Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C1C=CC(C(=O)C)=CC=1.C(O)(=O)C.[Br:18]Br.[Br:20][CH2:21][C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=1)=[O:23]>C(#N)C.O.O>[Br:20][CH:21]([Br:18])[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=1)=[O:23]
Reactant: BrBr
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Agent: CC(=O)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: O=C(c1ccc(C(F)(F)F)cc1)C(Br)Br
Temperature: 25 °C

Procedure:
This compound was synthesised by the general procedure represented in Scheme 2, a stirred solution of 1-(4-trifluoromethyl-phenyl)-ethanone (1 g, 5.3 mmol) ) and acetic acid (50 ml) was refluxed 1 h, then bromine (0.35 ml, 6.9 mmol) was added dropwise and the mixture refluxed 3 h. After cooling at room temperature, water (50 ml) was added and the mixture extracted with CH2Cl2 (50 ml), the organic layer was washed with water (50 ml), a solution of NaHCO3 saturated (50 ml) and finally with NaCl solution (50 ml), the organic layer was dried over sodium sulphate and the solvent evaporated under reduced pressure. The resulting residue was purified by column chromatography, using a mixture of ethyl acetate:hexane (1:8) as eluent giving two compounds, the titled compound 41 as a yellow solid (45%) m.p.: 40-41° C., 1H-NMR (CDCl3): δ8.2 (d, J=8.3 Hz, 2H, Ar), 7.8 (d, J=8.3 Hz, 2H, Ar), 6.6 (s, 1H, CH); 13C-NMR (CDCl3): δ184.1 (CO), 134.7 (q, J=272.9 Hz, C—CF3), 132.7 (C—CO), 129.2 (CH), 124.8 (CH), 119.5 (q, J=33.09, CF3), 38.2 (CH); M/z (EI): 348, 346, 344 (M+, 1, 6, 1%), 173 (M-CHBr2, 100%); HPLC: Column μ Bondapack C18, 5 μm, 300 A, (300×3.9 mm), Purity 97%, r.t.=9.96 min, acetonitrile/H2O (0.05% H3PO4+0.04% Et3N) 50/50. The second compound was identified as 2-bromo-1-(4-trifluoromethyl-phenyl)-ethanone (0,6%), described as the example 40.
Reaction SMILES: Br[C:2]1[C:3]([OH:13])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].[Cu](C#N)[C:15]#[N:16]>CN1CCCC1=O.C(OCC)(=O)C.Cl>[C:10]([C:4]1[C:3]([OH:13])=[C:2]([C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)[C:15]#[N:16])(=[O:12])[CH3:11]
Reactant: CC(=O)c1cc(Cl)c(C)c(Br)c1O
Reactant: N#C[Cu]C#N
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(=O)c1cc(Cl)c(C)c(C#N)c1O
Temperature: 200 °C
Yield: 98.1 %

Procedure:
A mixture of 1-(3-bromo-5-chloro-2-hydroxy-4-methylphenyl)ethanone (4.9 g, 18 mmol) and copper cyanide (2.5 g, 28 mmol) in N-methylpyrrolidinone (15 mL) was heated at 200° C. for 1 hour. The resulting mixture was allowed to cool to room temperature and was then diluted with ethyl acetate and 1 N HCl. The organic and aqueous layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate and concentrated to dryness under reduced pressure to give 3-Acetyl-5-chloro-2-hydroxy-6-methylbenzonitrile (3.7 g, 96%). LCMS calculated for C10H9ClNO2 (M+H)+: m/z=210.0. found: 210.1.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH:11][NH:12][C:13]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)=O)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.CC1(C)[SiH2][SiH]=NC(C)(C)C1(C)C>>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:13]1[N:3]=[C:4]2[N:11]([C:2]([NH2:1])=[N:7][C:6]3[NH:8][CH:9]=[CH:10][C:5]=32)[N:12]=1
Reactant: Nc1nc(NNC(=O)c2ccco2)c2cc[nH]c2n1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: CC1(C)N=[SiH][SiH2]C(C)(C)C1(C)C
Product: Nc1nc2[nH]ccc2c2nc(-c3ccco3)nn12
Temperature: 120 °C

