Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[CH:20][C:19](=[O:23])[N:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:17]=2[CH3:30])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[Br:31]N1C(=O)CCC1=O>CN(C)C=O>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20]([Br:31])[C:19](=[O:23])[N:18]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:17]=2[CH3:30])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(=O)n(-c2ccccc2)c(C)c1C(=O)N[C@H](c1cccc(F)c1)C1CCC1
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c(=O)c1Br
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
A mixture of 2,4-dimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (11.8 mg, 0.0292 mmol) and N-bromosuccinimide (5.7 mg, 0.032 mmol) in N,N-dimethylformamide (0.2 mL) was shaken at 40° C. for 30 min. It was quenched and shaken with diluted aq. HCl (ca 0.1 M, 4 ml) then filtered to give the title compound as colourless solid (9.0 mg, 64% yield). LC-MS (m/z) 483.2 & 485.3 (MH+); tR=1.54. 1H NMR (T=+70° C., 500 MHz, DMSO-d6, DMSO-d5=2.50 ppm): 1.75 (overlapping s, 3H, Me), 1.72-1.93 (overlapping m, 5H), 2.07 (br. m, 1H), 2.2 (s, 3H, Me), 2.67 (m, 1H, CH of Cb), 4.93 (t, J=9.2 Hz, CH—N), 7.02 (dt, J(t)=8.3 Hz, J(d)=1.9 Hz, 1H), 7.13 (br. d, J=10.1 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 7.22 (br. m, 2H, Ph), 7.35 (q (unres. Dt), J(t)=7.6 Hz, J(d)=6.6 Hz, 1H), 7.49 (t, J=7.3 Hz, 1H, para-H of Ph), 7.55 (t, J=6.8 Hz, 2H, two meta-H of Ph), 8.68 (d, J=8.3 Hz, 1H, NH).
Reaction SMILES: [Br-].[C:2]([C:6]1[S:10][C:9](/[N:11]=C/N(C)C)=[N+:8]([CH2:16][CH2:17][CH2:18][CH3:19])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]>Cl>[C:2]([C:6]1[S:10][C:9](=[NH:11])[N:8]([CH2:16][CH2:17][CH2:18][CH3:19])[N:7]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: CCCC[n+]1nc(C(C)(C)C)sc1/N=C/N(C)C
Agent: Cl
Agent: [Br-]
Product: CCCCn1nc(C(C)(C)C)sc1=N
Temperature: 25 °C

Procedure:
A solution of Example 16B (4 g, 11.45 mmol) in HCl (1 N, 12.6 mL) was heated at 65° C. for 12 hours. The mixture was cooled at room temperature and extracted with ether (2×20 mL). The aqueous phase was neutralized to pH 7 with concentrated ammonia and extracted with ether (2×25 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 using an Analogix® Intelliflash280™ (Hexanes-EtOAc: 0-80%) to give the title compound. LC/MS m/z 214 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[NH:6][C:7]([CH3:10])([CH3:9])[CH3:8])([O-:3])=[O:2].C(N(CC)CC)C.[C:22](Cl)([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:23]>O1CCCC1>[C:7]([N:6]([C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:23])[C:5]1[CH:11]=[CH:12][CH:13]=[CH:14][C:4]=1[N+:1]([O-:3])=[O:2])([CH3:10])([CH3:8])[CH3:9]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(C)(C)Nc1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)N(c1ccccc1[N+](=O)[O-])C(C)(C)C

