Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2.[CH2:28]([O:30][C:31](=[O:38])[C@@:32]([F:37])([CH3:36])[C:33](O)=[O:34])[CH3:29]>>[CH2:28]([O:30][C:31](=[O:38])[C@@:32]([F:37])([CH3:36])[C:33]([NH:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]2[CH:20]=[CH:21][CH:22]=[CH:23][C:5]=2[C:4]2[CH:24]=[CH:25][CH:26]=[CH:27][C:3]1=2)=[O:34])[CH3:29]
Reactant: CCOC(=O)[C@](C)(F)C(=O)O
Reactant: N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: CCOC(=O)[C@](C)(F)C(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-benzyloxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and (R)-2-fluoro-2-methyl-malonic acid monoethyl ester, the title compound was prepared in the same manner as described for example 1c. Light yellow oil (96%). MS: m/e=505(M+H+).
Reaction SMILES: [C:1]([O:9][CH2:10]C)(=[O:8])[CH2:2][C:3]([O:5][CH2:6]C)=[O:4].[CH2:12]([C:17]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[C:18](Cl)=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15].C1(C(CCC)(CCC)C(Cl)=O)C=CC=CC=1>>[CH2:12]([C:17]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)([CH2:21][CH2:22][CH:23]([CH3:24])[CH3:25])[C:18]([CH:2]([C:1]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4])=[O:19])[CH2:13][CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)CCC(CCC(C)C)(C(=O)Cl)c1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Agent: CCCC(CCC)(C(=O)Cl)c1ccccc1
Product: COC(=O)C(C(=O)OC)C(=O)C(CCC(C)C)(CCC(C)C)c1ccccc1

Procedure:
The title compound was prepared following the procedure of Example 1E, substituting dimethyl malonate for diethyl malonate, and substituting the product of Example 6D for the product of Example 1D. 1H NMR (300 MHz, CDCl3): δ 7.32 (m, 5 H), 4.54 (s, 1 H), 3.56 (s, 6 H), 2.00 (m, 4 H), 1.49 (m, 2 H), 0.87 (m, 16 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([N:65]([CH2:74][CH3:75])[CH2:66][CH2:67][CH:68]1[CH2:73][CH2:72][CH2:71][CH2:70][NH:69]1)[CH3:64]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:69]1[CH2:70][CH2:71][CH2:72][CH2:73][CH:68]1[CH2:67][CH2:66][N:65]([CH2:63][CH3:64])[CH2:74][CH3:75])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CCN(CC)CCC1CCCCN1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CCN(CC)CCC1CCCCN1C(=O)c1cc2ncnc(NC(C)c3nc4cc(Cl)ccc4[nH]3)c2cc1Cl

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-(2-diethylamino-ethyl)-piperidine in DMSO at ambient temperature.
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3](O)=O.N1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH:2]([C:3]1[C:13]2[C:12](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:11]=[CH:10][CH:9]=1)=[CH2:1]
Reactant: c1ccncc1
Reactant: O=C(O)CC(=O)O
Product: C=Cc1cccc2ccccc12

Procedure:
1-Hydrox-2-naphthylaldehyde was mixed with sodium ethoxide, and ethanol was removed to obtain sodium salt of 1-hydroxy-2-naphthylaldehyde. Subsequently, benzoyl chloride was dropped to the salt to obtain 1-benzoyloxy-2-naphthol-aldehyde. 0.9 mol of malonic acid was added to 0.25 mol of 1-benzoyloxy-2-naphthol-aldehyde, and 10 ml of pyridine was added thereto and reacted at a temperature of 110° C. for 2 hours to obtain 1-benzoyloxy-2-β-carboxyl)vinylnaphthalene. 0.14 mol of the 1-benzoyloxy-2-β-carboxyl)vinylnaphthalene 0.14 mol. of the 1-benzoyloxy2βcarboxyl)vinylnaphthalene) was dissolved in 100 ml of quinoline, and 5 g of copper powder was added thereto and reacted for further one hour at a temperature of 220° C. to obtain a 1-benzoyloxy-2-vinylnaphthalene. Next, 0.1 mol of 1-benzoyloxy-2-vinylnaphthalene was polymerized in benzene in the presence of AIBN in the same manner as in Synthetic Example 1 to obtain poly(1-benzoyloxynaphthalene). The poly(1-benzoyloxynaphthalene) of an amount corresponding to 0.5 mol of the monomer was dissolved in acetone, and 1 g of aqueous 1 N sodium hydroxide solution was added thereto and heated to obtain poly(vinylnaphthol) (Resin B). The obtained polymer was purified by reprecipitating it in an acetone-water-oxalic acid solution.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[CH:16][CH:15]=3)[C:9]([CH2:11][O:12][CH3:13])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.[Br:35]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([NH:23][C:24]4[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:25]=4[F:34])=[O:22])=[CH:16][CH:15]=3)[C:9]([CH2:11][O:12][CH3:13])=[C:10]([Br:35])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Solvent: CC#N
Product: COCc1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)cc2)c2c(N)ncnn2c1Br
Temperature: 0 °C
Yield: 5.7 %