Procedure:
A mixture of the title A compound, N′-(2-amino-7H-pyrrolo[2,3-d]pyrimidin-4-yl)furan-2-carbohydrazide (0.4 g, 1.55 mmol), N,O-bis(trimethylsilyl)acetamide (1.89 g, 9.3 mmol) and 2 mL of hexamethyldisilazine is heated at 120° C. overnight. After removing volatiles under vacuum, the residue is washed with 5 mL of water and the collected solid is purified by flash chromatography using EtOAc/MeOH (95/5) as eluent to give 2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=241.0). 1H NMR (DMSO-d6, 400 MHz) δ 6.57 (m, 1H), 6.70 (m, 1H), 7.01 (m, 1H), 7.18 (m, 1H), 7.36 (br s, 2H, NH2), 7.89 (s, 1H), 11.6 (br s, NH-pyrrole).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:21]([NH:23][C@H:24]([C:28]([NH:30][C@H:31]([C:33]([O:35][CH3:36])=[O:34])[CH3:32])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)=O)C1C=CC=CC=1>CN(C)C=O.[Pd]>[NH2:11][C@H:12]([C:21]([NH:23][C@H:24]([C:28]([NH:30][C@H:31]([C:33]([O:35][CH3:36])=[O:34])[CH3:32])=[O:29])[CH:25]([CH3:26])[CH3:27])=[O:22])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1)C(C)C
Agent: [Pd]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(C)C

Procedure:
2.99 g (6.0 mmol) of methyl benzyloxycarbonyl-L-tyrosyl-L-valyl-L-alaninate (Example 1, Step A2) are dissolved in 30 ml of dimethylformamide, 0.2 g of Pd/C catalyst is added, then the mixture is submitted to hydrogenation at about 20° C. The catalyst is filtered off and the filtrate is evaporated at a pressure of 2.0-2.5 kPa. The residue is rubbed with diethyl ether, filtered, washed with diethyl ether and dried in a vacuum desiccator.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O(CC)CC.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27](OCC)=O)[CH2:23][CH2:22]1>O>[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[NH:20][CH:21]1[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]1
Reactant: CCOC(=O)N1CCC(Nc2c(C)cccc2C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1cccc(C)c1NC1CCN(C)CC1
Temperature: 5 °C
Reaction time: 20 h

Procedure:
To a stirred and refluxing suspension of 2 parts of lithium aluminiumhydride in 120 parts of 1,1'-oxybisethane is added dropwise a solution of 13 parts of ethyl 4-[N-(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate in 40 parts of 1,1'-oxybisethane. After the addition is complete, stirring and refluxing is continued for 20 hours. The reaction mixture is cooled to 5° C. and 7 parts of water are added. The formed precipitate is filtered off, washed on the filter with 1,1'-oxybisethane and the filtrate is evaporated. The oily residue is distilled, yielding 5.8 parts of N-(2,6-dimethylphenyl)-1-methyl-4-piperidinamine; bp. 90°-93° C. at 0.003 mm. pressure. On standing the distillate solidifies, to yield solid N-(2,6-dimethylphenyl)-1-methyl-4-piperidinamine with a melting point of 45° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][N:15]=[C:16]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:11][C:10]=1[O:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=C2C(=CC=1OC)C(C1C=CC=CC=1)=NCC2)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH:16]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][C:10]=1[O:25][CH3:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(cc1OCc1ccccc1)C(c1ccccc1)=NCC2
Agent: COc1cc2c(cc1OCc1ccccc1)CCN=C2c1ccccc1
Product: COc1cc2c(cc1OCc1ccccc1)C(c1ccccc1)NCC2

