Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[CH2:47]([O:49][C:50]([C:52]1[N:53]=[C:54]([CH:57]2[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]2)[S:55][CH:56]=1)=[O:51])[CH3:48]>CN(C=O)C>[CH2:47]([O:49][C:50]([C:52]1[N:53]=[C:54]([CH:57]2[CH2:62][CH2:61][N:60]([C:8](=[O:10])[CH2:7][N:6]3[C:2]([CH3:1])=[CH:3][C:4]([C:11]([F:14])([F:13])[F:12])=[N:5]3)[CH2:59][CH2:58]2)[S:55][CH:56]=1)=[O:51])[CH3:48]
Reactant: CCOC(=O)c1csc(C2CCNCC2)n1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1csc(C2CCN(C(=O)Cn3nc(C(F)(F)F)cc3C)CC2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87.5 %

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (9.1 g, 36.1 mmol) in DMF (100 mL) is added diisopropylethylamine (45 mL, 216 mmol), followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (15.5 g, 39.7 mmol). After stirring 15 min at RT, 2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester hydrochloride (10 g, 36.1 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (300 mL), washed with saturated aqueous sodium bicarbonate solution (300 mL), 1M HCl solution (300 mL), and brine (100 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture is purified by column chromatography on silica gel (dichloromethane/methanol 10:1) to give 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazole-4-carboxylic acid ethyl ester (13.6 g, 88%). 1H-NMR (400 MHz, CDCl3): δ=1.40 (t, 3H), 1.70-1.85 (m, 2H), 2.16-2.30 (m, 2H), 2.32 (s, 3H), 2.79-2.89 (m, 1H), 3.22-3.43 (m, 1H), 4.03-4.12 (m, 1H), 4.42 (q, 3H), 4.54-4.69 (m, 1H), 4.93-5.08 (2d, 2H (diastereotopic)), 6.35 (s, 1H), 8.10 (br, 1H). MS: m/z=209 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=1>>[CH3:39][O:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][O:1][C:2]2[CH:3]=[C:4]([C:8]3[C:17]4[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=4)[N:11]=[CH:10][C:9]=3[C:22]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:23])[CH:5]=[CH:6][CH:7]=2)=[CH:33][CH:34]=1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1-c1cccc(O)c1
Reactant: COc1ccc(CBr)cc1
Product: COc1ccc(COc2cccc(-c3c(C(=O)c4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
The title compound was prepared from [4-(3-hydroxyphenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 1-Bromomethyl-4-methoxy-benzene following the procedure of Example 478: MS (ESI) m/z 514.
Reaction SMILES: [ClH:1].C([NH:9][C:10]([CH3:21])([CH3:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[ClH:1].[NH2:9][C:10]([CH3:21])([CH3:20])[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=1
Reactant: [H][H]
Reactant: CC(C)(CCc1ccc(O)cc1)NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(N)CCc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 16 h
Yield: 53.7 %

Procedure:
4-(3-Benzylamino-3-methylbutyl)phenol hydrochloride (3.84 g, 12.6 mmol) and 10% palladium on carbon (0.8 g) were suspended in methanol (95 ml) in a hydrogenation apparatus. The vessel was sealed and shaken for 16 hours at 50° C. and a 60 psi hydrogen atmosphere. The resulting suspension was filtered through Celite and concentrated in vacuo to yield a white solid (1.46 g, 54%). NMR, MS.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[NH3:31]>CO.O1CCOCC1>[NH2:31][C:2]1[CH:7]=[C:6]([C:8]2[N:13]3[CH:14]=[CH:15][N:16]=[C:12]3[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)=[CH:20][CH:19]=3)=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: CN1CCN(c2ccc(Nc3ncc(-c4ccnc(F)c4)n4ccnc34)cc2)CC1
Solvent: CO
Solvent: C1COCCO1
Product: CN1CCN(c2ccc(Nc3ncc(-c4ccnc(N)c4)n4ccnc34)cc2)CC1
Temperature: 120 °C
Reaction time: 96 h
Yield: 16 %

