Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[N:10][CH:9]=1)(C)C(O)=O.C1(O)C=CC=CC=1.C([O:43][C:44](=[O:56])[C:45]([CH3:55])([CH3:54])[CH2:46]SC1SC(N)=NC=1)C>>[CH3:46][C:45]([CH3:55])([CH2:54][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:15])=[N:10][CH:9]=1)[C:44]([OH:56])=[O:43]
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCOc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Solvent: Oc1ccccc1
Product: CC(C)(CSc1cnc(NC(=O)N(CCCOc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid using phenol and 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3].[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][CH2:24][C:25](=O)[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:15]1>C(O)C.[Pd]>[CH2:29]([O:28][C:26]([CH:25]([NH:1][C@H:2]([C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5])[CH3:3])[CH2:24][CH2:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:14][CH:15]=1)=[O:27])[CH3:30]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Reactant: CCOC(=O)C(=O)CCc1c[nH]c2ccccc12
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(CCc1c[nH]c2ccccc12)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A solution of L-alanyl-L-proline (0.35 g) and ethyl 4-(3-indolyl)-2-oxobutyrate (1.0 g) in 30 ml of ethanol was hydrogenated with 10% Pd on carbon in the presence of 3.2 g of powdered molecular sieves (4A) under 40 lbs of hydrogen pressure. After the reaction was complete the slurry was filtered and the filtrate concentrated to dryness. The residual oil was dissolved in 5 ml of methanol and chromatographed on a Sephadex LH-20 column to yield 0.67 g of crude product as an orange oil. A portion of the crude (0.3 g) was purified by solution in water and extraction with ether. Product was recovered by dilution of the aqueous phase with an equal volume of saturated NaCl solution and extraction with ethyl acetate to yield 80 mg of (N-[1-ethoxycarbonyl-3-(3-indolyl)propyl]-L-alanyl-L-proline as a yellow oil. Mass spectral analysis showed peaks at 559 for the di-silylated product and at 631 for the tri-silylated product.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[Cl:11].[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>ClCCl>[Cl:11][C:5]1[C:6]([Cl:10])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:3]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:18])[CH3:17])[CH2:2][NH:1][C:23](=[O:24])[NH:22][CH2:20][CH3:21]
Reactant: CC(C)(C)OC(=O)NC(CN)c1cccc(Cl)c1Cl
Reactant: CCN=C=O
Solvent: ClCCl
Product: CCNC(=O)NCC(NC(=O)OC(C)(C)C)c1cccc(Cl)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 192 mg (0.63 mmol) of the compound from Example 40A in 5.7 ml of dichloromethane was admixed at RT with 100 μl (1.26 mmol) of ethyl isocyanate. The reaction mixture was stirred overnight at RT and then freed from the solvent on a rotary evaporator. The residue was taken up in DMSO and purified by preparative HPLC [Method 20]. The product fraction was freed from the solvents on a rotary evaporator. Drying of the residue in an HV gave 173 mg (73% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]3[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:9]=3[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].CC1C=CC(S(O[CH2:29][CH2:30][C:31]2[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=2)(=O)=O)=CC=1>CN(C=O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:10]3[CH2:11][N:12]([CH3:15])[CH2:13][CH2:14][C:9]=3[N:8]([CH2:29][CH2:30][C:31]3[CH:32]=[N:33][C:34]([CH3:37])=[CH:35][CH:36]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C)nc2)cc1
Reactant: Cc1cnc2[nH]c3c(c2c1)CN(C)CC3
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc2c(c1)c1c(n2CCc2ccc(C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.3 %

Procedure:
To a solution of 3,6-dimethyl-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (201 mg, 1.0 mmol) in DMF (1 mL) was added a suspension of NaH (128.0 mg, 3.24 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-(6-methylpyridin-3-yl)ethyl 4-methylbenzenesulfonate (873 mg, 3.0 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 3 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel flash chromatography and 10% MeOH-DCM to yield 3,6-dimethyl-9-(2-(6-methylpyridin-3-yl)ethyl)-6,7,8,9-tetrahydro-5H-pyrrolo[2,3-b:4,5-c′]dipyridine (190 mg). 1H NMR (CDCl3, TFA salt) δ (ppm): 8.2 (s, 1H), 8.04 (s, 1H), 7.43 (s, 1H), 7.18 (d, 1H), 7.0 (d, 1H), 4.3 (t, 2H), 3.6 (s, 2H), 3.0 (t, 2H), 2.7 (t, 2H), 2.5 (s, 8H), 2.4 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20](B4OC(C)(C)C(C)(C)O4)[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[OH:35]O>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:8][C@@H:7]1[C:9]1[CH:10]=[CH:11][C:12]([O:15][C@H:16]2[C:24]3[C:19](=[C:20]([OH:35])[CH:21]=[CH:22][C:23]=3[F:25])[CH2:18][CH2:17]2)=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(B4OC(C)(C)C(C)(C)O4)ccc(F)c32)cc1
Reactant: OO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)[C@H]1C[C@@H]1c1ccc(O[C@@H]2CCc3c(O)ccc(F)c32)cc1
Reaction time: 1 h
Yield: 95.2 %

