Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2](N1[C@H](C2C=CC=CC=2)COC1=O)[C@@H:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1)[CH3:5].C(OCC)C.O.[BH4-].[Li+]>>[OH:1][CH2:2][C@@H:3]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@H:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:10][CH:11]=1)[CH3:5]
Reactant: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@H]1c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: C[C@@H](c1ccc(C(F)(F)F)cc1)[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 66.5 %

Procedure:
To a 250 mL round-bottomed flask was added tert-butyl (2S,3S)-1-oxo-1-((R)-2-oxo-4-phenyloxazolidin-3-yl)-3-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (4.80 g, 9.7 mmol), diethyl ether (50.00 mL, 481 mmol), and water (0.19 mL, 11 mmol). The resulting solution was cooled in an ice bath. Lithium borohydride (0.23 g, 11 mmol) was added in one portion and gas evolution was observed. The ice bath was removed, and the solution was stirred for about 12 hours. The reaction was followed by LCMS and once completed, was quenched by the addition of brine. The aqueous layer was extracted with EtOAc (×3), and the combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (120 g), eluting with a gradient of 20% to 60% EtOAc in hexane, to provide tert-butyl (2S,3S)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)butan-2-ylcarbamate (2.15 g, 66% yield).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1.Cl[CH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:24][C:25]4[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=4)[C:14]3=[O:21])[CH:10]=[N:9]2)=[C:5]([CH3:22])[O:4][N:3]=1
Reactant: N#Cc1ccc(CCl)cc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)NC(C)(C)C2=O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1Cn1cc(N2C(=O)N(Cc3ccc(C#N)cc3)C(C)(C)C2=O)cn1
Temperature: 25 °C
Yield: 30 %

Procedure:
3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5,5-dimethylimidazolidine-2,4-dione (Example 12-16a) (250 mg, 0.83 mmol), 4-(chloromethyl)benzonitrile (126 mg, 0.83 mmol), and cesium carbonate (536 mg, 1.65 mmol) were stirred in dimethylformamide (4 mL) at 80° C. for 5 hours. The reaction was allowed to cool to room temperature and then filtered. The filtrate was diluted with ethyl acetate (4 mL) and then water (2 mL) was added. The organic phase was collected, dried over anhydrous Na2SO4, and then concentrated under reduced pressure. The residue was purified by reverse phase HPLC (gradient 10% to 100% methanol in water) and further recrystallized from ethanol. Yield 30%. 1H NMR (DMSO-d6, 400 MHz): □s, 6H), 2.15 (s, 3H), 2.42 (s, 3H), 4.65 (s, 2H), 5.20 (s, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.81 (m, 3H), 8.20 (d, J=0.8 Hz, 1H). MS 419 (MH+). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.04 μM
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=1[F:35])=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:26][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:27])[C:10]3([CH:9]([C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=4[F:35])[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:25]2=[CH:24][CH:23]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of rac-(2′R,3′S,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (1 g, 1.9 mmol) in dichloromethane (20 mL) was added trifluoroacetic acid (10 g). The reaction mixture was stirred at room temperature for 18 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′R,3′S,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a off white solid (1.1 g, 99%).
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:13])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].S(=O)(=O)(O)O>>[F:12][C:9]1[CH:8]=[C:7]2[C:6](=[CH:11][CH:10]=1)[C:4](=[O:5])[CH:3]([CH3:13])[CH2:2]2
Reactant: CC(CCl)C(=O)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: CC1Cc2cc(F)ccc2C1=O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Ten grams (0.05 mole) of 3-chloro-4'-fluoro-2-methylpropiophenone is added to 20 ml. of concentrated sulfuric acid at 20°-25°C and the mixture is warmed to 50°C. After stirring for three hours at 50°C, the reaction is quenched in ice. The product is extracted into hexane. The hexane layer is concentrated in vacuo to give 5-fluoro-2-methyl-1-indanone.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:31][C:32]1[CH:37]=[C:36]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][S:2](=[O:1])(=[O:30])[CH2:3][CH2:4]2)=[O:9])[CH:35]=[CH:34][CH:33]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2cccc(Cl)c2)CC1
Yield: 21 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 3-chlorphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a light brown solid (21%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.[H-].[Na+].Br[CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[N:6]2[CH:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=C1Nc2cccc(Cl)c2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2cccc(Cl)c21
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
To a stirred solution of 4-chloroisatin (9.10 g, 50.0 mmol) in N,N-dimethylformamide (100 mL) was added sodium hydride (2.20 g, 55.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 h, followed by the addition of bromodiphenylmethane (14.80 g, 56.8 mmol). The mixture was stirred at ambient temperature for 20 h, diluted with ethyl acetate, washed with water and brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was recrystallized from diethyl ether and hexanes to afford 4-chloro-1-(diphenylmethyl)-1H-indole-2,3-dione (14.20 g, 81%): 1H NMR (300 MHz, CDCl3) δ7.37-7.17 (m, 11H), 6.98-6.95 (m, 2H), 6.42 (d, J=9.0 Hz, 1H); MS (ES+) m/z 369.9 (M+23), 371.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([OH:13])[CH:5]=1.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:5]=[C:6]([O:13][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH3:16])[CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)OC)cc([N+](=O)[O-])c1
Yield: 92.3 %

