Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC([CH:8]2[CH:12](C3C=CC(Cl)=CC=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3C=CC(C(C)(C)COC)=CC=3OCC)=[N:9]2)=CC=1.Cl.Cl.[CH3:40][S:41]([CH2:44][CH2:45]N1CCNCC1)(=[O:43])=[O:42]>>[CH3:40][S:41]([CH2:44][CH2:45][N:9]1[CH2:8][CH2:12][N:11]([CH:20]=[O:21])[CH2:10][CH2:23]1)(=[O:43])=[O:42]
Reactant: CCOc1cc(C(C)(C)COC)ccc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)CCN1CCNCC1
Agent: Cl
Product: CS(=O)(=O)CCN1CCN(C=O)CC1
Yield: 300.4 %

Procedure:
4,5-Bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazole-1-carbonyl chloride (60 mg, 0.107 mmol, example 153) was reacted with 1-(2-methanesulfonyl-ethyl)piperazine dihydrochloride (42.5 mg, 0.161 mmol, example 17) using the procedure described in example 25 to give 4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone (70.8 mg) as white solids. The enantiomers were separated by chiral chromatography (Diacel ChiralPak OD, eluting with 40/60 hexane/ethanol). The first peak coming off the column is the desired {(4S,5R)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(2-methoxy-1,1-dimethyl-ethyl)-phenyl]-4,5-dihydro-imidazol-1-yl}-[4-(2-methanesulfonyl-ethyl)-piperazin-1-yl]-methanone (32.1 mg, white solids). HR-MS (ES, m/z): observed 715.2485, calculated for C36H45Cl2N4O5S [(M+H)+] 715.2482.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12]([CH3:14])[N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc(C)c[nH]2)cc1
Reactant: O=[N+]([O-])O
Product: COc1ccc(-c2nc(C)c([N+](=O)[O-])[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
A mixture of 2-(p-methoxyphenyl)-4-methylimidazole (5.2 g, 0.0277 mole) and 3N HNO3 (125 ml) was stirred at room temperature. After 15 minutes, the mixture was placed in a preheated 90° C. bath. Heating was continued for 20 minutes and the hot solution was continued for 20 minutes and the hot solution was quenched in ice-water (250 ml). The yellow solid was collected, washed with water, and suspended in cold saturated NaHCO3 solution (25 ml). After a 15 minute period of stirring, the product was collected and recrystallized from 50% EtOH to yield 1.6 g (25%) of 41; m.p. 198°-204° C. A sample recrystallized from 50% EtOH melted at 199°-204° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:23])[N:14]([CH2:15][C:16]([CH3:22])([CH3:21])[CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[CH3:25][O:26][NH2:27]>>[CH3:25][O:26][N:27]=[C:18]([CH2:17][C:16]([CH3:21])([CH3:22])[CH2:15][N:14]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=[C:13]1[CH3:23])[CH3:19]
Reactant: CC(=O)CC(C)(C)Cn1c(C)nc2c(N)nc3ccccc3c21
Reactant: CON
Agent: Cl
Product: CON=C(C)CC(C)(C)Cn1c(C)nc2c(N)nc3ccccc3c21

Procedure:
By the general method described in Part F Example 30, 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one was reacted with O-methylhydroxylamine hydrochloride to provide 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-4,4-dimethylpentan-2-one O-methyloxime as about a 4.9 to 1 mixture of E and Z isomers as light yellow needles after recrystallization from aqueous methanol, mp 193-195° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([S:12]CC2C=CC=CC=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:27])[C:3]=1[F:28].Cl.[N:30]([O-])=O.[Na+].C([O-])(O)=O.[Na+]>C(O)(=O)C.O>[F:28][C:3]1[C:2]2[N:1]=[N:30][S:12][C:11]=2[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27]
Reactant: COC(=O)c1cc(SCc2ccccc2)c(N)c(F)c1Nc1ccccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc2snnc2c(F)c1Nc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.1 %