Procedure:
To a stirred solution of 2-nitro-N-tert-butylaniline (37 g) and triethylamine (35 ml) in tetrahydrofuran (400 ml) was added dropwise a solution of ethoxalyl chloride (25 ml) in tetrahydrofuran (50 ml). The mixture was then brought to reflux temperature for 8 h. The solvent was removed by evaporation, and the residue was partitioned between ether (300 ml) and water (500 ml). The organic phase was washed twice with water, dried over Na2SO4 and evaporated. This left the title compound as light yellow crystals, m.p. 73°-74° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:12]2[N:13]=[C:14]3[N:19]([CH:20]=2)[N:18]=[C:17]([O:21][CH2:22][CH3:23])[CH:16]=[CH:15]3)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[C:24]([Cu])#[N:25]>CN1CCOCC1.CO>[CH2:22]([O:21][C:17]1[CH:16]=[CH:15][C:14]2=[N:13][C:12]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([CH:3]=3)[C:24]#[N:25])=[CH:20][N:19]2[N:18]=1)[CH3:23]
Reactant: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(Br)c3)cn2n1
Reactant: N#C[Cu]
Solvent: CN1CCOCC1
Solvent: CO
Product: CCOc1ccc2nc(-c3ccc(C(F)(F)F)c(C#N)c3)cn2n1
Temperature: 220 °C
Yield: 70 %

Procedure:
A mixture of 2-[3-bromo-4-(trifluoromethyl)phenyl]-6-ethoxy-imidazo[2,1-f]pyridazine (0.050 g, 0.129 mmol) and CuCN (0.058 g) in 4-methylmorpholine (2.0 mL) is heated in the microwave at 220° C. for 10 min. The mixture is diluted with MeOH (10 mL) and the solids are removed by filtration. The crude solution is concentrated to remove the MeOH. Water (50 mL) is added and the solid precipitate is collected. The crude product is purified by silica gel chromatography (0-100% EtOAc in Hexanes) to give the title compound (0.03 g, 71% yield). LCMS m/z=333.3 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:18])[CH2:12][NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][C:4]=1[C:19]#[N:20]>>[NH2:2][C:3]1[C:4]([C:19]#[N:20])=[CH:5][C:6]([CH:11]([OH:18])[CH2:12][NH:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[CH:7][C:8]=1[C:9]#[N:10]
Reactant: CC(C)(C)NCC(=O)c1cc(C#N)c(N)c(C#N)c1
Agent: Cl
Product: CC(C)(C)NCC(O)c1cc(C#N)c(N)c(C#N)c1

Procedure:
m.p. of the hydrochloride: 251°-253° C. (decomp.), was prepared from 4'-amino-2-tert.butylamino-3',5'-dicyano-acetophenone analogous to Example 48.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].B.CNC.CO.Cl>O1CCCC1>[Br:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CBr)c1ccccc1
Agent: B
Agent: CNC
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: OC(CBr)c1ccccc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
2-Bromoacetophenone (1 g) was dissolved in tetrahydrofuran (8 ml), and a solution of borane-dimethylamine (326 mg) in tetrahydrofuran (6 ml) was added thereto at room temperature. After the reaction mixture was stirred at room temperature for 60 hours, methanol (1 ml) and 1 M hydrochloric acid aqueous solution (5 ml) were added thereto, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After removing the solvent by distillation from the organic layer, the residue was purified by silica gel column chromatography to obtain the title compound from a fraction eluted with hexane-ethyl acetate (5:1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:24]=[CH:25][CH:26]=[O:27])[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21].N1CCOCC1>>[OH:27][CH:26]1[CH2:25][CH:24]([C:16]2[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:10]2[C:2](=[C:3]3[CH:4]=[CH:5][N:6]([CH3:11])[C:7]3=[CH:8][CH:9]=2)[O:1]1
Reactant: Cn1ccc2c(O)cccc21
Reactant: COc1cc(C=CC=O)cc(OC)c1OC
Solvent: C1COCCN1
Product: COc1cc(C2CC(O)Oc3c2ccc2c3ccn2C)cc(OC)c1OC
Yield: 48 %