Procedure:
To a suspension of Intermediate AA (N-{4-[4-amino-6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]phenyl}-N′-[2-fluoro-5-(trifluoro-methyl)phenyl]urea (750 mg, 1.58 mmol)) in acetonitrile (7 ml) was added N-bromosuccinimide (365 mg, 2.0 mmol) and the mixture was heated at 60 C in a sealed vial for 1 h. After cooling to 0° C., the reaction was filtered and washed with cold CH3CN and ethyl ether (3×) to give the crude product as a solid, which was purified via flash column chromatography (95:5 v/v CH2Cl2-MeOH) to afford additional 50 mg of the title compound. 1H-NMR (DMSO-d6) δ 9.34 (s, 1H), 8.95 (d, J=3 Hz, 1H), 8.6 (m, 1H), 7.98 (s, 1H), 7.60 (d, J=3 Hz, 1H), 7.57 to 7.58 (m, 1H), 7.49 (m, 1H), 7.38 to 7.34 (m, 2H), 4.21 (s, 2H), 3.16 (s, 3H); MS [M+H]+=553; LCMS RT=3.24 min.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=3)[CH:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:7][C:6]2=[O:22])[CH2:3][CH2:2]1.[H-].[Na+].[CH2:25](I)[CH3:26]>CN(C)C=O>[CH:1]1([CH2:4][N:5]2[C:14]3[C:9](=[CH:10][C:11]([Cl:15])=[CH:12][CH:13]=3)[CH:8]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:7]([CH2:25][CH3:26])[C:6]2=[O:22])[CH2:2][CH2:3]1
Reactant: CCI
Reactant: O=C1NC(c2ccccc2)c2cc(Cl)ccc2N1CC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(=O)N(CC2CC2)c2ccc(Cl)cc2C1c1ccccc1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of 3.1 g. of 1-cyclopropylmethyl-4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinone in 50 ml. of dimethylformamide was added 0.42 g. of 63% sodium hydride, and the resulting mixture was stirred at 50° C. for 30 minutes. Thereafter, 3.1 g. of ethyl iodide was added, and the mixture was stirred at 60° C. for 4 hours. After cooling, the reaction mixture was poured into 300 ml. of water and extracted with chloroform, and the chloroform layer was washed with water, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was adsorbed on a silica gel column, eluted with chloroform to obtain yellow oily 1-cyclopropylmethyl-3ethyl-4-phenyl-6-chloro-3,4-dihydro-2(1H)-quinazolinone. Crystallization from petroleum benzine gave colorless prisms having a melting point of 88°-90° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl.C(N(CC)CC)C.[C:13]([C:15]1[CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:20]=1)#[N:14].Cl>CN(C=O)C>[NH:1]1[C:13]([C:15]2[CH:16]=[C:17]([C:27]([O:29][CH3:30])=[O:28])[CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:20]=2)=[N:14][N:3]=[N:2]1
Reactant: COC(=O)c1cc(C#N)cc(-c2ccccc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccccc2)cc(-c2nnn[nH]2)c1
Temperature: 100 °C
Reaction time: 9 h

