Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][S:2]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[N:7][C:6]=1[CH3:14])(=[O:4])=[O:3].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:56]1[CH:61]=[C:60]([O:62][CH3:63])[N:59]=[C:58]([S:64][CH2:65][C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[C:67]=2[F:73])[N:57]=1>O1CCOCC1.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]>[F:73][C:67]1[C:68]([F:72])=[CH:69][CH:70]=[CH:71][C:66]=1[CH2:65][S:64][C:58]1[N:57]=[C:56]([NH:1][S:2]([C:5]2[S:9][C:8]([NH:10][C:11](=[O:13])[CH3:12])=[N:7][C:6]=2[CH3:14])(=[O:3])=[O:4])[CH:61]=[C:60]([O:62][CH3:63])[N:59]=1
Reactant: COc1cc(Cl)nc(SCc2cccc(F)c2F)n1
Reactant: CC(=O)Nc1nc(C)c(S(N)(=O)=O)s1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cc(NS(=O)(=O)c2sc(NC(C)=O)nc2C)nc(SCc2cccc(F)c2F)n1

Procedure:
The title compound was prepared according to the procedure outlined in example 1 step (iv) using a mixture of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]acetamide (0.25 g), tris(dibenzylideneacetone)dipalladium (0) (64 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (33 mg), cesium carbonate (0.69 g) and 4-Chloro-2-[[(2,3-difluorophenyl)methyl]thio]-6-methoxypyrimidine (the product of Example 35, step i) (0.21 g) in dioxane (6 ml). The crude material was purified by column chromatography using EtOAc/isohexane (2.5:7.5 to 4:6 gradient) as eluent to give the title compound as a pale yellow solid. Yield: 85 mg.
Reaction SMILES: [F:1][C:2]([F:29])([S:25](F)(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[CH2:37]([NH2:44])[C:38]1C=[CH:42][CH:41]=[CH:40][CH:39]=1>O>[CH2:37]([NH:44][S:25]([C:2]([F:1])([F:29])[C:3]([F:23])([F:24])[C:4]([F:21])([F:22])[C:5]([F:20])([F:19])[C:6]([F:17])([F:18])[C:7]([F:15])([F:16])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])(=[O:26])=[O:27])[CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
50.21 (100.0 mmol) of perfluoroctanesulfonyl fluoride is added in drops to a mixture of 10.62 g (105.0 mmol) of triethylamine and 10.12 g (100.0 mmol) of benzylamine at 80° C. while being stirred vigorously. It is stirred for 2 days at 80° C., the reaction mixture is mixed with 300 ml of water and extracted three times with ethyl acetate. The combined organic extracts are dried on sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol=4/1).
Reaction SMILES: [CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:6]=2[S:5][C:4]=1[CH:16]=O)[CH3:2].[C:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]([O:31][CH3:32])=[O:30])=[C:23]([CH3:33])[CH:22]=1)(=[O:20])[CH3:19]>>[CH2:1]([C:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([F:13])([F:14])[F:15])=[CH:11][C:6]=2[S:5][C:4]=1[CH:16]=[CH:19][C:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH:28][C:29]([O:31][CH3:32])=[O:30])=[C:23]([CH3:33])[CH:22]=1)=[O:20])[CH3:2]
Reactant: COC(=O)C=Cc1ccc(C(C)=O)cc1C
Reactant: CCc1c(C=O)sc2cc(C(F)(F)F)ccc12
Product: CCc1c(C=CC(=O)c2ccc(C=CC(=O)OC)c(C)c2)sc2cc(C(F)(F)F)ccc12

