH2:52][C:50]4[S:51][C:47]([Cl:46])=[CH:48][CH:49]=4)[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7]
Reactant: ClCc1ccc(Cl)s1
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(Cl)s4)CC3)(c3ccc(F)c(F)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 37.2 using 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl) pyrrolidine and 5-chloro-2-(chloromethyl)thiophene to give, after purification on silica gel eluting with 1/2 methanol/ethyl acetate, the title compound: mp; 110-120° C. Rf=0.40 (silica gel, 1/2 methanol/ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)[CH:14]=[C:13]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:30]1(=[O:36])[O:35][C:33](=[O:34])[CH2:32][CH2:31]1>CN(C1C=CN=CC=1)C.ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[C:15]([N:17]3[CH2:18][CH2:19][CH:20]([O:23][C:30](=[O:36])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:21][CH2:22]3)[CH:14]=[C:13]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:12]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(Nc2nc(-c3ccccc3)cc(N3CCC(O)CC3)n2)cc1Cl
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CC(Cl)Cl
Product: COc1ccc(Nc2nc(-c3ccccc3)cc(N3CCC(OC(=O)CCC(=O)O)CC3)n2)cc1Cl
Temperature: 30 °C

Procedure:
A mixture of compound 1-[2-(3-chloro-4-methoxy-phenylamino)-6-phenyl-pyrimidin-4-yl]-piperidin-4-ol (1.0 g, 2.4 mmol), 4-(N,N-dimethyl)aminopyridine (0.45 g, 3.66 mmol) and succinic anhydride (0.73 g, 7.33 mmol) in dichloroethane (20 mL) was stirred at refluxing temperature for 48 hours. The mixture was cooled to temperature in the range of 20-40° C. and solvent was removed under reduced pressure. The residue was treated with water (20 mL) and the solid precipitated was filtered and washed with isopropanol to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]([OH:12])=[O:11]>C1COCC1.[Rh]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)C=Cc1ccccc1F
Agent: [Rh]
Solvent: C1CCOC1
Product: O=C(O)CCc1ccccc1F

Procedure:
3-(2-fluoro-phenyl)-acrylic acid (10.00 g, 60.30 mmol) in THF was mixed with Rh/Al2O3 (500 mg) and hydrogenated for 14 hours. The reaction mixture was filtered through celite and the filtrate was concentrated to give 3-(2-fluoro-phenyl)-propionic acid. 3-(2-chloro-phenyl)-propionic acid (10.0 g, 43.70 mmol) was then reacted with SOCl2 (6.60 mL, 90.48 mmol) and AlCl3 (9.00 g, 67.50 mmol) according to the protocols as outlined in general procedure C to afford the title compound. vi Musso, David L.; Cochran, Felicia R.; Kelley, James L.; McLean, Ed W.; Selph, Jeffrey L.; Rigdon, Greg C.; Orr, G. Faye; Davis, Ronda G.; Cooper, Barrett R.; Styles, Virgil L.; Thompson, James B.; Hall, William R. J. Med. Chem. 2003, 46, 399-408.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)[CH:18]=[O:19]>O1CCCC1.CCCCCC>[C:1]([O:5][C:6]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[N:11][CH:10]=2)[CH2:15][CH:18]1[OH:19])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: Cc1ccncc1NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1c2cnccc2CC1O
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-tert-butoxycarbonylamino-4-methylpyridine (step a, 1.47 g, 7.06 mmol) in tetrahydrofuran (50 ml) was cooled to -70° C. and treated with n-butyllithinum (6.2 ml, 2.5M in hexane, 15.5 mmol) at such a rate as to keep the temperature below -60° C. On complete addition the mixture was warmed to -20° C. and stirred for 30 minutes. The mixture was cooled to -30° C. and treated with dimethylformamide (0.66 ml, 8.47 mmol). The mixture was allowed to warm to 20° C., quenched with water (50 ml) and extracted with ethyl acetate (50 ml and 2×25 ml). The combined organic fractions were washed with saturated brine (50 ml), dried (Na2SO4), filtered and concentrated to residue in vacuo. The residue was purified by chromatography on silica gel (75% ethyl acetate/25% hexane) to afford the title compound as a colourless oil; yield: 1.26 g (81%) 1H NMR (CD2Cl2 /TMS): δ=1.6 (9H, s), 2.96 (1H, d, J=18 Hz), 3.35 (1H, dd, J=8 Hz & 18 Hz), 5.05 (1H, br.s), 5.98 (1H, br.s), 7.16 (1H, d, J=5 Hz), 8.15 (1H, d, J=5 Hz), 8.75 (1H, br.d).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26]CC)=[O:25])=[CH:22][CH:21]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:31])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[C:8]2[CH:7]=[C:6]([C:18]#[C:19][C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:29][CH:30]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccnc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2cccnc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3-pyridyl)-2-naphthalenyl)ethynyl]benzoate (Compound 11) 45.0 mg (0.110 mmol) in 3 ml of EtOH and 2 ml of THF was added 48.0 mg (1.20 mmol, 1.20 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ8.60 (1H, d, J=4.6 Hz), 8.55 (1H, s), 7.90 (2H, d, J=8.3 Hz), 7.76 (1H, d, J=7.5 Hz), 7.60 (2H, d, J=8.3 Hz), 7.51-7.46 (3H, m), 6.94 (1H, s), 6.14 (1H, t, J=4.5 Hz), 2.37 (2H, d, J=4.5 Hz), 1.31 (6H, s).