Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:24]1[CH2:25][CH2:26][CH:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23]1)=[O:15]
Reactant: c1ccc(C2CCNC2)cc1
Reactant: Cc1ccccc1-c1oncc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1oncc1C(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
5-(2-methylphenyl)-isoxazole-4-carboxylic acid (46.9 mg, 0.231 mmol), 3-phenylpyrrolidine (40 mg, 0.271 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (92.6 mg, 0.288 mmol) and diisopropylethylamine (49.7 mg, 0.384 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature over night. Solvent was evaporated in vacuo (0.5-1.0 mL) and the residue was taken up in dichloromethane (1 mL), filtered and purified by normal-phase chromatography (20-50% EtOAc:petroleum ether). The combined fractions were partitioned between H2O/acetic acid (pH 4) and ethyl acetate. The organic fractions were washed with H2O/brine and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O2: 332.1525, found 332.1531.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:3]=1.[NH4+:14].[OH-]>CC#N>[F:11][C:10]([F:13])([F:12])[CH2:9][S:8][C:4]1[N:3]=[C:2]([NH2:14])[CH:7]=[CH:6][N:5]=1
Reactant: FC(F)(F)CSc1nccc(Cl)n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC#N
Product: Nc1ccnc(SCC(F)(F)F)n1
Temperature: 90 °C
Reaction time: 24 h
Yield: 71.3 %

Procedure:
To solution of 4-chloro-2-(2,2,2-trifluoro-ethylsulfanyl)-pyrimidine (22 g, 0.096 mol) in 350 mL of CH3CN was added NH4OH (400 mL). The mixture was stirred for 24 hours at 90° C. in a sealed tube. The mixture was then cooled to room temperature and the solvent was concentrated in vacuo, the residue was extracted with ethyl acetate, dried over MgSO4 and the crude was purified by column chromatography on silica gel to give 2-(2,2,2-trifluoro-ethylsulfanyl)-pyrimidin-4-ylamine (14.3 g, 71.3%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C@@H:14]([C:16]2[CH:17]=[C:18](B(O)O)[C:19]([F:22])=[N:20][CH:21]=2)[CH3:15])[C@@H:10]([CH3:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]1[N:33]=[C:32]([CH3:34])[N:31]=[C:30]([N:35]([CH2:45][C:46]2[CH:51]=[CH:50][C:49]([O:52][CH3:53])=[CH:48][CH:47]=2)[CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[CH:29]=1.CC([O-])=O.[K+]>CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH3:53][O:52][C:49]1[CH:48]=[CH:47][C:46]([CH2:45][N:35]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=2)[C:30]2[N:31]=[C:32]([CH3:34])[N:33]=[C:28]([C:18]3[CH:17]=[C:16]([C@H:14]([N:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][C@@H:10]4[CH3:26])[CH3:15])[CH:21]=[N:20][C:19]=3[F:22])[CH:29]=2)=[CH:51][CH:50]=1
Reactant: C[C@H](c1cnc(F)c(B(O)O)c1)N1CCN(C(=O)OC(C)(C)C)C[C@@H]1C
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Cl)nc(C)n2)cc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(-c3cc([C@@H](C)N4CCN(C(=O)OC(C)(C)C)C[C@@H]4C)cnc3F)nc(C)n2)cc1
Temperature: 120 °C
Yield: 24.8 %

Procedure:
A glass microwave reaction vessel was charged with (5-((1R)-1-((2S)-4-(tert-butoxycarbonyl)-2-methyl-1-piperazinyl)ethyl)-2-fluoro-3-pyridinyl)boronic acid (Example 272, Step 2) (0.530 g, 1.443 mmol), 6-chloro-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (Example 177) (0.554 g, 1.443 mmol), PdCl2(AmPhos)2 (0.102 g, 0.144 mmol) and KOAc (0.425 g, 4.33 mmol). The tube was sealed and evacuated under vacuum and back-filled with nitrogen. Dioxane (3.75 mL) and water (0.375 mL) was added and Ar (g) was bubbled through the mixture for 5 minutes. The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 minutes. The crude material was adsorbed onto a plug of silica gel and purified by chromatography through a silica gel column (40 g), eluting with a gradient of 0% to100% EtOAc in hexane, to provide tert-butyl (3S)-4-((1R)-1-(5-(6-(bis(4-methoxybenzyl)amino)-2-methyl-4-pyrimidinyl)-6-fluoro-3-pyridinyl)ethyl)-3-methyl-1-piperazinecarboxylate (0.240 g, 0.358 mmol, 24.79% yield) as a yellow oil. m/z (ESI, +ve) 671.3 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.40 (dd, J=9.39, 2.54 Hz, 1H); 8.13 (d, J=1.37 Hz, 1H); 7.18 (d, J=8.02 Hz, 4H); 6.80-6.90 (m, 5H); 4.50-5.03 (m, 4H); 4.03 (d, J=5.28 Hz, 1H); 3.73-3.84 (m, 6H); 3.24-3.57 (m, 3H); 3.08-3.22 (m, 1H); 2.69-2.81 (m, 1H); 2.61 (s, 3H); 2.29-2.51 (m, 2H); 1.37-1.48 (m, 12H); 1.02 (d, J=6.26 Hz, 3H).