Procedure:
A solution of [5-(2-fluoro-pyridin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine (0.0272, 0.067 mmol) (from Example 125) in a mixture of aq. NH3 (2.5 mL):1M NH3 in MeOH (2.5 mL) is stirred at 100° C. overnight. Additional aq. NE3 (5 mL) and 0.5M NH3 in dioxane (2 mL) are added and the mixture stirred at 120° C. for 4 days. The mixture is concentrated in vacuo and purified by reverse phase HPLC affording the title compound (4.2 mg, 16%). LCMS: Rt 3.76 min (95%) m/z (APCI) 401 (M+H)+; 1H-NMR (400 MHz, d6-DMSO) δ (ppm). 2.26 (3H, s), 2.49-2.53 (4H, t), 3.12-3.15 (4H, m), 6.18 (2H, br s) 6.76 (1H, s), 6.81 (1H, d), 6.97 (2H, d), 7.51 (1H, s), 7.72 (1H, s), 7.88 (2H, d), 8.04 (1H, s), 8.09 (1H, d), 9.55 (1H, s).
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1.P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([S:10][CH3:11])[N:3]=1
Reactant: CSc1ncc(C#N)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Product: CSc1ncc(C#N)c(Cl)n1

Procedure:
A mixture of 4-hydroxy-2-methylsulfanyl-pyrimidine-5-carbonitrile (2.76 g) and phosphorus oxychloride (15 mL) was heated at reflux, under argon atmosphere, for 3 h. The reaction mixture was cooled and then evaporated under reduced pressure. Hexane was added to the residue and the mixture was heated at reflux, the resulting mixture was decanted and the same procedure was repeated for 4 times. The combined supernatant layers were evaporated to afford 1.13 g of 4-chloro-2-methylsulfanyl-pyrimidine-5-carbonitrile as a white powder.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([O:17][CH3:18])[CH:8]=1.CN([CH:22]=[O:23])C>C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([F:15])([F:16])[F:14])[CH:10]=[C:9]([O:17][CH3:18])[C:8]=1[CH:22]=[O:23]
Reactant: CN(C)C=O
Reactant: COc1cc(Cl)cc(C(F)(F)F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C(F)(F)F)cc(Cl)c1C=O
Temperature: 0 °C

Procedure:
A 2M n-BuLi solution (2.07 mL, 4.3 mmol) was added to a −78° C. THF solution (20 mL) of 1-chloro-3-methoxy-5-(trifluoromethyl)benzene (870 mg, 4.1 mmol). After 45 min neat DMF (0.39 mL, 5.0 mmol) was added, and the resulting solution was allowed to warm to 0° C. gradually, quenched with NH4Cl solution, and extracted with diethyl ether. The combined extracts were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH:10]([F:12])[F:11])[CH:5]=[CH:4][C:3]=1[N+:13]([O-])=O>C(O)C.[Pd]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH:10]([F:11])[F:12])[CH:5]=[CH:4][C:3]=1[NH2:13]
Reactant: COc1c(C(F)F)ccc([N+](=O)[O-])c1Cl
Agent: [Pd]
Solvent: CCO
Product: COc1c(C(F)F)ccc(N)c1Cl