Procedure:
To a solution of methyl 4-amino-5-(benzylthio)-3-fluoro-2-((2-chlorophenyl)amino)benzoate (2.50 g, 5.99 mmol) in acetic acid (60 mL) was added con. HCl (8 mL). The resultant was stirred at ambient temperature for 1 h. A solution of NaNO2 (0.45 g, 6.58 mmol) in water (10 mL) was added dropwisely at 0° C. in 20 min. After stirring for 3 h, the reaction was treated with saturated NaHCO3 (aq.) till the solution was neutral. The aqueous layer was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with water (30 mL) and brine (30 mL) sequentially, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel (petroleum ether/ethyl acetate, 5:1, v/v) to give the corresponding product (yellow solid, 1.82 g, 90.1% yield). 1H NMR (400 MHz, CDCl3): δ 8.83 (s, 1H), 8.59 (d, 1H), 7.45 (m, 1H), 7.24 (m, 1H), 6.95 (m, 2H), 4.03 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH:32]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH:32]([N:45]1[CH2:50][CH2:49][N:48]([C:21]([C:20]2[CH:24]=[CH:25][CH:26]=[C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:29])([F:31])[F:30])[C:9]=4[CH:17]=3)[CH:19]=2)=[O:22])[CH2:47][CH2:46]1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 1-benzhydrylpiperazine as in General Procedure 10 to give the title compound. LCMS: m/z=680.97 (M+H+); retention time=1.03 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:17])[CH2:9][CH2:10][N:11]([CH2:13][CH2:14][C:15]#[N:16])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]>N.[Ni]>[NH2:16][CH2:15][CH2:14][CH2:13][N:11]([CH3:12])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH3:17]
Reactant: CN(CCC#N)CCN(C)C(=O)OC(C)(C)C
Agent: [Ni]
Agent: N
Product: CN(CCCN)CCN(C)C(=O)OC(C)(C)C
Yield: 99.9 %

Procedure:
1.9 g of N-(tert-butoxycarbonyl)-N'-(2-cyanoethyl)-N,N'-dimethyl-ethylenediamine (Example 25-b) were dissolved in 100 ml of saturated methanolic ammonia and hydrogenated with 5 g of Raney nickel at RT under 10 atmospheres of H2 for 24 hours. The catalyst was filtered off and washed with MeOH and the filtrate was concentrated in vacuo. The residue was taken up in toluene, insoluble material was filtered off, the filtrate was concentrated in vacuo and the residue was dried. 1.93 g of product were obtained.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][CH:57]=1)[N:54]=[C:53]([CH2:58][CH:59]([CH3:61])[CH3:60])[C:52]([C:62]#[N:63])=[C:51]2[C:64]1[CH:69]=[CH:68][C:67]([CH3:70])=[CH:66][CH:65]=1.[NH:71]1[CH2:76][CH2:75][NH:74][CH2:73][C:72]1=[O:77].C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH2:58]([C:53]1[C:52]([C:62]#[N:63])=[C:51]([C:64]2[CH:69]=[CH:68][C:67]([CH3:70])=[CH:66][CH:65]=2)[C:50]2[C:55](=[CH:56][CH:57]=[C:48]([N:74]3[CH2:75][CH2:76][NH:71][C:72](=[O:77])[CH2:73]3)[CH:49]=2)[N:54]=1)[CH:59]([CH3:60])[CH3:61]
Reactant: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(Br)cc23)cc1
Reactant: O=C1CNCCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(C#N)c(CC(C)C)nc3ccc(N4CCNC(=O)C4)cc23)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
Palladium acetate (0.014 g, 0.063 mmol) and racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.12 g, 0.19 mmol) were added to 1,4-dioxane (30 ml) under a nitrogen atmosphere, and the mixture was stirred at 40° C. for 30 min. The reaction mixture was cooled to room temperature and 6-bromo-2-isobutyl-4-(4-methylphenyl)quinoline-3-carbonitrile (0.50 g, 1.3 mmol), 2-piperazinone (0.50 ml, 5.0 mmol) and cesium carbonate (0.57 g, 1.8 mmol) were added. The mixture was stirred under a nitrogen atmosphere at 80° C. for 2 days. The reaction mixture was cooled and partitioned between ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give 2-isobutyl-4-(4-methylphenyl)-6-(3-oxopiperazin-1-yl)quinoline-3-carbonitrile (0.35 g, yield 71%) as a yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]2=[O:17].[CH2:18](Br)[CH:19]=[CH2:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[S:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6][C:5]2=[O:17])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: CCOC(=O)c1cc(=O)c2cc(O)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1ccc2sc(C(=O)OCC)cc(=O)c2c1

