Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:9][C@@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][CH:11]1[C:34]([OH:36])=O)(=O)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=C(SSC2N=CC=CC=2)N=CC=1.[CH3:70][O:71][C:72]1[CH:73]=[C:74]([CH:77]=[CH:78][CH:79]=1)[NH:75][CH3:76]>C1COCC1>[OH:9][C@@H:10]1[C@H:14]([OH:15])[C@@H:13]([CH2:24][OH:25])[O:12][CH:11]1[C:34]([N:75]([C:74]1[CH:77]=[CH:78][CH:79]=[C:72]([O:71][CH3:70])[CH:73]=1)[CH3:76])=[O:36]
Reactant: CNc1cccc(OC)c1
Reactant: O=C(OC[C@H]1OC(C(=O)O)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: C1CCOC1
Product: COc1cccc(N(C)C(=O)C2O[C@H](CO)[C@@H](O)[C@H]2O)c1
Reaction time: 16 h
Yield: 42.5 %

Procedure:
(3R,4R,5R)-3,4-Bis(benzoyloxy)-5-(benzoyloxymethyl)tetrahydrofuran-2-carboxylic acid (3,4,6-Tri-O-benzoyl-2,5-anhydro-D-allonic acid, 2 g, 4 mmol) was dissolved in anhydrous THF (40 mL) under argon. Triphenylphosphine (2.1 g, 8 mmol) was then added, and the resulting mixture was stirred until it was completely dissolved. Subsequently 2,2′-dipyridyldisulfide (1.8 g, 8 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 2 hours, after which 3-methoxy-N-methylaniline (0.7 g, 5.6 mmol) was added and stirring was continued at room temperature for 16 hours. The solvent was evaporated to dryness, the residue was dissolved in chloroform (150 mL), the solution was washed twice with 0.1M NaOH solution (100 mL), twice with 0.2 M HCl solution (100 mL), once with saturated NaHCO3 solution (100 mL), and dried (Na2SO4). The solution was evaporated to dryness and the residue dissolved in 7M solution of ammonia in methanol (250 mL). The solution was stirred for 16 hours at room temperature and evaporated to dryness. The residue was dissolved in chloroform and applied to a column of silica gel. Elution with a mixture of chloroform-methanol (3:1) and evaporation of the appropriate fractions yielded the title compound as a colorless oil (0.51 g, 1.7 mmol, 42%): MS (ES) m/z 399 [M+H+C6H15N]+, 296 [M−H]−.
Reaction SMILES: [CH2:1]([C:3]([NH2:8])([CH2:6][CH3:7])[CH2:4][NH2:5])[CH3:2].[F:9][C:10]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:11]=1[CH2:12][O:13][C:14]1[C:15]2[N:16]([C:21]([C:25](O)=[O:26])=[C:22]([CH3:24])[N:23]=2)[CH:17]=[C:18]([CH3:20])[CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[NH2:8][C:3]([CH2:6][CH3:7])([CH2:1][CH3:2])[CH2:4][NH:5][C:25]([C:21]1[N:16]2[CH:17]=[C:18]([CH3:20])[CH:19]=[C:14]([O:13][CH2:12][C:11]3[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:10]=3[F:9])[C:15]2=[N:23][C:22]=1[CH3:24])=[O:26]
Reactant: CCC(N)(CC)CN
Reactant: Cc1cc(OCc2c(F)cccc2F)c2nc(C)c(C(=O)O)n2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Product: CCC(N)(CC)CNC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(C)cn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
70 mg (0.60 mmol) of 2-ethylbutane-1,2-diamine were added to 100 mg (0.30 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylic acid Example 21A, 145 mg (0.45 mmol) of TBTU and 0.13 ml (1.20 mmol) of 4-methylmorpholine in DMF (1.9 ml), and the reaction mixture was stirred at RT overnight. The mixture was then diluted with water/TFA and purified by preparative RP-HPLC (acetonitrile/water gradient with addition of 0.1% TFA). After concentration, the residue was taken up in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered off, concentrated and lyophilized. This gave 110 mg (85% of theory, purity 100%) of the target compound.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[N:18]=[C:17]([C:19]([N:21]2[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)=[O:20])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:30]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:31][C:32](=[CH2:40])[C:33]([O:35]C(C)(C)C)=[O:34])[CH:15]=2)[N:10]=1>ClCCl>[CH2:44]([O:43][C:41](=[O:42])[CH:30]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([NH2:8])[N:18]=[C:17]2[C:19]([N:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1)=[O:20])[CH2:31][C:32](=[CH2:40])[C:33]([OH:35])=[O:34])[CH3:45]
Reactant: C=C(CC(C(=O)OCC)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(CC(C(=O)OCC)c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1)C(=O)O
Temperature: 23 °C
Reaction time: 3 h