Reaction SMILES: C([Li])CCC.CCCCCC.[N:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][CH:13]=1.CN(C)CCN(C)C.[B:34](OC)([O:37]C)[O:35]C.[Cl-].[NH4+]>C1COCC1>[C:21]([O:20][C:19]([NH:18][C:15]1[CH:14]=[CH:13][N:12]=[CH:17][C:16]=1[B:34]([OH:37])[OH:35])=[O:25])([CH3:22])([CH3:24])[CH3:23]
Reactant: COB(OC)OC
Reactant: CC(C)(C)OC(=O)Nc1ccncc1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccncc1B(O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 71.8 %

Procedure:
A 2.5 M solution of n-butyl lithium in hexane (100 mL, 250 mmol) was added over 20 minutes to a stirred solution of tert-butyl pyridin-4-ylcarbamate (19.4 g, 100 mmol) and N,N,N′,N′-tetramethylethylenediamine (31.4 g, 270 mmol) in THF (500 mL) at −78° C. tert-Butyl pyridin-4-ylcarbamate is available from a literature procedure (Spivey, A. C. et al. J. Org. Chem. 1999, 64, 9430-9443). A white solid appeared and the mixture was stirred for 10 minutes at −78° C., then was allowed to warm slowly to −4° C. before cooling to −78° C. again. Trimethyl borate (39.5 g, 380 mmol) was added over 15 minutes. The solution was allowed to warm to 0° C., then was poured into saturated aqueous ammonium chloride (500 mL). The mixture was stirred for 2 minutes. After standing at ambient temperature overnight, the mixture was partitioned between diethyl ether and brine. The organic layer was separated and washed with brine. A white solid formed in the organic layer and was isolated by filtration. The solid was washed sequentially with diethyl ether, water, and diethyl ether, then was dried to provide 17.1 g of 4-[(tert-butoxycarbonyl)amino]pyridin-3-ylboronic acid as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:23]#[C:24]Br.C1COCC1.C(=O)([O-])O.[Na+]>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:21]3[N:22]=[C:24]2[NH2:23])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CBr
Reactant: Nc1cccnc1Nc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 27 %

Procedure:
A mixture of N2-[4-(benzyloxy)phenyl]pyridine-2,3-diamine (3.96 g), cyanogen bromide (2.88 g), THF (60 mL) and water (15 mL) was stirred at room temperature for 48 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/tetrahydrofuran), treated with activated carbon, and recrystallized from methanol/water to give the title compound (1.16 g).
