Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([CH:7]=O)[N:4]([CH3:9])[N:3]=1.[Cl-].[CH3:11][C:12]1[N:17]2[N:18]=[C:19]([CH2:21][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:20]=[C:16]2[C:15]([CH3:41])=[CH:14][N:13]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[Br:1][C:2]1[N:6]=[C:5](/[CH:7]=[CH:21]/[C:19]2[N:20]=[C:16]3[N:17]([C:12]([CH3:11])=[N:13][CH:14]=[C:15]3[CH3:41])[N:18]=2)[N:4]([CH3:9])[N:3]=1
Reactant: Cc1cnc(C)n2nc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc12
Reactant: Cn1nc(Br)nc1C=O
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Cc1cnc(C)n2nc(/C=C/c3nc(Br)nn3C)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
To a solution of 3-bromo-1-methyl-1H-1,2,4-triazole-5-carbaldehyde (120 mg, 632 μmol, Eq: 1.00) in tetrahydrofuran (25 ml) were added ((5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidin-2-yl)methyl)triphenylphosphonium chloride (290 mg, 632 μmol, Eq: 1.00) (prepared as described in WO2011150156, pp 123-125, Expl. 24 g) and DBU (106 mg, 105 μl, 695 μmol, Eq: 1.1). The resulting solution was stirred for 18 hours at 25° C. The crude material was applied on silica gel and purified by flash chromatography over a 20 g silica gel column using ethyl acetate methanol 0-10% as eluent affording 2-[(E)-2-(5-bromo-2-methyl-2H-[1,2,4]triazol-3-yl)-vinyl]-5,8-dimethyl-[1,2,4]triazolo[1,5-c]pyrimidine (154 mg, 73%) as a white solid. MS: m/z=336.63537 (M+H+)
Reaction SMILES: C(OC(N1CCN2C(=O)C3C=C(C(F)(F)F)C=C(Br)C=3C[C@@H]2C1)=O)(C)(C)C.B1(C=C)OB(C=C)OB(C=C)O1.C1C=CN=CC=1.C([O-])([O-])=O.[K+].[K+].C(OC([N:59]1[CH2:79][CH2:78][N:62]2[C:63](=[O:77])[C:64]3[CH:65]=[C:66]([C:73]([F:76])([F:75])[F:74])[CH:67]=[C:68]([CH2:71][CH3:72])[C:69]=3[CH2:70][C@@H:61]2[CH2:60]1)=O)(C)(C)C.[ClH:80].O1CCOCC1>COCCOC.CCOC(C)=O.CCO.[Pd].C(OCC)C.O>[ClH:80].[CH2:71]([C:68]1[C:69]2[CH2:70][C@@H:61]3[CH2:60][NH:59][CH2:79][CH2:78][N:62]3[C:63](=[O:77])[C:64]=2[CH:65]=[C:66]([C:73]([F:74])([F:76])[F:75])[CH:67]=1)[CH3:72]
Reactant: CCc1cc(C(F)(F)F)cc2c1C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C2=O
Agent: [Pd]
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: CC(C)(C)OC(=O)N1CCN2C(=O)c3cc(C(F)(F)F)cc(Br)c3C[C@@H]2C1
Solvent: CCO
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CCc1cc(C(F)(F)F)cc2c1C[C@@H]1CNCCN1C2=O
Temperature: 90 °C
Yield: 40 %

