Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25](=[O:59])[NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][C:28]=2[C:39]2[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:57])([F:56])[F:55])[CH:49]=3)[CH:42]=[CH:41][N:40]=2)[N:20]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11](OC(C)(C)C)=O)[CH2:7][CH2:6]1.ClCCl.C(O)(C(F)(F)F)=O.CN(CC1N=C(C(NC2C=CC(N3CCCCC3)=CC=2C2C=C(C(=O)NCC3C=CC=C(C(F)(F)F)C=3)C=CN=2)=O)C=CC=1)CCN1CCNCC1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C=O>O1CCCC1>[CH3:1][N:2]([CH2:18][C:19]1[N:20]=[C:21]([C:25]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]3)=[CH:29][C:28]=2[C:39]2[CH:44]=[C:43]([C:45](=[O:58])[NH:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[C:50]([C:54]([F:55])([F:57])[F:56])[CH:49]=3)[CH:42]=[CH:41][N:40]=2)=[O:59])[CH:22]=[CH:23][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH3:11])[CH2:7][CH2:6]1
Reactant: CN(CCN1CCN(C(=O)OC(C)(C)C)CC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)n1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CN(CCN1CCNCC1)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)n1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(CCN(C)Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
The tert-butoxycarbonyl group of tert-butyl 4-(2-(methyl((6-((4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)carbamoyl)pyridin-2-yl)methyl)amino)ethyl)piperazine-1-carboxylate 52 was cleaved by stirring for 1 hour in 1:1 dichloromethane/TFA and the resultant amine converted to the free base by partitioning between ethyl acetate and aqueous sodium bicarbonate solution. Into a 8-mL sealed tube, was placed a solution of 6-((methyl(2-(piperazin-1-yl)ethyl)amino)methyl)-N-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)picolinamide (100 mg, 0.14 mmol, 1.00 equiv) in tetrahydrofuran (3 mL), NaBH(OAc)3 (90 mg, 0.42 mmol, 3.00 equiv), and formaldehyde (2 mL). The resulting solution was stirred for overnight at 40° C. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 53.7 mg (27%) of as a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.44 (s, 1H), 9.82 (s, 1H), 9.58 (t, J=5.4 Hz, 1H), 9.06 (d, J=5.1 Hz, 1H), 8.33 (d, J=9.0 Hz, 1H), 8.26 (s, 1H), 8.21-8.15 (m, 2H), 7.90-7.84 (m, 2H), 7.71-7.55 (m, 4H), 7.47 (s, 1H), 7.25 (d, J=8.1 Hz, 1H), 4.64-4.58 (m, 4H), 3.36-3.29 (m, 8H), 2.97 (s, 4H), 2.86 (s, 3H), 2.76 (s, 5H), 2.33-2.27 (m, 2H), 1.71-1.58 (m, 6H). MS (ES, m/z): 729 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[F:20])#[N:2]>N.CO.[Ni]>[NH2:2][CH2:1][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:5][C:4]=1[F:20]
Reactant: COC(=O)c1c(F)cccc1-c1cnc(C#N)c(F)c1
Agent: [Ni]
Agent: N
Solvent: CO
Product: COC(=O)c1c(F)cccc1-c1cnc(CN)c(F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.7 %

Procedure:
To a stirred solution of the above ester (0.75 g, 2.7 mmol) in NH3/MeOH (5 mL, 2.0 M) was added Raney 2800 nickel (slurry in water). The mixture was stirred under a H2 atmosphere (balloon) at room temperature for 6 hours. The mixture was then filtered through glass filter paper, washing with additional MeOH. The resultant solution was concentrated under vacuum and azeotroped three times with toluene to provide crude title compound (0.65 g, 2.34 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:14]2([C:18](=[O:19])[N:17]([OH:20])[C:16](=[O:21])[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:25][N+:26]([O-:28])=[O:27]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:14]2([C:18](=[O:19])[N:17]([O:20][CH2:25][N+:26]([O-:28])=[O:27])[C:16](=[O:21])[CH2:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])CBr
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CC(=O)N(O)C2=O
Product: O=C(OCc1ccccc1)N1CCC2(CC1)CC(=O)N(OC[N+](=O)[O-])C2=O