Procedure:
Substitution of a like quantity of 7-benzyloxy-6-methoxy-1-phenyl-3,4-dihydroisoquinoline for the 6-benzyloxy-7-methoxy-1-phenyl-3,4-dihydroisoquinoline used above and substantial repetition of the foregoing procedure affords 7-benzyloxy-6-methoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline, melting at about 123°-125°C.
Reaction SMILES: [CH:1]([NH:3][CH2:4][CH:5]([NH:16]C(=O)OC(C)(C)C)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=[O:2].[ClH:24]>ClCCl.O1CCOCC1>[ClH:24].[NH2:16][CH:5]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:7]=1)[CH2:4][NH:3][CH:1]=[O:2]
Reactant: CC(C)(C)OC(=O)NC(CNC=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(CNC=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Of the compound from Example 23A, 66 mg (0.2 mmol) were introduced in 1.5 ml of dichloromethane and admixed at RT with 1.56 ml of a 4N solution of hydrogen chloride in dioxane. The reaction mixture was stirred at RT for 1 h. The reaction mixture was freed from the volatile components on a rotary evaporator and dried in an HV. This gave 50 mg (94% of theory) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([CH2:13][OH:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([CH:13]=[O:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1c(OC)nc2nc(CO)cn2c1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCc1c(OC)nc2nc(C=O)cn2c1C
Yield: 72.1 %

Procedure:
To a solution of 15.25 g (69 mmol) of 6-ethyl-7-methoxy-5-methylimidazo-[1,2-a]pyrimidin-2-yl methanol in 200 ml of chloroform was added 40 g of activated manganese dioxide and the stirred mixture was refluxed for 18 hours. A further 20 g of the oxidizing agent were added and the mixture was refluxed for a further 4 hours. The cooled mixture was filtered through celite and the filtrate was evaporated to obtain 10.9 g (72% yield) of 6-ethyl-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxaldehyde as a white crystalline solid melting at 185°-186° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:37])=[C:4]([CH:23]2[CH2:26][N:25](C(OCC3C=CC=CC=3)=O)[CH2:24]2)[C:5]([O:20][CH2:21][CH3:22])=[C:6]([CH:8]([NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][NH:15]3)[CH3:9])[CH:7]=1.Cl.O>CO.[Pd]>[NH:25]1[CH2:26][CH:23]([C:4]2[C:5]([O:20][CH2:21][CH3:22])=[C:6]([CH:8]([NH:10][C:11]3[N:19]=[CH:18][N:17]=[C:16]4[C:12]=3[N:13]=[CH:14][NH:15]4)[CH3:9])[CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:37])[CH2:24]1
Reactant: CCOc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CCOc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(C)c1C1CNC1
Reaction time: 8 h

Procedure:
Benzyl 3-{3-chloro-6-ethoxy-2-methyl-5-[1-(9H-purin-6-ylamino)ethyl]phenyl}azetidine-1-carboxylate (83 mg, 0.16 mmol) and 5% palladium (74 mg) was combined in methanol (5 mL), to which was added 0.25 M HCl in water (1.6 mL, 0.40 mmol). The suspension was hydrogenated under balloon pressure of H2 at room temperature overnight. The suspension was filtered and concentrated to give N-[1-(3-azetidin-3-yl-5-chloro-2-ethoxy-4-methylphenyl)ethyl]-9H-purin-6-amine. LCMS calculated for C19H24ClN6O (M+H)+: m/z=387.2. found: 387.1. The azetidine made above was combined with DIPEA (0.1 mL, 0.6 mmol) in methanol (0.5 mL)/acetonitrile (0.5 mL)/THF (0.5 mL), followed by the addition of 37% formaldehyde (0.1 mL, 2 mmol). The mixture was stirred at room temperature for 10 min before the addition of sodium triacetoxyborohydride (0.17 g, 0.80 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with MeOH and purified on RP-HPLC (XBridge C18 Column, eluting with a gradient of acetonitrile in water with 0.2% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. LCMS calculated for C20H26ClN6O (M+H)+: m/z=401.2. found: 401.1.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:17][N:18]([CH3:23])[S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:17][N:18]([CH3:23])[S:19]([N:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1)(=[O:21])=[O:20]
Reactant: c1nc2c([nH]1)CCCC2
Reactant: CN(C)S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)n1cnc2c1CCCC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 76.9 %