Procedure:
Sodium azide (880 mg) and triethylamine hydrochloride (1.9 g) were added to a DMF (40 mL) solution of methyl 5-cyanobiphenyl-3-carboxylate (1.09 g), and stirred at 100° C. for 9 hours. With cooling with ice, diluted hydrochloric acid was added to it, the formed precipitate was taken out through filtration, washed with water, and dried to obtain the title compound as a white powder.
Reaction SMILES: [O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC.[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[N:26]1[C:31](=[O:43])[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]([CH3:42])[CH3:41])=[CH:36][CH:35]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:44]([O:51][C:52]1[CH:59]=[CH:58][C:55]([CH:56]=[O:57])=[CH:54][CH:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.[Cl-].[Na+].OO>ClCCl.C(N(CC)CC)C.CO>[CH2:18]([C@H:25]1[CH2:29][O:28][C:27](=[O:30])[N:26]1[C:31](=[O:43])[C@@H:32]([O:33][C:34]1[CH:39]=[CH:38][C:37]([CH:40]([CH3:41])[CH3:42])=[CH:36][CH:35]=1)[C@@H:56]([C:55]1[CH:58]=[CH:59][C:52]([O:51][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[CH:53][CH:54]=1)[OH:57])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)c1ccc(OCC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)cc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Agent: OO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1ccc(O[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)[C@H](O)c2ccc(OCc3ccccc3)cc2)cc1
Reaction time: 1 h
Yield: 80.3 %

Procedure:
A solution of dibutylboron triflate in dichloromethane (1M, 67.9 ml) and triethylamine (10.2 ml) was added to a solution of (S)-4-benzyl-3-[(4-isopropylphenoxy)acetyl]oxazolidine-2-one (20.0 g) in dichloromethane (150 ml) at 0° C. The mixture was stirred at the same temperature for 1 hour. To the reaction mixture a solution of 4-benzyloxybenzaldehyde (13.2 g) in dichloromethane (20 ml) was added dropwise at −78° C. and then stirred at the same temperature for 40 minutes. The reaction mixture was further stirred at 0° C. for 1 hour. At the end of this time a mixture of saturated aqueous sodium chloride solution/methanol=1/1 (50 ml) and aqueous hydrogen peroxide solution (31%)/methanol=2/1 (150 ml) was added to the reaction mixture and stirred for 1 hour. The mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water and the layers were separated. The ethyl acetate layer was washed with aqueous hydrogen chloride solution (1N), saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=3/1-1/1 as the eluant to afford the desired compound (25.7 g) as a mass of foam.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10].Br.Br[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:5]=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:10]
Reactant: O=C(c1ccc(O)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: BrCc1ccncc1
Agent: Br
Product: O=C(c1ccc(OCc2ccncc2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure B using (2-Fluoro-4-hydroxy-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 4-(bromomethyl)pyridine hydrobromide. MS (ES+) 384.2
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])=[N:5][N:6]2[CH3:11].C[O-].[Na+].CO.C(O)(=O)C[C:23](CC(O)=O)(C(O)=O)[OH:24]>CS(C)=O>[CH3:23][O:24][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])=[N:5][N:6]2[CH3:11]
Reactant: Cn1nc(S(N)(=O)=O)c2c(F)cccc21
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: COc1cccc2c1c(S(N)(=O)=O)nn2C
Temperature: 130 °C
Reaction time: 1 h
Yield: 60.9 %

Procedure:
A solution containing 5 g (21.8 mmol) of 4-fluoro-1-methyl-1H-indazole-3-sulfonamide and 12.6 g of sodium methoxide (a 28% methanol solution) (65 mmol) in DMSO (50 ml), was stirred at 130° C. for one hour. After confirming the disappearance of the starting material by thin layer chromatography (TLC), the mixture was poured into ice water and acidified with citric acid. Formed crystals were collected by filtration and washed with water and IPE to obtain 3.2 g (yield: 60.9%) of the desired product. Melting point: 268°-270° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH2:27][CH2:26]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.N>Cl>[NH:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]([OH:34])=[O:33])[CH2:27][CH2:26]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Agent: Cl
Agent: N
Product: O=C(O)CN1CCC(c2n[nH]c3cc(/C=C/C4CCNCC4)ccc23)CC1
Reaction time: 18 h
Yield: 72.8 %