Procedure:
Employing 8-benzyloxycarbonyl-2-hydroxy-2,8-diazaspiro[4,5]decane-1,3-dione (0.64 g) and bromonitromethane (140 μl), reaction was conducted in the same manner as in Example 40 to obtain 0.25 g of a colorless solid, m.p. 137° to 139° C.
Reaction SMILES: [OH:1][C:2]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][S:5][C:4](=[S:7])[N:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[BH4-].[K+]>CO.O.C1CCCCC1.C(OCC)(=O)C>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:3][C:4](=[S:7])[S:5][CH2:6][CH:2]([OH:1])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: OC1(c2ccccc2)CSC(=S)N1c1ccccn1
Agent: [BH4-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: OC(CSC(=S)Nc1ccccn1)c1ccccc1
Reaction time: 0.5 h
Yield: 64.3 %

Procedure:
The procedure of Example 3 is followed, but a suspension of 4-hydroxy-4-phenyl-3-(pyrid-2-yl)-thiazolidine-2-thione (23.0 g) in methanol (240 cc) and a solution of potassium borohydride (4.3 g) in distilled water (60 cc) are used as the starting materials at a maximum of 35° C. The reaction is allowed to proceed for 30 minutes at 25°-35° C. The crude product (26.1 g) is dissolved in a mixture of cyclohexane (200 cc) and ethyl acetate (50 cc). The solution is chromatographed on silica (0.2-0.5 mm) (280 g) contained in a column of diameter 4 cm. Elution is carried out with a mixture of cyclohexane (480 cc) and ethyl acetate (120 cc) and then with a mixture of cyclohexane (280 cc) and ethyl acetate (120 cc), these eluates being discarded. Elution is continued with a mixture of cyclohexane (700 cc) and ethyl acetate (300 cc), this eluate being collected and evaporated to dryness under reduced pressure (20 mm Hg) at 45° C. The chromatographed product (18.1 g) is purified by recrystallisation from a mixture of ethyl ether (90 cc) and petroleum ether (b.p. 40° to 65° C., 30 cc). 2-Hydroxy-2-phenylethyl pyrid-2-yldithiocarbamate (14.9 g), which melts at 82° C., is obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][NH2:26]>>[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][NH:26][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: NCc1nccs1
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCc3nccs3)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (thiazol-2-ylmethyl)-amine to afford the title compound. MS: m/e=355 (M+H).
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]=[CH:14][C:15](/[CH:18]=[CH:19]/[C:20]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=3)=[O:21])=[N:16][CH:17]=2)=[CH:8][CH:7]=1>ClCCl>[Cl:3][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:20](=[O:21])/[CH:19]=[CH:18]/[C:15]2[CH:14]=[CH:13][C:12]([C:9]3[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=3)=[CH:17][N:16]=2)=[CH:24][CH:25]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(/C=C/c1ccc(-c2ccc(Cl)cc2)cn1)Nc1ccc(CO)cc1
Solvent: ClCCl
Product: O=C(/C=C/c1ccc(-c2ccc(Cl)cc2)cn1)Nc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50 μL (0.680 mmol) thionyl chloride was added to a suspension of 0.190 g (0.520 mmol) (E)-3-[5-(4-chloro-phenyl)-pyridin-2-yl]-N-(4-hydroxymethyl-phenyl)-acrylamide (Z38a) in 20 mL dichloromethane and the mixture was stirred for 2 h at RT . Another 50 μL thionyl chloride were added and the mixture was again stirred for 3 h. The solvent was concentrated by evaporation i. vac., the residue taken up twice in toluene and concentrated by evaporation i. vac. The crude product was obtained as the HCl salt and used in the next reaction step without any further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[CH:5].CCN(CC)CC.[CH3:13][O:14][C:15]([C:17]1[C:22]([NH2:23])=[CH:21][C:20](Br)=[CH:19][N:18]=1)=[O:16].O>C1COCC1.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>[CH3:13][O:14][C:15]([C:17]1[C:22]([NH2:23])=[CH:21][C:20]([C:5]#[C:4][CH2:3][O:2][CH3:1])=[CH:19][N:18]=1)=[O:16]
Reactant: COC(=O)c1ncc(Br)cc1N
Reactant: C#CCOC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COCC#Cc1cnc(C(=O)OC)c(N)c1
Temperature: 80 °C