Procedure:
To solution of 4,5,6,7-tetrahydro-1H-benzoimidazole (1.9992 g, 16.4 mmol) and triethylamine (4.60 mL, 32.8 mmol) in CH2Cl2 (20 mL) at 0° C. was added dropwise a solution of dimethyl sulfamoyl chloride (1.76 mL, 16.4 mmol) in CH2Cl2 (10 mL). The reaction was warmed to room temperature and stirred for 3.5 hours. CH2Cl2 (80 mL) was added and the organic phase was washed with distilled water (1×80 mL). The aqueous washing was extracted with CH2Cl2 (2×40 mL), and the combined organic extracts were washed with brine (1×80 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (2:1 hexanes-EtOAc) provided 2.89 g (77%) of 4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide as a white solid. 1H NMR (CDCl3) δ 1.77-1.86 (m, 4H), 2.58-2.61 (m, 2H), 2.72 (t, 2H, J=6 Hz), 2.87 (s, 6H), 7.77 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([CH:13]=O)[O:11][C:10]([CH3:16])([CH3:15])[N:9]2[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br-].[CH2:25]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:26][CH3:27].[NH2-].[Na+]>O1CCCC1>[CH:13](/[C@H:12]1[O:11][C:10]([CH3:16])([CH3:15])[N:9]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[C@H:8]1[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[CH:25]/[CH2:26][CH3:27]
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](C=O)OC1(C)C
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC/C=C\[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1.4 g (4.3 mmol) of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-formyl-2,2-dimethyl-3-oxazolidinecarboxylate (WO 87/05302) and 1.79 g (4.3 mmol) of instantylide, consisting of propyltriphenylphosphonium bromide and sodium amide, in 50 ml of tetrahydrofuran is stirred at room temperature under nitrogen for 30 minutes. Subsequently, the reaction mixture is partitioned between water and ethyl acetate. The organic phase is separated, dried over sodium sulphate and evaporated under reduced pressure. For purification, the residue is chromatographed on 80 g of silica gel using a 1:1 mixture of methylene chloride and petroleum ether as the eluent. There are obtained 900 mg of tert-butyl (4S,5R)-5-[(Z)-1-butenyl]-4-(cyclohexylmethyl)-2,2-dimethyl-3-oxazolidinecarboxylate as a resin; MS: 352 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH2:8]([N:11]=[C:12]=[O:13])[CH2:9][CH3:10]>>[CH2:8]([NH:11][C:12]([N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)=[O:13])[CH2:9][CH3:10]
Reactant: CCCN=C=O
Reactant: O=C1CCNCC1
Product: CCCNC(=O)N1CCC(=O)CC1

Procedure:
To piperid-4-one (11.8 g) was added n-propyl isocyanate in small portions at room temperature with stirring. After stirring 48 hr the solvent was removed in vacuo, and the residue was treated with diethyl ether, yielding (D.31) (19.1 g, 86%) as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:23])([CH3:22])[CH3:21])[N:15]=2)[CH:3]=1.CO.[NH3:26]>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:26])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([OH:23])([CH3:22])[CH3:21])[N:15]=2)[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C(C)(C)O)n1
Solvent: CO
Product: CC(C)(O)c1cccc(Nc2cc(Cl)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.3 %