Procedure:
A solution of crude 2-chloro-4-difluoromethyl-3-methoxy-1-nitrobenzene in ethanol (50 mL) containing 5% palladium on charcoal (250 mg) was hydrogenated (50 psi) for 5 hours. The solution was filtered and concentrated to give 2-chloro-4-difluoromethyl-3-methoxyaniline (1.3 g, 48 mmol): LC/MS (m/z=207).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]([NH:13][NH:14][C:15]([NH:17][CH3:18])=[S:16])=O.[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]1[N:17]([CH3:18])[C:15]([SH:16])=[N:14][N:13]=1
Reactant: CNC(=S)NNC(=O)CNc1c(C)cccc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C)c1NCc1nnc(S)n1C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a stirred hot solution of 52.8 g (0.198 mol) 1[alpha-(2,6-dimethylphenylamino)acetyl]-4-methylthiosemicarbazide in 560 ml ethanol was added quickly 8 g (0.198 mol) sodium hydroxide. The reaction mixture was heated under reflux for 2 hours and allowed to stand overnight. The ethanol was then evaporated under reduced pressure to give a solid residue. Water (500 ml) was added to the solid residue and the resulting aqueous mixture was filtered to remove a small amount of a solid. The filtrate was neutralized with concentrated hydrochloric acid, the colorless solid was filtered, washed with water and partially dried in vacuuo over potassium hydroxide pellets at 50° C. The nearly dried product was dissolved in dichloromethane and the aqueous layer separated. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 43.5 g of the product as a colorless solid, m.p. 172°-173° C. The product is tabulated in Table I as Compound No. 3.
Reaction SMILES: [F:1][C:2]1([F:13])[C:4]2([CH2:9][CH2:8][N:7](C(O)=O)[CH2:6][CH2:5]2)[CH2:3]1.[ClH:14]>ClCCl.O1CCOCC1>[ClH:14].[F:1][C:2]1([F:13])[C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[CH2:3]1
Reactant: O=C(O)N1CCC2(CC1)CC2(F)F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: FC1(F)CC12CCNCC2
Reaction time: 4 h

Procedure:
1.2 g of tert-butyl ester of 1,1-difluoro-6-aza-spiro[2.5]octane-6-carboxylic acid is put in 24 mL of dichloromethane. 24 mL of 4M hydrochloric acid in dioxane is added at room temperature. The solution is stirred for 4 h and is evaporated to dryness. 1 g of 1,1-difluoro-6-aza-spiro[2.5]octane hydrochloride is obtained.
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:14][C:15](=[O:25])[C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][C:17]=1[O:23][CH3:24])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10]C=1.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C.Cl>O1CCCC1>[CH2:6]([NH:14][C:15]([C:16]1[CH:21]=[CH:20][C:19]([B:26]([OH:31])[OH:27])=[CH:18][C:17]=1[O:23][CH3:24])=[O:25])[C:7]1[CH:8]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cc(Br)ccc1C(=O)NCCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)ccc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
n-Butyl lithium(1.6 M in hexane solution, 8.5 ml, 13.54 mmol) was added slowly to a solution of N1-phenethyl-4-bromo-2-methoxybenzamide (1.81 g, 5.41 mmol) in tetrahydrofuran (40 mL) at −78° C. After 30 minutes, triisopropyl borate (1.87 mL, 8.12 mmol) was added rapidly. The reaction mixture was allowed to warm up to room temperature after 13 minutes and stirred for 3 hours. Hydrochloric acid (2.5N, 40 mL) was added and the mixture was stirred overnight. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile to give 4-[(benzylamino)carbonyl]-3-methoxyphenylboronic acid (0.916 g, 56%). 1H NMR (DMSO-d6) δ 2.85 (m, 2H), 3.53 (m, 2H) 3.88 (s, 3H), 7.31 (m, 7H), 7.70 (d, J=7.61 Hz, 1H), 8.19 (m, 2H), 9.10 (m, 1H).
Reaction SMILES: [S:1]1[C:5]([C:6]23[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH:10]2[CH2:9][O:8][NH:7]3)=[CH:4][CH:3]=[N:2]1.C(O)(=O)C>C(OCC)(=O)C.[Zn]>[NH2:7][C:6]1([C:5]2[S:1][N:2]=[CH:3][CH:4]=2)[CH:10]([CH2:9][OH:8])[CH2:11][N:12]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC2CONC2(c2ccns2)C1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC(CO)C(N)(c2ccns2)C1
Temperature: 40 °C
Reaction time: 8 h
Yield: 64.8 %