Procedure:
(1S,2S)-2-{4-[(R)-7-Fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-phenyl}-cyclopropanecarboxylic acid ethyl ester (Intermediate 4, 1.31 g, 2.8 mmol) is suspended in acetic acid (8 mL) and hydrogen peroxide solution (35% in water, 0.97 mL, 11.2 mmol) is added. The mixture is stirred for 1 hour then diluted with water and extracted with ethyl acetate. The organic extracts are washed with water and brine, dried over sodium sulfate and the solvent removed. The residue is dried under vacuum to give the title compound (Yield 0.95 g). LC (METHOD 6): tR=0.57 min; Mass spectrum (ES+): m/z=357 [M+H]+.
Reaction SMILES: CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:14][N+:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1.[C:23]([C:25]1[N:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][N:26]=1)#[CH:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:32][O:31][C:29]1[CH:28]=[CH:27][N:26]=[C:25]([C:23]2[CH:24]=[N:14][N:15]3[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=23)[N:30]=1
Reactant: N#Cc1cc[n+](N)cc1
Reactant: C#Cc1nccc(OC)n1
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccnc(-c2cnn3ccc(C#N)cc23)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.8 %

Procedure:
1-Amino-4-cyanopyridinium 2,4,6-trimethylbenzenesulfonate (Preparation 2, 12.10 g, 37.88 mmol) was added in portions over 6 hours to a stirred suspension of 2-ethynyl-4-methoxypyrimidine (Preparation 1b, 2.54 g, 18.94 mmol) and potassium carbonate (3.93 g, 28.43 mmol) in anhydrous N,N′-dimethylformamide (47 mL) at 0° C. and the resulting mixture was stirred at ambient temperature for 48 hours. The solvent was evaporated and dichloromethane was added to the residue. The solid formed was filtered and the filtrate evaporated to dryness. The crude product was purified by flash chromatography (4:1 hexanes/ethyl acetate) to give the title compound (3.51 g, 74%) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:34])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:10]([CH3:27])[C:11]([C:25]#[N:26])=[C:12]3[C:16]=2[O:15][C:14](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:13]3)[CH2:4]1.Cl.C(O)C.[H][H]>C(O)C>[CH3:34][N:2]([CH3:1])[C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[C:9]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[C:10]([CH3:27])[C:11]([C:25]#[N:26])=[C:12]3[C:16]=2[O:15][C:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:13]3)[CH2:4]1
Reactant: [H][H]
Reactant: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(/C=C/c3ccccc3)nc2c1C#N
Agent: Cl
Solvent: CCO
Product: Cc1c(-c2ccccc2)c(N2CC[C@H](N(C)C)C2)c2oc(CCc3ccccc3)nc2c1C#N
Yield: 16.1 %

Procedure:
7-[(3S)-3-(Dimethylamino)pyrrolidin-1-yl]-5-methyl-6-phenyl-2-[(E)-2-phenylethenyl]-1,3-benzoxazole-4-carbonitrile (I-93) (100 mg, 0.22 mmol) and 1 N hydrochloric acid/ethanol solution (223 μl, 10.22 mmol) were dissolved in ethanol (2 ml), 10% carbon-held palladium catalyst was added, followed by stirring at room temperature under atmospheric pressure of hydrogen for 3 hours. After filtration through Celite, the solvent was concentrated under reduced pressure, ethyl acetate and an aqueous saturated sodium hydrogencarbonate solution were added to make the aqueous layer basic, followed by fractionation. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated away, the resulting residue was subjected to preparative thin-layer silica gel column chromatography, eluted with a mixed solvent of chloroform/methanol (20:1, v/v), recrystallized and purified with n-hexane/ethyl acetate/diisopropyl ether to obtain the entitled compound (16 mg, 16%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:8]=[CH:9][CH3:10])[CH:7]=1.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:24]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:8]=[CH:9][CH2:10][Br:24])[CH:7]=1
Reactant: CC=Cc1cc(Br)ccc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)cc1C=CCBr

