Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:23]=[C:24]([CH3:26])[CH:25]=1)[O:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].[CH:27]([N:30]=[C:31]=[O:32])([CH3:29])[CH3:28].C(N(CC)CC)C>C(Cl)Cl>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([O:5][C:4]2[CH:3]=[C:2]([CH3:1])[CH:25]=[C:24]([CH3:26])[CH:23]=2)=[C:7]([S:14]([N:17]2[CH2:22][CH2:21][N:20]([C:31]([NH:30][CH:27]([CH3:29])[CH3:28])=[O:32])[CH2:19][CH2:18]2)(=[O:16])=[O:15])[CH:8]=1)#[N:11]
Reactant: CC(C)N=C=O
Reactant: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(Oc2ccc(C#N)cc2S(=O)(=O)N2CCN(C(=O)NC(C)C)CC2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 11.4 %

Procedure:
To a solution of compound 24 (0.100 g, 0.27 mmol) in CH2Cl2 (3 mL) was added isopropyl isocyanate (0.032 g, 0.38 mmol) and triethylamine (0.039 g, 0.38 mmol). Reaction was stirred for 20 hrs at room temperature, whereupon the starting material was consumed (TLC, 1% MeOH in CH2Cl2). The reaction mixture was then concentrated in vacuo, redissolved in a minimal amount of CH2Cl2, and chromatographed over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder, which was then triturated with CH2Cl2/hexanes and vacuum filtered to yield a powder. The powder was redissolved in CH2Cl2 and chromatographed for a second time over normal phase silica (MeOH/CH2Cl2). The fractions containing the desired product were combined and concentrated in vacuo to yield a white powder, which was then triturated with hexanes and vacuum filtered to afford compound 58 as a white powder (0.014 g, 11.3% yield, 99.1% HPLC purity). 1H NMR (500 MHz, CDCl3): 8.27 (d, J=2 Hz, 1H), 7.67 (dd, J1=9 Hz, J2=2 Hz, 1H) 6.93 (s, 1H), 6.89 (s, J=9 Hz, 1H), 6.69 (s, 2H), 4.17 (m, 1H), 3.95 (m, 1H), 3.44 (m, 4H), 335 (m, 4H), 2.34 (s, 6H), 1.14 (d, J=7 Hz, 6H); MS (ESI, EE): m/z=457 (MH+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[C:18]([F:35])=[C:19](/[CH:23]=[C:24](/[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[CH3:34])\[C:25]#[N:26])[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:23]([C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([Cl:16])[C:18]=2[F:35])[C:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[CH3:34])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(Cl)ccc1/C(C#N)=C/c1cccc(Cl)c1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Cl)ccc1C1(C#N)C(CC(C)(C)C)NC(C(=O)OC(C)(C)C)C1c1cccc(Cl)c1F
Yield: 48.8 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (2.1 g, 10 mmol) was reacted with (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-2-methyl-phenyl)-acrylonitrile (2.3 g, 7.5 mmol) prepared in Example 57a, AgF (1.3 g, 10 mmol), and triethylamine (2.8 g, 28 mmol) in dichloromethane (100 mL) at room temperature for 20 h to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (1.9 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]([CH:9]2[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH3:8])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([CH:9]2[CH2:10][NH:11][CH2:12]2)[CH3:8])=[CH:20][CH:21]=1
Reactant: CC(Oc1ccc(Cl)cc1)C1CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Oc1ccc(Cl)cc1)C1CNC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 59.9 %