Procedure:
The title compound was prepared following the procedure described in Example 18 using 4-hydroxy-N-methyl indole (15 mg; 0.1 mmol) and 3-(3,4,5-trimethoxy-phenyl)-propenal (25 mg; 0.11 mmol) with morpholine (10 μl; 0.11 mmol) as a base (yield: 48%). 1H NMR (acetone-d6) 6.96 (d, J=2.7 Hz) and 6.94 (d, J=3.1 Hz) (1H), 6.70 (d, J=8.2 Hz) and 6.68 (d, J=7.2 Hz) (1H), 6.45 (d, J=8.6 Hz), 6.43 (s) and 6.40 (d, J=9.0 Hz) (3H), 6.29 and 6.28 (d each, J=3.3 Hz, 1H), 6.01 (d, J=6.8 Hz) and 5.91 (d, J=4.3 Hz) (1H), 5.57-5.60 (m) and 5.42-5.44 (m) (1H), 4.19 (dd, J=6.2, 10.0 Hz; 1H), 3.63, 3.62 and 3.59 (s each, 12 H), 2.23-2.28 (m) and 2.00-2.11 (m) (2H).
Reaction SMILES: O[CH2:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([O:15][CH3:16])[C:6]=2[C:7]=1[CH3:8].P(Br)(Br)[Br:18]>ClCCl.N1C=CC=CC=1>[Br:18][CH2:2][C:3]1[O:4][C:5]2[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]([O:15][CH3:16])[C:6]=2[C:7]=1[CH3:8]
Reactant: BrP(Br)Br
Reactant: COc1c(C#N)ccc2oc(CO)c(C)c12
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1c(C#N)ccc2oc(CBr)c(C)c12
Reaction time: 8 h
Yield: 93.9 %

Procedure:
A solution of 2-hydroxymethyl-4-methoxy-3-methyl benzofuran-5-carbonitrile (0.17 g; 0.76 mmol) in dichloromethane (5 mL) was cooled to 0° C. To this solution was added, successively, neat phosphorus tribromide (0.11 mL; 0.32 g; 1.2 mmol; 1.5 eq) and pyridine (2 drops). The ice bath was removed and the reaction was allowed to come to room temperature overnight with stirring. After quenching with ice, the crude product was isolated by ethyl acetate extraction. The organic layer was washed with saturated sodium bicarbonate, then dried over magnesium sulfate, filtered and concentrated in vacuo to give 2-bromomethyl-4-methoxy-3-methyl benzofuran-5-carbonitrile (0.20 g; 95% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][CH:14]=2)[N:10]=1.[CH2:35](P(=O)(OCC)OCC)[P:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39].CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:34])=[C:9]([CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:35]/[P:36](=[O:43])([O:40][CH2:41][CH3:42])[O:37][CH2:38][CH3:39])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:32][CH:33]=2)[N:10]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)cc1)OCC
Reaction time: 15 h
Yield: 64.7 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.37 g), tetraethyl methylenediphosphonate (0.26 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.04 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}benzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenylphosphonate as colorless crystals (0.31 g, yield 65%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 131-132° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=1.[CH:15]([NH:18][C:19]1[CH:23]=[CH:22][NH:21][N:20]=1)([CH3:17])[CH3:16]>ClCCl>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[N:3]=[C:2]([N:21]2[CH:22]=[CH:23][C:19]([NH:18][CH:15]([CH3:17])[CH3:16])=[N:20]2)[CH:11]=1
Reactant: COc1ccc2c(Cl)cc(Cl)nc2c1
Reactant: CC(C)Nc1cc[nH]n1
Solvent: ClCCl
Product: COc1ccc2c(Cl)cc(-n3ccc(NC(C)C)n3)nc2c1
Temperature: 115 °C
Yield: 82.1 %