Procedure:
tert-Butyl 6a-isothiazol-5-yl-3,3a,4,6-tetrahydro-1H-pyrrolo[3,4-c]isoxazole-5-carboxylate (400.0 g, 1.35 mol), acetic acid (4.00 L) and zinc (439.78 g, 6.73 mol) are added together. The reaction mixture is heated to 40° C. and stirred at 40° C. for 8 hours and then cooled to room temperature. The reaction mixture is diluted with ethyl acetate (4 L), filtered through diatomaceous earth, washed with ethyl acetate, and evaporated under reduced pressure. The yellow oily residue is dissolved in toluene (2 L) and concentrated. The dissolution process with toluene is repeated 3 times. The foamy oil residue is suspended in 10% w/w aq. citric acid (3.2 L), MTBE (4 L) is added and the mixture is stirred for 15 minutes at room temperature. The biphasic mixture is filtered through diatomaceous earth (slow filtration) to remove the gel-like solids. The layers are separated and the aqueous layer is washed with MTBE (4×600 mL). The aqueous layer (pH 4.0) is added to ethyl acetate (3.0 L), and the mixture is neutralized with NaOH 50% w/w to adjust the pH=9.0-9.5 and the mixture is vigorously stirred. The organic layer is separated and the aqueous layer is extracted with ethyl acetate (3×1 L). The organic layers are combined, dried over sodium sulfate, filtered, and evaporated under reduced pressure to give the title compound as a white solid, (262.00 g, 65.1%). ES/MS (m/e): 300 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([F:14])[CH:3]=1.[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:15][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)Cc1ccc(Br)cc1F
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1ccc(Br)cc1F
Temperature: 90 °C
Reaction time: 9 h
Yield: 96.1 %

Procedure:
To a stirring solution of ethyl 2-(4-bromo-2-fluorophenyl)acetate (3.92 g, 15.0 mmol) in carbon tetrachloride (50 mL) was slowly added N-bromosuccinimide (2.67 g, 15.0 mmol) and then azobisisobutyronitrile (0.37 g, 2.3 mmol). The reaction mixture was stirred for 9 h at 90° C. and then cooled to room temperature. The residue was purified by flash chromatography (0-100% ethyl acetate/hexanes) to provide the title product (4.9 g, 96% yield). MS(ES)+ m/e 340.9 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[N:14]=[CH:13][N:12]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(CCCl)cc1
Reactant: O=c1cc(OCc2ccccc2)nc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccccc2)ncn1CCc1ccc(CO)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To 3.00 g (14.8 mmol) 6-benzyloxy-3H-pyrimidin-4-one in 15 mL DMF is added 2.66 g (15.6 mmol) [4-(2-chloro-ethyl)-phenyl]-methanol (preparation 1b) and 5.13 g (37.1 mmol) potassium carbonate. The reaction mixture is stirred 3 h at 100° C., filtered and the solvent is evaporated. The residue is put on silica gel and is purified by chromatography (silica gel; PE/EtOAc 1:1 to 2.5:7.5)
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[S:6][C:7]=1[C:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH:9]=1)[CH3:2]>C(O)C.FC(F)(F)CO.[Pd]>[CH2:1]([C:3]1[C:4]2[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=2[S:6][C:7]=1[CH:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[CH3:2]
Reactant: CCc1c(C2=CCNCC2)sc2ccccc12
Agent: [Pd]
Solvent: OCC(F)(F)F
Solvent: CCO
Product: CCc1c(C2CCNCC2)sc2ccccc12
Reaction time: 24 h
Yield: 84.3 %