Procedure:
A mixture of 4.3 g (0.02 mol) of 5-bromo-2-fluoro-1-(1-propenyl) benzene, 100 ml of carbon tetrachloride, 0.07 g of azobisisobutyronitrile and 3.6 g (0.02 mol) of N-bromosuccinimide is heated for 5 h at reflux. The solid is filtered, the filtrate is evaporated under vacuum and the residue used without other purification in the following stage: Yd.: 5.4 g (91%)
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:28]=1[S:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22]>>[CH3:12][C:6]1[N:7]=[C:8]2[C:3]([C:2]([NH:13][C:14]3[CH:15]=[C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH:26]=[CH:27][C:28]=3[S:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:5]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Sc2ccccc2)c(N)c1
Product: Cc1ccc2c(Nc3cc(CNC(=O)OC(C)(C)C)ccc3Sc3ccccc3)ccnc2n1

Procedure:
The product from Example 1d (557 mg, 3.12 mmol) was reacted with the product from Example 90b (1.032 mg, 3.12 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid (310 mg, 17%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.37 (s, 9H) 2.76 (s, 3H) 4.19 (d, J=6.25 Hz, 2H) 6.29 (d, J=6.99 Hz, 1H) 7.25 (s, 5H) 7.31 (s, 1H) 7.37 (d, J=3.31 Hz, 2H) 7.44-7.56 (m, 1H) 7.79 (d, J=8.82 Hz, 1H) 8.42 (d, J=6.99 Hz, 1H) 8.94 (d, J=8.46 Hz, 1H) 11.05 (s, 1H) 14.43 (s, 1H); MS (ESI+) m/z 473 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([I:21])[CH:16]=1)=O>CO>[CH3:2][O:3][N:4]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([I:21])[CH:16]=1)[CH3:12]
Reactant: CON
Reactant: CC(=O)c1cccc(I)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CON=C(C)c1cccc(I)c1
Temperature: 60 °C

Procedure:
To a solution of O-methyl hydroxylamine hydrochloride (2.5 g, 30.48 mmol) in methanol (25 ml), was added triethylamine (30.48 mmoles) followed by 3-iodo acetophenone (5 g, 20.3 mmol) and the mixture was heated at 60° C. for 3 hours. On completion of the reaction, the mixture was concentrated to remove methanol, to give 1-(3-iodo-phenyl)-ethanone O-methyl-oxime (crude), which was dissolved in glacial acetic acid (50 ml). Sodium cyanoborohydride (2.5 g, 40 mmol) was added portion wise. The mixture was allowed to stirr overnight at ambient temperature. The reaction mixture was concentrated to remove acetic acid and diluted with water. The aqueous layer was extracted with ethyl acetate (3×80 ml), the combined organic layer is washed with brine (40 ml) and dried over sodium sulphate. Organic layer was concentrated under vacuum to obtain 5.6 g crude material, which was subjected to column purification (60-120μ mesh silica gel, 15% ethyl acetate in hexane) to give 3.4 g (54% of theory) of N-[1-(3-Iodo-phenyl)-ethyl]-O-methyl-hydroxylamine.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=O.[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.C(O)(=O)C.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:3]=1[C:8](=[O:9])[N:19]([CH2:18][C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1)[C:5]2=[O:7]
Reactant: NCc1ccc(F)cc1
Reactant: O=C1OC(=O)c2c(F)cccc21
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2cccc(F)c2C(=O)N1Cc1ccc(F)cc1
Temperature: 110 °C
Yield: 104.6 %