Procedure:
200 μl of trifluoroacetic acid are added to 100 mg of O1-tert-butyl O5-ethyl 4-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]-2-methylenepentanedioate in 1 ml of dichloromethane, and the mixture is stirred at 23° C. for 3 h. The mixture is subsequently evaporated to dryness in vacuo and reacted further directly.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15]Cl)(=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].[OH:17][P:18]([CH2:30][C:31]([N:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[O:32])([CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:19]>CN(C)C=O.C(OCC)(=O)C>[CH3:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[O:14][CH2:15][O:19][P:18]([CH2:30][C:31]([N:33]1[CH2:47][CH2:46][CH2:45][C@H:34]1[C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])=[O:32])([CH2:20][CH2:21][CH2:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:17]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1C(=O)CP(=O)(O)CCCCc1ccccc1
Reactant: CC(C)(C)C(=O)OCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OCOP(=O)(CCCCc1ccccc1)CC(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Triethylamine (1.9 ml) and chloromethyl pivalate (2.0 ml) are added to a solution of 3.0 g of [[hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline, benzyl ester in dimethylformamide under an argon atmosphere and the resulting mixture is stirred at room temperature for 6 hours. The reaction mixture is diluted with ethyl acetate, washed with water, brine, dried (MgSO4), and evaporated. The crude product (3.7 g) is chromatographed on silica (80 g) eluting with ethyl acetate/dichloromethane to give 2.96 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: COc1ccc(-c2nc(Nc3cc[nH]n3)cc3ccccc23)cc1OC

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3,4-dimethoxy-phenylboronic acid to give [1-(3,4-dimethoxy-phenyl)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 347(MH+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[CH:7]=[CH:6]2)#[CH:2].[N:19]([Si](C)(C)C)=[N+:20]=[N-:21].[OH-].[Na+].Cl>ClCCl>[F:18][C:15]1[CH:16]=[CH:17][C:12]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([C:1]4[N:19]=[N:20][NH:21][CH:2]=4)=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)=[CH:13][CH:14]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: C#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Fc1ccc(-n2ccc3cc(-c4c[nH]nn4)ccc32)cc1
Temperature: 170 °C
Reaction time: 2 h
Yield: 103.9 %

Procedure:
A mixture of 5-ethynyl-1-(4-fluorophenyl)-1H-indole (9.6 g) and neat azidotrimethylsilane (21.7 g) was heated in a sealed tube at 170° C. for 24 h. The reaction mixture was cooled to 0° C. and a mixture of dichloromethan (150 mL) and 2 N aqueous sodium hydroxide was added. After stirring at room temperature for 2 h, the mixture was acidified with concentrated hydrochloric acid. The phases were separated and the aqueous phase was extracted with dichloromethane (2×200 mL). The combined organic phases were washed with brine (200 mL), dried (MgSO4) and the volatile solvents evaporated in vacuo affording pure title compound 19a as an oil (11.8 g): 1H NMR (CDCl3) δ 6.80 (d, 1H), 7.25 (t, 2H), 7.40 (d, 1H), 7.55 (dd, 2H), 7.60 (d, 1H), 7.75 (broad d, 1H), 8.05 (s, 1H), 8.20 (broad s, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.C(N1CCOCC1)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O1CCCCC1ONC([C@H]([C@@H:57]([CH2:66][CH:67]([CH3:69])[CH3:68])[C:58]([NH:60][NH:61][CH2:62][CH:63]([CH3:65])[CH3:64])=[O:59])C/C=C/C1C=CC=CC=1)=O>CN(C)C=O>[CH2:62]([N:61]([C:4](=[O:6])[CH2:3][O:2][CH3:1])[NH:60][C:58](=[O:59])[CH2:57][CH2:66][CH:67]([CH3:69])[CH3:68])[CH:63]([CH3:65])[CH3:64]
Reactant: COCC(=O)O
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COCC(=O)N(CC(C)C)NC(=O)CCC(C)C
Reaction time: 1 h

