Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:53]([CH3:56])[CH2:54][CH3:55])[C@H:26]([O:51][CH3:52])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:49][CH3:50])[C@@H:36]([CH3:48])[C:37](=[O:47])[NH:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:58][CH2:59][CH2:60][C:61]([OH:63])=[O:62].C([BH3-])#N.[Na+]>>[C:61]([CH2:60][CH2:59][CH2:58][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:53]([CH3:56])[CH2:54][CH3:55])[C@H:26]([O:51][CH3:52])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:49][CH3:50])[C@@H:36]([CH3:48])[C:37](=[O:47])[NH:38][CH2:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:19])[CH3:20])=[O:15])[CH:11]([CH3:13])[CH3:12])([OH:63])=[O:62]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
The title compound was synthesized by analogy with the synthesis process of Example 1 by reacting 57 mg (71 μmol) N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-[(2-phenylethyl)amino]propyl}pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetic acid salt (intermediate 25) with a 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]([OH:11])[CH2:9][OH:10].[CH:12](O)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>S(=O)(=O)(O)O.CCOCC>[CH:12]([O:10][CH2:9][CH2:8][OH:11])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: OCCO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: OCCOC(c1ccccc1)c1ccccc1
Temperature: 90 °C

Procedure:
8 ml of toluene and 2 drops of concentrated sulfuric acid were added to 621 mg (10.0 mmol) of ethylene glycol, and they were heated to 90° C. 737 mg (4.0 mmol) of benzhydrol was added dropwise to the obtained mixture for the duration of 50 minutes. 30 minutes after, 621 mg (10.0 mmol) of ethylene glycol was added thereto and they were stirred under heating for 40 minutes. Ether was added to the reaction mixture, and the organic layer was successively washed with water, saturated aqueous sodium hydrogencarbonate solution, water and finally saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1.F[B-](F)(F)F.[C:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[CH:45]([CH2:49][CH3:50])[C:46]([NH2:48])=[O:47])#[CH:38].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:48][C:46](=[O:47])[CH:45]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:37]#[C:38][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:3]=1)[CH2:49][CH3:50]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ccccc1C(CC)C(N)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(C(N)=O)c1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 68.2 %

Procedure:
A mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (K3) (193 mg, 0.422 mmol), PdCl2(PPh3)2 (15 mg, 0.021 mmol), t-Bu3PH.BF4 (6 mg, 0.021 mmol), CuI (4 mg, 0.021 mmol) and 2-(2-ethynylphenyl)butanamide (K1) (87 mg, 0.47 mmol) in DMF (3.0 mL) was degassed with nitrogen for 10 minutes. Et3N (1.0 mL) was added and the resulting mixture was heated under microwave irradiation at 120° C. for 20 minutes. The volatiles were removed under reduced pressure and the residue was adsorbed onto silica gel then purified by column chromatography (Biotage Isolera, SiO2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C.) to give the title compound A1 as a yellow solid (175 mg, 68%); 1H NMR (400 MHz, d6-DMSO) δ 10.39 (s, 1H), 8.88-8.76 (m, 1H), 7.67 (d, J=8.5 Hz, 2H), 7.63-7.47 (m, 3H), 7.37 (td, J=7.4, 1.6 Hz, 1H), 7.27-7.17 (m, 3H), 7.01 (s, 1H), 4.07 (s, 2H), 3.89 (dd, J=8.6, 6.4 Hz, 1H), 2.80 (br, 2H), 2.64 (J m, 1H), 1.98-1.90 (m, 1H), 1.74 (d, J=12.7 Hz, 2H), 1.70-1.60 (m, 1H), 1.55-1.44 (m, 2H), 1.42 (s, 9H), 0.87 (t, J=7.3 Hz, 3H). LCMS-A: rt 6.726 min; m/z 606 [M−H]−.
Reaction SMILES: C([N:8]1[CH2:16][C:15](=[N:17][O:18][CH3:19])[C:10]2([CH2:13][N:12]([CH3:14])[CH2:11]2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:19][O:18][N:17]=[C:15]1[C:10]2([CH2:11][N:12]([CH3:14])[CH2:13]2)[CH2:9][NH:8][CH2:16]1
Reactant: CON=C1CN(Cc2ccccc2)CC12CN(C)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CON=C1CNCC12CN(C)C2
Yield: 87.9 %