Procedure:
Scheme IA, Step C: To a mixture of 4-(3-ethylbenzo[b]thiophen-2-yl)-1,2,5,6-tetrahydropyridine (0.465 g, 1.91 mmol) in ethanol (15 mL) and 2,2,2-trifluoroethanol (5 mL) was added 10% palladium on carbon (0.25 g). The mixture was hydrogenated at one atmosphere for 24 hours. The mixture was carefully filtered and evaporated to give the intermediate title compound as a yellow amorphous solid (0.395 g, 84%). FDMS m/e=246 (M++1).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[NH:20]2)=[CH:9]1)(C)(C)C.Br[CH:32]([CH3:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[CH:9]=[C:10]2[CH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21](=[O:29])(=[O:28])[N:20]1[CH:32]([CH3:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(Br)Cc1ccccc1
Reactant: COc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Product: COc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1C(C)Cc1ccccc1)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 4, step c) and (2-bromo-propyl)-benzene. MS: ESI (negative): 489 (M−H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:27](Cl)([CH3:30])(=[O:29])=[O:28]>O>[CH2:1]([O:8][CH2:9][CH:10]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[O:11][S:27]([CH3:30])(=[O:29])=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC(O)COCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(COCc1ccccc1)OS(C)(=O)=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
1-O-benzyl-3-O-t-butyldimethylsilylglycerol (1.63 g) was added to pyridine (6 ml), and the mixture was cooled to 5° C., and mesyl chloride (0.5 ml) was added dropwise thereto, and the resultant mixture was stirred overnight at room temperature. Upon confirming the completion of the reaction, the reaction liquid was cooled to 5° C., water (0.5 ml) was added thereto and the mixture stirred at the same temperature for 30 minutes.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH3:11])[N:5]=[C:4](Cl)[N:3]=1.[C@H:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]C1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH3:11])[N:5]=[C:4]([NH:23][C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]2)[N:3]=1
Reactant: CCc1nc(Cl)nc(N)c1C#N
Reactant: N[C@@H]1CCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCc1nc(N[C@@H]2CCc3ccccc32)nc(N)c1C#N
Yield: 92 %

Procedure:
0.25 g (1.09 mmol) of 4-amino-2-chloro-6-ethylpyrimidine-5-carbonitrile, 0.19 g (1.31 mmol) of (1R)-1,2,3,4-tetrahydronaphthalen-1-amine and 0.45 g (3.28 mmol) of potassium carbonate in 2 ml of N,N-dimethylacetamide are heated at 140° C. in a closed cell in a microwave for 30 minutes. The crude mixture obtained in this way is absorbed on silica gel and purified by means of column chromatography using heptane/ethyl acetate as eluent. Following concentration by evaporation, 0.28 g of 4-amino-2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-6-ethylpyrimidine-5-carbonitrile is obtained (yield 82% at 95% purity).
Reaction SMILES: C([O:8][C:9]1[CH:21]=[CH:20][C:12]([O:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C1COCC1>[Pd].CCO>[N:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:20]=[CH:21][C:9]([OH:8])=[CH:10][CH:11]=2)=[CH:19][CH:18]=1
Reactant: c1ccc(COc2ccc(Oc3ccncc3)cc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1ccc(Oc2ccncc2)cc1
Yield: 94.4 %

