Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH3:13])[CH:8]=1.CN(C)[CH:16]=[O:17]>C1COCC1>[CH3:13][C:9]1[CH:8]=[C:7]([CH:16]=[O:17])[CH:12]=[CH:11][N:10]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)ccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(C=O)ccn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium (1.6 M solution in hexanes, 6.32 mL, 12.6 mmol) in THF (50 mL) was cooled to −78° C. A solution of 4-bromo-2-methyl-pyridine (2.00 g, 11.6 mmol.) in anhydrous THF (5 mL) was added. The resulting mixture was stirred for 5 minutes, then anhydrous N,N dimethylformamide (3.39 g, 46.4 mmol,) was added. The solution was stirred for 90 min at −78° C. and quenched with saturated aqueous NH4Cl solution (30 mL). The reaction mixture was warmed to room temperature. The mixture was extracted with ethyl acetate (3×100 mL), and the combined organic phase was washed with brine (100 mL) and dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to give 2-methyl-pyridine-4-carbaldehyde. Yield: 1.20 g, (85%).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3[C:17]3[CH:18]=[C:19]([C:22]([OH:24])=O)[S:20][CH:21]=3)[CH:13]=2)[CH:3]=1.[F:25][C:26]([F:37])([F:36])[CH:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)[NH2:28].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>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:9]=[N:10][C:11]3[N:12]([N:14]=[CH:15][C:16]=3[C:17]3[CH:18]=[C:19]([C:22]([NH:28][CH:27]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=4)[C:26]([F:25])([F:36])[F:37])=[O:24])[S:20][CH:21]=3)[CH:13]=2)[CH:3]=1
Reactant: Cc1cccc(C(N)C(F)(F)F)n1
Reactant: O=C(O)c1cc(-c2cnn3cc(-c4cccnc4)cnc23)cs1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(C(NC(=O)c2cc(-c3cnn4cc(-c5cccnc5)cnc34)cs2)C(F)(F)F)n1

Procedure:
A solution of 4-(6-pyridin-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)thiophene-2-carboxylic acid hydrochloride (20 mg, 0.06 mmol), 2,2,2-trifluoro-1-(6-methylpyridin-2-yl)ethanamine (step C, 12 mg, 0.06 mmol), BOP (41 mg, 0.09 mmol) and N,N-diisopropylethylamine (16 □L, 0.09 mmol) in DMF (0.6 mL) was stirred at 40° C. for 4 hours. The reaction was partitioned between water and ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated in vacuo. Purification by reverse phase LC gave 4-(6-pyridin-3-ylpyrazolo[1,5-a]pyrimidin-3-yl)-N-[2,2,2-trifluoro-1-(6-methylpyridin-2-yl)ethyl]thiophene-2-carboxamide. 1H NMR (600 MHz, CDCl3): δ 9.42 (bs, 1H), 9.11 (s, 1H), 9.00 (d, J=2.4 Hz, 1H), 8.84 (d, J=5.3 Hz, 1H), 8.81 (d, J=2.3 Hz, 1H), 8.55 (s, 2H), 8.34 (d, J=8.3 Hz, 1H), 8.17 (s, 1H), 7.99 (t, J=8.5 Hz, 1H), 7.85 (dd, J=7.9, 5.3 Hz, 1H), 7.58 (d, J=7.4 Hz, 1H), 7.48 (m, 1H), 6.13 (m, 1H), 3.48 (s, 3H). LC-MS EIMS: m/z 495.1 [M+H]+.