Procedure:
A mixture of 2,4-dichloro-7-methoxy-quinoline (1.34 g, 5.88 mmol) and isopropyl-(1H-pyrazol-3-yl)-amine (1.10 g, 8.80 mmol) was heated at 115° C. for 3 h while stirring in a sealed tube. After ˜20 min of heating, the pressure built up in the tube was released by using a needle. The mixture was then dissolved in dichloromethane and loaded onto a silica gel column. Elution with dichloromethane and methanol afforded [1-(4-chloro-7-methoxy-quinolin-2-yl)-1H-pyrazol-3-yl]-isopropyl-amine (1.53 g, 82%).
Reaction SMILES: [H-].[Na+].CCCCCC.C(OP([C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([CH2:23][CH2:24][CH2:25][C:26](=[O:28])[CH3:27])[CH:22]=1)(OCC)=O)C.[CH2:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=O)[C:32]=1[NH:39][C:40](=[O:56])[CH2:41][CH:42]1[C:55]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[O:49][C:48]2[C:43]1=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH3:30]>CN(C)C=O>[CH2:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=[CH:27][C:26](=[O:28])[CH2:25][CH2:24][CH2:23][C:21]2[CH:22]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:32]=1[NH:39][C:40](=[O:56])[CH2:41][CH:42]1[C:55]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[O:49][C:48]2[C:43]1=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH3:30]
Reactant: CCOP(=O)(OCC)c1cccc(CCCC(C)=O)c1
Reactant: CCc1cccc(C=O)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCc1cccc(C=CC(=O)CCCc2ccccc2)c1NC(=O)CC1c2ccccc2Oc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
49 mg (1.13 mmol) of sodium hydride (as a 55% w/w suspension in mineral oil) were washed twice, each time with hexane, and were suspended in 6 ml of dimethylformamide. 2 ml of a dimethylformamide solution containing 289 mg (0.97 mmol) of 5-diethoxyphosphoryl-1-(4-oxopentyl)benzene were added to the suspension, whilst ice-cooling. The reaction mixture was then immediately allowed to return to room temperature, after which it was stirred for 30 minutes. 300 mg (0.808 mmol) of N-(2-ethyl-6-formylphenyl)-2-(9H-xanthen-9-yl)acetamide were then added to the reaction mixture, once again whilst ice-cooling. The mixture was then stirred for 1 hour at the ice-cooling temperature and then for 3 hours at room temperature. At the end of this time, the reaction solution was poured into ice-water and extracted with diethyl ether. The organic extract was washed with water. The solvent was removed by distillation under reduced pressure, and the resulting residue was recrystallized from a mixture of methylene chloride and diethyl ether, to give 220 mg (yield 53%) of the title compound as crystals, melting at 168°-170° C.
Reaction SMILES: Cl[CH2:2][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4]1.[F:14][C:15]([F:24])([F:23])[CH2:16][CH2:17][CH:18]([C:21]#[N:22])[C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:3]([CH2:2][C:18]([CH2:17][CH2:16][C:15]([F:14])([F:23])[F:24])([C:19]#[N:20])[C:21]#[N:22])[CH:4]=1)=[O:13]
Reactant: O=Cc1cn(CCl)c2ccccc12
Reactant: N#CC(C#N)CCC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1cc(C=O)c2ccccc21
Yield: 53.8 %

Procedure:
3.02 g of 1-(chloromethyl)-3-formyl-1H-indole and 2.53 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 45 ml of N,N-dimethylformamide. 4.35 g of potassium carbonate was added to the solution under ice cooling with stirring, followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture, and then extracted with MTBE. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.68 g of [{3-formyl-1H-indole-1-yl}methyl](3,3,3-trifluoropropyl)malononitrile(referred to as the compound of the present invention (40), hereinafter) shown by below formula.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[N:9][CH:10]=[C:4]2[CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[NH4+].CN(C)[CH:20]=[O:21]>>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[N:9][C:10]([CH:20]=[O:21])=[C:4]2[CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccn2cncc2c1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ncn2ccc(Br)cc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A solution of 4.93 g of 7-bromoimidazo[1,5-a]pyridine in 2.2 ml of dry N,N-dimethylformamide is cooled in an ice bath to 0-5° C. Phosphorus oxychloride (5.37 g) is added dropwise at 0-5° C. and the reaction mixture is subsequently stirred at 100° C. over 1 hour. The reaction mixture is cooled and poured onto ice-water. The quenched solution is basified with 25% ammonium hydroxide solution and extracted with dichloromethane (3×200 ml). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: [NH2:1][C:2]([CH3:32])([CH3:31])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([N:13]2[CH2:18][CH2:17][C@:16]([CH2:25][C:26]([OH:29])([CH3:28])[CH3:27])([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:15][C:14]2=[O:30])[CH3:12])=[CH:7][CH:6]=1.Cl[C:34]([O:36][CH3:37])=[O:35]>>[OH:29][C:26]([CH3:27])([CH3:28])[CH2:25][C@@:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:15][C:14](=[O:30])[N:13]([C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:4]#[C:3][C:2]([NH:1][C:34](=[O:35])[O:36][CH3:37])([CH3:31])[CH3:32])=[CH:6][CH:7]=2)[CH3:12])[CH2:18][CH2:17]1
Reactant: COC(=O)Cl
Reactant: C[C@@H](c1ccc(C#CC(C)(C)N)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: COC(=O)NC(C)(C)C#Cc1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1