Procedure:
A solution of 0.180 g of methoxyacetic acid in 10 ml of dimethylformamide was treated in sequence with 0.254 ml of N-ethylmorpholine, 0.270 g of 1-hydroxybenzotriazole and 0.384 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride. Stirring was continued at room temperature for 1 hour and then 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide was added. Stirring was continued at room temperature overnight and then the solvent was evaporated and replaced by ethyl acetate. The ethyl acetate layer was washed with 5% aqueous citric acid, 5% aqueous sodium hydrogen carbonate and brine and then dried over anhydrous magnesium sulphate. Evaporation and trituration with diethyl ether gave 0.543 g of (E)-2(R)-[1(S)-(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-2′-(2-methoxyacetyl)-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.[CH3:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[O:19].[C:27]([O:34][CH2:35][CH3:36])(=[O:33])[C:28]([O:30]CC)=O>C(OCC)C>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:18](=[O:19])[CH:17]([CH3:16])[C:28](=[O:30])[C:27]([O:34][CH2:35][CH3:36])=[O:33])=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(=O)c1ccc(Cl)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(=O)C(C)C(=O)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 33.7 %

Procedure:
A 1.0 M solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (30 mL, 30 mmol) in anhydrous diethyl ether (120 mL) under argon was cooled to −78° C. in a dry ice/acetone bath. A solution of 4-chloropropiophenone (5.0 g, 29.7 mmol) in anhydrous ether (24 mL) was added dropwise and the mixture was stirred an additional 45 minutes at −78° C. Diethyl oxalate (4.6 mL, 33.9 mmol) was added in one portion; the reaction was warmed to room temperature, and stirred overnight. The light yellow precipitate that formed was collected, washed with ether and dried under vacuum to obtain the lithium enolate of ethyl 4-(4-chlorophenyl)-3-methyl-2,4-dioxobutanoate (2.75 g, 10.0 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[CH:14][CH:15]=2)[CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:28][C:29]1[C:38](I)=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[Si:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:9]([C:38]1[C:29]([Cl:28])=[N:30][C:31]3[C:36]([CH:37]=1)=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:10]2)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: Clc1nc2ccccc2cc1I
Reactant: CC(C)(C)OC(=O)n1c(B(O)O)cc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1c(-c2cc3ccccc3nc2Cl)cc2cc(O[Si](C)(C)C(C)(C)C)ccc21
Temperature: 90 °C

Procedure:
A deoxygenated mixture of 1-(tert-butoxycarbonyl)-5-{[tert-butyl (dimethyl)silyl]oxy}-1H-indol-2-ylboronic acid 1-6 (4.10 g, 10.5 mmol, 1 equiv), 2-chloro-3-iodo-quinoline (1-2, 3.64 g, 12.6 mmol, 1.20 equiv), potassium phosphate (6.67 g, 31.4 mmol, 3.00 equiv), and tetrakis(triphenylphosphine)palladium (0.605 g, 0.524 mmol, 0.050 equiv) in dioxane (100 mL) was heated at 90° C. for 20 hours. The reaction mixture was cooled, then partitioned between a mixture of water and ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by flash column chromatography (20% dichloromethane in hexanes, grading to 90% dichloromethane in hexanes) to give tert-butyl 5-{[tert-butyl(dimethyl)silyl]oxy}-2-(2-chloro-3-quinolinyl)-1H-indole-1-carboxylate (1-7) as a tan-colored foam. 1H NMR (400 MD, CDCl3) δ 8.16 (s, 1H), 8.15 (d, 1H, J=9.0 Hz), 8.07 (d, 1H, J=8.2 Hz), 7.86 (d, 1H, J=7.8 Hz), 7.77 (br t, 1H, J=8.4 Hz), 7.60 (br t, 1H, J=8.1 Hz), 7.03 (d, 1H, J=2.4 Hz), 6.92 (dd, 1H, J=9.0, 2.4 Hz), 6.55 (s, 1H), 1.26 (s, 9H), 1.02 (s, 9H), 0.23 (s, 6H).
Reaction SMILES: I[CH2:2][CH:3]([CH3:5])[CH3:4].C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[NH:18][C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=1>CN(C)C=O.Cl>[Cl:12][C:13]1[N:18]([CH2:2][CH:3]([CH3:5])[CH3:4])[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[CH:14]=1
Reactant: Cn1c(=O)cc(Cl)[nH]c1=O
Reactant: CC(C)CI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(Cl)cc(=O)n(C)c1=O
Temperature: 90 °C
Yield: 55.6 %