Reaction SMILES: [F:1][C:2]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11]CC2C=CC=CC=2)[CH2:7][CH2:6]1)([F:4])[CH3:3].[H][H]>CO.[Pd]>[F:1][C:2]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([OH:11])[CH2:7][CH2:6]1)([F:4])[CH3:3]
Reactant: [H][H]
Reactant: CC(F)(F)[C@H]1CC[C@@H](OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC(F)(F)[C@H]1CC[C@@H](O)CC1

Procedure:
Compounds ((cis-4-(1,1-difluoroethyl)cyclohexyloxy)methyl)benzene (480 mg, 1.89 mmol) and Pd—C (2.0 g, 0.38 mmol, 0.2 eq.) were dissolved in CH3OH (20 mL). Then the mixture was stirred at 50° C. under 40 atm. of hydrogen atmosphere for 6 h. When the reaction completed by TLC, the mixture was filtrated and the filtrate was concentrated and purified by silica gel column chromatography using petroleum ether/ethyl acetate (10/1) as eluent to give product (140 mg, 45%) as a slight yellow oil. 1H NMR (400 MHz, CDCl3) δ 4.07-4.05 (m, 1H), 1.86-1.83 (m, 2H), 1.75-1.72 (m, 2H), 1.63-1.48 (m, 8H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:20]([O:22]C)=[O:21])=[CH:13]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN1CCN(C(Cl)=O)CC1.C(O)C=C.N1C=CC=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14]([C:20]([OH:22])=[O:21])=[CH:13]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1cc2c3c(ccc2[nH]1)N(C(=O)OC(C)(C)C)CC3
Agent: CN1CCN(C(=O)Cl)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C=CCO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCc2c1ccc1[nH]c(C(=O)O)cc21
Yield: 85.8 %

Procedure:
40 mg (0.27 mMol) of 5 was reacted overnight with 160 mg (0.81 mMol) of commercially available 4-methylpiperazine carbonylchloride hydrochloride in 17 mL of DCM with 1.7 mL of allylalcohol and 214 μL pyridine. The aolvent was evaporated and the crude compound was purified over silica with 5% MeOH/DCM as eluent to give 70 mg (40% yield) of 6. M+1=645.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([CH:13]3[CH2:16][C:15]4([CH2:19][C:18](=[O:20])[CH2:17]4)[CH2:14]3)[O:10][N:9]=2)=[CH:4][C:3]=1[NH:21][C:22]([C:24]1[N:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]2=[N:26][CH:25]=1)=[O:23].[BH4-].[Na+]>CO>[OH:20][CH:18]1[CH2:19][C:15]2([CH2:14][CH:13]([C:11]3[O:10][N:9]=[C:8]([C:5]4[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:21][C:22]([C:24]5[N:28]6[CH:29]=[CH:30][CH:31]=[CH:32][C:27]6=[N:26][CH:25]=5)=[O:23])[CH:4]=4)[N:12]=3)[CH2:16]2)[CH2:17]1
Reactant: Cc1ccc(-c2noc(C3CC4(CC(=O)C4)C3)n2)cc1NC(=O)c1cnc2ccccn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(-c2noc(C3CC4(CC(O)C4)C3)n2)cc1NC(=O)c1cnc2ccccn12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirring solution of N-(2-methyl-5-(5-(6-oxospiro[3.3]heptan-2-yl)-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-a]pyridine-3-carboxamide (F76) (100 mg, 0.23 mmol) in anhydrous methanol (1 mL) was added sodium borohydride (10.6 mg, 0.28 mmol). The reaction mixture was stirred at room temperature for 12 hours. The reaction was quenched with water and the solvent was concentrated. Purification by silica gel using 10% MeOH in dichloromethane afforded N-(5-(5-(6-hydroxyspiro[3.3]heptan-2-yl)-1,2,4-oxadiazol-3-yl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (F100). MS m/z 430.1 (M+1)+.