Procedure:
340 mg of 6-benzyl-8-(methoxyimino)-2-methyl-2,6-diazaspiro[3,4]octane was dissolved in 10 ml of methanol and thereto 300 mg of 10% Pd-C was added. The resulting mixture was stirred for 2 hours at 50° C. under the pressure of hydrogen, filtered and concentrated under the reduced pressure to give 195 mg of the titled compound(yield: 85.2%).
Reaction SMILES: OS(O)(=O)=O.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]([CH3:29])([CH3:28])[C:15]([CH:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20]CC)=O)=[O:16])[CH:10]=[CH:11][C:12]=1[Cl:13]>CCOC(C)=O>[Cl:13][C:12]1[CH:11]=[C:10]2[C:9](=[CH:8][C:7]=1[Cl:6])[C:14]([CH3:29])([CH3:28])[C:15](=[O:16])[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:18]2[OH:20]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(O)c2cc(Cl)c(Cl)cc2C(C)(C)C1=O
Temperature: 0 °C
Yield: 93.9 %

Procedure:
Concentrated H2SO4 (52.5 mL, 621 mmol) was added dropwise via an addition funnel to diethyl 2-(2-(3,4-dichlorophenyl)-2-methylpropanoyl)malonate (11.66 g, 31.1 mmol) cooled to 0° C. The reaction mixture was allowed to slowly warm to ambient temperature and then poured into a beaker of ice, diluted with 200 mL of EtOAc, added to a separatory funnel, partitioned with water, washed 2 times with 50 mL of water, separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (9.61 g) as a white amorphous solid. MS (m/z)=329 (M+H)+.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[NH2:55][C:56]1[C:57]([CH3:69])=[C:58]([CH3:68])[C:59]2[O:63][C:62]([CH3:65])([CH3:64])[C:61](=[O:66])[C:60]=2[CH:67]=1.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1>[NH2:55][C:56]1[C:57]([CH3:69])=[C:58]([CH3:68])[C:59]2[O:63][C:62]([CH3:64])([CH3:65])[C:61](=[O:66])[C:60]=2[C:67]=1[Br:1]
Reactant: Cc1c(N)cc2c(c1C)OC(C)(C)C2=O
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(Br)c1N)C(=O)C(C)(C)O2
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
Tetrabutylammonium tribromide (31.0 g, 64.2 mmol) was added to a tetrahydrofuran solution (200 mL) containing 5-amino-2,2,6,7-tetramethyl-1-benzofuran-3(2H)-one (6.59 g, 32.1 mmol) synthesized in Reference Example 20 at 0° C., and the mixture was stirred at 0° C. for 2 hours. To the mixture, a saturated sodium sulfite aqueous solution was added, and extraction was performed using ethyl acetate. The extract was dried using anhydrous magnesium sulfate. After that, the solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate 98:2 to 85:15) to give 6.60 g of the title compound (yield: 72%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH2:15])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[CH2:16]([C:23]1[CH:31]=[C:30]([Br:32])[CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.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>>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:30]([Br:32])=[CH:31][C:23]=2[CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(O)c1ccc(Br)cc1Cc1ccccc1
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2ccc(Br)cc2Cc2ccccc2)Cc2ccccc2C1
Yield: 86.2 %