Procedure:
3-Iodo-2-methylpropane (4.6 g) and potassium carbonate (8.62 g) were added to a solution of 6-Chloro-3-methylpyrimidine-2,4[1H,3H]-dione (2.0 g) in dimethylformamide (10 ml). The mixture was heated at 90° C. for 18 hours then cooled to room temperature. The solution was diluted with 5% aqueous HCl solution until solution becomes acidic and extracted twice with diethyl ether. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography over silica eluting with hexanes: ethyl acetate (1:1) to give the subtitle compound (1.5 g).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([CH3:19])[C:16](O)=[O:17])=[CH:11][CH:10]=2)[S:6][CH:7]=1.[NH3:22]>C(Cl)Cl>[F:1][C:2]([F:21])([F:20])[C:3]1[N:4]=[C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([CH3:19])[C:16]([NH2:22])=[O:17])=[CH:11][CH:10]=2)[S:6][CH:7]=1
Reactant: N
Reactant: C[C@@H](C(=O)O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Solvent: ClCCl
Product: C[C@@H](C(N)=O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Temperature: 25 °C
Yield: 79 %

Procedure:
To a cooled mixture (0-5° C.) of (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid (1 g, 3.16 mmol) in CH2Cl2 (20 mL), 1,1-carbonyldiimidazole (CDI) (0.512 g, 3.16 mmol) was added. After stirring for 1 h at 0-5° C. gaseous ammonia was bubbled into the mixture for 4 h and then left stirring at room temperature until the complete disappearance of the starting material. The reaction was quenched adding a H3PO4/H2PO4− buffer solution (pH=2.0, 5 ml), the two phases were separated and the organic one washed with the same buffer (3×10 mL) and water (3×10 mL), dried over anhydrous Na2SO4 and evaporated under vacuum to give (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl) propanamide (788 mg, 2.5 mmol) as a white solid (79%) used without further purification.
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH:11]=O)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].[OH:13][C@H:14]1[CH2:18][NH:17][C@H:16](C(O)=O)[CH2:15]1>CN(C)C=O>[OH:13][CH:14]1[CH2:18][N:17]2[CH:16]([CH2:3][CH:2]3[CH:11]2[CH2:10][N:4]([C:5]([O:6][CH2:7][CH3:8])=[O:9])[CH2:1]3)[CH2:15]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CCN(CC=O)C(=O)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)N1CC2CC3CC(O)CN3C2C1

Procedure:
8.6 g (50 mmol) of ethyl N-allyl-N-(2-oxoethyl) -carbamate are heated at 120° C. overnight with 6.6 g (50 mmol) of trans-4-hydroxyproline in 200 ml of dimethylformamide. The mixture is concentrated and the residue is distilled.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([OH:13])=[O:12].N1C=CC=CC=1.[C:21]([C@@H:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:25]=1)#[N:22]>C(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:13][C@H:23]([C:21]#[N:22])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:25]=1)=[O:12]
Reactant: COC(=O)/C=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.3 %

Procedure:
7 g of the product of Step C, 7.3 g of dicyclohexylcarbodiiumide and 3 ml of pyridine were added to 50 ml of methylene chloride and after the addition of 8 g of (S)α-cyano-3-phenoxy-benzyl alcohol, the mixture was stirred at room temperature for 16 hours. The mixture was filtered and the filtrate was evaporated to dryness under reduced pressure. The 20 g of residue were crystallized from isopropyl ether to obtain 10.5 g of (S)-α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-(methoxycarbonyl)-ethenyl]-cyclopropane-carboxylate melting at 98° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:15]([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:11][C:8]1[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:10][CH:9]=1)[CH3:21])[CH3:20]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CCOC(=O)C(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 99.9 %

Procedure:
4-t-Butylphenol (7.52 g, 50 mmol) in anhydrous DMF (40 mL) was added dropwise to NaH (2.2 g, 55 mmol, 60% w/w in mineral oil) at 0° C. under an atmosphere of nitrogen. After five min, ethyl 2-bromopropionate (6.49 mL, 50 mmol, d=1.394) was added rapidly dropwise and the resultant mixture was allowed to stir for 18 h, gradually warming to ambient temperature. The reaction mixture was diluted with ethyl acetate (300 mL) and extracted twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce a colorless oil (12.5 g, 100%) 1H NMR (300 MHz, CDCl3): δ 7.28 (d, 2H, J=5.5), 6.80 (d, 2H, J=5.5), 4.70 (q, 1H, J=6.6), 4.22 (q, 2H, J=7.1), 1.59 (d, 3H, J=6.6), 1.28 (s, 9H), 1.25 (t, 3H, J=7.1). MS [EI+] 251 (M+H)+, 268 (M+NH4)+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[CH:19]=1)=[C:12]2[CH2:26][CH2:27][N:28]1[C:36](=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]1=[O:38])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:25][C:20]1[CH:19]=[C:18]([C:13]2[NH:14][C:15]3[C:11]([C:12]=2[CH2:26][CH2:27][N:28]2[C:36](=[O:37])[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29]2=[O:38])=[CH:10][C:9]([OH:8])=[CH:17][CH:16]=3)[CH:23]=[C:22]([CH3:24])[CH:21]=1
Reactant: [H][H]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(OCc4ccccc4)cc3c2CCN2C(=O)c3ccccc3C2=O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(O)cc3c2CCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C