Procedure:
A mixture of 1.7 g (8.6 mmol) of 3-hydroxy-5-nitrobenzoic acid methyl ester [prepared as described by D. J. Abraham, D. M. Gazze, P. E. Kennedy and M. Mokotoff, J. Med. Chem. 27, 1549 (1984)], 3.2 g (9.5 mmol) of 1-bromooctadecane and 1.8 g (12.9 mmol) of potassium carbonate in 35 ml of anhydrous DMF was stirred and heated at 75° for 25 hours. After cooling, 150 ml of methylene chloride was added and the insoluble salts were removed by filtration. The filtrate was concentrated at reduced pressure to a solid which was purified by HPLC using 30% methylene chloridehexane to give 3.57 g (92% yield, mp 64°-66°) of 3-nitro-5-(octadecyloxy)benzoic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:4][C:3]=1[N+:18]([O-])=O.[CH3:21][N:22]([CH3:26])[C:23](Cl)=[O:24].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[NH2:18][C:3]1[CH:4]=[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[CH:6]=[CH:7][C:2]=1[NH:1][C:23](=[O:24])[N:22]([CH3:26])[CH3:21]
Reactant: Nc1ccc(NCc2ccc(Cl)cc2Cl)cc1[N+](=O)[O-]
Reactant: CN(C)C(=O)Cl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CN(C)C(=O)Nc1ccc(NCc2ccc(Cl)cc2Cl)cc1N
Yield: 35.1 %

Procedure:
A suspension of 31.2 g (100 mmol) 2-amino-5-(2,4-dichlorobenzylamino)-nitrobenzene is hydrogenated in a manner analogous with Example 1 (variant A) and worked up appropriately with 13.9 g (101 mmol) N,N-dimethylcarbamoyl chloride. 12.4 g of the end product are obtained in the form of the dihydrochloride. This forms colorless to pale pink crystals.
Reaction SMILES: C(OC(=O)C)C.[ClH:7].[O:8]=[C:9]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[CH:17][CH:16]=2)[C:13]([S:27][CH2:28][CH2:29][NH:30]C(=O)OC(C)(C)C)=[N:12][C:11]2=[CH:38][S:39][CH:40]=[C:10]12>CO>[ClH:7].[NH2:30][CH2:29][CH2:28][S:27][C:13]1[N:14]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]([F:24])([F:26])[F:25])=[CH:19][CH:20]=2)[C:9](=[O:8])[C:10]2[C:11](=[CH:38][S:39][CH:40]=2)[N:12]=1
Reactant: CC(C)(C)OC(=O)NCCSc1nc2cscc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: NCCSc1nc2cscc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixed solution of 4N hydrogen chloride ethyl acetate solution (20 ml) and methanol (10 ml) was added tert-butyl [2-({4-oxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-3,4-dihydrothieno[3,4-d]pyrimidin-2-yl}sulfanyl)ethyl]carbamate (1.7 g), and the mixture was stirred at room temperature for 14 hr. The reaction mixture was concentrated under reduced pressure, and the residue was washed with a mixture of ethyl acetate/ether (1/1) to give the title compound (1.48 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][C:10]1[C:11](F)=[CH:12][C:13]([F:20])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Br:9][C:10]1[C:11]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:12][C:13]([F:20])=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: Oc1ccc(Cl)cc1
Reactant: COC(=O)c1cc(Br)c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(Br)c(Oc2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.6 %