Procedure:
A mixture of 12.5 parts of ethyl 6-hydroxy-1-thiachromone-2-carboxylate, 6.8 parts of allyl bromide and 9.7 parts of anhydrous potassium carbonate in 80 parts of acetone was heated under reflux for 20 hours. The mixture was filtered and the solution was evaporated. The residual material was dissolved in chloroform and the solution was washed with water, then the chloroform was evaporated and the remaining material was crystallised from ethanol to give 11.8 parts of ethyl 6-allyloxy-1-thiachromone-2-carboxylate, melting point, 107.5°-8°C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)([O-:13])(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O[C@H]1CCN(Cc2ccccc2)C1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 98 %

Procedure:
This was prepared from (S)-1-benzyl-3-pyrrolidinol and p-toluenesulfonyl chloride in 98% yield according to the procedures similar to those described in Preparation 24.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3OS(C(F)(F)F)(=O)=O)[CH2:12]2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH3:38])[N:32]=1>CC([O-])=O.CC([O-])=O.[Pd+2].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:12][C:13]3[C:18](=[C:17]([NH:29][CH2:30][C:31]4[CH:36]=[CH:35][N:34]=[C:33]([NH:37][CH3:38])[N:32]=4)[CH:16]=[CH:15][CH:14]=3)[C:19]2=[O:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1nccc(CN)n1
Reactant: CC(C)(C)c1ccc(N2Cc3cccc(OS(=O)(=O)C(F)(F)F)c3C2=O)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CNc1nccc(CNc2cccc3c2C(=O)N(c2ccc(C(C)(C)C)cc2)C3)n1

Procedure:
Trifluoromethanesulfonic acid 2-(4-t-butyl-phenyl)-3-oxo-2,3-dihydro-1H-isoindol-4-yl ester (42 mg, Step A), (4-aminomethyl-pyrimidin-2-yl)-methyl-amine (19.2 mg), Pd(OAc)2 (3.4 mg), dppf (9.5 mg), CeCO3 (70 mg) and toluene (1 mL) were put into a microwave reaction tube and subjected to 120° C., for a total of 55 min of microwave. The solid was removed by filtration and solvent was evaporated. The resulting residue was purified by Gilson HPLC purification system to obtain 2-(4-t-butyl-phenyl)-7-[(2-methylamino-pyrimidin-4-ylmethyl)-amino]-2,3-dihydro-isoindol-1-one.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:31]2([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:11][C:10]=1[O:38][C:39]([F:42])([F:41])[F:40])C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[OH:37][C:31]1([CH:15]([C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([O:38][C:39]([F:41])([F:42])[F:40])[CH:11]=2)[C:16]([N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]2)=[O:17])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2ccc(OCc3ccccc3)c(OC(F)(F)F)c2)C2(O)CCCCC2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(c2ccc(O)c(OC(F)(F)F)c2)C2(O)CCCCC2)CC1
Yield: 70.7 %

Procedure:
A mixture of tert-Butyl 4-[[4-(benzyloxy)-3-(trifluoromethoxy)phenyl](1-hydroxycyclohexyl)acetyl]piperazine-1-carboxylate (1.7 g, 2.87 mmol) (See Example 268, Step 5), ammonium formate (0.95 g, 15.0 mmol), and a catalytic amount of palladium on carbon was heated at 50° C. for 1 hr in methanol (25 mL). At the end of this time the solution was concentrated and the residue taken up in ethyl acetate and filtered through a plug of silica gel eluting with 30% ethyl acetate:hexane. The filtrate was concentrated to afford 1.02 g of tert-butyl 4-[(1-hydroxycyclohexyl)[4-hydroxy-3-(trifluoromethoxy)phenyl]acetyl}piperazine-1-carboxylate. MS (ESI) m/z 503; HRMS: calcd for C24H33F3N2O6+H+, 503.23635; found (ESI, [M+H]+), 503.2343.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1.[NH:21]([CH3:46])[C@H:22]([C:26]([N:28]([CH3:45])[C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:40])[CH3:39])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24].O>C1COCC1>[NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:11]([N:21]([CH3:46])[C@H:22]([C:26]([N:28]([CH3:45])[C@H:29]([C:42]([NH2:44])=[O:43])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([C:38]([CH3:41])([CH3:39])[CH3:40])[CH:32]=1)=[O:27])[CH:23]([CH3:25])[CH3:24])=[O:13])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[CH:5]=1
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccc(F)c1)C(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1cccc(F)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of Boc-Phe(3-F)—OH (0.20 g, 0.706 mmol), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.21 g, 0.578 mmol) and CMPI (0.20 g, 0.783 mmol) in THF (6 ml), TEA (0.30 ml, 2.15 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol:aqueous ammonia=60:1:0.05) to give Boc-Phe(3-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (0.33 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][N:31]([C:25]4[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=4[CH3:23])[CH2:32][CH2:33]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(-c4ccccc4)n3)CC2)c(C)c1