Reaction SMILES: Br[C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[C:15](B(O)O)=[CH:14][CH:13]=[N:12]1.C([O-])(O)=O.[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][C:9]1[C:2]([C:13]2[NH:12][N:11]=[CH:15][CH:14]=2)=[C:3]([CH:6]=[CH:7][CH:8]=1)[C:4]#[N:5]
Reactant: N#Cc1cccc(F)c1Br
Reactant: OB(O)c1ccn[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cccc(F)c1-c1ccn[nH]1
Temperature: 23 °C
Yield: 20.7 %

Procedure:
2-Bromo-3-fluorobenzonitrile (1.0 g, 5.0 mmol) and (1H-pyrazol-5-yl)boronic acid (647 mg, 4.6 mmol) were combined and dissolved in degassed DME (15 mL) then treated with NaHCO3 (1260 mg, 8.4 mmol) in water and the reaction purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3)4 (288 mg, 0.2 mmol) and then purged with bubbling for 5 minutes in a sealed vessel and then heated to reflux for 2 h. Cooled to 23° C. filtered and solid rinsed with EtOAc and the layers separated. The organic layers were combined, dried and concentrated under reduced pressure. Chromatography (0-30% ethyl acatate/hexanes) afforded 3-fluoro-2-(1H-pyrazol-5-yl)benzonitrile (178 mg, 19%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][NH2:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[C:31]1([CH2:37][S:38]([NH:23][CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(Cc1ccccc1)NCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a stirred solution of {4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-yl}methylamine (200 mg, 0.628 mmol) and triethylamine (106 μL, 0.754 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of α-toluenesulfonylchloride (143 mg, 0.754 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated and washed with water, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound (207 mg, 69%). 1H NMR (400 MHz, CDCl3) δ7.27-7.22 (m, 3H), 7.16-7.14 (m, 2H), 7.07 (d, 2H), 6.83 (d, 2H), 4.05 (s, 2H), 3.95 (t, 2H), 3.68-3.63 (m, 2H), 3.55 (t, 1H), 3.49-3.44 (m, 2H), 3.01 (d, 2H), 2.57 (t, 2H), 2.47 (s, 4H), 2.02-1.93 (m, 4H), 1.78-1.72 (m, 6H).
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].O=S(Cl)[Cl:15].C(Cl)Cl>N1C=CC=CC=1.O>[CH2:1]([Cl:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCCCCCCCCO
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C=CCCCCCCCCCCl
Temperature: 65 °C
Yield: 84.7 %

Procedure:
To a solution of 100 g (0.588 mole) of 10-undecenyl alcohol and 2 g of pyridine was added 75 g (0.63 mole) of SOCl2 dropwise over a period of 45 minutes at 25° C. The solution was heated at 65° C. for 5 hours. CH2Cl2 (100 mL) was added and the solution was water washed twice, dried with MgSO4, filtered, and the CH2Cl2 evaporated. The residue (103 g) by GC analysis showed a purity of 99.3% VIII with 0.7% alcohol; IR showed no OH band and absorbence at 1641-1. Distillation (15.24 centimeter jacketed Vigreaux column) gave 94 g VIII (bp 104°-105° C. at 6 mm) (GC showed no alcohol; 100% VIII).
Reaction SMILES: Cl[CH:2]([C:8]([CH3:10])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:11]([NH2:14])(=[S:13])[CH3:12]>C(O)C>[CH3:12][C:11]1[S:13][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH3:10])[N:14]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: CC(N)=S
Solvent: CCO
Product: CCOC(=O)c1sc(C)nc1C
Temperature: 90 °C
Reaction time: 5 h
Yield: 83.4 %

Procedure:
The mixture of ethyl 2-chloroacetoacetate (111.2 g, 0.68 mol) and thioacetamide (40 g, 0.68 mol) in 150 ml ethanol was heated to 90° C. and stirred for 5 h. After cooling to room temperature, the solvent was removed under vacuum to afford the title compound (105 g, y=83%).