Procedure:
A mixture of 4-chlorophenol (94.7 mg, 0.74 mmol), methyl 5-bromo-2,4-difluorobenzoate (Preparation 18, 168 mg, 0.67 mmol), and potassium carbonate (277 mg, 2.01 mmol) in dimethyl sulfoxide (3 mL) was stirred for 16 hours at room temperature under a nitrogen atmosphere. The reaction was diluted with water (30 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were successively washed with aqueous sodium hydroxide solution (1.0 M, 20 mL), brine (2×30 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a colourless oil (199 mg, 83%).
Reaction SMILES: O[CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].N1CCCCC1.S(Cl)([Cl:23])(=O)=O>C(Cl)(Cl)(Cl)Cl>[Cl:23][CH2:2][CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(NCCO)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: C1CCNCC1
Product: O=S(=O)(NCCCl)c1ccccc1

Procedure:
40.2 g. of N-(β-hydroxyethyl)-benzene sulfonamide was slurried in 100 ml. of carbon tetrachloride containing 5 drops of piperidine. Then, 47.6 g. of sulfonyl chloride was added over 10 minutes, keeping the temperature at 20°-25° C. during the addition. The reaction was completed by heating on a steam bath for one hour. The mixture was concentrated on the steam bath, dissolved in benzene and washed twice with dilute aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and the benzene evaporated on the steam bath with air. The product was crystallized from benzene cyclohexane to yield 28.0 g. of product, m.p. 58°-62° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[N:9](S(C3C=CC(C)=CC=3)(=O)=O)[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)=[CH:11][C:3]=12.C([Sn](CCCC)(CCCC)[C:39]1[CH:40]=[CH:41][C:42]([C:45]2([OH:49])[CH2:48][CH2:47][CH2:46]2)=[N:43][CH:44]=1)CCC>CN(C)C=O.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>[Cl:8][C:7]1[C:2]([C:39]2[CH:40]=[CH:41][C:42]([C:45]3([OH:49])[CH2:48][CH2:47][CH2:46]3)=[N:43][CH:44]=2)=[C:3]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)[NH:9][C:4]2=[N:5][CH:6]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2(O)CCC2)nc1
Reactant: Cc1ccc(S(=O)(=O)n2c(-c3ccc(CN4CCCC4)cc3)cc3c(Cl)c(Cl)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: OC1(c2ccc(-c3c(Cl)cnc4[nH]c(-c5ccc(CN6CCCC6)cc5)cc34)cn2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4,5-dichloro-2-(4-(pyrrolidin-1-ylmethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (198 mg, 0.396 mmol) (Example 128B), 1-(5-(tributylstannyl)pyridin-2-yl)cyclobutanol (Example 143A) (260 mg, 0.593 mmol), and bis(triphenylphosphine)palladium dichloride (19.43 mg, 0.028 mmol) in N,N-dimethylformamide (1.318 mL) was heated to 100° C. for 16 hours. The reaction was cooled to room temperature and quenched by the addition of an aqueous potassium fluoride solution (3 g potassium fluoride in 6 mL water) and ethyl acetate (10 mL). The mixture was stirred vigorously for 16 hours and filtered through diatomaceous earth, eluting with ethyl acetate. The eluent was washed with aqueous saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in a solvent mixture of 2 N aqueous sodium hydroxide solution (1.0 mL) and methanol (3 mL). The solution was heated to 105° C. by microwave irradiation (Biotage, Initiator) for 5 minutes. The reaction was cooled to room temperature and diluted with dimethyl sulfoxide (1 mL). The resulting solution was purified by reverse phase high performance liquid chromatography (RP HPLC, 19×150 mm Atlantis Prep T3 OBD 5 m column, eluting with a gradient of 5% B in A to 75% B in A over 25 minutes, wherein A is water containing 0.1% v/v trifluoroacetic acid and B is acetonitrile containing 0.1% v/v trifluoroacetic acid) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 12.50 (bs, 1H), 8.77 (dd, J=2.3, 0.8 Hz, 1H), 8.34 (s, 1H), 8.02 (dd, J=8.1, 2.3 Hz, 1H), 7.94-7.86 (m, 2H), 7.78 (dd, J=8.1, 0.8 Hz, 1H), 7.40-7.33 (m, 2H), 6.72 (s, 1H), 5.86 (s, 1H), 3.59 (s, 2H), 2.74-2.61 (m, 2H), 2.46-2.39 (m, 4H), 2.35-2.22 (m, 2H), 2.05-1.82 (m, 2H), 1.78-1.61 (m, 4H); MS ESI(+) m/z 459.2 [M+H]+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[C:5]#[N:6].[CH3:14][C:15]1[NH:16][CH:17]=[CH:18][N:19]=1>>[CH3:14][C:15]1[N:16]([C:2]2[CH:3]=[C:4]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=2)[C:5]#[N:6])[CH:17]=[CH:18][N:19]=1
Reactant: N#Cc1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1cc(C#N)cc(C(F)(F)F)c1