Procedure:
A mixture of 3-fluorophthalic anhydride (20 g, 120 mmol) and 4-fluorobenzylamine (20 g, 160 mmol) was stirred in 150 mL toluene. Glacial acetic acid (4 mL) was added dropwise, and the reaction was stirred at 110° C. Water was trapped with a Dean-Stark trap for 16 h. The reaction was cooled to 0° C. Product was isolated by filtration as an off-white solid, after washing with hexane. Obtain the title compound (34.3 g, quant.).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:15][C:16]([C:18]1[N:19]=[C:20]([N:23]2[CH2:26][CH:25](OS(C)(=O)=O)[CH2:24]2)[S:21][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:32]([O-:35])(=[S:34])[CH3:33].[K+]>CN(C)C=O>[C:32]([S:34][CH:25]1[CH2:26][N:23]([C:20]2[S:21][CH:22]=[C:18]([C:16](=[O:17])[NH:15][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[CH2:11][CH:12]([CH3:13])[CH3:14])[N:19]=2)[CH2:24]1)(=[O:35])[CH3:33]
Reactant: CC(C)C[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)CC(C)C)cs2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-3-methylbutylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (840 mg, 1.71 mmol) (obtained as described in Reference Example 37(5)) in dimethylformamide (42 ml) was added potassium thioacetate (1.17 mg, 10.2 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:1) as the eluant to afford 3-acetylthio-1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-3-methyl-butylcarbamoyl]-1,3-thiazol-2-yl}azetidine (452 mg, yield 56%) as a pale brown oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[NH:22]1[CH2:25][CH:24]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[NH:34][C:35]4[N:51]=[C:39]([NH:40][C:41]5[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=5)[CH2:46][CH2:47][C:48]=2[CH:49]=3)[N:38]=[CH:37][C:36]=4[Cl:52])=[O:28])[CH2:23]1.[NH:53]1[C:57]([C:58](O)=[O:59])=[CH:56][CH:55]=[N:54]1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:52][C:36]1[CH:37]=[N:38][C:39]2[NH:40][C:41]3[CH:42]=[N:43][CH:44]=[C:45]([CH:50]=3)[CH2:46][CH2:47][C:48]3[CH:49]=[C:33]([NH:34][C:35]=1[N:51]=2)[CH:32]=[CH:31][C:30]=3[NH:29][C:27](=[O:28])[CH2:26][CH:24]1[CH2:23][N:22]([C:58]([C:57]2[NH:53][N:54]=[CH:55][CH:56]=2)=[O:59])[CH2:25]1
Reactant: O=C(CC1CNC1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Reactant: O=C(O)c1ccn[nH]1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC1CN(C(=O)c2ccn[nH]2)C1)Nc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2
Yield: 66 %

Procedure:
The desired compound was prepared according to the procedure of Example D97, step A, using 2-azetidin-3-yl-N-[6-chloro-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]acetamide tris(trifluoroacetate) and 1H-pyrazole-5-carboxylic acid as the starting materials in 66% yield. LCMS for C26H25ClN9O2 (M+H)+: m/z=530.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[C:15]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)([CH3:18])([CH3:17])[CH3:16].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:15]([C:19]1[CH:34]=[CH:33][C:22]([CH2:23][N:24]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([F:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:21][CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: O=C(O)c1c(F)c(F)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(CN(CCc2ccccc2)C(=O)c2c(F)c(F)cc3cc[nH]c23)cc1
Temperature: 25 °C
Yield: 33 %

Procedure:
87 mg (0.44 mol) of 5,6-difluoro-1H-indol-7-carboxylic acid, 106 mg (0.40 mmol) of (4-tert-butyl-benzyl)-[2-phenyl-ethyl]-amine and 84 mg (0.44 mmol) of EDC.HCl were dissolved in 4 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was purified by column chromatography (20 g silica gel; heptane/EtOAc 4:1) to yield 59 mg (33%) product as a colorless viscous oil. MS (ISP) 447.2 (M+H)+.
Reaction SMILES: [ClH:1].Cl.[C:3]1([C@H:9]2[C@@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:16][C:17]([C:26]1[CH:27]=[CH:28][C:29]([O:34][CH3:35])=[C:30]([CH:33]=1)[CH:31]=O)([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19].Cl.Cl.FC1C=CC(C(F)(F)F)=CC=1CNC1CCCNC1C1C=CC=CC=1>>[ClH:1].[ClH:1].[C:3]1([C@H:9]2[C@@H:14]([NH:15][CH2:31][C:30]3[CH:33]=[C:26]([C:17]([F:16])([C:18]([F:19])([F:20])[F:21])[C:22]([F:23])([F:24])[F:25])[CH:27]=[CH:28][C:29]=3[O:34][CH3:35])[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1C=O
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Agent: Fc1ccc(C(F)(F)F)cc1CNC1CCCNC1c1ccccc1
Product: COc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 1 and Compound 17 in the same manner of Compound 2.
Reaction SMILES: Br.C(=O)(O)[O-].[Na+].[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:18]C)=[C:12]2[C:16]=1[C:15](=[O:17])[CH2:14][CH2:13]2>>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:18])=[C:12]2[C:16]=1[C:15](=[O:17])[CH2:14][CH2:13]2
Reactant: COc1ccc(N)c2c1CCC2=O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Product: Nc1ccc(O)c2c1C(=O)CC2
Yield: 100 %