Procedure:
To a flask charged with tert-butyl 3-(1-(4-chlorophenoxy)ethyl)azetidine-1-carboxylate (140 mg, 0.449 mmol) was added CH2Cl2 (1796 μL) followed by TFA (242 μL, 3.14 mmol). The reaction mixture was stirred at RT for 72 h. The yellow solution was dried under reduced pressure and purified with a 2 g SCX-2 column loading and washing with MeOH, then washing with 2M NH3 in MeOH to afford 3-(1-(4-chlorophenoxy)ethyl)azetidine (57 mg, 0.269 mmol, 60.0% yield, about 10% impurity present) as a light pink oil.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7]1=[O:15].[H-].[Na+].Br[CH2:20][C:21]1[C:26]2[S:27][CH:28]=[CH:29][C:25]=2[CH:24]=[CH:23][CH:22]=1>CC(N(C)C)=O.C(OCC)(=O)C>[S:27]1[C:26]2[C:21]([CH2:20][N:8]3[C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[N:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:16])[C:7]3=[O:15])=[CH:22][CH:23]=[CH:24][C:25]=2[CH:29]=[CH:28]1
Reactant: BrCc1cccc2ccsc12
Reactant: COC(=O)CCn1c(=O)[nH]c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: O=C(O)CCn1c(=O)n(Cc2cccc3ccsc23)c2ccccc21
Temperature: 120 °C
Yield: 6.2 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid methyl ester (200 mg, 0.91 mmol) in DMA (5 ml) was added sodium hydride (60% oil dispersion, 55 mg, 1.4 mmol). The resulting mixture was stirred for 10 minutes at ambient temperature after which time 7-bromomethyl-benzo[b]thiophene (206 mg, 0.91 mmol) was added. The reaction was heated at 120° C. in a microwave for 20 minutes. Upon cooling to ambient temperature the reaction was diluted with ethyl acetate and washed with NaHCO3 (sat.) and brine. The aqueous phase was acidified using 1M HCl and extracted once with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to give the crude product which was purified via column chromatography (silica gel, 5% methanol/dichloromethane). The product-containing fractions were combined and concentrated to give 20 mg (6%) of the desired product. LCMS (ESMS): m/z 353.41 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][S:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[N:10]1([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:11][CH2:12][S:13][CH2:14][CH2:15]1
Reactant: O=[N+]([O-])c1ccc(N2CCSCC2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCSCC2)cc1
Reaction time: 3 h
Yield: 80.7 %

Procedure:
4-(4-Nitro-phenyl)-thiomorpholine (3.0 g, 13.4 mmol), as prepared in Reference Example 13a above, was dissolved in ethanol (250 mL) and 10% palladium on carbon (250 mg) was added. This mixture was shaken on a Parr hydrogenator for 3 h. The reaction mixture was then filtered through diatomaceous earth and concentrated under vacuum. The residue was triturated with hexane to yield an gray solid (2.1 g).
Reaction SMILES: [Br-].[Br:2][CH2:3][CH2:4][CH2:5][NH3+:6].[OH-].[Na+].[O:9]1[CH2:20][CH:10]1[CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[C:13]1[N+:17]([O-:19])=[O:18].C>C(O)C.C(OCC)C>[BrH:2].[N+:17]([C:13]1[N:12]([CH2:11][CH:10]([OH:9])[CH2:20][NH:6][CH2:5][CH2:4][CH2:3][Br:2])[CH:16]=[CH:15][N:14]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1nccn1CC1CO1
Reactant: [NH3+]CCCBr
Agent: [Br-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Product: Br
Product: O=[N+]([O-])c1nccn1CC(O)CNCCCBr
Temperature: 20 °C
Reaction time: 1 h
Yield: 119.6 %

Procedure:
A solution containing 3-bromopropylammonium bromide (6.47 g, 29.6 mmol) and sodium hydroxide (1.18 g, 29.5 mmol) in ethanol (40 cm3) was stirred at 20° C.; after 1 hour, diethyl ether (40 cm3) was added and the mixture filtered. 1-(2,3-epoxypropyl)-2-nitroimidazole (5.00 g, 29.6 mmol) was added to the filtrate and the solution heated to reflux for 45 minutes. The reaction mixture was then treated with decolourising charcoal (0.5 g), filtered, concentrated under reduced pressure and treated with aqueous hydrobromic acid (48% w/w HBr, 2.0 cm3). The solid which appeared upon refrigeration was recrystallised from aqueous ethanol to give 1-(2-nitro-1-imidazolyl)-3-(3-bromopropylamino)-2-propanol hydrobromide (6.87 g, 59.9%) as a hygroscopic yellow crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: Brc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cccc(Oc2ccccn2)c1
Temperature: 130 °C
Reaction time: 30 h
Yield: 30.3 %

