Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][CH3:20])=[CH:15][C:14](Br)=[CH:13][CH:12]=3)=[O:5])[CH3:2].C(NCC)C.[CH3:27][N:28]([CH3:32])[CH2:29][C:30]#[CH:31]>[Cl-].[Cl-].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Pd+2].CN1CCCC1=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][CH3:20])=[CH:15][C:14]([C:31]#[C:30][CH2:29][N:28]([CH3:32])[CH3:27])=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: C#CCN(C)C
Reactant: CCOC(=O)c1ncc2[nH]c3ccc(Br)cc3c2c1CC
Agent: [Pd+2]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: [Cl-]
Solvent: CCNCC
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1ncc2[nH]c3ccc(C#CCN(C)C)cc3c2c1CC
Yield: 48.7 %

Procedure:
347 mg of 6-bromo-4-ethyl-beta-carboline-3-carboxylic-acid-ethylester, 32 mg of palladium-bis-(tri-o-tolylphosphine)-dichloride, 32 mg of cuprous iodide, 5 ml of diethylamine, 5 ml of N-methyl-2-pyrrolidone and 250 mg of 3-dimethylamino-1-propine are heated anhydrously and under nitrogen for 7.5 h at 80°-90° C. After concentration in an oil pump vacuum, the residue is chromatographed on 30 g of silica gel with methylene-chloride/methanol (10/2) as the eluant. The correspondingly consolidated fractions are separated by preparative film chromatography and 170 mg of 6-(3-dimethylamino-1-propinyl)-4-ethyl-beta-carboline-3-carboxylic-acid-ethylester is obtained in the form of an oil.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[F:9][C:10]([F:20])([F:19])[O:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.S(=O)(=O)(O)O>C(O)(=O)C.O>[I:1][C:14]1[CH:13]=[C:12]([O:11][C:10]([F:19])([F:20])[F:9])[CH:17]=[CH:16][C:15]=1[OH:18]
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: Oc1ccc(OC(F)(F)F)cc1I
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 94 %