Procedure:
The title compound is prepared using an analogous method as described in Example 1.1, utilising 3-fluoro-5-(trifluoromethyl)-benzonitrile (Lancaster Synthesis GmbH) and 2-methyl-imidazole (Fluka, Buchs, Switzerland), with a reaction temperature of 145° C. for 24 hours.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][CH:6]=1.[Li]CCCC.C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C>C1COCC1>[CH3:29][C:24]1([CH3:30])[C:25]([CH3:28])([CH3:27])[O:26][B:22]([C:2]2[CH:3]=[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:5][CH:6]=2)[O:23]1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Brc1coc(-c2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2coc(-c3ccccc3)c2)OC1(C)C
Reaction time: 0.25 h
Yield: 19.1 %

Procedure:
To a solution of 4-bromo-2-phenylfuran (1.3 g, 5.8 mmol) in THF (15 mL) was added n-BuLi (2.5M, 2.8 mL, 7.0 mmol) at −78° C. The reaction mixture was kept at −55° C. for 15 min and then 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.3 g, 7.0 mmol) was added at −78° C. The reaction mixture was stirred for 1.5 h and then poured into water/ice solution, extracted with petroleum ether (3×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford 4,4,5,5-tetramethyl-2-(5-phenylfuran-3-yl)-1,3,2-dioxaborolane as a red oil (300 mg, 19%).
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1)=[O:6].Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]2[N:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[N:30]=[CH:31][C:24]=12>C1COCC1.C(OCC)(=O)C>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:29]1[C:25]2=[N:26][CH:27]=[N:28][C:23]([O:3][C@@H:4]([CH2:15][O:16][C@H:17]([CH3:21])[CH2:18][O:19][CH3:20])[C:5]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)=[O:6])=[C:24]2[CH:31]=[N:30]1
Reactant: COC[C@@H](C)OC[C@H](O)C(=O)Nc1cnc(C)cn1
Reactant: Clc1ccccc1-n1ncc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC[C@@H](C)OC[C@H](Oc1ncnc2c1cnn2-c1ccccc1Cl)C(=O)Nc1cnc(C)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62.8 %