Reaction SMILES: [CH:1](=[C:8]1[CH2:17][CH2:16][C@@H:15]2[C@:10]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=3)([CH2:11][CH2:12][N:13]([CH2:18][CH3:19])[CH2:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-].Cl[Si](C)(C)C>C(#N)C>[CH2:1]([C:8]1[CH2:9][C@:10]2([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=3)[C@@H:15]([CH2:16][CH:17]=1)[CH2:14][N:13]([CH2:18][CH3:19])[CH2:12][CH2:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CC(=Cc3ccccc3)CC[C@H]2C1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CCN1CC[C@]2(c3cccc(O)c3)CC(Cc3ccccc3)=CC[C@H]2C1
Yield: 10 %

Procedure:
The reaction was conducted as described in Example 10, using 0.93 g (2.6 mmol) of (±)-trans-6-benzylidene-1,2,3,4,4a,5,6,7,8,8a-decahydro-2-ethyl4a-(3-methoxyphenyl)isoquinoline, 1.54 g (10.3 mmol) of NaI, 1.3 ml (10.3 mmol) of chlorotrimethylsilane and 20 ml of acetonitrile. The crude reaction mixture was purified by flash chromatography, eluting with a mixture CH2Cl2 /MeOH/conc. NH4OH 90:7:0.7 respectively. The resulting solid was crystallised from Et2O, yielding 0.09 g of the title compound. M.p.=160-162° C.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([O:29][CH2:30][CH3:31])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([O:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.C(O)C.O>[CH2:30]([O:29][CH:4]([CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([O:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:8][CH:7]=1)[C:3]([OH:32])=[O:2])[CH3:31]
Reactant: CCOC(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c2ccoc12)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c2ccoc12)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
Potassium carbonate (37 mg, 300 μmol, 1.4 eq.) and potassium iodide (4 mg, 30 μmol, 0.1 eq.) were added to a solution of [rac]-2-ethoxy-3-(4-hydroxy-benzofuran-7-yl)-propionic acid methyl ester (50 mg, 189 μmol) and 4-chloromethyl-5-methyl-2-phenyl-oxazole (39 mg, 189 μmol, 1 eq.) in N,N-dimethylformamide (0.5 ml). The mixture was shaken at 80° C. for 12 h, filtered off and the filtrate evaporated in vacuo to give [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzofuran-7-yl]-propionic acid methyl ester. Crude [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzofuran-7-yl]-propionic acid methyl ester was dissolved in a 2:1:1 mixture of THF/ethanol/water. Lithium hydroxide (40 mg, 945 μmol, 5 eq.) was added and the solution was shaken at ambient temperature for 12 h. Acidification with 25% aqueous hydrochloric acid and evaporation of the solvent in vacuo were followed by purification through a preparative HPLC column to give the title compound (28 mg, 66 μmol, 35%) as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[N:15]=[C:14]3[N:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:17](=[O:20])[CH2:18][NH:19][C:13]3=[N:12][CH:11]=2)[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].CC1C=C(B2OC(C)(C)C(C)(C)O2)C=[C:31]([NH2:44])C=1N.BrC1N=C2N(CC3CCOCC3)C(=O)CNC2=NC=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(O)(C)C.O1CCOCC1>[NH2:44][C:31]1[NH:1][C:2]2[CH:3]=[C:4]([C:10]3[N:15]=[C:14]4[N:16]([CH2:21][CH:22]5[CH2:27][CH2:26][O:25][CH2:24][CH2:23]5)[C:17](=[O:20])[CH2:18][NH:19][C:13]4=[N:12][CH:11]=3)[CH:5]=[C:6]([CH3:9])[C:7]=2[N:8]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(N)c1N
Reactant: Cc1cc(-c2cnc3c(n2)N(CC2CCOCC2)C(=O)CN3)cc(N)c1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(-c2cnc3c(n2)N(CC2CCOCC2)C(=O)CN3)cc2[nH]c(N)nc12
Temperature: 100 °C
Yield: 99 %

Procedure:
7-(3,4-Diamino-5-methylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. 3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene-1,2-diamine (0.523 g, 2.109 mmol), 7-bromo-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.600 g, 1.834 mmol), [1,1′-bis(diphenylphosphino)-ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (0.150 g, 0.183 mmol), sodium carbonate (1 M in water, 5.50 mmol), 1,4-dioxane (4.1 mL) and isopropanol (1.4 mL) were combined in a sealable vessel with a stirbar. The system was purged with nitrogen. The resulting mixture was sealed, stirred vigorously and heated at 100° C. for 3.5 h. The resulting mixture was diluted with 20% methanol in dichloromethane and all volatiles removed under reduced pressure. The residue was taken up in 20% methanol in dichloromethane and concentrated under reduced pressure with silica gel. The residue was purified using flash chromatography (1-10% methanol in dichloromethane) to give the desired product (0.669 g, 1.818 mmol, 99% yield) as a brown solid. MS (ESI) m/z 369.1 [M+1]+.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=3[O:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH2:7][CH2:6]2)[CH2:2]1.[Br:28][C:29]1[N:30]=[C:31](Br)[C:32]2[N:33]([CH:35]=[CH:36][N:37]=2)[CH:34]=1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CC(O)C.C(Cl)Cl>[Br:28][C:29]1[N:30]=[C:31]([NH:15][C:14]2[CH:16]=[CH:17][C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH:3]4[CH2:2][O:1][CH2:4]4)[CH2:6][CH2:7]3)=[C:12]([O:18][CH2:19][CH2:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[CH:13]=2)[C:32]2[N:33]([CH:35]=[CH:36][N:37]=2)[CH:34]=1
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: Nc1ccc(N2CCN(C3COC3)CC2)c(OCCOC2CCCCO2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CC(C)O
Product: Brc1cn2ccnc2c(Nc2ccc(N3CCN(C4COC4)CC3)c(OCCOC3CCCCO3)c2)n1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
To a solution of 4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)aniline XXIV (619 mg, 2.17 mmol) and 6,8-dibromoimidazo[1,2-a]pyrazine (601 mg, 2.2 mmol) in IPA (15 mL) was added N,N-Diisopropylethylamine (0.95 ml, 5.43 mmol). The mixture was stirred at 110° C. for 16 h. After this time, DCM (10 mL) and sat aqueous NaHCO3 (15 mL) were added. The aqueous layer was separated and extracted with DCM (2×10 mL). The combined organic extracts were washed with brine (10 mL) and dried over sodium sulfate. The resulting residue was purified by column chromatography ISCO Rf (24 g column) eluting with a gradient of 100% DCM—60:35:5 DCM:Et2O:MeOH to provide 6-bromo-N-(4-(4-(oxetan-3-yl)piperazin-1-yl)-3-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)phenyl)imidazo[1,2-a]pyrazin-8-amine XXV.
Reaction SMILES: [ClH:1].Cl.N[C@@H](CC)[C@H](O)[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7].[NH2:15][C@@H:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:17][OH:18]>>[ClH:1].[ClH:1].[NH2:15][C@@H:16]([CH2:19][CH:20]([CH3:22])[CH3:21])[C@H:17]([OH:18])[C:6]([NH:8][CH:9]1[CH2:11][CH2:10]1)=[O:7]
Reactant: CC(C)C[C@H](N)CO
Reactant: CC[C@H](N)[C@H](O)C(=O)NC1CC1
Agent: Cl
Product: CC(C)C[C@H](N)[C@H](O)C(=O)NC1CC1

Procedure:
The title compound was prepared in analogy to (2S,3S)-3-amino-N-cyclopropyl-2-hydroxypentanamide dihydrochloride, Representative Procedure A, starting with (S)-2-amino-4-methylpentan-1-ol in the first step (A1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([CH3:32])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[NH:11][C:10]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:4][CH:3]=1.[C:33](Cl)([Cl:35])=[O:34].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH3:32])[C:12]([C:14]3[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=3)([CH3:13])[N:11]([C:33]([Cl:35])=[O:34])[C:10]([C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCOc1cc(C#N)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1