Procedure:
4-{2-[3-(1-tert-Butoxycarbonylmethyl-piperidin-4-yl)-1H-indazol-6-yl]-(E)-vinyl}-piperidine-1-carboxylic acid tert-butyl ester (54.0 g) was added portionwise (ca. 9 portions) over 0.75 h to a stirred solution of 5M hydrochloric acid (270 ml) at 20°-25°, and the mixture was stirred at 20°-23° for 18 h. 880 Ammonia (54 ml) was added dropwise with caution over 0.75 h, maintaining the temperature between 18°-26°. The resulting solution (pH 1-2) was filtered through 1 micron graded glass fibre filter paper and the filter washed through with water (54 ml). Further 880 ammonia (36.2 ml) was added dropwise over 0.5 h maintaining the temperature between 22°-26° (pH 9-9.5). The suspension was stirred at 22°-230° for 3 h, and the resulting precipitate filtered off, washed with water (2×148 ml) and dried in vacuo to give the title compound as a white solid (27.6 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:25]=[CH:24][C:13]2[C@:14]3([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=2[CH:11]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3.[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:3]4[CH:4]=[C:5]([F:9])[CH:6]=[C:7]([F:8])[C:2]=4[F:1])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: CC(C)(C)O
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cc(F)cc(F)c3F)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc(F)cc(F)c4F)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2,3,5-trifluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (35 mg, 0.10 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (34 mg, 0.30 mmol). Methyl iodide (0.019 mL, 0.30 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 30 mg (83%) of the title compound as a foam. FDMS: m/e=359.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][C:33]1[NH:34][C:35]2[C:40]([CH:41]=1)=[CH:39][CH:38]=[CH:37][C:36]=2B1OC(C)(C)C(C)(C)O1.CN1C2C(=CC=CC=2B2OC(C)(C)C(C)(C)O2)C=C1>O1CCOCC1.C(OCC)(=O)C.CCOCC.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>[C:14]([NH:13][C:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:36]3[CH:37]=[CH:38][CH:39]=[C:40]4[C:35]=3[NH:34][C:33]([CH3:32])=[CH:41]4)[N:3]=2)[N:8]([CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH:9]=1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Reactant: Cc1cc2cccc(B3OC(C)(C)C(C)(C)O3)c2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cn1ccc2cccc(B3OC(C)(C)C(C)(C)O3)c21
Agent: O=C([O-])[O-]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc2cccc(-c3cnc4c(n3)c(C(=O)NC(C)(C)C)cn4COCC[Si](C)(C)C)c2[nH]1
Temperature: 80 °C
Yield: 73.6 %

Procedure:
2-Bromo-N-tert-butyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (79 mg, 185 μmol), potassium carbonate (51.1 mg, 370 μmol) and 2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (95.1 mg, 370 μmol) were dissolved in dioxane (5 mL) and water (0.5 mL), then the reaction was purged with nitrogen for 1 minute. Tetrakis(triphenylphosphine)palladium(0) (21.4 mg, 18.5 μmol) was then added, and the reaction was placed under a nitrogen atmosphere and the mixture heated at to 80° C. for 2 h. Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (45 mg), was added and the reaction was heated at 80° C. for an additional 2 h. The reaction mixture was cooled, diluted with ethyl acetate/ether (ca 3:1), washed water and brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by chromatography (silica gel, 3-15% ethyl acetate in hexanes) to give N-tert-butyl-2-(2-methyl-1H-indol-7-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (65 mg) as an oil. MS (M+H)+=478.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10]O)=[CH:4][CH:3]=1.[BrH:12]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][Br:12])=[CH:4][CH:3]=1
Reactant: Br
Reactant: Cc1ccc(CCCO)cc1
Product: Cc1ccc(CCCBr)cc1

Procedure:
3-(4-Methylphenyl)propanol (2.13 g) was heated in 7 ml of 47% aqueous hydrobromic acid under reflux for 5 hours. The solvent was then distilled off under reduced pressure and, after addition of water, the residue was extracted with ether. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was distilled under reduced pressure to give 1.75 g of 3-(4-methylphenyl)propyl bromide. Boiling point: 65° C./0.7 mmHg.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C@@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1.[C:28]1(O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[O:15]([C@H:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 63.5 %