Procedure:
A suspension of 2-bromopyridine (commercially available) (2.0 g, 13.6 mmol), 3-bromophenol (CAS591-20-8) (4.4 g, 24.9 mmol), K2CO3 (5.2 g, 40 mmol) in DMF (30 mL) was stirred at 130° C. for 30 h. The mixture was filtered, concentrated, and purified by column chromatography to give titled compound (1.0 g, 30.3%).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[Cl-].[NH4+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)C=Cc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(O)CCc1ccc(Br)cc1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
Under nitrogen atmosphere in a 250 mL round bottomed flask containing 4-bromocinnamic acid (5.0 g, 22 mmoles) in 45 mL of N,N-dimethylformamide (0.5 M) was added benzenesulfonylhydrazide (7.6 g, 44 mmoles). The mixture was stirred at reflux for 12 hours. The solution was cooled at room temperature, aqueous saturated ammonium chloride was added and the aqueous layer was extracted with ethyl acetate 3 times. Combined organic layers were washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuo. The resulting solid was purified by flash chromatography eluting with 5% methanol: 95% dichloromethane to afford 3.66 g (73%) of beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9](O)[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:15]N1C(=O)CCC1=O.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>C(Cl)Cl>[Br:15][CH:9]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: OC(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)C(Br)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Yield: 39.8 %

Procedure:
To a stirred solution of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanol (4.0 g, 16.3 mmol) in CH2Cl2 (50 mL), were added N-bromosuccinimide (NBS; 2.9 g, 16.3 mmol) and triphenyl phosphite (5.06 g, 16.3 mmol), and the resultant reaction mixture was heated at reflux for 18 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to 25° C. and was concentrated under reduced pressure. Purification by flash column chromatography (SiO2, 100-200 mesh; eluting with 100% pentane) afforded the title compound as a liquid (2.0 g, 40%): 1H NMR (400 MHz, CDCl3) δ 7.41 (s, 3H), 5.00 (m, 1H); EIMS m/z 306 ([M]+).
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[C:15]([Si:19]([CH3:34])([CH3:33])[O:20][CH2:21][CH2:22]OC1C=CC(I)=CC=1C=O)(C)(C)C.C[Si](Cl)(C)C.[CH2:40]([N:42](CC)CC)C.C(Cl)(=O)C>C(OCC)C.O1CCCC1>[CH3:15][Si:19]([CH3:34])([CH3:33])[O:20][C:21](=[CH2:22])[N:42]=[CH2:40]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(I)cc1C=O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CC(=O)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=NC(=C)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 1,1,1,3,3,3-hexamethyldisilazane (4.36 mL, 21 mmol) (Aldrich) under nitrogen at room temperature was added n-butyllithium (2.5 M, 8.4 mL, 21 mmol) (Aldrich). The reaction mixture was stirred at room temperature for 10 minutes. Then dry tetrahydrofuran (60 mL) was added, followed by the addition of 2-[2-(tert-butyl -dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde (8.53 g, 21 mmol). After the mixture was stirred at room temperature for 0.5 h, trimethylsilyl chloride (2.66 mL, 21 mmol) (Aldrich) was added dropwise. Then the temperature of the mixture was lowered to 0° C. on a cooling ice bath. To this mixture was added triethylamine (3.8 mL, 27.2 mmol) in one portion, followed by the dropwise addition of a solution of acetyl chloride (1.94 mL, 27.2 mmol) in diethyl ether (100 mL). The cooling bath was removed, and the mixture was stirred at room temperature for 1 h. The mixture was quickly filtered on celite under nitrogen, and filtrate was concentrated under reduced pressure to give crude 1-[2-(tert -butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-phenyl]-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow oil and used for the next step without further purification.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]#[N:13].[H-].[Na+].Br[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1>C1COCC1.ClCCl>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1)[C:12]#[N:13]
Reactant: N#CCc1ccc2ccccc2c1
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#CC(CCOC1CCCCO1)c1ccc2ccccc2c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 33.5 %