Reactant: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C#N)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of rac-4-[(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-2-yl]-3-ethoxy-benzonitrile (190 mg, 0.31 mmol) in dichloromethane was cooled to 0° C. and treated with phosgene (2.5 mL, 0.47 mmol, 1.9 M in toluene) and triethylamine (0.66 g, 0.65 mmol). After 1 h, the reaction was charged with the same quantities of phosgene and triethylamine. After an additional 1 h at 0° C., the reaction was worked up in ice water and dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to give an oil. It was purified by a short plug of silica gel (eluting with 20% ethyl acetate/hexane) to give rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-(4-cyano-2-ethoxy-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:9][CH2:8][N:7]2[C:10]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:12]=[C:6]2[C:5]21[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2.[CH:22]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][C:27]=1[O:35][CH3:36])([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH:22]([O:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([N:19]2[CH2:20][CH2:21][C:5]3([N:4]([CH3:3])[CH2:9][CH2:8][N:7]4[C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=[C:6]34)[CH2:17][CH2:18]2)=[O:31])=[CH:28][C:27]=1[O:35][CH3:36])([CH3:24])[CH3:23]
Reactant: COc1cc(C(=O)O)ccc1OC(C)C
Reactant: CN1CCn2c(C(F)(F)F)ccc2C12CCNCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCC3(CC2)c2ccc(C(F)(F)F)n2CCN3C)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2′-methyl-6′-(trifluoromethyl)-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]dihydrochloride (69 mg, 0.20 mmol), 4-isopropoxy-3-methoxybenzoic acid (42 mg, 0.20 mmol), HATU (76 mg, 0.20 mmol), Et3N (112 μL, 0.80 mmol) and DMF (2 mL) was allowed to stir at room temperature for 3 h. The mixture was filtered and purified by reverse-phase preparatory HPLC (10-99% ACN/water). The desired fractions were concentrated to give (4-isopropoxy-3-methoxyphenyl)(2′-methyl-6′-(trifluoromethyl)-3′,4′-dihydro-2′H-spiro[piperidine-4,1′-pyrrolo[1,2-a]pyrazine]-1-yl)methanone as an amorphous white solid. ESI-MS m/z calc. 465.2, found 466.3 (M+1)+; Retention time: 1.23 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 7.01 (d, J=1.7 Hz, 1H), 6.97 (dd, J=8.2, 1.7 Hz, 1H), 6.88 (d, J=8.3 Hz, 1H), 6.53 (d, J=3.0 Hz, 1H), 5.94 (d, J=3.5 Hz, 1H), 4.57 (dt, J=12.2, 6.1 Hz, 1H), 4.52 (s, 1H), 3.99 (s, 2H), 3.87 (s, 3H), 3.69 (s, 1H), 3.40 (s, 1H), 3.34 (t, J=5.4 Hz, 3H), 2.39 (s, 3H), 2.11 (s, 2H), 1.82 (s, 2H), 1.38 (d, J=6.1 Hz, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH:8](O)[CH2:7]2.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][CH2:9][CH:8]([N:16]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH3:15])[CH2:7]2
Reactant: CCCNCCC
Reactant: OC1COc2c(Br)cccc2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: CCCN(CCC)C1COc2c(Br)cccc2C1
Reaction time: 8 h

Procedure:
8-Bromo-3-chromanol (80% according to GC, 0.8×0.69 g, 0.8×3.0=2.4 mmol) was dissolved in dry benzene and di-n-propylamine (2 ml) and p-toluenesulfonic acid (60 mg) was added. The reaction mixture was refluxed under N2 and water separation in a Dean-Stark apparatus. The solvents were removed under reduced pressure and the residue was dissolved in MeOH (50 ml) and NaBH3CN (2.0 g) was added and the mixture was stirred overnight. Water (50 ml) and 15% NaOH (5 ml) was added and the product was extracted to CH2Cl2. The organic layer was washed with water, dried (Na2SO4), filtered and the solvents were removed under reduced pressure, leaving 700 mg of the raw product, which was chromatographed (SiO2, 100 g) using petroleum ether:ether (9:1) as the eluant. The fractions containing pure product were pooled and the solvent was evaporated. The residual oil was converted into the hydrochloride with HCl-saturated EtOH. Crystals (248 mg) melting at 135° C. were obtained from EtOAc/ether. GC/MS showed M+ /M+2 at m/e=311.05(7.7%)/313.05(8.7%) and the base peak pair at m/e=281.95(98%)/283.95(100%).