Reaction SMILES: [CH3:1][C:2]([C:6]1([OH:11])[CH2:10][CH2:9][NH:8][CH2:7]1)([CH3:5])[CH2:3][CH3:4].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([C:22](O)=[O:23])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([C:22]([N:8]3[CH2:9][CH2:10][C:6]([C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])([OH:11])[CH2:7]3)=[O:23])[CH2:20][CH2:21]2)=[CH:17][CH:18]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: CCC(C)(C)C1(O)CCNC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)(C)C1(O)CCN(C(=O)C2(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(1,1-Dimethylpropyl)pyrrolidin-3-ol (29.5 mg, 0.000188 mol) was dissolved in DMF and to this solution were added 1-(4-chlorophenyl)cyclopropanecarboxylic acid (44.3 mg, 0.000225 mol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (99.6 mg, 0.000225 mol) and N,N-diisopropylethylamine (49 μL, 0.00028 mol), and the resulting solution was stirred at rt overnight. The product was purified by prep-HPLC. LCMS (M+H)=336
Reaction SMILES: CC(C)([O-])C.[K+].IP(C1C=CC=CC=1)(C1C=CC=CC=1)(C1C=CC=CC=1)[CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]1.[Br:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[C:40]([F:46])[CH:39]=1>C1COCC1>[Br:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=[CH:9][CH:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH3:18])[CH2:12][CH2:11]2)=[C:40]([F:46])[CH:39]=1
Reactant: CCCC1CCC(CP(I)(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Reactant: O=Cc1ccc(Br)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC1CCC(C=Cc2ccc(Br)cc2F)CC1
Temperature: -30 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
Under a nitrogen atmosphere, potassium t-butoxide (30.4 g, 271.0 mmol) was added, at −30° C. or lower, to a THF (500 mL) suspension of iodotriphenyl((4-propylcyclohexyl)methyl)phosphine (73) (143.0 g, 271.0 mmol). The reaction mixture was agitated at −30° C. or lower for 1 hour, and then a THF (100 mL) solution of 4-bromo-2-fluorobenzaldehyde (50.0 g, 246.0 mmol) was added dropwise thereto. The reaction mixture was returned to room temperature, and then quenched with 500 mL of water, and extracted with 200 mL of toluene three times. Combined organic layers were washed with water and saturated brine, and then dried over magnesium sulfate, and a solvent was distilled off by an evaporator. The residue was purified by silica gel column chromatography, and thus 4-bromo-2-fluoro-1-(2-(4-propylcyclohexyl)vinyl)benzene (75) (75.0 g, yield 94.0%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:11][N:12]([CH:15]3[CH2:17][CH2:16]3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH3:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:24][C:25]2[CH:26]=[C:27]([CH3:33])[C:28](=[O:32])[N:29]([CH3:31])[CH:30]=2)[C:9]2[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:11][N:12]([CH:15]3[CH2:17][CH2:16]3)[C:13]=2[CH3:14])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1nn(C2CC2)c(C)c1C(O)c1ccc(Cl)cc1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(C2CC2)c(C)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-5-methyl-1H-pyrazole-3-carboxylate (Step 17.5) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.59 min (HPLC 1); tR: 1.05 min (LC-MS 2); ESI-MS: 455 [M+H]+ (LC-MS 2); Rf=0.45 (CH2Cl2/MeOH 9:1).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[CH:14][C:13]3[CH:16]=[N:17][N:18]([C:19]4[N:24]=[C:23]([N:25]5[CH2:30][CH2:29][CH2:28][C@H:27]([NH:31]C(=O)OC(C)(C)C)[CH2:26]5)[CH:22]=[CH:21][CH:20]=4)[C:12]=3[CH:11]=2)[CH:7]=[N:8][CH:9]=1)([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[CH:14][C:13]3[CH:16]=[N:17][N:18]([C:19]4[N:24]=[C:23]([N:25]5[CH2:30][CH2:29][CH2:28][C@H:27]([NH2:31])[CH2:26]5)[CH:22]=[CH:21][CH:20]=4)[C:12]=3[CH:11]=2)[CH:7]=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](NC(=O)OC(C)(C)C)C3)n2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1cncc(-c2cc3c(cn2)cnn3-c2cccc(N3CCC[C@H](N)C3)n2)c1