Procedure:
The titled compound was prepared from 3-ethyl-6-(trifluoromethyl)benzothiophen-2-carboxaldehyde [WO 2005077926] (185 mg, 0.716 mmol) and methyl 3-(4-acetyl-2-methylphenyl)acrylate (156 mg, 0.715 mmol) in a procedure similar to that of Example 7 (1) as a yellow crystal (186 mg, yield 57%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[CH2:11][CH2:12][C:13]3([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:3]1=2.C(N(CC)CC)C.Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=1.[Cl-].[Na+]>ClCCl>[CH3:35][O:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][N:16]2[CH2:17][CH2:18][C:13]3([C:3]4[N:2]([CH3:1])[C:10]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=5[C:4]=4[CH2:11][CH2:12]3)[CH2:14][CH2:15]2)=[CH:29][CH:30]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cn1c2c(c3ccccc31)CCC21CCNCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CCC3(CCc4c3n(C)c3ccccc43)CC2)cc1
Reaction time: 8 h
Yield: 40 %

Procedure:
A solution of 1,4-dihydro-4-methylspiro[cyclopent[b]indole-3(2H), 4'-piperidine] (2.5 g) and triethylamine (2.9 ml) in dichloromethane (100 ml) and 4-(chloromethyl)anisole (1.95 g) was allowed to stand overnight at ambient temperature, under nitrogen, with stirring. Saturated sodium chloride solution was added and the mixture was extracted with dichloromethane. The layers were separated, and the organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was flash chromatographed (silica gel), eluting with 7.5% acetone/dichloromethane. The appropriate fractions were collected and concentrated to give 1.5 g (40%) of product, mp 39-40° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2Cl.[CH2:17]([N:19]([CH2:27][CH3:28])[CH:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)[CH3:18]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([S:12]([CH3:15])(=[O:14])=[O:13])=[C:5]2[NH:26][CH:23]1[CH2:22][CH2:21][CH:20]([N:19]([CH2:27][CH3:28])[CH2:17][CH3:18])[CH2:25][CH2:24]1
Reactant: CS(=O)(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CCN(CC)C1CCC(N)CC1
Product: CCN(CC)C1CCC(Nc2c(S(C)(=O)=O)cnc3ccc(Br)cc23)CC1
Yield: 86.7 %

Procedure:
Following general procedure B, 6-bromo-4-chloro-3-(methylsulfonyl)quinoline (161 mg, 0.500 mmol) was reacted with N1,N1-diethylcyclohexane-1,4-diamine (170 mg, 1.00 mmol) to afford the desired product (197 mg, 87%) as a white solid: ESI MS m/z 454 [C20H28BrN3O2S+H]+.
Reaction SMILES: [OH:1][CH:2]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].CCN(CC)CC.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C1COCC1>[OH:1][CH:2]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCCCCc1ccc(OCC(O)CC#CCCCC(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCc1ccc(OCC(O)CCCCCCC(=O)O)cc1

Procedure:
A mixture of 3.5 g of 8-hydroxy-9-(4-pentylphenoxy)-5-nonynoic acid, 0.3 g of Lindlar's catalyst, 2.5 ml of Et3N and 80 ml of THF was hydrogenated under 1 atm of hydrogen until the uptake hydrogen ceased. The solvent and catalyst were removed. The crude product was recrystallized in toluene to yield the title compound, mp 105.0°-105.5°. CI-MS (high resolution) (M+1=337.2298).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][NH:13][CH2:14]3)[CH2:10]2)[N:3]=1.[F:17][C:18]1[C:19]([N:27]2[N:31]=[CH:30][CH:29]=[N:28]2)=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](O)=[O:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(OCC)(=O)C.CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:16][CH:15]3[CH:11]([CH2:12][N:13]([C:21]([C:20]4[CH:24]=[CH:25][CH:26]=[C:18]([F:17])[C:19]=4[N:27]4[N:31]=[CH:30][CH:29]=[N:28]4)=[O:22])[CH2:14]3)[CH2:10]2)[N:3]=1
Reactant: O=C(O)c1cccc(F)c1-n1nccn1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4cccc(F)c4-n4nccn4)CC3C2)n1
Yield: 56.2 %