Procedure:
2-Napthylacetonitrile (3.3442 g, 20 mmol) in THF (50 mL) was added to sodium hydride (0.528 g, 22 mmol, 1.1 eq.) in THF (50 mL) at -78° C. under nitrogen. The slurry was allowed to warm to 20° C. and stir for 2 hours. The slurry was cooled to 0° C. and 2-(2-bromo-ethoxy)-tetrahydro-pyran (4.1786 g, 20 mmol, 1 eq.) was added. The solution was allowed to stir at 20° C. for 16 hours and then diluted with dichloromethane and washed with water. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with a gradient from 5% ethyl acetate in hexane to ethyl acetate to give 1.9774 g (66%) of the title compound. 12.2 Synthesis of 3-cyano-3-naphthalen-2-yl-5-(tetrahydro-pyran-2-yloxy)-pentanoic acid ethyl ester (003F143).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[C:29]([CH3:42])=[C:30]([CH3:41])[C:31]4[O:35][C:34]([CH3:37])([CH3:36])[C:33](=[O:38])[C:32]=4[C:39]=3[CH3:40])[CH2:24][CH2:23]2)=[CH:18][CH:17]=1.O>C1COCC1>[OH:38][C:33]1([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:32]2[C:39]([CH3:40])=[C:28]([N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([O:15][CH3:14])=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)[C:29]([CH3:42])=[C:30]([CH3:41])[C:31]=2[O:35][C:34]1([CH3:37])[CH3:36]
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Reactant: Cc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(C)cc3)C(C)(C)O4)CC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
n-Butyllithium (hexane solution 1.50 M, 3.40 mL, 5.10 mmol) was added dropwise to solution of 4-bromotoluene (1.10 g, 6.43 mmol) in THF (10 ml) under a stream of argon at −70° C. or less and the mixture was stirred for 30 minutes. To the mixture was added dropwise a solution of 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine (1.00 g, 2.5 mmol) obtained in Reference Example 13 in THF (3 ml) at −70° C. or less and the mixture was allowed to warm to 0° C. After stirring under ice cooling for 30 minutes, the resulting mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 1.11 g (yield 90%) of the title compound via recrystallization (ethyl acetate-hexane). mp. 145–147° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3](O)=O.CS(O[CH:13]([C:35]1[CH:40]=C[C:38](C(F)(F)F)=[CH:37][CH:36]=1)[C:14]([N:16]1[CH2:21][CH2:20][N:19]2[CH2:22][C@H:23]([O:25][C:26]3[CH:31]=[N:30][C:29]([CH:32]4[CH2:34][CH2:33]4)=[CH:28][N:27]=3)[CH2:24][C@H:18]2[CH2:17]1)=[O:15])(=O)=O.[F:45][CH:46]([F:49])[CH2:47][NH2:48].C(N)C>>[CH:32]1([C:29]2[N:30]=[CH:31][C:26]([O:25][C@H:23]3[CH2:22][N:19]4[CH2:20][CH2:21][N:16]([C:14](=[O:15])[CH:13]([NH:48][CH2:47][CH:46]([F:49])[F:45])[C:35]5[CH:36]=[CH:37][CH:38]=[C:3]([C:2]([F:7])([F:6])[F:1])[CH:40]=5)[CH2:17][C@@H:18]4[CH2:24]3)=[N:27][CH:28]=2)[CH2:33][CH2:34]1
Reactant: CS(=O)(=O)OC(C(=O)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1)c1ccc(C(F)(F)F)cc1
Reactant: NCC(F)F
Reactant: O=C(O)C(F)(F)F
Agent: CCN
Product: O=C(C(NCC(F)F)c1cccc(C(F)(F)F)c1)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1

Procedure:
The title compound was prepared as a trifluoroacetic acid salt according to the procedure described in Example 194B, substituting the product from Example 179A for the product from Example 194A, and substituting 2,2-difluoroethanamine for ethylamine. 1H NMR (300 MHz, CDCl3) δ ppm 0.89-1.07 (m, 4 H) 7.52-7.66 (m, 3 H) 7.67-7.80 (m, 1 H) 7.87-7.97 (m, 1 H) 7.97-8.12 (m, 1 H); MS (ESI) m/z 526 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:25][C:26](Br)=[O:27].[CH:29]1([NH2:39])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:25][C:26]([NH:39][CH:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1)=[O:27]
Reactant: O=C(Br)CBr
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OC)c(OC)c1
Reactant: NC1CCCc2ccccc21
Product: COc1ccc2c(c1)CCN(CC(=O)NC1CCCc3ccccc31)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[N:20]1([C:26]([C:28]2[S:32][C:31]([CH:33]=O)=[CH:30][CH:29]=2)=[O:27])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:33][C:31]4[S:32][C:28]([C:26]([N:20]5[CH2:21][CH2:22][O:23][CH2:24][CH2:25]5)=[O:27])=[CH:29][CH:30]=4)[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=Cc1ccc(C(=O)N2CCOCC2)s1
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1Nc2ncnc(Nc3ccc(F)c(Cl)c3)c2C1=Cc1ccc(C(=O)N2CCOCC2)s1
Temperature: 90 °C
Yield: 26.4 %