Procedure:
To a mixture of (R)-2-N-(t-butoxycarbonyl)-10-bromo-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-one (61 mg, 0.135 mmol) and 2,4,6-trivinylcyclotriboroxane pyridine complex (33 mg, 0.135 mmol) in DME (2 mL) was added K2CO3 (20 mg, 0.135 mmol) and water (1 mL). The mixture was degassed under reduced pressure and purged with argon; tetrakis(triphenylphospine)palladium (0) (20 mg, 0.135 mmol) was added. The reaction mixture was heated to 90° C. for 18 h. The reaction was cooled to room temperature, and diluted with EtOAc (50 mL). The EtOAc layer was dried over Na2SO4, filtered, and concentrated in vacuo to afford crude alkene 6a as a yellow oil. MS (ESI) 340 (M+H). Crude (R)-2-N-(t-butoxycarbonyl)-10-ethyl-8-trifluoromethyl-1,2,3,4,11,11a-hexahydropyrazino[1,2-b]isoquinolin-6-one was dissolved in EtOH (2 mL) and hydrogenated [10% Pd/C (50 mg), H2 (30 psi)]. The reaction mixture was filtered through diatomaceous earth, and then purified by flash column chromatography (silica gel, 4:1 hexanes/EtOAc). The resulting material was deprotected using 4 N HCl in 1,4-dioxane (200 μL, 0.8 mmol), followed by trituration with diethyl ether, to provide the desired product (18 mg, 40% over 3 steps) as a white solid. MS (ESI) 299 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[F:19][C:20]([F:29])([F:30])[C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:16]([C:14]2[O:15][C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])=[CH:12][CH:13]=2)=[O:18])=[CH:23][CH:22]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCc1cc(-c2ccc(C(=O)O)o2)c(C)[nH]c1=O
Product: CCc1cc(-c2ccc(C(=O)NCc3ccc(C(F)(F)F)cc3)o2)c(C)[nH]c1=O
Yield: 60 %

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5-(5-ethyl-2-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-furan-2-carboxylic acid and 4-trifluoromethyl-benzylamine to afford the title compound (60% yield). LC/MS: RT 2.95 min; m/e 405 (M+H).
Reaction SMILES: [CH:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([C:13]([OH:15])=O)[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:23][NH:24][OH:25]>O1CCCC1.CN(C)C=O.[OH-].[Na+]>[CH:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([C:13]([N:24]([OH:25])[CH3:23])=[O:15])[CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCC(C2CCCCC2)CC1
Reactant: CNO
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(O)C(=O)C1CCC(C2CCCCC2)CC1
Reaction time: 1 h
Yield: 20.4 %

Procedure:
To a solution of 4-cyclohexyl-cyclohexanecarboxylic acid (1.47 g, 7 mmol) in 50 ml of tetrahydrofuran was added oxalyl chloride (0.67 ml, 7.7 mmol) and a few drops of dimethylformamide. After stirring for one hour, the reaction mixture was concentrated to about 1/3 of the original volume and added dropwise into a cold (~0° C.), stirred solution of N-methylhydroxylamine hydrochloride (1.17 g, 14 mmol) in 40 ml of 1N sodium hydroxide. The mixture was stirred for two hours and extracted three times with ethyl acetate. The combined ethyl acetate extracts were washed twice with water, dried with anhydrous sodium sulfate and concentrated. Purification by flash chromatography and crystallization afforded 0.342 g of 4-cyclohexyl-N-hydroxy-N-methylcyclohexanecarboxamide as a white solid (m.p. 89°-90° C.).
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[CH3:28][O:29][C:30]([C:32]1[C:40]2[O:39][CH2:38][CH2:37][C:36]=2[CH:35]=[C:34](B(O)O)[CH:33]=1)=[O:31].C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([C:34]2[CH:33]=[C:32]([C:30]([O:29][CH3:28])=[O:31])[C:40]3[O:39][CH2:38][CH2:37][C:36]=3[CH:35]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1cc(B(O)O)cc2c1OCC2
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCCCc1nc(C)n(-c2cc3c(c(C(=O)OC)c2)OCC3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.0 g), [7-(methoxycarbonyl)-2,3-dihydro-1-benzofuran-5-yl]boronic acid (1.64 g), triethylamine (4.0 mL), pyridine (2.0 mL) and molecular sieves 4 A (4.0 g) in methylene chloride (30 mL) was added copper(II) acetate (2.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.24 g, 8%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][OH:17])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][C:19]([Si:22](Cl)([CH3:24])[CH3:23])([CH3:21])[CH3:20].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[CH2:16][O:17][Si:22]([C:19]([CH3:21])([CH3:20])[CH3:18])([CH3:24])[CH3:23])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
The title compound is prepared by the procedure of Example 50 using 20.0 g of (R)-2-pyrrolidinemethanol, 44.0 g of benzyl chloroformate and 200 ml of diethyl ether to give 56.4 g of (R)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenyl methyl ester. Forty-five g of (R)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenylmethyl ester is reacted with 38.4 g of (1,1-dimethylethyl)dimethylsilylchloride, 58 ml of triethylamine, 1.3 g of 4-(dimethylamino)pyridine and 450 ml of methylene chloride to give 41.5 g of the desired product as a colorless oil. [α]D26° =+45° (methylene chloride).
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:32])[C@@H:17]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:10])C1C=CC=CC=1.C(OC(N[C@H](C1C=CC=CC=1)C(N1CCC[C@H]1C(O)=O)=O)=O)(C)(C)C>>[C:28]([O:27][C:25]([NH:24][C@@H:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:32])=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)c1ccccc1