Procedure:
A mixture of 2-(4,6-dimethyl-pyrimidin-2-yl)-octahydro-pyrrolo[3,4-c]pyrrole (437.3 mg, 2.0 mmol), 3-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (415 mg, 2.0 mmol), HATU (1.14 g, 3.0 mmol) and DIPEA (777 mg, 6.0 mmol) was stirred into DMF (20 mL) at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (250 mL) and washed with water (2×500 mL). The organic phase was dried (Na2SO4), filtered and concentrated to dryness. The crude product was purified using Agilent HPLC (basic system) to yield pure title compound (458.0 mg, 56%). MS (ESI) mass calcd. for C21H22FN7O, 407.45; m/z found 408.2 [M+H]+. 1H NMR (CDCl3): 7.79 (s, 2H), 7.52-7.45 (m, 1H), 7.36-7.28 (m, 1H), 7.25-7.22 (m, 1H), 6.30 (s, 1H), 3.82 (dd, J=11.6, 7.5, 1H), 3.75-3.66 (m, 2H), 3.58-3.41 (m, 4H), 3.13 (dd, J=10.9, 5.2, 1H), 3.02-2.87 (m, 2H), 2.36-2.24 (m, 6H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH2:14][O:15][CH:16]([C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=2)[CH2:17][OH:18])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:39]>>[ClH:39].[C:33]1([C:11]2([CH2:14][O:15][CH:16]([C:19]3[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([C:29]([F:32])([F:30])[F:31])[CH:20]=3)[CH2:17][OH:18])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Agent: Cl
Product: OCC(OCC1(c2ccccc2)CCNCC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
The compound of step (d) above was dissolved in methanolic hydrogen chloride for 2 hours then concentrated and triturated with diethyl ether and filtered to give the title compound as a white solid, m.p. 198°-202° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[I:12]Cl>C(O)(=O)C.C(Cl)(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][C:11]=1[I:12]
Reactant: COC(=O)c1ccc(O)cc1
Reactant: ClI
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(O)c(I)c1
Temperature: 45 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a 500 mL 3-necked flask equipped with a magnetic stirrer, a thermometer, and a condenser were added 10.0 g of methyl 4-hydroxybenzoate (Aldrich) and 30 mL of glacial acetic acid. To this suspension was added a solution of 11.74 g of iodine monochloride in 30 mL of glacial acetic acid via addition funnel. The solution was heated at 80° C. for 1 h, 45° C. for 18 h, and 90° C. for an additional 4 h. Cooling to RT afforded a thick red-orange suspension which was transferred to a 1 L separatory funnel and dissolved in 500 mL of CHCl3 by shaking vigorously. The dark purple solution was washed with water (2×100 mL), saturated aqueous sodium thiosulfate (2×100 mL), and 5% aqueous NaHCO3 (2×100 mL). A light yellow solution resulted which was dried over MgSO4, and concentrated in vacuo to give a white solid. This material was recrystallized from water-MeOH to afford 14.92 g (82%) of methyl 4-hydroxy-3-iodobenzoate as a white crystalline solid, m.p. 145-146° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C(Cl)Cl>[CH2:12]([NH:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCOCc1ccccc1
Reactant: O=Cc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(CNCCOCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
2-(Benzyloxy)ethane amine (12.3146 g; manufactured by Bionet) was dissolved in CH2Cl2 (150 mL), added with benzaldehyde (8.7219 g; manufactured by Kanto Chemical Co., Inc.) and anhydrous sodium sulfate (67.7879 g; manufactured by Wako Pure Chemical Industries, Ltd.), and then stirred overnight at room temperature. After filtering the reaction solution, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in methanol (150 mL), added with sodium borohydride (3.4129 g; manufactured by Kanto Chemical Co., Inc.), and then stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, added with water and then extracted twice with ethyl acetate. The organic layer was washed twice with water and once with brine, and dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to obtain the title compound (20.188 g).
Reaction SMILES: F[C:2](F)(F)[C:3](O)=O.[OH:8][N:9]1[C:14]([CH3:16])([CH3:15])[CH2:13][CH:12]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11][C:10]1([CH3:27])[CH3:26].OO.S([O-])([O-])=O.[Na+].[Na+]>O.F[P-](F)(F)(F)(F)F.C1C=CC=C1.[CH-]1C=CC=C1.[Fe+2].C1CCCCC1.C(#N)C>[CH:3]1([O:8][N:9]2[C:14]([CH3:16])([CH3:15])[CH2:13][CH:12]([O:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:11][C:10]2([CH3:27])[CH3:26])[CH2:2][CH2:12][CH2:11][CH2:10][CH2:26]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: [Fe+2]
Agent: C1=CCC=C1
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: C1CCCCC1
Product: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1OC1CCCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 514.6 %