Procedure:
96 mg (70%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.272 mmol), 1-(2,4-dimethylphenyl)piperazine (52 mg, 0.272 mmol), DIPEA (0.071 mL, 0.408 mmol) and NaBH(OAc)3 (173 mg, 0.816 mmol).
Reaction SMILES: [Br:1][C:2]1[C:7](F)=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[F:12].C(=O)([O-])[O-].[NH4+].[NH4+].C[N:20](C=O)C.CCN(CC)CC>O>[Br:1][C:2]1[C:3]([F:12])=[CH:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:20]
Reactant: CN(C)C=O
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1F
Agent: O=C([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1c([N+](=O)[O-])ccc(F)c1Br
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
Prepared according to WO 2010/046388. 2-Bromo-1,3-difluoro-4-nitrobenzene (600a) (27.15 g, 114 mmol) was treated with ammonium carbonate (Sigma Aldrich, 10.96 g, 114 mmol) and DMF (200 mL) followed by Et3N (47.7 mL, 342 mmol) and stirred at RT for 48 h. The mixture was treated with water and extracted with DCM (300 mL). The DCM layer was washed with water (3×200 mL) and brine (3×200 mL), dried over MgSO4, filtered and concentrated affording crude 2-bromo-3-fluoro-6-nitroaniline (25.99 g, 111 mmol, 97% yield) as a bright yellow amorphous solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.22 (1H, dd, J=9.6, 5.9 Hz), 6.81 (2H, br. s.), 6.56 (2H, dd, J=9.6, 7.2 Hz). 19F NMR (376 MHz, CDCl3) δ ppm −90.92 (1F, s). m/z (ESI, +ve ion) 234.9/236.9 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH2:16][C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20][CH2:21][O:22][CH3:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].[Li+].[CH3:25]C([N-]C(C)C)C.C(=O)=O.CC(C)=O.IC.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH2:1]([C:5]12[CH2:17][CH:16]([CH3:25])[C:15](=[O:18])[C:14]([CH3:19])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:20][CH2:21][O:22][CH3:23])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12CCC(=O)C(C)=C1c1ccc(OCOC)cc1C2
Reactant: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CC(C)=O
Product: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(C)C2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 9a-butyl-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (162 mg, 0.52 mmol) in anhydrous THF (2.5 mL) was cooled in an ice bath and stirred under a nitrogen atmosphere while 0.4M LDA in THF (1.55 mL, 0.62 mmol) was added by syringe. After stirring at 0° C. for 30 minutes, the solution was cooled to −78° C. (dry ice-acetone bath) and treated with iodomethane (0.162 mL, 2.6 mmol). The resulting mixture was allowed to slowly warm to room temperature, then stirred at room temperature overnight. The mixture was diluted with EtOAc (60 mL) and shaken with saturated aqueous NH4Cl (40 mL). The aqueous phase was extracted with more EtOAc (20 mL). The combined organics were washed with 5% NaHCO3, water, and brine, dried over MgSO4, filtered, and concentrated under vacuum to a yellow oil. The crude product was purified by preparative layer chromatography (PLC) on a 0.1×20×20 cm silica gel GF plate using 4:1 hexanes-EtOAc as developing solvent. The band at Rf 0.44-0.56 was extracted with EtOAc and the extracts evaporated under vacuum to provide (2SR,9aSR)-9a-butyl-2,4-dimethyl-7-methoxymethoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one (111 mg) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]([OH:17])[CH2:8][CH2:9][NH:10][C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[S:5][CH:6]=1.[C:18]([C:20]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)#[CH:19]>CCN(CC)CC.[Cu]I>[F:13][C:12]([F:15])([F:14])[C:11]([NH:10][CH2:9][CH2:8][CH:7]([OH:17])[C:4]1[S:5][CH:6]=[C:2]([C:19]#[C:18][C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:3]=1)=[O:16]
Reactant: C#CC1(O)CCCCC1
Reactant: O=C(NCCC(O)c1cc(Br)cs1)C(F)(F)F
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: O=C(NCCC(O)c1cc(C#CC2(O)CCCCC2)cs1)C(F)(F)F
Reaction time: 8 h