Procedure:
To 2.28 g of 7-amino-4-methoxyindane-1-one 110 ml of 47% hydrobromic acid was added and the mixture was heated under reflux for 3.5 hours. The reaction mixture was charged into ice, the mixture was neutralized by adding sodium bicarbonate, and then extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate. The solvent was evaporated to dryness to yield 2.10 g of 7-amino-4-hydroxyindane-1-one.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1.[C:11]([C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1)([CH3:14])([CH3:13])[CH3:12]>>[C:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:19][C:7]([C:6]2[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)=[NH:8])=[CH:20][CH:21]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: CSc1ccc(C#N)cc1
Product: CSc1ccc(C(=N)Nc2ccc(C(C)(C)C)cc2)cc1
Yield: 62.13 %

Procedure:
The title compound was prepared from 4-methylthiobenzonitrile (1 g, 6.7 mmol) and 4-tert-butylaniline (1 g, 6.7 mmol) by following the procedure described in preparation 10 (1.24 g, yield 62.13%, purity 98.67% by HPLC). 1H-NMR (CDCl3):δ 1.32 (s, 9H), 2.51 (s, 3H), 4.81 (bs, 2H, D2O exchangeable), 6.90-6.92 (d, 2H), 7.26-7.29 (m, 2H), 7.35-7.37 (m, 2H), 7.78-7.8 (d, 2H). MS m/z:299.4 (M+).
Reaction SMILES: [Br:1][CH:2]([CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)[C:3]([OH:5])=[O:4].[CH3:12]O>>[Br:1][CH:2]([CH2:6][C:7]1[N:8]=[CH:9][NH:10][CH:11]=1)[C:3]([O:5][CH3:12])=[O:4]
Reactant: O=C(O)C(Br)Cc1c[nH]cn1
Reactant: CO
Product: COC(=O)C(Br)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Hydrogen chloride was bubbled through an ice-cooled solution of 2-bromo-3-(1H-imidazol-4-yl)propanoic acid (500 mg, 2.3 mmol) in methanol (15 ml) for 10 minutes, and the mixture was stirred at room temperature for 18 hours. The solution was evaporated under reduced pressure, the residue was suspended in ice-cooled sodium bicarbonate solution, and the suspension was extracted with dichloromethane (4×20 ml). The combined organic solutions were dried (Na2SO4) and evaporated under reduced pressure to afford the title compound as an oil, 600 mg. 1H-NMR (CDCl3, 300 MHz) δ: 3.24 (dd, 1H), 3.44 (dd, 1H), 3.78 (s, 3H), 4.58 (dd, 1H), 6.92 (s, 1H), 7.60 (s, 1H). LRMS: m/z (ES+) 233, 235 [MH+].
Reaction SMILES: CO.C(=O)([O-])[O-].[Na+].[Na+].Br[C:10]1[CH:11]=[C:12]([F:25])[C:13]([C:16]#[C:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[N:14][CH:15]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](OB(O)O)=[CH:29][CH:28]=1>O1CCOCC1>[Si:18]([C:17]#[C:16][C:13]1[C:12]([F:25])=[CH:11][C:10]([C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)=[CH:15][N:14]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)C#Cc1ncc(Br)cc1F
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)(C)[Si](C)(C)C#Cc1ncc(-c2ccc(Cl)cc2)cc1F

Procedure:
10 mL of MeOH, 10 mL of 2N aqueous sodium carbonate solution, and 94 mg (0.13 mmol) of [1,1′-bis(diphenylphosphine)ferrocene]palladium (II) chloride were added to a solution of 1.61 g (5.14 mmol) of 5-bromo-2-[(tert-butyldimethylsilanyl)ethynyl]-3-fluoropyridine and 0.90 g (5.65 mmol) of 4-chlorophenylboric acid in 30 mL of 1,4-dioxane and the mixture was refluxed for 15 minutes. The reaction mixture was evaporated down in vacuo and diluted with EtOAc. The organic phase was washed with water and semisaturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and evaporated down in vacuo. The residue was purified by column chromatography (silica gel, PE/DCM 1:1). Yield: 1.25 g (70% of theoretical); C19H21ClFNSi (M=345.913); calc.: molpeak (M+H)+: 346/348 (Cl); found: molpeak (M+H)+: 346/348 (Cl); HPLC-MS: 8.83 minutes (method B).