Procedure:
In a 50 mL round bottom flask, ethyl 6-chloro-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxylate (792 mg, 2.35 mmol) was suspended in ammonia 7M in methanol (7.87 g, 10.0 mL, 70.0 mmol). Sealed and stirred at room temperature for 5 h. The solvents were evaporated and the residue purified by flash chromatography (spherical silica 20-45 μM, 50 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2 to give 6-chloro-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide (241 mg, 33.3% yield) as an off-white solid. 1H NMR (CHLOROFORM-d) δ: 11.64 (s, 1H), 8.96 (s, 1H), 8.18 (br. s., 1H), 7.71 (t, J=7.9 Hz, 1H), 7.25 (d, J=7.6 Hz, 1H), 6.86 (d, J=8.3 Hz, 1H), 5.70 (br. s., 1H), 1.64 (s, 6H); LC-MS 308.0, 310.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:11]([N:6]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5]1[C:7]([F:9])=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[F:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cc(Br)cc(F)c1N(Cc1ccccc1)Cc1ccccc1
Yield: 85.6 %

Procedure:
A suspension of 416 g of 4-bromo-2,6-difluoroaniline, 752 g of benzyl bromide and 608 g of potassium carbonate in 2 l of acetonitrile is refluxed for 48 hours. The mixture is subsequently evaporated in a rotary evaporator, the residue is dissolved in toluene and extracted with hydrochloric acid (10%), the toluene phase is evaporated in a rotary evaporator, and the product is stirred into heptane and stirred with silica gel for about 4.5 hours, filtered with suction and evaporated in a rotary evaporator, giving dibenzyl(4-bromo-2,6-difluorophenyl)amine, yield 85.6%.
Reaction SMILES: [N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1[CH:11]=O)=[N+:2]=[N-:3].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1[NH2:21].C(N(CC)CC)C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:1]([C:4]1[C:9]([F:10])=[CH:8][N:7]=[CH:6][C:5]=1/[CH:11]=[N:21]/[C:15]1[C:16]([F:20])=[CH:17][CH:18]=[CH:19][C:14]=1[Cl:13])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1c(F)cncc1C=O
Reactant: Nc1c(F)cccc1Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=Nc1c(F)cncc1/C=N/c1c(F)cccc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 4-azido-5-fluoropyridine-3-carbaldehyde (10.0 g, 60.0 mmol) and 2-chloro-6-fluorophenylamine (8.7 g, 60.0 mmol) in DCM (200 mL) was cooled to 0° C. under an atmosphere of nitrogen. Triethylamine (25 mL, 180 mmol) was added, followed by titanium (IV) chloride solution (1 N in DCM, 36 mL, 36 mmol) dropwise. The reaction mixture was stirred at 0° C. then allowed to reach room temperature overnight. The resultant mixture was concentrated under reduced pressure and the residue was suspended in toluene and filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to afford the title compound which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][CH:35]=[CH:34][C:3]=1[C:4]([C:6]1[C:7]([O:31][CH2:32][CH3:33])=[N:8][N:9]([C:22]2[C:27]([Cl:28])=[CH:26][C:25]([Cl:29])=[CH:24][C:23]=2[Cl:30])[C:10]=1[N:11]1C(=O)C2=CC=CC=C2C1=O)=[O:5].O.NN>C(O)C>[NH2:11][C:10]1[N:9]([C:22]2[C:23]([Cl:30])=[CH:24][C:25]([Cl:29])=[CH:26][C:27]=2[Cl:28])[N:8]=[C:7]([O:31][CH2:32][CH3:33])[C:6]=1[C:4](=[O:5])[C:3]1[CH:34]=[CH:35][CH:36]=[CH:37][C:2]=1[Cl:1]
Reactant: CCOc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N2C(=O)c3ccccc3C2=O)c1C(=O)c1ccccc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1C(=O)c1ccccc1Cl

Procedure:
A suspension of 184 mg of the compound of Step D in 10 mL of ethanol was treated with 0.5 mL of 55% hydrazine hydrate and refluxed for 1 hour. Solids in the cooled reaction mixture were filtered off and discarded and the filtrate was evaporated to a gum which was triturated with ether and filtered. The filtrate was again evaporated to a foam which was shown to be 104 mg of the analytically pure title compound. Anal. Calcd. for C18H13O2N3Cl4 : C, 48.57; H, 2.94; N, 9.44. Found, C, 48.41; H, 2.52; N, 9.43.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.C([Si](C)(C)C)#C.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][CH2:19][C:20](=[O:21])[C:13]=12>C1COCC1.O>[C:1]([C:20]1([OH:21])[C:13]2=[N:12][CH:17]=[CH:16][CH:15]=[C:14]2[CH2:18][CH2:19]1)#[CH:2]
Reactant: [Li]CCCC
Reactant: O=C1CCc2cccnc21
Agent: C#C[Si](C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: C#CC1(O)CCc2cccnc21
Temperature: 25 °C