Procedure:
2-Amino-indane-2-carboxylic acid ethyl ester (2) (250 mg, 1.2 mmol), 2-benzyl-4-bromo-benzoic acid (239) (354 mg, 1.2 mmol) and HATU (555 mg, 1.46 mmol) are taken in a vial, evacuated and refilled with nitrogen. Anhydrous DMF (2 mL) is added and stirring is initiated. After few min, DIPEA (0.302 mL, 1.82 mmol) is added and stirred at RT overnight. Analysis by tlc of the reaction mixture (silica, 50% EtOAc/heptanes) indicates complete consumption of the starting amine. Water (10 mL) is added, extracted with EtOAc (3×5 mL), dried over Na2SO4, concentrated and the crude product is chromatographed on a 25 g silica gel column using 20-50% EtOAc in heptane as a gradient to afford 2-(2-benzyl-4-bromo-benzoylamino)-indan-2-carboxylic acid ethyl ester (495 mg, 86%).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:38])[CH2:7][N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([O:27]CC3C=CC(OC)=CC=3)=[CH:13][CH:14]=2)[C:9]1=[O:37])([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)Cl>>[C:1]([NH:5][C:6](=[O:38])[CH2:7][N:8]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[C:20]([O:25][CH3:26])[CH:19]=2)=[CH:16][C:15]2[C:10](=[CH:11][C:12]([OH:27])=[CH:13][CH:14]=2)[C:9]1=[O:37])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(COc2ccc3cc(-c4ccc(F)c(OC)c4)n(CC(=O)NC(C)(C)C)c(=O)c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2cc3ccc(O)cc3c(=O)n2CC(=O)NC(C)(C)C)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
N-tert-Butyl-2-(3-(4-fluoro-3-methoxyphenyl)-7-(4-methoxybenzyloxy)-1-oxo-1H-isoquinolin-2-yl)acetamide (120 mg, 0.231 mmol) was treated with TFA:DCM (1:1 v/v, 5 mL) and stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the crude residue was purified by preparative HPLC giving N-tert-butyl-2-(3-(4-fluoro-3-methoxyphenyl)-7-hydroxy-1-oxo-1H-isoquinolin-2-yl)acetamide (INTERMEDIATE III.1) (25 mg, 0.063 mmol, 27%).
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:34][NH2:35]>O1CCCC1>[CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:35][CH2:34][C:33]1[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=[C:31]([C:30]([F:29])([F:43])[F:44])[CH:32]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48 %