Yield: 37 %

Procedure:
The aforesaid tert-butyl N-[(3S)-1-[6-[6-(5-isopropyl-3-pyridyl)pyrazolo[4,3-c]pyridin-1-yl]-2-pyridyl]-3-piperidyl]carbamate in DCM (5 mL) and TFA (5 mL) was stirred at room temperature for 1 h. The mixture was concentrated and the residue was purified by reverse phase HPLC to afford 108 (33.9 mg, 37%). 1H NMR (400 MHz, DMSO) δ 9.35-9.30 (s, 1H), 9.13-9.10 (d, J=2.0 Hz, 1H), 9.06-9.02 (s, 1H), 8.66-8.61 (s, 1H), 8.58-8.55 (d, J=2.0 Hz, 1H), 8.35-8.31 (d, J=1.9 Hz, 1H), 7.78-7.70 (t, J=8.1 Hz, 1H), 7.23-7.17 (d, J=7.7 Hz, 1H), 6.84-6.78 (d, J=8.5 Hz, 1H), 4.32-4.14 (dd, J=37.4, 11.8 Hz, 2H), 3.12-3.01 (td, J=12.8, 5.7 Hz, 2H), 2.87-2.70 (ddd, J=15.5, 13.1, 7.6 Hz, 2H), 1.96-1.74 (m, 2H), 1.64-1.51 (dd, J=24.5, 11.5 Hz, 2H), 1.33-1.31 (d, J=7.0 Hz, 6H); MS (ESI) m/z: 414.1 [M+H]+
Reaction SMILES: [CH:1]1([C:6]([OH:19])([CH2:9][C:10]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:11])[CH2:7][OH:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.CS(C)=O>C(N(CC)CC)C>[CH:1]1([C:6]([OH:19])([CH2:9][C:10]([CH3:11])([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:18])[CH:7]=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(CC(O)(CO)C1CCCC1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(CC(O)(C=O)C1CCCC1)c1ccccc1

Procedure:
185 mg of 2-cyclopentyl-4-methyl-4-phenyl-1,2-pentanediol is converted with 438 mg of pyridine-sulfur trioxide complex, 2.5 ml of DMSO and 0.5 ml of triethylamine into 160 mg of aldehyde.
Reaction SMILES: O[CH2:2][CH2:3][C@@H:4]([CH3:14])[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(OCC)(=O)C>[CH3:14][C@@H:4]1[CH2:3][CH2:2][N:7]([C:8]2[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=2)[C:5]1=[O:6]
Reactant: C[C@H](CCO)C(=O)Nc1ccn(C)n1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C[C@@H]1CCN(c2ccn(C)n2)C1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 49.4 %

Procedure:
To a solution of (2R)-4-hydroxy-2-methyl-N-(1-methyl-1H-pyrazol-3-yl)butanamide (216 mg) and tri-n-butylphosphine (0.54 mL) in THF (10 mL) was added 40% diethyl azodicarboxylate toluene solution (1.0 mL). The reaction mixture was stirred at room temperature for 15 hr, and diluted with ethyl acetate. The diluted solution was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and then HPLC (C18, mobile phase: water/acetonitrile (containing 0.1% TFA)), and to the obtained fraction was added ethyl acetate. The mixture was washed with saturated aqueous sodium carbonate solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was concentrated under reduced pressure to give the title compound (97 mg).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]#[N:13])=[CH:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]([Mg]Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CC(O)CC.[BH4-].[Na+]>O1CCCC1.CO>[C:15]1([CH2:14][CH:12]([C:11]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[N:9][CH:10]=2)[NH2:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: N#Cc1cnnn1-c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCC(C)O
Product: NC(Cc1ccccc1)c1cnnn1-c1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 9C (280 mg, 1.63 mmol) in tetrahydrofuran (5 mL), benzylmagnesium chloride (2M in THF) (1.23 mL, 2.46 mmol) was added dropwise. After 3 hours, 3 mL of 2-butanol was added to the reaction and sodium borohydride (0.5 g) was added to the mixture by portion. The reaction was monitored by LC/Mass until it was done. Methanol (5 mL) was added to the mixture. The organic layer was washed with brine and extracted with ethyl acetate (50 mL twice). The organic layer was dried with Na2SO4, filtered and concentrated. The crude product was purified by flash column (Rf: 0.3, 3% MeOH/DCM) to provide the desired product. MS (m/z) 265 [M+H]+.