Procedure:
To a suspension of N-iodosuccinimide (6.95 g, 31 mmol) in glacial acetic acid (2 ml) was added 4-trifluoromethoxy phenol (4.0 ml, 31 mmol) and, after 5 minutes, concentrated sulphuric acid (0.5 ml, 9 mmol). The pale brown suspension was stirred at room temperature under nitrogen for 48 hours before diluting with water and extracting with dichloromethane. Organic extract was washed with water, saturated aqueous sodium thiosulphate solution, water, dried over magnesium sulfate and decolourising charcoal added. The resulting suspension was left to stand for 30 minutes before filtering through a short pad of silica gel eluting with dichloromethane. The solvent was evaporated in vacuo to give the title compound as an oil, 8.78 g, 94% yield.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([S:19][C@@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([OH:23])=O)(=[O:18])[CH3:17].[NH2:31][C@H:32]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35].O.OC1C2N=NNC=2C=CC=1>O1CCCC1>[C:16]([S:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:21]([NH:31][C@H:32]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])=[O:23])(=[O:18])[CH3:17]
Reactant: CC(=O)S[C@@H](Cc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)SC(Cc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This salt is converted to the free acid. Dicyclohexylcarbodiimide in tetrahydrofuran is added to a solution of (S)-2-acetylthio-3-phenylpropionic acid, (L)-leucine, 1,1-dimethylethyl ester, and hydroxybenzotriazole hydrate in tetrahydrofuran at -8° and the reaction mixture is stirred overnight warming to room temperature, and is then worked up according to the procedure of Example 37 to yield (S)-N-[2-(acetylthio)-1-oxo-3-phenylpropyl]-L-leucine, 1,1-dimethylethyl ester as a clear, light yellow, viscous oil.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.[I:9]Cl.S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][N:4]=1
Reactant: CNc1ccccn1
Reactant: ClI
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CNc1ccc(I)cn1
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
2-(N-Monomethylamino)pyridine (98, 1.00 g, 5.55 mmol) was dissolved in dichloromethane (20 mL) and a 1 M iodine monochloride (ICl, 6.10 mL, 6.10 mmol) dichloromethane solution was slowly added at 0° C., and stirred for 30 minutes. To the reaction mixture was added a 10% aqueous solution of sodium sulfite (Na2S2O3) and organic compounds were extracted with dichloromethane and evaporated after a treatment with sodium sulfate. Purification was performed by column chromatograph to give the target compound 2-(N-monomethylamino)-5-iodopyridine (99, 800 mg, 62%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[N:11]=[N:10]2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][CH3:28])[NH2:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:23][C:15]([C:12]2[N:11]=[N:10][N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:13]=2[CH3:14])=[O:17])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: Cc1c(C(=O)O)nnn1Cc1ccc(F)cc1
Reactant: COc1ccc(N)cc1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2nnn(Cc3ccc(F)cc3)c2C)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[(4-fluorophenyl)methyl]-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (0.2 g, 0.85 mmol), 3,4-bis(methyloxy)aniline (0.156 g, 1.2 eq), HATU (0.485 g, 1.5 eq) and DIPEA (240 μL, 1.5 eq) in DMF was stirred at room temperature overnight. The solvent was evaporated and the residue was washed with water and extracted with DCM. The organic phase was dried over sodium sulphate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography eluting with DCM to give after precipitation from ether, the title compound as a white solid (180 mg, 57%). HRMS calculated for C19H19FN4O3 (M+H)+371.1519, found: 371.1500, Rt: 2.78 min. MP: 119.7° C.
Reaction SMILES: [Li]CCCC.[Br-].[CH2:7]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].[CH:37]([C:39]1[CH:40]=[N:41][N:42]([CH:44]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:43]=1)=O>C1COCC1>[CH:37]([C:39]1[CH:40]=[N:41][N:42]([CH:44]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:43]=1)=[CH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH3:7]
Reactant: CCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C(c1ccccc1)n1cc(C=O)cn1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCCC=Cc1cnn(C(C(=O)OCC)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of n-BuLi (127 mL, 254 mmol, 2.0M in hexanes) was added dropwise to a suspension of n-undecyl-triphenylphosphonium bromide (121.6 g, 244 mmol, obtained from triphenylphosphine and undecylbromide) in 500 mL THF at -78° C. under an atmosphere of N2. The resulting orange solution was stirred for 1 hour before a solution of ethyl (±)-4-formyl-α-phenyl-1H-pyrazole-1-acetate in 250 mL THF was added dropwise. Warmed to room temperature and stirred for 16 hours. Quenched by adding 150 mL water and concentrating in vacuo. The residue was partitioned between water and dichloromethane. The organic layer was dried over MgSO4, filtered, and concentrated to give an oily tan solid. Triturated with boiling hexanes and filtered to remove triphenylphosphine oxide. The filtrate was concentrated and chromatographed (10% EtOAc/hexanes on silica) to give the title compound as a yellow oil, a 1:2 E/Z mixture (44.4 g, 50%).
Reaction SMILES: [NH2:1][CH2:2][P:3](=[O:18])([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>C1C=CC=CC=1>[CH:19](=[N:1][CH2:2][P:3](=[O:18])([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[O:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: NCP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: O=P(CN=Cc1ccccc1)(Oc1ccccc1)Oc1ccccc1

Procedure:
A solution of diphenyl aminomethylphosphonate (102.8 g) and benzaldehyde (41.6 g) in benzene (1000 ml) is heated at reflux in a Dean-Stark apparatus until water separation ceases. The resulting solution is evaporated under reduced pressure to yield diphenyl N-benzylideneaminomethylphosphonate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[C:6]1[CH2:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:9]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:8]=2[NH:7]1)[CH3:2].[N:26]([O-])=[O:27].[Na+]>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:25])[C:5](=[N:26][OH:27])[C:6]1[CH2:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:9]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:8]=2[N:7]=1)[CH3:2]
Reactant: O=N[O-]
Reactant: CCOC(=O)C=C1CN=C(c2ccccc2F)c2cc(Cl)ccc2N1
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Reaction time: 0.08 h