Procedure:
To a solution of 255 mg (1.2 mmol) 2-benzylbenzoic acid in 1.5 ml tetrahydrofuran at 0° C. were added 195 mg (1.2 mmol) 1,1′-carbonyldiimidazole. After stirring for 2.5 h at room temperature, a solution of 243 mg (1.0 mmol) 3,5 bis(trifluoromethyl)benzylamine in 0.5 ml tetrahydrofuran was added and stirring was continued overnight. The solvent was removed in vacuo and the residue was purified by flash chromatography to give 210 mg (49%) of the title compound as white crystals.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[Br:21][C:22]1[S:31][C:25]2[N:26]=[CH:27][N:28]=[C:29](Cl)[C:24]=2[CH:23]=1.C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[Br:21][C:22]1[S:31][C:25]2[N:26]=[CH:27][N:28]=[C:29]([NH:1][C@H:2]([C:4]3[N:9]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:8](=[O:16])[C:7]4=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]4[N:5]=3)[CH3:3])[C:24]=2[CH:23]=1
Reactant: Clc1ncnc2sc(Br)cc12
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)(C)O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4sc(Br)cc34)n(-c3ccccc3)c(=O)c12
Yield: 42.7 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (219 mg, 0.72 mmol) was treated with 6-bromo-4-chlorothieno[2,3-d]pyrimidine (179 mg, 0.72 mmol), N,N-diisopropylethylamine (751 μl, 4.31 mmol) and tert-butanol as a solvent according to the method described in Example 17. The crude was purified using SP1® Purification (0% to 30%, hexane-ethyl acetate) to give 148 mg (42% yield) of the title compound as a white solid. Purity 97%.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl-].[Li+].[S:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[O:13]=[C:14]1[CH2:19][CH2:18][CH:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1>C1COCC1>[OH:13][C:14]1([C:9]2[S:8][CH:12]=[CH:11][N:10]=2)[CH2:15][CH2:16][CH:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: c1cscn1
Reactant: CC(C)(C)OC(=O)C1CCC(=O)CC1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1CCC(O)(c2nccs2)CC1
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a flask containing TI-IF (82 mL) was added isopropylmagnesium chloride/lithium chloride (1.2 M in THF, 37.7 mL, 45 mmol). A solution of thiazole (3.5 g, 41 mmol) in THF (20 mL) was added slowly. The reaction was stirred for one hour. A solution of tert-butyl 4-oxocyclohexanecarboxylate (12.23 g, 62 mmol) in THF (20 mL) was added and the reaction was stirred for 3 hours. The reaction was then quenched slowly with saturated ammonium chloride and diluted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated. Flash chromatography was used for purification to yield tert-butyl 4-hydroxy-4-(1,3-thiazol-2-yl)cyclohexanecarboxylate (9.25 g, 33 mmol, 79% yield). MS ESI: [M+H]+ m/z 284.1.
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].[CH:7]1([CH3:24])[CH2:12][CH2:11][CH:10]([CH:13]([CH3:15])[CH3:14])[CH:9]([O:16][CH:17]([CH2:19]S([O-])(=O)=O)C)[CH2:8]1.C(OC(C)C)(C)C>CN(C)C=O>[CH:7]1([CH3:24])[CH2:12][CH2:11][CH:10]([CH:13]([CH3:14])[CH3:15])[CH:9]([O:16][CH2:17][CH2:19][O:3][CH2:2][CH2:1][OH:4])[CH2:8]1
Reactant: CC1CCC(C(C)C)C(OC(C)CS(=O)(=O)[O-])C1
Reactant: OCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CN(C)C=O
Product: CC1CCC(C(C)C)C(OCCOCCO)C1
Temperature: 72 °C
Yield: 10997.7 %

Procedure:
Under the ice-cooling and stirring conditions, a mixture solution of 50 ml of dimethyl formamide (DMF) and 49.6 g (0.8 mmol) of ethylene glycol was dropwise added to a mixture of 4.4 g (0.11 mol) of 60% NaH and 50 ml of DMF under stirring and then the resulting mixture was stirred at a room temperature for 1 hour. Thereafter the mixture was heated to 70 to 74° C., and 50 ml of DMF solution containing 27.8 g (0.1 mole) of the l-menthyloxyethylmethane sulfonate obtained as described in (2) was dropwise added to the mixture in 50 minutes. After being stirred for 3 hours at this temperature, the reaction mixture was cooled to a room temperature, mixed with 100 ml of diisopropyl ether, and then washed with 50 ml of water three times, and the separated organic layer was concentrated under reduced pressure and then distilled to obtain 21.5 g of diethylene glycol monomenthyl ether (bp: 102-105° C./40 Pa, chemical purity (GC): 98.5%) in form of a colorless and transparent oily substance. Yield: 88.0%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].N1C=CC=CC=1.[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:37]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:38])[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Reactant: O=C(Cl)N1CCOCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCOCC3)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (324 mg, 1 mmol) in dichloromethane (5 mL) and pyridine (0.5 mL, 6 mmol) was added a solution of morpholine-4-carbonyl chloride (0.12 mL, 1 mmol) in dichloromethane (2 mL) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was extracted with dichloromethane (2×50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-{3-[(morpholine-4-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (437 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C25H31N3O4 (M+H)+: 438.54, observed: 438.2.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([F:26])[C:24]=1[F:25]>>[O:15]=[C:14]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=[C:2]([C:21]4[CH:20]=[C:19]([F:18])[C:24]([F:25])=[C:23]([F:26])[CH:22]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][NH:13]1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Product: N#Cc1cc(-c2cc(F)c(F)c(F)c2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (71 mg, 83%), MS (ISP) m/z=342.4 [(M+H)+], mp 304.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 3,4,5-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:12]=3)=[CH:9][N:8]([C@H:25]3[CH2:28][C@H:27]([CH2:29]O)[CH2:26]3)[C:4]=2[N:5]=[CH:6][N:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:50]1(=[O:60])[NH:54][C:53](=[O:55])[C:52]2=[CH:56][CH:57]=[CH:58][CH:59]=[C:51]12.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:12]=3)=[CH:9][N:8]([C@H:25]3[CH2:26][C@H:27]([CH2:29][N:54]4[C:50](=[O:60])[C:51]5[C:52](=[CH:56][CH:57]=[CH:58][CH:59]=5)[C:53]4=[O:55])[CH2:28]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ncnc2c1c(-c1cccc(OCc3ccccc3)c1)cn2[C@H]1C[C@H](CN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 27 h