Reaction SMILES: C(NC(C)C)(C)C.CC(C)([O-])C.[K+].C([Li])CCC.[Br:19][C:20]1[CH:29]=[CH:28][C:23]2[S:24][CH:25]=[C:26]([CH3:27])[C:22]=2[CH:21]=1.[C:30](=[O:32])=[O:31]>CCOCC>[Br:19][C:20]1[CH:29]=[CH:28][C:23]2[S:24][C:25]([C:30]([OH:32])=[O:31])=[C:26]([CH3:27])[C:22]=2[CH:21]=1
Reactant: O=C=O
Reactant: Cc1csc2ccc(Br)cc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(C)NC(C)C
Product: Cc1c(C(=O)O)sc2ccc(Br)cc12
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A mixture of diisopropylamine (4.44 g.) and potassium t-butoxide (5.02 g.) in dry ether was cooled to -78° C. under an atmosphere of dry nitrogen and n-butyl lithium (28.4 ml. of 1.55M solution in hexane) was added with stirring over 5 minutes. The mixture was stirred at -78° for 30 minutes and then a solution of 5-bromo-3-methylbenzo[b]thiophene (9.10 g.) in dry ether (25 ml.) was added over 5 minutes. The resulting mixture was stirred at -78° C. for 30 minutes and then poured onto a mixture of crushed solid carbon dioxide and ether. When all the carbon dioxide had evaporated the mixture was shaken with water and the ether layer was separated. The aqueous layer was acidified with acetic acid and the solid was filtered off, washed with water and crystallized from acetic acid to give 5-bromo-3-methylbenzo[b]thiophene-2-carboxylic acid (7.30 g.), m.p. >300°.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH:12]([OH:16])[CH2:13][CH2:14][NH2:15])[CH:3]=1.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18].[Cl:24][C:25]1[N:26]=[C:27](Cl)[C:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[C:29]=2[N:30]=1.C(N(C(C)C)C(C)C)C>C(#N)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH:12]([OH:16])[CH2:13][CH2:14][NH:15][C:27]2[C:28]3[CH2:33][CH2:32][CH:31]([C:34]4[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=4)[C:29]=3[N:30]=[C:25]([Cl:24])[N:26]=2)[CH:3]=1.[C:17]([OH:23])([C:19]([F:22])([F:21])[F:20])=[O:18]
Reactant: N#Cc1ccc(N)cc1OCC(O)CCN
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: N#Cc1ccc(N)cc1OCC(O)CCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The mixture of 4-amino-2-(4-amino-2-hydroxybutoxy)benzonitrile, 2 TFA salt (Preparation Z, 50 mg, 0.111 mmol), 2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation R, 31.5 mg, 0.111 mmol) and N-ethyl-N-isopropylpropan-2-amine (97 μL, 0.556 mmol) in acetonitrile (556 μL) was stirred at rt for 24 h. The reaction mixture was concentrated and purified by Prep-HPLC to obtain 4-amino-2-(4-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)-2-hydroxybutoxy)benzonitrile, TFA (14.73 mg, 22.75% yield). LC-MS (M+H)+=468.2. 1H NMR (500 MHz, methanol-d4) δ 7.27-7.15 (m, 3H), 7.14-7.01 (m, 2H), 6.40-6.24 (m, 2H), 4.44-4.33 (m, 1H), 4.17-4.04 (m, 2H), 4.03-3.95 (m, 1H), 3.89-3.66 (m, 2H), 2.94-2.81 (m, 1H), 2.81-2.67 (m, 2H), 2.14 (td, J=7.5, 4.0 Hz, 1H), 2.10-2.00 (m, 1H), 1.95 (dd, J=14.0, 6.4 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:37])([F:36])[C:20]([C:22]1[S:26][C:25]([C:27]2[CH:28]=[N:29][CH:30]=[C:31]([CH:35]=2)[C:32](O)=[O:33])=[CH:24][CH:23]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:32](=[O:33])[C:31]3[CH:35]=[C:27]([C:25]4[S:26][C:22]([C:20](=[O:21])[C:19]([F:36])([F:18])[F:37])=[CH:23][CH:24]=4)[CH:28]=[N:29][CH:30]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1nc(-c2ccc(F)cc2)n[nH]1
Reactant: O=C(O)c1cncc(-c2ccc(C(=O)C(F)(F)F)s2)c1
Product: CC(C)(CNC(=O)c1cncc(-c2ccc(C(=O)C(F)(F)F)s2)c1)c1nc(-c2ccc(F)cc2)n[nH]1
Yield: 20 %

Procedure:
This compound was synthesized from 2-(3-(4-fluorophenyl)-1H-1,2,4-triazol-5-yl)-2-methylpropan-1-amine and 5-(5-(2,2,2-trifluoroacetyl)thiophen-2-yl)nicotinic acid as described in example 8 step 6 (28 mg, yield 20%) as a yellow viscous liquid. 1H NMR (400 MHz, DMSO-d6) δ 9.20 (d, J=2.3 Hz, 1H), 9.01-8.98 (m, 1H), 8.80-8.77 (m, 1H), 8.51-8.48 (m, 1H), 8.21-8.19 (m, 1H), 8.01-7.96 (m, 4H), 7.24-7.19 (m, 2H), 3.59-3.57 (d, J=6.2 Hz, 2H), 1.42 (s, 6H). MS (ESI) m/z: Calculated for C24H19F4N6O2S: 517.12. found: 516.4 (M−H)−.