Procedure:
The crude 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-ylideneacetic acid ethyl ester obtained by reduction of 10 g. of the end produce of Example 15 as described above was dissolved in 40 ml. of glacial acetic acid. Sodium nitrite, 2.45 g., was added with stirring over a period of 5 minutes. Following the addition the mixture was stirred at room temperature for 15 minutes. The product started to crystallize and was further precipitated by addition of 50 ml. of water. The crystals were collected, washed with water, ethanol and ether to yield the end product. The analytical sample was recrystallized from tetrahydrofuran/ethanol to give pale yellow crystals with mp 230-°233°.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[NH2:10][C:11]([NH2:13])=[O:12].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[F:1][C:2]([F:9])([F:8])[CH:3]1[CH2:7][NH:13][C:11](=[O:12])[NH:10][C:4]1=[O:5]
Reactant: C=C(C(=O)O)C(F)(F)F
Reactant: NC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1
Temperature: 90 °C
Reaction time: 5 h
Yield: 42 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5.0 mmoles) and urea (318 mg; 5.3 mmoles) in DMF (5 ml) was heated at 90° C. with stirring for 5 hours. After cooling to 0° C., a solution of DCC (1.09 g; 5.3 mmoles) in DMF (3 ml) was added dropwise. The mixture was stirred for 1 hour, and the precipitated solid was filtered off and washed with ethyl acetate. The solvents were evaporated under reduced pressure from the combined filtrates. The residue was purified by a column chromatography on silica gel (ethyl acetate) to give 382 mg (yield: 42%) of 5-trifluoromethyl-5,6-dihydrouracil. m.p.: 203°-205° C. (dec.) [value reported in the literature 203°-205° C. (dec.)].
Reaction SMILES: FC1C=C(CN)C=NC=1.[F:10][C:11]1[C:12]([CH2:17][NH2:18])=[N:13][CH:14]=[CH:15][CH:16]=1.[CH:19]1([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34](O)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])[CH2:21][CH2:20]1>>[CH:19]1([CH2:22][N:23]2[CH2:27][CH2:26][N:25]([C:28]3[S:29][C:30]([C:34]([NH:18][CH2:17][C:12]4[C:11]([F:10])=[CH:16][CH:15]=[CH:14][N:13]=4)=[O:35])=[C:31]([CH3:33])[N:32]=3)[C:24]2=[O:37])[CH2:20][CH2:21]1
Reactant: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)O
Reactant: NCc1ncccc1F
Agent: NCc1cncc(F)c1
Product: Cc1nc(N2CCN(CC3CC3)C2=O)sc1C(=O)NCc1ncccc1F
Yield: 60 %

Procedure:
Following the procedure as describe in Example 12, making variations as required to replace (5-fluoropyridin-3-yl)methanamine with (3-fluoropyridin-2-yl)methanamine to react with 2-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white solid in 60% yield: mp 142-144° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.38-8.31 (m, 2H), 7.69-7.62 (m, 1H), 7.39-7.33 (m, 1H), 4.51-4.54 (m, 2H), 4.00-3.95 (m, 2H), 3.64-3.59 (m, 2H), 3.06 (d, J=6.0 Hz, 2H), 2.44 (s, 3H), 0.96-0.87 (m, 1H), 0.49-0.42 (m, 2H), 0.21-0.16 (m, 2H); 13C NMR (75 MHz, DMSO-d6) δ 162.2, 159.1, 157.9, 155.7, 151.2, 146.2, 145.4, 124.5, 123.6, 118.2, 48.2, 42.5, 42.3, 40.8, 17.5, 9.3, 3.6; MS (ES+) m/z 389.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[C:9](O)([CH3:12])([CH3:11])[CH3:10].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])=[C:4]([OH:8])[CH:3]=1
Reactant: Oc1cccc(Br)c1
Reactant: CC(C)(C)O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 84 h