Procedure:
Compound 22 was synthesized from compound 21, following the procedure as described for compound 3a, as a foam. MS (ESI, EY) m/z=347 (MH−).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[O:15][C:14](=[O:16])[NH:13][C@H:12]2[CH3:17])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][C:19](C)([O-])C.[K+].ICC.O>CN(C)C=O.O1CCCC1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C@@H:11]2[O:15][C:14](=[O:16])[N:13]([CH2:18][CH3:19])[C@H:12]2[CH3:17])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[O-]
Reactant: C[C@@H]1NC(=O)O[C@H]1c1ccc(C(C)(C)C)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCI
Product: CCN1C(=O)O[C@@H](c2ccc(C(C)(C)C)cc2)[C@@H]1C
Temperature: 70 °C

Procedure:
To a solution of 1 g (4.3 mmole) (4S,5S)-5-(4-tert-butylphenyl)-4-methyl-oxazolidin-2-one p in 10 mL N,N-dimethylformamide was added 5.2 mL (5.2 mmole) 1 M potassium tert-butoxide in tetrahydrofuran. To the resulting gel was added 0.4 mL (4.7 mmole) iodoethane. The reaction mixture was heated at 70° C. for 1 hr. Cold water (25 mL) was added and the mixture was extracted with 30 mL ethyl acetate. The organic phase was washed with two 10 mL portions water, dried (magnesium sulfate) and concentrated under reduced pressure. (4S,5S)-5-(4-tert-Butylphenyl)-4-methyl-3-ethyl-oxazolidin-2-one Q was isolated as a crystalline solid from ethyl acetate/hexane, 1.06 g. M+H=261.
Reaction SMILES: B(Cl)(Cl)Cl.[CH3:5][O:6][C:7]1[C:8]2[O:35]C[O:33][C:9]=2[CH:10]=[C:11]([CH2:13][CH:14]2[CH2:19][O:18][C:16](=[O:17])/[C:15]/2=[CH:20]/[C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)[CH:12]=1>ClCCl>[OH:33][C:9]1[CH:10]=[C:11]([CH2:13][CH:14]2[CH2:19][O:18][C:16](=[O:17])/[C:15]/2=[CH:20]/[C:21]2[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[C:23]([O:31][CH3:32])[CH:22]=2)[CH:12]=[C:7]([O:6][CH3:5])[C:8]=1[OH:35]
Reactant: COc1cc(/C=C2/C(=O)OCC2Cc2cc(OC)c3c(c2)OCO3)cc(OC)c1OC
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1cc(CC2COC(=O)/C2=C/c2cc(OC)c(OC)c(OC)c2)cc(O)c1O
Reaction time: 0.67 h
Yield: 76.7 %