Procedure:
To a solution of 3-methoxy-propyne (421 mg, 6 mmol), bis(triphenylphosphine)palladium(II) chloride (84 mg, 0.12 mmol), copper(I) iodide (23 mg, 0.12 mmol) and NEt3 (1.17 ml, 8.4 mmol) in THF (10 ml) under Argon was added 3-amino-5-bromo-pyridine-2-carboxylic acid methyl ester (277 mg, 1.2 mmol) and the mixture was heated to 80° C. for 5 h. At 0° C. water (12 ml) was added and the mixture was extracted with EtOAc, the combined organic layers were washed with half-saturated aq. sodium chloride, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1:4) to provide the title compound as orange solid.
Reaction SMILES: [C:1]([CH2:3][C:4]1[NH:5][C:6]([C:10]2[C:11]([CH3:20])=[CH:12][C:13]([CH3:19])=[C:14]([CH:18]=2)[C:15]([OH:17])=O)=[C:7]([CH3:9])[N:8]=1)#[N:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:46][C:47]1([C:51]2[CH:58]=[CH:57][C:54]([C:55]#[N:56])=[CH:53][CH:52]=2)[CH2:50][NH:49][CH2:48]1.C(N(CC)CC)C>CN(C)C=O.C(#N)C.O>[C:1]([CH2:3][C:4]1[NH:5][C:6]([C:10]2[C:11]([CH3:20])=[CH:12][C:13]([CH3:19])=[C:14]([CH:18]=2)[C:15]([N:49]2[CH2:48][C:47]([C:51]3[CH:52]=[CH:53][C:54]([C:55]#[N:56])=[CH:57][CH:58]=3)([F:46])[CH2:50]2)=[O:17])=[C:7]([CH3:9])[N:8]=1)#[N:2]
Reactant: N#Cc1ccc(C2(F)CNC2)cc1
Reactant: Cc1cc(C)c(-c2[nH]c(CC#N)nc2C)cc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(-c2[nH]c(CC#N)nc2C)cc1C(=O)N1CC(F)(c2ccc(C#N)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.1 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 5-(2-(cyanomethyl)-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoic acid (compound 222.6, 190 mg, 0.71 mmol) and HBTU (538 mg, 1.42 mmol) in NA-dimethylformamide (3 mL). To the above were added a solution of 4-(3-fluoroazetidin-3-yl)benzonitrile hydrochloride (compound 43.4, 160 mg, 0.75 mmol) and triethylamine (197 μL, 1.42 mmol) in N,N-dimethylformamide (3 mL) dropwise. The reaction mixture was stirred for 1 h at room temperature. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, XBridge Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase, Water with 50 mmol NH4HCO3 and acetonitrile (30% acetonitrile up to 44% in 7 min, hold 44% in 1 min, up to 100% in 1 min, down to 30% in 1 min); Detector, Waters 2489, 254 and 220 nm. This resulted in 45.9 mg (15%) of the title compound as a white solid. m/z (ES+) 428 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][C@H:12]1[O:17][C@@H:16]([CH3:18])[CH2:15][NH:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CC(OC)(C)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:14]2[CH2:13][CH:12]([CH3:11])[O:17][CH:16]([CH3:18])[CH2:15]2)=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: CC1CN(c2ccc(Br)cc2C=O)CC(C)O1
Temperature: 120 °C
Yield: 91.7 %

Procedure:
A mixture of 5-bromo-2-fluorobenzaldehyde (16.0 g, 78.6 mmol), cis-2,6-dimethylmorpholine (9.32 g, 80.9 mmol), and potassium carbonate (15.0 g, 108 mmol) in DMF (75 mL) is heated in a 120° C. oil bath for 14 hours. The mixture is diluted with MTBE (250 mL) and washed with water (4×200 mL). (Ethyl acetate is added as needed to maintain the homogeneity of the organic layer). The organics are filtered through a 1″ plug of silica gel and evaporated to give 21.5 g of brown solid. This material is approximately 90% pure as judged by HPLC and is used without further purification. 1H NMR (DMSO-d6) δ 10.11, 7.78, 7.75, 7.17, 3.77-3.86, 3.12, 2.56, 1.11.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CN(C=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:25]=[CH:24]5)[N:17]=3)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCBr
Reactant: FC(F)(F)c1sc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCn1ccc2cc(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)ccc21
Reaction time: 2 h

Procedure:
D2 (100 mg) was dissolved in DMF (1.2 ml), treated with K2CO3 (50 mg) then ethyl 3-bromopropionate (90 mg) and heated to 130° C. overnight. After this time LCMS showed the reaction to be incomplete so further ethyl 3-bromopropionate was added (45 mg) and stirring continued at 130° C. for 2 hours. LCMS showed no change so the reaction mixture was evaporated then partitioned between DCM and H2O. The organic layer was removed and the aqueous solution extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated to give the crude product (148 mg). This was purified on a silica cartridge (25+S), eluting with a 0 to 25% mixture of EtOAc in petroleum ether and then again on a 25+M cartridge with a 0 to 30% mixture of EtOAc in petroleum ether to give the title compound MF105672-144A3 (38 mg) as a white solid. δH (CDCl3, 400 MHz): 1.21 (3H, t), 2.85 (2H, t), 4.12 (2H, q), 4.50 (2H, t), 6.60 (1H, d), 7.21 (1H, d), 7.42-7.52 (6H, m), 7.91 (1H, s), 8.00 (1H, d), 8.46 (1H, s). MS (ES+): C26H20F3N3O3S requires 511; found 512 (MH+).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[N:10]=[CH:9][CH:8]=1.[OH-].[Na+]>CN(C=O)C>[Cl:3][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=2)[N:10]=[CH:9][CH:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1ccc2nccc(O)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc2nccc(Cl)c2c1