Procedure:
To a solution of 29.46 g (170.3 mmol) of 3-bromophenol (distilled) and 16.41 g (20.9 ml, 221.3 mmol) of t-butanol in 100 ml of carbon tetrachloride was added 20.0 ml of conc. sulfuric acid. The clear, colorless solution turned a dark magenta color and became hot. The solution was cooled in water (ambient temperature) and allowed to stir at room temperature for 84 hours. The reaction mixture was neutralized with sat. aqueous NaHCO3 solution (pH -7.0), partitioned between 300 ml of water and 500 ml of dichloromethane, and the organic and aqueous layers were separated. The aqueous phase was washed with 2×500 ml-portions of dichloromethane. All organic phases were combined, washed with 400 ml of brine solution, dried over MgSO4, filtered and concentrated in vacuo to a purple oil. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) followed by kugelrohr distillation yielded the title compound as a clear, slightly yellow oil.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:23]=[CH:22][C:13]([CH2:14][CH:15]3[S:19][C:18](=[O:20])[NH:17][C:16]3=[O:21])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1.CN(C=O)C.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32]>O>[O:20]=[C:18]1[N:17]([CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:16](=[O:21])[CH:15]([CH2:14][C:13]2[CH:12]=[CH:11][C:10]([N:7]3[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]3)=[CH:23][CH:22]=2)[S:19]1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)SC(Cc2ccc(N3CCC(=O)CC3)cc2)C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
Sodium hydride (60% in mineral oil, 66 mg, 1.65 mmol) was added into a mixture of 5-[4-(4-oxo-1-piperidinyl)benzyl]-1,3-thiazolidine-2,4-dione (500 mg, 1.65 mmol) (which was obtained in Example 38), and DMF. The mixture was stirred for 1 hour at room temperature, and then tert-butyl bromoacetate (0.36 mL, 2.47 mmol) was added. The new mixture was stirred for 30 minutes, poured into water, and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexanes/ethyl acetate 3/1) gave a viscous oil (525 mg, 76% yield); 1H NMR (300 MHz, DMSO-d6) δ 1.40 (s, 9 H), 2.40 (m, 4H), 2.9 (m, 1H), 3.45 (m, 1H), 3.56 (m, 4H), 4.20 (s, 2H), 5.05 (m, 1H), 6.97 (m, 2H), 7.18 (m, 2H); MS (ES) m/z: 419 (MH+); Anal. Calcd. for C15H16N2O3S: C, 60.27; H, 6.26; N, 6.69. Found: C, 60.21; H, 6.44; N, 6.52.
Reaction SMILES: [NH2:1][C:2]([NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[C:9]=1[CH3:15])(=[O:7])=[O:6])=[S:3].Br[CH:17]([CH:23]=O)[CH2:18][C:19]([O:21][CH3:22])=[O:20]>N1C=CC=CC=1>[Cl:14][C:10]1[C:9]([CH3:15])=[C:8]([S:5]([NH:4][C:2]2[S:3][C:17]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:23][N:1]=2)(=[O:6])=[O:7])[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)NC(N)=S
Reactant: COC(=O)CC(Br)C=O
Solvent: c1ccncc1
Product: COC(=O)Cc1cnc(NS(=O)(=O)c2cccc(Cl)c2C)s1

Procedure:
N-(aminocarbonothioyl)-3-chloro-2-methylbenzenesulfonamide (0.4 g, 1.5 mmol) and methyl 3-bromo-4-oxobutanoate (0.3 g, 1.5 mmol), dissolved in pyridine (5 mL), were irradiated in a microwave oven for 2.5 min at 130° C. The solvent was removed under reduced pressure and the product separated from the starting materials using preparative HPLC (yield 0.2 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13](=[O:26])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=2)=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][NH:9][CH2:8][CH2:7]2.Br[CH2:28][CH2:29][O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]>CN(C)C=O>[Si:31]([O:30][CH2:29][CH2:28][N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([Cl:1])[C:3]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:15]=3)=[CH:4][CH:5]=2)[CH2:10]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CNCC3)cc1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc3c(c2Cl)CN(CCO[Si](C)(C)C(C)(C)C)CC3)cc1C(F)(F)F
Temperature: 80 °C
Yield: 33.2 %