Procedure:
Diisopropyl azodicarboxylate (1.19 g, 5.87 mmol) was added to an ice cooled mixture of tert-butyl (3R)-3-hydroxypyrrolidine-1-carboxylate (1 g, 5.34 mmol), phenol (0.5 g, 5.34 mmol) and triphenylphosphine (1.5 g, 5.8 mmol) in THF (14 mL). The mixture was stirred at room temperature for 20 h. The mixture was then concentrated under vacuum and the residue was twice triturated with diethyl ether. The resultant solid was filtered off and discarded. The filtrate was washed with 1M aq. sodium hydroxide, dried over sodium sulfate and concentrated. The residue was purified by FCC, eluting with 10% EtOAc in heptane to afford the title compound (0.893 g, 63%). Method B HPLC-MS: MH+ requires m/z=208 Found: m/z=208, Rt=2.20 min (91%).
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@@H:22]4[C:30]5[C:25](=[CH:26][C:27]([CH3:31])=[CH:28][CH:29]=5)[CH2:24][C@H:23]4[C:32]([O:34]C)=[O:33])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@@H:22]4[C:30]5[C:25](=[CH:26][C:27]([CH3:31])=[CH:28][CH:29]=5)[CH2:24][C@H:23]4[C:32]([OH:34])=[O:33])=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@@H]1Cc2cc(C)ccc2[C@H]1NC(=O)c1c(C)nc2c(OCC3CCCCC3)cccn12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)C[C@@H](C(=O)O)[C@@H]2NC(=O)c1c(C)nc2c(OCC3CCCCC3)cccn12
Temperature: 80 °C
Reaction time: 4 h
Yield: 87.1 %

Procedure:
To a suspension of 149 mg of methyl (1S,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-5-methylindane-2-carboxylate in 6 ml of dioxane was added 6 ml of 3 M hydrochloric acid, followed by stirring at 80° C. for 4 hours. After leaving to be cooled, the solvent was evaporated under reduced pressure, and then to the obtained residue were added a saturated aqueous sodium hydrogen carbonate solution, an aqueous citric acid solution, and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. To the obtained residue was added diisopropyl ether, and the insoluble material was collected by filtration and dried to obtain 126 mg of (1S,2R)-1-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-5-methylindane-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]5([CH2:31][CH2:30]5)[C:22]4=[O:32])[CH2:14][CH2:13]3)[C:11](=[O:33])[N:10]([CH2:34][C:35]3[CH:36]=[C:37]([CH:45]=[CH:46][CH:47]=3)[C:38]([O:40]C(C)(C)C)=[O:39])[CH2:9]2)=[CH:4][CH:3]=1>C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3([CH2:13][CH2:14][N:15]([CH2:18][CH2:19][CH2:20][N:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:23]5([CH2:30][CH2:31]5)[C:22]4=[O:32])[CH2:16][CH2:17]3)[C:11](=[O:33])[N:10]([CH2:34][C:35]3[CH:36]=[C:37]([CH:45]=[CH:46][CH:47]=3)[C:38]([OH:40])=[O:39])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCN4C(=O)C5(CC5)c5ccccc54)CC3)C2=O)c1
Solvent: O=CO
Product: O=C(O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCN4C(=O)C5(CC5)c5ccccc54)CC3)C2=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl 3-((1-(4-fluorophenyl)-4-oxo-8-(3-(2′-oxospiro[cyclopropane-1,3′-indoline]-1′-yl)propyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (2.84 g, 0.31 mmol, 1 equiv) was added concentrated formic acid. After stirring at room temperature for 16 hours, the reaction mixture was concentrated in vacuo and purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.5, gradient—1%-15% methanol in dichloromethane). The pure fractions were evaporated to dryness under reduced pressure. The pure residue was converted to the hydrogen chloride salt using 4M hydrogen chloride solution in dioxane. The resulting residue was lyophilized in acetonitrile/water (1:1) to obtain the title compound as a hydrogen chloride salt (1.8 g, 70%); 1H NMR (DMSO-d6): δ 1.50 (t, 2H, J=7.6 Hz), 1.57 (t, 2H, J=7.6 Hz), 1.70 (d, 2H, J=14 Hz), 1.83 (t, 2H, J=6.8 Hz), 2.29-2.37 (m, 2H), 2.54 (t, 2H, J=6.4 Hz), 2.87-2.89 (m, 4H), 3.80 (t, 2H, J=6.8 Hz), 4.57 (d, 4H, J=12 Hz), 6.91-7.23 (m, 8H), 7.48-7.51 (m, 2H), 7.86-7.88 (m, 2H), 8.14 (s, 1H); MS for C34H35FN4O4 m/z 583.16 (M+H)+.