Procedure:
To a stirred solution of 2-[2-[5-benzyloxy-2-(3,5-dimethylphenyl)-1H-indol-3-yl]ethyl]isoindole-1,3-dione (510 mg in 20 mL dry ethyl acetate was added 197 mg of 10% palladium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 37 hours the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo to provide the title compound (418 mg).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23](I)[CH:22]=2)=[O:18].[CH3:39][S:40]([NH2:43])(=[O:42])=[O:41].N(CC(O)=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>CN1CCCC1=O.[Cu]I>[NH2:1][C:2]1[N:6]([C:7]2[CH:16]=[CH:15][C:10]3[NH:11][C:12]([CH3:14])=[N:13][C:9]=3[CH:8]=2)[N:5]=[CH:4][C:3]=1[C:17]([C:19]1[N:20]([S:29]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:31])=[O:30])[C:21]2[C:26]([CH:27]=1)=[CH:25][CH:24]=[C:23]([NH:43][S:40]([CH3:39])(=[O:42])=[O:41])[CH:22]=2)=[O:18]
Reactant: CS(N)(=O)=O
Reactant: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3ccc(I)cc32)cc1
Agent: [Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CN1CCCC1=O
Product: Cc1ccc(S(=O)(=O)n2c(C(=O)c3cnn(-c4ccc5[nH]c(C)nc5c4)c3N)cc3ccc(NS(C)(=O)=O)cc32)cc1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
[5-Amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazol-4-yl]-[6-iodo-1-(toluene-4-sulfonyl)-1H-indol-2-yl]-methanone (80.3 mg, 0.126 mmol), copper (I) iodide (37.5 mg, 0.197 mmol), methanesulfonamide (37.5 mg, 0.394 mmol), sarcosine (36.2 mg, 0.406 mmol), and tripotassium phosphate (86.0 mg, 9.405 mmol) were dissolved in anhydrous 1-methyl-2-pyrrolidinone (0.36 ml), and heated at 140° C. with stirring under an argon atmosphere for 30 minutes. The reaction mixture was added dropwise to an aqueous solution (20 ml) of 20% ammonium chloride, and extracted with ethyl acetate, the organic layer was washed with an aqueous solution of 20% sodium chloride and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by amino gel column chromatography (dichloromethane/methanol=15/1) to give N-[2-[5-amino-1-(2-methyl-1H-benzimidazol-5-yl)-1H-pyrazole-4-carbonyl]-1-(toluene-4-sulfonyl)-1H-indol-6-yl]methanesulfonamide as a yellow amorphous material (17.9 mg with a yield of 24%).
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([OH:8])[CH:2]=1.Cl[C:10]([F:14])([F:13])[CH2:11][Cl:12].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[Cl:12][CH2:11][C:10]([F:14])([F:13])[O:8][C:3]1[CH:4]=[CH:5][C:6]([NH2:7])=[CH:1][CH:2]=1
Reactant: FC(F)(Cl)CCl
Reactant: Nc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Nc1ccc(OC(F)(F)CCl)cc1

Procedure:
2.5 g (22.9 mmol) of p-aminophenol, 3.09 g (22.9 mmol) of 1,2-dichloro-1,1-difluoroethane, 5.48 g (39.6 mmol) of K2CO3 and 40 ml of dry acetonitrile were stirred together at room temperature for 5 days. The mixture was poured into water and extracted two times into ether. The combined ether extracts were washed with water, dried over MgSO4 and filtered: HCl gas was bubbled into the ether solution causing the above-named aniline to precipitate as the hydrochloride salt, which was collected by filtration and recrystallized twice from CH3CN to give 0.9 g (16 percent of theoretical d 245°-250° C.) of a white solid.