Procedure:
The mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (90 mg, 0.32 mmol), 5-(morpholine-4-carbonyl)-thiophene-2-carbaldehyde (82 mg, 0.36 mmol), and triethylamine (2 drops) in ethanol (3 mL) was heated at 90° C. oil bath for 2 hours, and cooled to room temperature. The solvent was evaporated and the residue was purified on a silica gel column eluting with methylene chloride-methanol (98:2 and 95:5) to provide pure 4-(3-chloro-4-fluoro-phenylamino)-5-{ 1-[5-(morpholine-4-carbonyl)-thiophen-2-yl]-methylidene-}-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (41 mg, 28%). MS 486 [M++1].
Reaction SMILES: [C:1]([Si:5]([CH3:32])([CH3:31])[O:6][CH:7]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:8][CH2:9][CH2:10][C:11]([N:13]1[CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][O:15][C:14]1=[O:24])=[O:12])([CH3:4])([CH3:3])[CH3:2].[CH3:33][O:34][C:35]1[CH:51]=[CH:50][C:38]([CH:39]=[N:40][C:41]2[CH:46]=[CH:45][C:44]([N+:47]([O-:49])=[O:48])=[CH:43][CH:42]=2)=[CH:37][CH:36]=1.C(N(C(C)C)CC)(C)C.C[Si](Cl)(C)C.S([O-])(O)=O.[Na+]>C(O)(=O)C>[C:1]([Si:5]([CH3:32])([CH3:31])[O:6][CH:7]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:8][CH2:9][CH:10]([CH:39]([C:38]1[CH:50]=[CH:51][C:35]([O:34][CH3:33])=[CH:36][CH:37]=1)[NH:40][C:41]1[CH:42]=[CH:43][C:44]([N+:47]([O-:49])=[O:48])=[CH:45][CH:46]=1)[C:11]([N:13]1[CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:16][O:15][C:14]1=[O:24])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(C=Nc2ccc([N+](=O)[O-])cc2)cc1
Reactant: CC(C)(C)[Si](C)(C)OC(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(Nc2ccc([N+](=O)[O-])cc2)C(CCC(O[Si](C)(C)C(C)(C)C)c2ccccc2)C(=O)N2C(=O)OCC2c2ccccc2)cc1
Temperature: -30 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
To 5.4 g (12.0 mmol) of product 1 and 6.2 g (24 mmol) of product 2 in 135 ml of methylenehloride 8 ml of diisopropylethylamine is added at 10° C. and 4.8 ml of trimethylsilylchloride is added dropwise. After 1 h 14 ml of a 1 molar solution of titantetrachloride in methylenehloride is added dropwise at −10° C. It is stirred for 3 h at −10° C. and further 12 h at −30° C. stored without stirring. Afterwards 8 ml of acetic acid and 140 ml of a 7% aqueous solution of tartratic acid is added and it is stirred for further 2 h at room temperature. After addition of 50 ml of a 20% aqueous solution of sodiumhydrogensulfit it is stirred for another 1 h and extracted with methylenehloride. The organic phase is dried by magnesium sulfate, evaporated and purified by chromatography on silica gel/Ethylacetate/heptane=1/3->1/1. 6.3 g (74%) of product 3 is obtained in form of a light yellow solid compound: C40H47N3O7Si (709.92) MS (ESI+) 710 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[N:15]=[N:16][C:17]([CH:20]([NH:22][C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH3:21])=[CH:18][N:19]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O>ClCCCl>[CH3:21][C:20]1[N:22]=[C:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:16]2[C:17]=1[CH:18]=[N:19][C:14]([NH:13][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)=[N:15]2
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3)nn2)cc(OC)c1OC
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4ccccc4)n3n2)cc(OC)c1OC
Temperature: 25 °C
Yield: 9.4 %

Procedure:
To a solution of N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (150 mg, 0.38 mmol) in 1,2-dichloroethane (10 mL) was added phosphorus oxychloride (0.28 mL, 3.0 mmol). The mixture was heated to reflux for 24 hours. After cooling to room temperature, the excess phosphorus oxychloride was quenched with water and silica gel (0.5 g) was added to the reaction mixture, followed by evaporation of the volatiles under reduced pressure. The pre-adsorbed solids were loaded into a solid loading cartridge and subjected to a gradient elution using ethyl acetate:hexane (25:75) to ethyl acetate (100%) using a RediSep silica gel cartridge (4.2 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to give 5-methyl-7-phenyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.014 g) as an off-white solid. 1H NMR (CDCl3): δ8.78 (s, 1H), 8.43 (d, J=6.9 Hz, 2H), 7.49-7.35 (m, 3H), 6.94 (s, 1H), 6.68 (s, 2H), 3.83 (s, 3H), 3.81 (s, 6H), 2.59 (s, 3H). MS m/z 392 (M+1).