Procedure:
A dichloromethane solution (1.0M, 4.7 ml, 4.7 mmol) of boron trichloride was added at 0° C. to a solution of (RS)-(E)-3-[1-(5-methoxy-3,4-methylenedioxyphenyl)methyl]-2-(3,4,5-trimethoxybenzylidene)butanolide (1.0 g, 2.34 mmol) in dichloromethane (5 ml), followed by stirring at the same temperature for 40 minutes. The solvent was distilled off under reduced pressure. The residue was added with 15 ml of methanol and 4N-HCl, followed by stirring at room temperature for 45 minutes. The reaction mixture was dissolved in 20 ml of ethyl acetate. The resulting mixture was washed with water and then with saturated NaCl. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby 747 mg of the title compound were obtained as yellow foam (yield: 77%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([OH:17])=[CH:16][C:10]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(N(CC)CC)C>CC(C)=O>[C:1]([O:5][C:6]([NH:7][C:8]1[NH:12][C:11]2[CH:13]=[CH:14][C:15]([O:17][S:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)(=[O:28])=[O:27])=[CH:16][C:10]=2[N:9]=1)=[O:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc2cc(O)ccc2[nH]1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(F)cc3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
5.98 g of (5-hydroxy-1H-benzoimidazol-2-yl)-carbamic acid tert-butyl ester were combinated with 4.67 g of 4-fluorobenzenesulfonyl chloride and 6.75 ml of trietylamine in 100 ml acetone. The reaction mixture was stirred at room temperature for 1 hour. Solvents were evaporated under reduced pressure yielding 6.45 g crude 4-fluoro-benzenesulfonic acid 2-tert-butoxycarbonylamino-1H-benzoimidazol-5-yl ester.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH2:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:8]3[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:7]=3[N:6]2[CH:26]=1.C(=O)([O-])[O-:28].[Na+].[Na+].Cl>O1CCOCC1.O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:9]1[C:8]2[CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=[CH:22][C:7]=2[N:6]2[CH:26]=[C:3]([CH2:2][OH:28])[N:4]=[C:5]2[CH2:11][N:10]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1F)=NCc1nc(CCl)cn1-2
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1F)=NCc1nc(CO)cn1-2
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 50.9 %

Procedure:
A solution of 12 g of 2-chloromethyl-6-(2-fluorophenyl)-8-nitro-4H-imidazo [1,2-a][1,4]benzodiazepine in 100 ml of dioxan was treated with a solution of 3.5 g of sodium carbonate in 50 ml of water and stirred at 80° C. for 2.5 h. Then, the mixture was made weakly acidic (pH 6 to 7) with aqueous 3N hydrochloric acid and evaporated in a vacuum. The residue was taken up in chloroform, washed twice with water, dried over sodium sulphate and evaporated in a vacuum. The residue was dissolved in chloroform and chromatographed over 250 g of silica gel. With chloroform/ethanol 98:2 there were isolated a small amount of impurities, with chloroform/,6thanol 98:2 there was eluted 6-(2-fluorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol. After recrystallization from chloroform there were obtained 5.8 g of 6-(2-fluorophenyl)-8-nitro-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 230-231° C. This was converted into the hydrochloride of m.p. 239-241° C.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2Cl)=[O:11])[CH2:4][CH2:3]1.[C:25]1(B(O)O)[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([C:2]4[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[C:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=2)=[O:11])[CH2:4][CH2:3]1
Reactant: OB(O)C1=CCCCC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(NCC1CCC(F)(F)CC1)c1c(C2=CCCCC2)ccc2nc(C3=CCCCC3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 125 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexyl methyl)-amide, cyclohexene-1-yl-boronic acid, cesium carbonate and tetrakis(triphenylphosphine)palladium (0). 1H NMR (400 MHz, DMSO-d6): δ 8.83 (t, J=5.9 Hz, 1H), 7.89-8.00 (m, 3H), 7.73-7.76 (m, 1H), 6.91 (s, 1H), 3.27 (t, J=6.2 Hz, 2H), 2.65-2.66 (m, 2H), 2.31-2.32 (m, 2H), 1.86-2.01 (m, 2H), 1.74-1.76 (m, 3H), 1.65-1.67 (m, 6H), 1.27-1.30 (m, 2H). m/z: 419 [M+H]+
Reaction SMILES: [N:1]([CH2:4][C:5](=[O:18])[C:6]([C:9]1[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=1)[C:14]#[N:15])([CH3:8])[CH3:7])=[N+]=[N-].[ClH:19]>CCO.O=[Pt]=O>[ClH:19].[NH2:1][CH2:4][C:5](=[O:18])[C:6]([C:9]1[CH:10]=[CH:11][C:12]([F:17])=[C:13]([CH:16]=1)[C:14]#[N:15])([CH3:8])[CH3:7]
Reactant: CC(C)(C(=O)CN=[N+]=[N-])c1ccc(F)c(C#N)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CC(C)(C(=O)CN)c1ccc(F)c(C#N)c1
Reaction time: 12 h
Yield: 65 %