Procedure:
The title compound was prepared following a procedure analogous to that described in Example 15 using (S)-3-((S)-1-(4-(3-amino-3-methylbut-1-ynyl)phenyl)ethyl)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-1,3-oxazinan-2-one and methyl chloroformate. LC-MS Method 1 tR=1.65 min, m/z=493, 435; 1H NMR (CDCl3) 1.12 (s, 3H), 1.18 (s, 3H), 1.49 (d, 3H), 1.67 (s, 6H), 2.14 (m, 1H), 2.21 (s, 2H), 2.25-2.40 (2H), 2.78 (m, 1H), 5.65 (q, 1H), 6.88 (d, 2H), 7.17 (d, 2H), 7.30-7.40 (5H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]([O:20][CH3:21])[C:13]=2[F:22])=[C:8]2[C:3]=1[N:4]=[CH:5][CH:6]=[N:7]2.[C:23]([Cu])#[N:24]>CN1C(=O)CCC1.C(Cl)Cl>[F:22][C:13]1[C:14]([O:20][CH3:21])=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=1[C:9]1[C:8]2[N:7]=[CH:6][CH:5]=[N:4][C:3]=2[C:2]([C:23]#[N:24])=[CH:11][CH:10]=1
Reactant: N#C[Cu]
Reactant: COc1cc(OC)c(F)c(-c2ccc(Br)c3nccnc23)c1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: COc1cc(OC)c(F)c(-c2ccc(C#N)c3nccnc23)c1
Temperature: 160 °C
Reaction time: 6.5 h
Yield: 62 %

Procedure:
A mixture of 5-bromo-8-(2-fluoro-3,5-dimethoxy-phenyl)-quinoxaline (Step 94.3) (3.09 g, 8.5 mmol) and CuCN (918 mg, 10.2 mmol, 1.2 equiv) in NMP (30 mL) was stirred for 6.5 h at 160° C., under an argon atmosphere. The reaction mixture was allowed to cool to rt, diluted with DCM/(10% aqueous solution of ethylenediamine) (200 mL, v/v 1:1), filtered through celite and the filtrate extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated in DCM to provide 1.63 g of the title compound as a white solid: ESI-MS: 310.1 [M+H]+; tR=4.41 min (System 1).
Reaction SMILES: C(NC(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:27]1([CH2:33][CH2:34][OH:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O[C:37]1[C:38]([CH:60]2[CH2:64][CH2:63][CH2:62][N:61]2[C:65](=[O:67])[CH3:66])=[CH:39][C:40]2[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:43]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=3)=[N:42][C:41]=2[CH:59]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:34]([O:35][C:37]1[C:38]([CH:60]2[CH2:64][CH2:63][CH2:62][N:61]2[C:65](=[O:67])[CH3:66])=[CH:39][C:40]2[N:44]([CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[C:43]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][N:54]=3)=[N:42][C:41]=2[CH:59]=1)[CH2:33][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: OCCc1ccccc1
Reactant: CC(=O)N1CCCC1c1cc2c(cc1O)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(=O)N1CCCC1c1cc2c(cc1OCCc1ccccc1)nc(-c1ccccn1)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
0.019 ml of diisopropylamine, 27.6 mg of triphenyl phosphine and 0.011 ml of 2-phenyl-ethanol were added in order to a tetrahydrofuran (1 ml) solution of 29.2 mg of 1-(2-(6-hydroxy-2-pyridin-2-yl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-benzimidazol-5-yl)pyrrolidin-1-yl)-ethanone obtained in Example 121 (step 10), and the reaction liquid was stirred for 6 hours at room temperature. 0.040 ml of diisopropylamine, 53.2 mg of triphenyl phosphine and 0.023 ml of 2-phenyl-ethanol were added in order to the reaction liquid, and the reaction liquid was stirred overnight at room temperature. Aqueous saturated sodium bicarbonate was added to the reaction liquid, and this was extracted with ethyl acetate, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), ethyl acetate) to obtain the entitled compound as a brown oily substance.
Reaction SMILES: Cl.Cl.Cl.[NH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([Cl:25])=[C:23]([Cl:26])[N:22]=[C:21]([NH:27][CH3:28])[N:20]=3)[CH2:15][CH2:14]2)[CH2:7][CH2:6]1.C(N(CC)CC)C.[O-:36][C:37]#[N:38].[K+]>CO>[Cl:25][C:24]1[C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][CH2:11][C@H:8]3[CH2:9][CH2:10][C@H:5]([NH:4][C:37]([NH2:38])=[O:36])[CH2:6][CH2:7]3)[CH2:18][CH2:17]2)=[N:20][C:21]([NH:27][CH3:28])=[N:22][C:23]=1[Cl:26]
Reactant: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)n1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CO
Product: CNc1nc(Cl)c(Cl)c(N2CCN(CC[C@H]3CC[C@H](NC(N)=O)CC3)CC2)n1