Procedure:
The same procedure from Example 143, step 2 was followed using the product from step 1 (306 mg, 0.905 mmol), THF (3 ml), EtOH (9 ml), 10% Pd/C (300 mg, 0.0905 mmol) to give the title compound (160 mg, 95%).
Reaction SMILES: [C:1]([C:3]1[C:18]([O:19][CH2:20][C@@H:21]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH:23]([CH3:25])[CH3:24])=[CH:17][C:6]2[N:7]([CH3:16])[C:8](=[O:15])[C:9]3[C:14]([C:5]=2[CH:4]=1)=[CH:13][CH:12]=[N:11][CH:10]=3)#[N:2].Cl.O1CCOCC1>CO>[NH2:26][C@@H:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:20][O:19][C:18]1[C:3]([C:1]#[N:2])=[CH:4][C:5]2[C:14]3[C:9](=[CH:10][N:11]=[CH:12][CH:13]=3)[C:8](=[O:15])[N:7]([CH3:16])[C:6]=2[CH:17]=1
Reactant: CC(C)C[C@@H](COc1cc2c(cc1C#N)c1ccncc1c(=O)n2C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)C[C@H](N)COc1cc2c(cc1C#N)c1ccncc1c(=O)n2C
Temperature: 0 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
In a 25 mL round-bottomed flask, (S)-tert-butyl (1-((9-cyano-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (75 mg, 0.167 mmol) was taken up in MeOH (4 mL) and cooled to 0° C. The mixture was treated with 4M solution of HCl in 1,4-dioxane (2 mL, 8 mmol) and stirred for 2 h at RT. The MeOH was removed and the crude product was dissolved in EtOAc (20 mL). The ethyl acetate layer was washed with water (2×10 mL) and dried over sodium sulfate. Removal of the solvent gave crude product which was purified by silica-gel column (MeOH—CHCl3 mixture) to obtain (S)-8-((2-amino-4-methylpentyl)oxy)-6-methyl-5-oxo-5,6 dihydrobenzo[c][2,7]naphthyridine-9-carbonitrile (4 mg, 0.01 mmol, 7% yield over 2 steps) as a yellow solid. LC/MS (ESI) m/e 351.2. [(M+H)+, calcd for C20H23N4O2, 351.4]; LC/MS retention time (method B): tR=1.43 min. HPLC retention time (method A): tR=9.69 min; HPLC retention time (method B): tR=9.31 min. 1H NMR (400 MHz, CD3OD) δ ppm 9.56 (bs, 1H), 8.93 (s, 2H), 8.37 (d, J=4.77 Hz, 1H), 7.25 (s, 1H), 4.63 (dd, J=10.67, 3.14 Hz, 1H), 4.47 (dd, J=10.79, 6.02 Hz, 1H), 3.81-3.89 (m, 4H), 1.83-1.91 (m, 2H), 1.72 (t, J=6.53 Hz, 1H), 1.08 (d, J=5.02 Hz, 6H).
Reaction SMILES: [OH:1][N:2]=[CH:3][C:4]1[N:9]=[C:8]2[CH2:10][O:11][C:12]3([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[C:7]2=[CH:6][CH:5]=1.C1C(=O)N(Cl)C(=O)C1.[Cl:31][C:32]1[CH:37]=[C:36]([C:38]([C:40]([F:43])([F:42])[F:41])=[CH2:39])[CH:35]=[C:34]([Cl:44])[C:33]=1[F:45]>CN(C=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([C:38]2([C:40]([F:43])([F:42])[F:41])[O:1][N:2]=[C:3]([C:4]3[N:9]=[C:8]4[CH2:10][O:11][C:12]5([CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]5)[C:7]4=[CH:6][CH:5]=3)[CH2:39]2)[CH:35]=[C:34]([Cl:44])[C:33]=1[F:45]
Reactant: C=C(c1cc(Cl)c(F)c(Cl)c1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1nc(C=NO)ccc12
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1nc(C3=NOC(c4cc(Cl)c(F)c(Cl)c4)(C(F)(F)F)C3)ccc12
Temperature: 45 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a stirred solution of tert-butyl 2′-((hydroxyimino)methyl)-7′H-spiro[azetidine-3,5′-furo[3,4-b]pyridine]-1-carboxylate (0.520 g, 1.705 mmol, 1 eq) in DMF (12 mL) was added NCS (0.272 g, 2.046 mmol, 1.2 eq) at room temperature in dark under nitrogen atmosphere. Resulting reaction mixture was stirred at 45° C. for 1 hour. After chloro intermediate formation, 1,3-dichloro-2-fluoro-5-(1-trifluoromethyl-vinyl)-benzene (0.530 g, 2.046 mmol, 1.2 eq) was added followed by addition of KHCO3 (0.255 g, 2.557 mmol, 1.5 eq). Resulting reaction mixture was stirred at room temperature for 16 hours in dark under nitrogen atmosphere. After complete consumption of chloro intermediate, reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (3×100 mL). Combined organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to get brown thick oil (1.2 g, Crude). Crude compound was purified by column chromatography in 100-200 mesh size silica gel. Desired compound was eluted in 10% ethylacetate in hexanes to afford title compound as white semisolid (0.800 g, impure). Impure compound was used as such for next reaction. 1H NMR (400 MHz, CDCl3) δ: 1.46 (s, 9H), 3.84 (d, J=18.2 Hz, 1H), 4.10 (dd, J1=2.54 Hz, J2=9.5 Hz, 2H), 4.22 (d, J=18.16 Hz, 1H), 4.33 (dd, J1=3 Hz, J2=9.44 Hz, 2H), 5.02-5.10 (m, 2H), 7.56 (d, J=6 Hz, 2H), 7.84 (d, J=8.04 Hz, 1H), 8.03 (d, J=8.04 Hz, 1H). LC-MS (m/z): 59.6 (M−H).