Procedure:
Solution of N-(3-(4-bromothiophen-2-yl)-3-hydroxypropyl)-2,2,2-trifluoroacetamide (0.77 g, 2.32 mmol) and 1-ethynylcyclohexanol (0.48 g, 3.87 mmol) in Et3N (10 mL) was degassed by bubbling Ar for 5 min. CuI (0.0482 g, 0.253 mmol) and PdCl2(Ph3P)2 (0.0874 g, 0.125 mmol) were added to the reaction mixture and degassed by alternating vacuum/Ar once. The reaction mixture was stirred at +80° C. overnight, partitioned between EtOAc and aqueous NH4Cl (25%). Aqueous layer was additionally extracted with EtOAc and combined organic layers were washed with brine. Concentration under reduced pressure followed by flash chromatography purification (10%-75% EtOAc—hexanes gradient) gave 2,2,2-trifluoro-N-(3-hydroxy-3-(4-((1-hydroxycyclohexyl)ethynyl)thiophen-2-yl)propyl)acetamide as a light yellow oil. Yield (0.52 g, 60%); 1H NMR (400 MHz, DMSO-d6) δ 9.37 (br.s, 1H), 7.52 (d, J=1.3 Hz, 1H), 6.92 (d, J=1.3 Hz, 1H), 5.78 (d, J=4.7 Hz, 1H), 5.34 (s, 1H), 4.74-4.81 (m, 1H), 3.20-3.30 (m, 2H), 1.84-1.91 (m, 2H), 1.74-1.84 (m, 2H), 1.56-1.65 (m, 2H), 1.38-1.56 (m, 6H).
Reaction SMILES: N1C=CC=CC=1.[NH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1.[CH2:24]([O:28][C:29](Cl)=[O:30])[CH:25]([CH3:27])[CH3:26]>C(Cl)Cl>[CH2:24]([O:28][C:29]([N:7]1[CH2:12][CH2:11][CH:10]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:9][CH2:8]1)=[O:30])[CH:25]([CH3:27])[CH3:26]
Reactant: c1cc(-c2noc(C3CCNCC3)n2)ccn1
Reactant: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)COC(=O)N1CCC(c2nc(-c3ccncc3)no2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of pyridine (18 μl, 0.22 mmol) and 4-(5-piperidin-4-yl-[1,2,4]oxadiazol-3-yl)pyridine (Example 51, 50 mg, 0.22 mmol) in CH2Cl2 (4 ml) was treated with isobutylchloroformate (54 mg, 0.43 mmol). The reaction was stirred at rt for 18 h then quenched with saturated aqueous NaHCO3 (1 ml). The organic phase was separated, evaporated and the residue purified by flash chromatography (IH-EtOAc, 1:1 to 0:1) to afford the title compound: RT=3.42 min, m/z (ES+)=331.2 [M+H]+.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=O)[CH:2]([CH3:4])[CH3:3].C(O)=O.C(OCC)C.C([NH2:22])=O>O>[CH3:3][CH:2]([CH3:4])[CH:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:22]
Reactant: CC(C)C(=O)c1ccccc1
Reactant: NC=O
Solvent: O=CO
Solvent: CCOCC
Solvent: O
Product: CC(C)C(N)c1ccccc1
Reaction time: 48 h
Yield: 61 %

Procedure:
A solution of isobutyrophenone (5.1 mL, 33.7 mmol) and formic acid (1.3 mL, 33.7 mmol) in formamide was stirred at 165-180° C. for 20 h. The mixture was cooled, diluted with water, and extracted with benzene. The benzene was concentrated down and the residue was boiled in 3 M HCl (10 mL) for 48 h. The cooled reaction mixture was added to diethyl ether and extracted with water. The combined water extracts were basified with 20% NaOH, and extracted with dichloromethane. The combined extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo to yield 3.09 g (61%) of the desired amine: 1H NMR (400 MHz, CD3OD): δ 7.33-7.23 (m, 4H), 7.22-7.20 (m, 1H), 3.49 (d, 1H), 1.87 (m, 1H), 1.00 (d, 3H), 0.73 (d, 3H). MS (ESI) m/z: Calculated: 149.12; Observed: 149.9 (M++1).