Procedure:
0.6 g (1.3 mmol) trans-(4-{4-[2-(4-amino-cyclohexyl)-ethyl]-piperazin-1-yl}-5,6-dichloro-pyrimidin-2-yl)-methyl-amine trihydrochlorid was suspended in methanol. Triethylamine (0.36 ml, 2.6 mmol) was added followed by the addition potassium cyanate (0.26 g, 3.12 mmol). The mixture was refluxed for 10 hours. The solvent was removed in vacuo. The residue was triturated with water, and the precipitate was filtered to give the title compound (0.42 g 75%) MS (EI): 431.2 (MH+). 1H NMR (300 MHz, DMSO-d6 (TMS)+1 drop of cc. DCl, □ (ppm)): 0.91-1.12 m (2H); 1.15-1.36 m (3H); 1.56-1.92 m (6H); 2.76 s (3H); 3.00-3.21 m (4H); 3.30-3.61 m (5H); 4.15-4.31 m (2H).
Reaction SMILES: C(OC([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12](C(O)=O)[CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.ClC(OCC)=O.[NH2:31][C:32]1[C:41]([NH2:42])=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35].C(=O)(O)[O-].[Na+]>O1CCCC1>[NH2:31][C:32]1[C:41]([NH:42][C@H:12]2[CH2:13][CH2:14][C@@H:9]([NH2:8])[CH2:10][CH2:11]2)=[CH:40][CH:39]=[CH:38][C:33]=1[C:34]([O:36][CH3:37])=[O:35]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(N[C@H]2CC[C@@H](N)CC2)c1N
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2.4 g (9.9 mmol) of cis-4-(tert-butoxycarbonylamino)-cyclohexanecarboxylic acid and 2.7 ml (19.7 mmol) of triethylamine were dissolved in 70 ml of anhydrous tetrahydrofuran and, at −10° C., a solution of 0.94 ml (9.9 mmol) of ethyl chloroformate in 25 ml of anhydrous tetrahydrofuran was added dropwise. The mixture was then stirred at 0° C. for 1 hour. After this, 1.6 g (9.9 mmol) of methyl 2,3-diaminobenzoate were added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice-water and made alkaline with aqueous sodium bicarbonate solution. This aqueous phase was extracted with ethyl acetate. The organic phase was then washed with aqueous sodium bicarbonate solution and water, dried and concentrated in vacuo. 2.7 g of the product were obtained.