Procedure:
Phosphorus oxychloride (0.518 ml) was added to DMF (9 ml) at an inner temperature of 5-7° C. while stirring under ice-cooling, and the mixture was stirred at room temperature for 0.5 hr. 4-Hydroxy-6-quinolinecarbonitrile (860 mg) was added while stirring under ice-cooling and the mixture was stirred under ice-cooling for 1 hr. 1N aqueous sodium hydroxide solution (18 ml) was added and the mixture was stirred at room temperature for 10 min. The precipitate was collected by filtration and washed with water to give a pale brown powder. The obtained powder was purified by silica gel column chromatography (eluent: chloroform-methanol=50/1) to give the object compound (800 mg) as a pale yellow powder.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1([CH3:20])[C:10]2[CH:11]=[C:12]([C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7]1.[Br:21]Br.Cl>ClCCl>[Br:21][C:14]1[C:9]2[O:8][CH2:7][C:6]([CH3:5])([CH3:20])[C:10]=2[CH:11]=[C:12]([C:15](=[O:19])[CH:16]([CH3:17])[CH3:18])[CH:13]=1
Reactant: CC(C)C(=O)c1ccc2c(c1)C(C)(C)CO2
Reactant: BrBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)C(=O)c1cc(Br)c2c(c1)C(C)(C)CO2
Reaction time: 6 h
Yield: 107.2 %

Procedure:
To a solution of AlCl3 (1.5 g, 11.32 mmol) in dry dichloromethane (30 mL) was added dropwise at room temperature 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-2-methyl-propan-1-one (989 mg, 4.52 mmol) in dichloromethane (15 mL) followed by bromine (0.28 mL, 5.43 mmol) and the reaction stirred for 6 hours. 1N HCl was added slowly and the layers separated. The aqueous layer was extracted twice with dichloromethane. The combined organic layers were washed successively with aq. K2CO3, water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated to give 1.44 g of 1-(7-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-2-methyl-propan-1-one (91%). 1H NMR (300 MHz; CDCl3): δ 1.21 (d, J=6.9 Hz, 6H), 1.39 (s, 6H), 3.47 (m, 1H), 4.43 (s, 2H), 7.70 (s, 1H), 7.95 (s, 1H). e. 1-(3,3-dimethyl-2,3-dihydro-benzofuran-5-yl)-2-methyl-propan-1-one.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:35]#[C:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:8][C:9]=1[N:10]([C:26]([C@H:28]1[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]1)=[O:27])[C@H:11]1[CH2:16][CH2:15][C@H:14]([N:17]2[CH:21]=[C:20]([Si](C)(C)C)[N:19]=[N:18]2)[CH2:13][CH2:12]1)=[O:4].CCCC[N+](CCCC)(CCCC)CCCC.[F-].O.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:35]#[C:36][C:37]([CH3:38])([CH3:40])[CH3:39])=[CH:8][C:9]=1[N:10]([C:26]([C@H:28]1[CH2:29][CH2:30][C@H:31]([CH3:34])[CH2:32][CH2:33]1)=[O:27])[C@H:11]1[CH2:12][CH2:13][C@H:14]([N:17]2[CH:21]=[CH:20][N:19]=[N:18]2)[CH2:15][CH2:16]1)=[O:4]
Reactant: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](n2cc([Si](C)(C)C)nn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1sc(C#CC(C)(C)C)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](n2ccnn2)CC1
Reaction time: 24 h