Procedure:
To a stirred solution of 5-(4-azido-2-methyl-3-oxobutan-2-yl)-2-fluorobenzonitrile (6.1 g, 24.7 mmol) in EtOH (100 mL) was added conc HCl (20 mL) and PtO2 (112 mg, 0.49 mmol, 0.02 eq). The mixture was stirred at 1 atm of H2 gas for 12 h, filtered through Celite™ and evaportated in vacuo. The residue was partitioned in DCM and water, and the aqueous layer was evaporated in vacuo. The resulting residue was triturated with Et2O-Hex to give 5-(4-amino-2-methyl-3-oxobutan-2-yl)-2-fluorobenzonitrile hydrochloride as a yellow solid (6 g, 65%). 1H NMR (400 MHz, CD3OD) δ 7.74-7.68 (m, 2H), 7.37 (t, J=8.8 Hz, 1H), 3.89 (s, 2H), 1.58 (s, 6H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([C:8]([OH:10])=O)[NH:6][C:5](=[O:11])[NH:4]1)[CH3:2].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O>[CH2:1]([CH:3]1[NH:4][C:5](=[O:11])[NH:6][CH:7]1[C:8](=[O:10])[C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[CH3:2]
Reactant: CCC1NC(=O)NC1C(=O)O
Reactant: Fc1ccccc1
Solvent: O
Product: CCC1NC(=O)NC1C(=O)c1ccc(F)cc1
Temperature: 100 °C

Procedure:
In 100 g PPA are suspended 15.8 g 4-ethyl-2-oxoimidazolidine-5-carboxylic acid and 10 g fluorobenzene. The mixture is heated to 100° C. for 10 hours with rapid stirring and poured into water. The product separates and is collected.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH:7]([O:10][C:11]1[N:20]=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32])[C:14]([C:22]([OH:24])=[O:23])=[C:15]([CH3:21])[NH:16]2)([CH3:9])[CH3:8].[CH2:35]([N:42]([CH2:44][CH2:45]O)[CH3:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[OH-].[Na+].C(O)(=O)/C=C/C(O)=O>C(OCC)(=O)C.N1C=CC=CC=1.ClCCl.O.CN(C)C=O>[CH3:43][N:42]([CH2:44][CH2:45][O:23][C:22]([C:14]1[CH:13]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:33])([F:34])[F:32])[C:12]2[C:17](=[CH:18][CH:19]=[N:20][C:11]=2[O:10][CH:7]([CH3:9])[CH3:8])[NH:16][C:15]=1[CH3:21])=[O:24])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC1=C(C(=O)O)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1
Reactant: CN(CCO)Cc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)OCCN(C)Cc2ccccc2)C(c2ccccc2C(F)(F)F)c2c(ccnc2OC(C)C)N1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
6.29 g oxalyl chloride in 73 mL ethyl acetate are added to a solution of 11.3 mL absolute dimethylformamide in 220 mL absolute ethyl acetate cooled to 0° C., followed by stirring for 15 minutes at 0° to 5° C. After adding of 12.8 g (-)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-trifluoromethylphenyl)-1,6-naphthyridine-3-carboxylic acid there are added dropwise 3.9 g pyridine, dissolved in 73 mL ethyl acetate and the mixture is stirred for 60 minutes at 0° C. After adding of 10.26 g 2-(N-benzyl-N-methylamino)-ethanol, dissolved in 3.03 g pyridine and 146 mL methylene chloride the mixture is stirred for 1 hour at 5° to 10° C. The reaction mixture is subsequently stirred with 3×140 mL water and 2×140 mL 1N sodium hydroxide. The organic phase is separated off, dried over sodium sulfate and evaporated to dryness. The oily residue is purified over silica gel with toluene:ethyl acetate (7:3) as elution agent. After distilling off the elution agent there is obtained an oily product. The oil is dissolved with 2.52 g fumaric acid in 350 mL ethyl acetate under heating to reflux temperature. After filtration the reaction mixture is evaporated to about 50 mL. The precipitated product is filtered off with suction, dispersed in 10 mL toluene and stirred with 5 mL 1M aqueous ammonium hydroxide solution. The toluene phase is washed with 2×5 mL of water. The organic phase is after drying over sodium sulfate evaporated to dryness. There is obtained an oily product, yield 5.3 g (32% of theory); [α]D =-40.8° (c=1/dichloromethane).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[C:9]=1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].OS(O)(=O)=O.[CH3:22]O>>[C:1]([NH:5][C:6]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[C:9]=1[C:14]([O:16][CH3:22])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CO
Reactant: Cc1noc(C(=O)NC(C)(C)C)c1C(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)c1c(C)noc1C(=O)NC(C)(C)C
Reaction time: 48 h