Procedure:
To a solution of 5 g (12.48 mmol) of trans-{3-[4-amino-5-(3-benzyloxy-phenyl)pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutyl}-methanol, which is prepared as described in Example 47(b) of WO 97/28161, in 100 ml of dry THF are added under argon 4.91 g (18.72 mmol) of triphenylphosphine and 2.75 g (18.7 mmol) of phthalimide; 3.36 g (3.02 ml; 18.7 mmol) of diethyl azodicarboxylate (96%) are added dropwise thereto. The reaction mixture is stirred at RT for 27 h. The reaction mixture is concentrated to dryness and the crude compound is purified by flash-chromatography (ethylacetate) to obtain trans-2-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-isoindole-1,3-dione. Analytical HPLC: tR=12.12 min (Grad 1); ES-MS: m/eo=529.9.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38]>O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)n[nH]c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Yield: 80.8 %

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1H-indazole (3.5 g, 16 mmol), K2CO3 (2.2 g), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (3.8 g, 16 mmol) acetonitrile (90 ml) was refluxed for 16 hours. The reaction was poured into water and the resulting white solid, which precipitated from solution, was collected to afford 5.5 g of the desired product. The compound was recrystallized from dimethylformamide (twice) to afford 3.0 g (44%) of 1-[4-[3-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]propoxy]-methoxyphenyl]ethanone as a white solid, m.p.=202°-204° C.
Reaction SMILES: [C:1]1([CH:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])[CH2:8]C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[C:31](=O)(O)[O-].[Na+]>>[C:1]1([C:7]([NH:10][C:11]2[N:12]=[C:13]([NH2:29])[C:14]3[N:15]=[CH:16][N:17]([C:27]=3[N:28]=2)[C@@H:18]2[O:26][C@H:23]([CH2:24][OH:25])[C@@H:21]([OH:22])[C@H:19]2[OH:20])([CH3:8])[CH3:31])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C([O-])O
Reactant: CCC(Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Agent: Cl
Agent: [Na+]
Product: CC(C)(Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1

Procedure:
Treat the secondary amine (3) (249 mg, 0.57 mmol) with 1M hydrochloric acid (20 ml) and heat the reaction to 50° C. for 30 minutes. Cool the reaction and pour into saturated sodium bicarbonate (200 ml). Extract the reaction with chloroform (3×150 ml). Combine the organic extracts, dry over anhydrous magnesium sulfate, filter, and concentrate under vacuum. Purify the residue by radial chromatography (2% to 4% to 8% to 15% methanol/chloroform, 4 mm plate) four times to provide the title compound (105 mg) as the free base. Treat this with ethereal hydrogen chloride, filter, and dry the solid under high vacuum over phosphorous pentoxide to provide the hydrochloride salt of the Formula I (48 mg), m.p. 153° C. dec.; [α]D20 =30° (c=1.04, H2O)