Procedure:
A mixture of N-(8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.192 g) and 2-bromoethoxy-tert-butyldimethylsilane (0.24 g) were combined in dimethylformamide and warmed to 80° C. for 18 h. Solvent was removed at reduced pressure, the residue dissolved in dichloromethane and washed with saturated sodium hydrogen carbonate. The organic phase was dried (MgSO4) and solvent removed at reduced pressure. The residue was column chromatographed (silica gel, ammonia/methanol/dichloromethane mixtures as eluant) to give N-(2-(2-tert-butyldimethylsilyloxyethyl)-8-chloro-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-methoxy-3-trifluoromethylbenzamide (0.09 g)
Reaction SMILES: C[O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[CH2:22]([C:24]1[S:28][C:27]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)=[N:26][C:25]=1[CH2:36][CH2:37]O)[CH3:23]>>[NH2:5][C@@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:37][CH2:36][C:25]2[N:26]=[C:27]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[S:28][C:24]=2[CH2:22][CH3:23])=[CH:18][CH:19]=1)[C:3]([OH:2])=[O:21]
Reactant: CCc1sc(-c2ccc(F)cc2)nc1CCO
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Product: CCc1sc(-c2ccc(F)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Yield: 94 %

Procedure:
Intermediate 56 was prepared as described above for the preparation of intermediate 52. From 534 mg of N-(Boc)-L-Tyrosine methyl ester and 500 mg of Intermediate 11B was prepared 900 mg of BOC-protected intermediate methyl ester (94% yield; 1H NMR (CDCl3, 300 MHz) δ7.9 (dd, 2H, 8.7, 5.2), 7.13 (t, 2H, J=8.6), 7.04 (d, 2H, J=8.5), 6.85 (d, 2H, J=8.6), 4.97 (d, 1H, J=7.9), 4.55 (m, 1H), 4.32 (t, 2H, J=6.8), 3.73 (s, 3H), 3.21 (t, 2H, J=6.7), 3.10-3.02 (m, 2H), 2.89 (q, 2H, J=7.5), 1.44 (s, 9H), 1.36 (t, 3H, J=7.5); From 850 mg of protected intermediate was prepared 900 mg of intermediate 56 as a solid. 1H NMR (DMSO-d6, 300 MHz) δ8.0 (br s, 2H), 7.91-7.87 (m, 2H), 7.30 (dt, 2H, J=8.8, 2.1), 7.14 (d, 2H, J=8.6), 6.90 (d, 2H, J=8.6), 4.27 (t, 2H, J=6.5), 4.12 (m, 1H), 3.11 (t, 2H, J=6.5), 3.0 (m, 2H), 2.86 (q, 2H, J=7.5), 1.26 (t, 3H, J=7.5); low resolution MS (ES+)m/e 414.85 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:5][C:6]=1[C:7]#[N:8].[C:15](Cl)(=[O:17])[CH3:16]>N1C=CC=CC=1>[C:7]([C:6]1[S:5][C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][C:2]=1[NH:1][C:15](=[O:17])[CH3:16])#[N:8]
Reactant: N#Cc1sc(N2CCOCC2)nc1N
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(N2CCOCC2)sc1C#N
Temperature: 80 °C
Yield: 81.8 %