Procedure:
5.0 g of 5-tert-butylaminocarbonyl-3-methylisoxazole-4-carboxylic acid are dissolved in 200 ml of methanol, and 5 ml of concentrated H2SO4 are added. After 2 days, the mixture is evaporated down, the residue is partitioned between ethyl acetate and water and the organic phase is evaporated down. 4.0 g of methyl 5-tert-butylaminocarbonyl-3-methylisoxazole-4-carboxylate are obtained as a colorless oil (compound No. 1007).
Reaction SMILES: C([O-])=O.[NH4+].C([N:12]1[CH2:17][CH2:16][C:15]2([C:25]3[C:20](=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])[N:19]([C:31]3[C:32]4[C@H:39]([CH2:40][CH3:41])[CH2:38][CH2:37][C:33]=4[N:34]=[CH:35][N:36]=3)[CH2:18]2)[CH2:14][CH2:13]1)C1C=CC=CC=1>CO.[Pd]>[CH2:40]([C@H:39]1[C:32]2[C:31]([N:19]3[C:20]4[C:25](=[C:24]([CH2:26][NH:27][CH:28]([CH3:29])[CH3:30])[CH:23]=[CH:22][CH:21]=4)[C:15]4([CH2:16][CH2:17][NH:12][CH2:13][CH2:14]4)[CH2:18]3)=[N:36][CH:35]=[N:34][C:33]=2[CH2:37][CH2:38]1)[CH3:41]
Reactant: CC[C@@H]1CCc2ncnc(N3CC4(CCN(Cc5ccccc5)CC4)c4c(CNC(C)C)cccc43)c21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC[C@@H]1CCc2ncnc(N3CC4(CCNCC4)c4c(CNC(C)C)cccc43)c21
Reaction time: 2 h

Procedure:
Ammonium formate (21.5 mg, 0.341 mmol) was added to a mixture of (R)-N-((1′-benzyl-1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine (16.9 mg, 0.0341 mmol) and 10% Pd/C (10 mg) in methanol (1 mL) and refluxed. LCMS suggested debenzylation was complete after 2 hours. The reaction was concentrated and partitioned between DCM and saturated NaHCO3 solution. The aqueous portion was extracted a second time, and the combined organics were dried over Na2SO4. The DCM solution was decanted and concentrated under vacuum to provide the free-base product, (R)-N-((1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine. 1H NMR (CDCl3, 400 MHz) δ 8.62 (s, 1H), 7.31 (d, 1H), 7.14 (t, 1H), 6.93 (d, 1H), 3.85-4.01 (m, 4H), 3.29 (m, 1H), 3.08 (dd, 2H), 2.90-2.97 (m, 4H), 2.58 (m, 1H), 2.01-2.26 (m, 4H), 1.85 (m, 1H), 1.68 (dd, 2H), 1.46 (m, 2H), 1.03-1.11 (m, 7H), 0.78 (t, 3H). The product was dissolved in THF (1 mL) and converted to the hydrochloride salt by treatment with a 1M HCl solution in Et2O (1 mL). The reaction was sonicated, and the solvent was removed under vacuum providing (R)-N-((1-(5-ethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine trihydrochloride (11 mg, 0.021 mmol, 62% yield) as a powder. MS (APCI+) [M+H]: 406.3.