Procedure:
To a solution of 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-[trans-4-(4-trimethylsilanyl-[1,2,3]triazol-1-yl)-cyclohexyl]-amino]-thiophene-2-carboxylic acid methyl ester (0.48 g, 0.82 mmol) in THF (2.0 ml) is added TBAF 1.0 M in THF (1.23 ml, 1.23 mmol). The reaction mixture is stirred for 24 h and treated with water and saturated ammonium chloride solution. The aqueous layer is extracted with ethyl acetate. The organic layer is washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (50% ethyl acetate/hexane to 100% ethyl acetate) to give 5-(3,3-dimethyl-but-1-ynyl)-3-[(trans-4-methyl-cyclohexanecarbonyl)-(trans-4-[1,2,3]triazol-1-yl-cyclohexyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [NH2:1][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].Cl[C:15]1[CH:16]=[C:17]([N:26](CC2C=CC(OC)=CC=2)[CH2:27][CH2:28][O:29][CH3:30])[C:18]2[N:19]([C:21]([C:24]#[N:25])=[CH:22][N:23]=2)[N:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.Cl.CC#N>CC(N(C)C)=O.[Cu]I.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CO>[C:5]([C:4]1[CH:3]=[C:2]([NH:1][C:15]2[CH:16]=[C:17]([NH:26][CH2:27][CH2:28][O:29][CH3:30])[C:18]3[N:19]([C:21]([C:24]#[N:25])=[CH:22][N:23]=3)[N:20]=2)[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=1)#[N:6]
Reactant: N#Cc1cc(N)cc(C(F)(F)F)c1
Reactant: COCCN(Cc1ccc(OC)cc1)c1cc(Cl)nn2c(C#N)cnc12
Agent: [Cu]I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: COCCNc1cc(Nc2cc(C#N)cc(C(F)(F)F)c2)nn2c(C#N)cnc12
Temperature: 125 °C
Reaction time: 0.33 h
Yield: 67.3 %

Procedure:
A solution of 3-amino-5-(trifluoromethyl)benzonitrile (0.075 g, 0.40 mmol) in DMA (1 mL) was placed in a 1-dram vial with a teflon-lined septum cap, and the solvent was purged with argon. 15A (0.100 g, 0.269 mmol), cesium carbonate (0.351 g, 1.076 mmol), copper (I) iodide (0.026 g, 0.134 mmol), Xantphos (0.031 g, 0.054 mmol), and Pd2(dba)3 (0.025 g, 0.027 mmol) were added in one portion, and the suspension was pump/purged three times with argon. The vessel was heated to 125° C. for 45 min. and then cooled to room temperature. The solids were removed via filtration through CELITE® and washed with THF. The filtrate was concentrated under reduced pressure and diluted with water and EtOAc. The layers were separated, and the aqueous phase extracted with EtOAc (3×10 mL). The organics were combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was dissolved in DCM and purified by flash chromatography (SiO2, hexanes to 40% EtOAc/hexanes, 12 g column, 30 mL/min., 20 min. gradient, monitoring at 254 nm). The fractions were concentrated, dissolved in DCM (1 mL) and treated with triethylsilane (0.430 mL, 2.7 mmol) and TFA (0.3 mL) at room temperature. After 20 minutes, the volatiles were removed via a stream of nitrogen, and the residue was triturated with MeOH. The solid was isolated via filtration, suspended in 1:1 1N HCl/MeCN, and lyophilized overnight, furnishing Example 15, (0.080 g, 0.181 mmol, 67.3% yield) as a gray solid. HPLC: Rt=4.160 min. (YMC S5 ODS 4.6×50 mm, 10-90% aqueous methanol containing 0.2% H3PO4, 4 min. gradient, monitored at 220 nm). MS (ES): m/z=402.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.98 (1H, s), 8.52 (1H, s), 8.25 (1H, s), 8.20 (1H, s), 7.82 (1H, s), 7.68 (1H, s), 5.99 (1H, s), 3.54-3.62 (2H, m), 3.40-3.52 (2H, m), 3.30 (3H, s).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>CN(C=O)C.C(O)C.O.ClCCl>[F:12][C:13]1[CH:18]=[C:17]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[NH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: OB(O)c1cccc(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1ncnc2[nH]nc(-c3cccc(F)c3)c12
Temperature: 80 °C
Reaction time: 12 h
Yield: 18.2 %

Procedure:
To a solution of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.50 g, 5.74 mmoles) in DMF (12 ml), ethanol (7 ml) and water (7 ml), 3-Fluorophenyl boronic acid (1.6 g, 11.49 mmoles) and sodium carbonate (3.0 g, 28.73 mmoles) were added and the system is degassed for 30 min. Palladium tetrakis triphenylphosphine (1.90 g, 1.72 mmoles) was added under nitrogen atmosphere and heated to 80° C. After 12 h, the reaction mixture neutralised with 1.5N HCl, extracted with ethyl acetate. The organic layer was dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as yellow solid (0.240 g, 18% yield). 1H-NMR (δ ppm, DMSO-d6, 400 MHz): δ 13.66 (s, 1H), 8.21 (s, 1H), 7.59 (m, 1H), 7.50 (d, J=7.6, 1.2 Hz, 1H), 7.45 (m, 1H), 7.31 (m, 1H).