Procedure:
To a 5 L round bottom flask equipped with a mechanical stirrer was added 4-amino-2-(4-morpholinyl)-1,3-thiazole-5-carbonitrile (200 g, 951 mmol) and N,N-dimethylaminopyridine (23.24 g, 190 mmol). The solids were taken up in Pyridine (2000 mL) and to this reaction solution was added acetyl chloride (74.7 g, 951 mmol) via an addition funnel. The reaction was heated to 80° C. and monitored by LCMS for conversion to product. Upon complete conversion (˜2 hours), the reaction was cooled to room temperature and the reaction was concentrated to a slurry, then subsequently diluted with a mixture of 0.1N NaOH (2 L) solution and methanol (140 mL). The mixture was rapidly stirred using a mechanical stirrer for 15 min, then the resulting precipitate was collected by filtration to provide the desired N-[5-cyano-2-(4-morpholinyl)-1,3-thiazol-4-yl]acetamide (218.2 g, 778 mmol, 82% yield) as a brown solid (1H NMR (400 MHz, DMSO-d6) δ ppm 2.04 (s, 3H) 3.40-3.53 (m, 4H) 3.62-3.77 (m, 4H) 10.88 (s, 1H)).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([O:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)(=[O:21])=[O:20])=[CH:17][C:11]=2[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH3:41])[CH2:35]Br.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH2:35][C:34]1[CH:37]=[CH:38][C:39]([O:40][CH3:41])=[C:32]([Cl:31])[CH:33]=1)[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([O:18][S:19]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)(=[O:20])=[O:21])[CH:15]=[CH:14][C:12]=2[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc2cc(OS(=O)(=O)c3ccc(F)cc3)ccc2[nH]1
Reactant: COc1ccc(CBr)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN(C(=O)OC(C)(C)C)c2nc3ccc(OS(=O)(=O)c4ccc(F)cc4)cc3[nH]2)cc1Cl
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
A stirred solution of 4-fluoro-benzenesulfonic acid 2-tert-butoxycarbonylamino-3H-benzoimidazol-5-yl ester (Example 55 (step 3), 200 mg) in dry dimethylformamide (3 ml) was treated with sodium hydride (12 mg, 60% dispersion in mineral oil). After stirring for 30 minutes the mixture was treated with a solution of 3-chloro-4-methoxy-benzyl bromide (94 mg) in dimethylformamide (1 ml) and stirring was continued for a further 3 hours. The reaction mixture was poured into water (10 ml) and then extracted three times with ethyl acetate (10 ml). The combined extracts were dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:2, v/v) to give 4-fluoro-benzenesulfonic acid 2-[tert-butoxycarbonyl-(3-chloro-4-methoxy-benzyl)-amino]-3H-benzoimidazol-5-yl ester (70 mg) as a beige solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([Br:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1.CC(OC([NH:42][C@@H:43]([C:45](O)=[O:46])[CH3:44])=O)(C)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.O1CCOCC1>[NH2:42][C@@H:43]([C:45]([NH:1][CH2:2][C@@H:3]([NH:21][C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]([CH3:32])[CH3:31])=[C:25]([Cl:33])[CH:24]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]3[C:18]([Br:19])=[CH:17][CH:16]=[CH:15][N:14]3[CH:20]=2)=[CH:7][CH:6]=1)=[O:46])[CH3:44]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)Oc1ccc(C(=O)N[C@H](CN)Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)Oc1ccc(C(=O)N[C@H](CNC(=O)[C@@H](C)N)Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 25 %

Procedure:
A solution of N-((1S)-2-amino-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-3-chloro-4-[(1-methylethyl)oxy]benzamide (0.28 mmol), N-{[(1,1-dimethylethyl)oxy]carbonyl}-D-alanine (0.56 mmol), EDCI (0.56 mmol), and TEA (1.12 mmol) stirred in methylene chloride (2 mL) at RT for 18 h. The reaction was then treated with 4 M HCl in 1,4-dioxane (2 mL) and stirred at RT for 1 h. The mixture was then concentrated in vacuo, redissolved in ethyl acetate (25 mL) and washed with saturated aqueous sodium bicarbonate solution (1×10 mL). The organic layer was concentrated in vacuo, and purification of the residue by Gilson reverse phase HPLC afforded the title product as a white solid (25%). ESMS [M+H]+: 613.2.