Procedure:
Sodium hydride (14.26 mg, 0.36 mmol) was added to (S)-2-hydroxy-3-((R)-1-methoxypropan-2-yloxy)-N-(5-methylpyrazin-2-yl)propanamide (Intermediate Y12) (64 mg, 0.24 mmol) in anhydrous THF (5 mL) at 0° C. under nitrogen. The resulting mixture was stirred for 10 minutes at 0° C. and 4-chloro-1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidine (86 mg, 0.32 mmol) was added and the reaction was allowed to warm up to room temperature and stirred for 1 hour. The reaction mixture was diluted with ethyl acetate (20 mL), and washed sequentially with water (10 mL) and saturated brine (5 mL). The organic layer was dried (MgSO4) and evaporated. The crude product was purified by flash silica chromatography, eluting with 0-100% ethyl acetate in isohexane to afford the product (75 mg, 63.4%). 1H NMR (400 MHz, CDCl3) δ 1.16 (d, 3H), 2.52 (s, 3H), 3.33-3.48 (m, 5H), 3.80-3.89 (m, 1H), 4.16-4.27 (m, 2H), 6.01 (t, 1H), 7.45-7.55 (m, 3H), 7.60-7.64 (m, 1H), 8.11-8.12 (m, 1H), 8.41 (s, 1H), 8.59 (s, 1H), 8.94 (s, 1H), 9.42 (d, 1H). m/z (ESI+) (M+H)+=498.36; HPLC tR=2.19 min.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][N:10]3[C:15]=2[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:13][C:12]([C:24]2([NH:27]C(=O)OC(C)(C)C)[CH2:26][CH2:25]2)=[N:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C:24]1([C:12]2[N:13]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:15]3=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:8]=[CH:9][N:10]3[N:11]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.9 %

Procedure:
To a stirred solution of tert-butyl (1-(5-phenyl-4-((pyridin-2-ylmethyl)amino) pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)carbamate (200 mg, 0.438 mmol) in DCM (15 mL) was added TFA (0.169 mL, 2.19 mmol) and the reaction mixture was stirred at RT for 5 h then concentrated under reduced pressure. The residue was dissolved in (100 mL) and washed with 10% NaHCO3 solution (2×30 mL). The combined organic portion was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using CombiFlash ISCO (REDISEP®, SiO2, 12 g, 50% EtOAc/petroleum ether) to give 2-(1-aminocyclopropyl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (120 mg, 77.0%) as brown solid. LCMS Condition B-41: retention time 0.62 min, [M+1]=357.1. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.80-0.87 (m, 2H), 1.13-1.18 (m, 2H), 4.68 (d, J=4.8 Hz, 2H), 6.68 (d, J=2.7 Hz, 1H), 7.02 (s, 1H), 7.22-7.30 (m, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.41-7.58 (m, 5H), 7.68-7.80 (m, 2H), 8.34-8.40 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.C([O:10][CH:11]=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>C1(C)C(C)=CC=CC=1>[CH3:7][C:4]1[S:3][C:2]2=[N:1][CH:18]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](=[O:10])[N:6]2[CH:5]=1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Cc1cnc(N)s1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cnc2sc(C)cn2c1=O
Temperature: 25 °C
Yield: 88.3 %

Procedure:
A mixture of 2-amino-5-methyl thiazole (1.14 g) and diethyl ethoxymethylenemalonate (2.16 g) is heated at 135° C. in xylene (20 mL) for 2 h allowing for removal of the ethanol product. After the solvent is removed, the mixture is suspended in diphenyl ether (10 mL). The mixture is then heated to reflux with removal of ethanol for 30 min. The reaction mixture is cooled to rt and hexanes (20 mL) is added. The resulting precipitate is filtered, washed with diethyl ether (2×10 mL) and dried to afford 2.1 g (86%) of the title compound as a tan solid. Physical characteristics: 1H NMR (DMSO) δ 8.61, 8.05, 4.25, 2.48, 1.28; MS (ESI+) m/z 239 (M+H)+.