Reaction SMILES: [Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:10]=CO[N:7]=1)=[O:4].[NH2:11][C:12]1[CH:17]=NC=CN=1>>[Br:1][CH2:2][C:3]([NH:5][C:6]1[CH:10]=[N:11][CH:12]=[CH:17][N:7]=1)=[O:4]
Reactant: O=C(CBr)Nc1ccon1
Reactant: Nc1cnccn1
Product: O=C(CBr)Nc1cnccn1

Procedure:
This compound is prepared by an analogous method to 2-bromo-N-isoxazol-3-yl-acetamide (Intermediate A) by replacing 3-aminoisoxazole with 2-aminopyrazine
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C@@H:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)[CH3:14])[CH:6]=[N:5]2.[C:23]([N:30]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[N:31]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>O1CCOCC1>[C:26]([O:25][C:23]([N:30]1[CH:34]=[C:33]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([NH:12][C@@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)[CH3:14])[CH:6]=[N:5]3)[CH:32]=[N:31]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1cccc([C@@H](C)Nc2cnc3cc(Br)ccc3n2)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: C1COCCO1
Product: COc1cccc([C@@H](C)Nc2cnc3cc(-c4cnn(C(=O)OC(C)(C)C)c4)ccc3n2)c1
Temperature: 110 °C

Procedure:
(6-Bromo-quinoxalin-2-yl)-[(R)-1-(3-methoxy-phenyl)-ethyl]-amine (0.3 g, 0.83 mmol), N-Boc-4-pyrazole boronic acid pinacol ester (0.27 g, 0.92 mmol), caesium carbonate (1.08 g, 3.34 mmol) and potassium iodide (0.014 g, 0.083) were dissolved in 1,4-dioxane (15 mL). The reaction mixture was degassed at RT under vacuum and placed under an atmosphere of nitrogen. The process was repeated twice and Fu's catalyst (Bis(tri-tert-butylphosphine)palladium(0)) (0.021 g, 0.041 mmol) was added at RT. The reaction mixture was heated at 110° C. in a microwave reactor for 180 minutes. The organic mixture was diluted with ethyl acetate (150 mL), washed with water (15 mL×2) and brine (15 mL) and was then dried over Na2SO4. The organic volatiles were evaporated in vacuo to afford crude product.
Reaction SMILES: C([SiH](CC)CC)C.[Br:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([CH3:20])([CH3:19])[CH2:14][C:15]2=O)=[C:11]([F:21])[CH:10]=1>C(O)(C(F)(F)F)=O>[Br:8][C:9]1[CH:17]=[C:16]2[C:12](=[C:11]([F:21])[CH:10]=1)[C:13]([CH3:20])([CH3:19])[CH2:14][CH2:15]2
Reactant: CC1(C)CC(=O)c2cc(Br)cc(F)c21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CCc2cc(Br)cc(F)c21
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Triethylsilane (1.59 g, 2.17 mL, 13.63 mmol) was added to a solution of 6-bromo-4-fluoro-3,3-dimethylindan-1-one (1.5 g, 5.83 mmol) in TFA (30 mL) at room temperature, and the mixture was stirred at room temperature for 40 hr. To the reaction mixture was added ice water at 0° C., and the mixture was extracted with ethyl acetate (×2). The organic layer was washed with aqueous sodium hydroxide solution (the pH of the aqueous layer was adjusted to 7.0) and 10% brine, dried over sodium sulfate, and concentrated under reduced pressure to give crude 5-bromo-7-fluoro-1,1-dimethylindane as an orange oil.