Procedure:
This compound was prepared according to a procedure similar to that described in Procedure B. To a solution of 2.5 M n-butyllithium in hexanes (3.91 ml) in THF (3 ml) at −78° C. was added dropwise ethynyl(trimethyl)silane (1.28 ml, 9.01 mmol). The reaction was stirred at −78° C. for 10 min before addition of a solution of 5,6-dihydro-7H-cyclopenta[b]pyridin-7-one (1 g, 7.51 mmol) in THF (7 ml). The reaction mixture was stirred and allowed to warm up to RT for 3 hr. The mixture was then diluted with water and the volatiles removed. The product was extracted with CHCl3:IPA (2:1 ratio, 2×25 ml). The organic phase was washed with water (20 mL) followed by brine (20 mL); dried over (Na2SO4), and the solvent removed in vacuo. Purification by column chromatography (25 g Isolute column, 100% DCM to 5% MeOH in DCM) followed by the second column chromatography (30% EtOAc-heptane) gave the title compound: 1H NMR (500 MHz, CDCl3) δ 2.49 (1H, ddd, J=13.44, 8.24, 6.07 Hz), 2.63-2.76 (2H, m), 2.90-3.02 (1H, m), 3.03-3.13 (1H, m), 3.42 (1H, s), 7.22 (1H, dd, J=7.57, 4.89 Hz), 7.62 (1H, d, J=7.57 Hz), 8.51 (1H, d, J=4.73 Hz); LC-MS: 459.95 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[CH:18]([CH2:22][NH:23][CH:24]=O)[CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.B.C1COCC1.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:21]=[CH:20][C:19]3[CH:18]([CH2:22][NH:23][CH3:24])[CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=CNCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CNCC1CCCc2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a solution of 0.17 grams (0.469 mmoles) 3-fluoro-N-(5-formylaminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide in 5 mL THF was added 2 mL 1.0M borane-THF. The reaction mixture was stirred at 23° C. for 18 hours. 1.0 mL 6N hydrochloric acid was added and the mixture was heated under reflux for 15 minutes. The solution was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic phase was dried (magnesium sulfate) and concentrated under reduced pressure. 3-Fluoro-N-(5-methylaminomethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzenesulfonamide was isolated as the crystalline oxalate salt, 0.05 grams (24%), m.p. 135-136° C., M+H=349.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][C:20]([C:21](=[O:28])[NH:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:44]>C(OCC)(=O)C>[ClH:44].[ClH:44].[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][NH:22][C:21]([C:20]1[N:19]=[C:18]([C:29]([F:30])([F:31])[F:32])[N:15]2[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][C@H:8]([NH2:7])[CH2:33][C:34]3[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=3[F:42])[CH2:13][C:14]=12)=[O:28]
Reactant: CN(C)CCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: CCOC(C)=O
Product: CN(C)CCNC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F)CC2
Yield: 63 %

Procedure:
(R)-[3-[1-(2-Dimethylamino-ethylcarbamoyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 29a (0.10 g, 0.16 mmol) was dissolved in 2 mL of ethyl acetate under stirring. A solution of 2.4 N hydrochloric acid in 6 mL of ethyl acetate was then added to the above solution. The reaction mixture was reacted at room temperature for 4 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure, and 5 mL of ethyl acetate was added to the residue and filtered. The resulting white solid was rinsed with ethyl acetate to obtain the title compound (R)-7-[3-amino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (2-dimethylamino-ethyl)-amide dihydrochloride 29(80 mg, yield 63%) as a white solid.