Procedure:
A suspension of 0.237 g (0.72 mmol) of ferrocenium hexafluorophosphate in 0.269 g (2.4 mmol) of trifluoroacetic acid and 3 ml of water is added to a mixture of 5.01 g (18.1 mmol) of 1-oxyl-4-benzoyloxy-2,2,6,6-tetramethylpiperidine, 25 ml of acetonitrile, and 16 ml of cyclohexane. The reaction mixture is heated to 50° C. A solution of 5.0 g (73 mmol) of 50% aqueous hydrogen peroxide is added dropwise over 2 hours to the reaction mixture while the temperature is brought to and maintained at 62° C. After the peroxide is added, the reaction mixture is heated at 62° C. for 30 minutes. The reaction mixture is cooled slowly to room temperature and stirred overnight. Peroxide is decomposed by the addition of aqueous sodium sulfite solution. Work-up with ethyl acetate and purification by flash chromatography afford 4.44 g (68% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=1)[C:2]#[CH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:34]>>[Cl:34][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][O:4][CH2:1][C:2]#[CH:3])=[CH:7][CH:8]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: C#CCOCc1ccc(CO)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C#CCOCc1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
A mixture of (4-prop-2-ynyloxymethyl-phenyl)-methanol (190 mg, 1.1 mmol) described in Manufacturing Example 194-1-1, triphenylphosphine (340 mg, 1.3 mmol), and carbon tetrachloride (3 mL) was stirred for 6 hours under reflux. The reaction mixture was cooled to room temperature, after which the reaction mixture was concentrated under a reduced pressure. The residue was purified by neutral silica gel column chromatography (ethyl acetate:heptane=1:10) to obtain the title compound (180 mg, 84%).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:6]3=[CH:5][C:4]=2[CH:3]=1.CN(C=O)C.N1CCCC1.[CH:32](=[O:36])[CH2:33][CH2:34][CH3:35]>CCOC(C)=O.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].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:32]([C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C:6]3=[CH:5][C:4]=2[CH:3]=1)(=[O:36])[CH2:33][CH2:34][CH3:35]
Reactant: CCCC=O
Reactant: CC(C)(C)OC(=O)N1CCn2c(cc3cc(Br)ccc32)C1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CCCC(=O)c1ccc2c(c1)cc1n2CCN(C(=O)OC(C)(C)C)C1
Temperature: 115 °C
Yield: 73 %

Procedure:
To a vial was added tert-butyl 8-bromo-3,4-dihydropyrazino[1,2-a]indole-2(1H)-carboxylate (1.4 g, 4.0 mmol), Pd(dba)2 (75 mg, 2 mol %), BINAP (75 mg, 3 mol %), and crushed 4 Å MS (2.0 g). The vial was evacuated and backfilled under argon. To the vial was then added DMF (15 mL), pyrrolidine (660 μL, 8.0 mmol), and butyraldehyde (1.0 mL, 12 mmol). The vial was then sealed under argon and heated to 115° C. for 6 h. The reaction mixture was then cooled to room temperature, diluted with EtOAc (50 mL), and filtered through celite. The filtrate was washed with H2O (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to afford a crude residue that was purified on silica gel (1:1 hexanes/EtOAc) to afford the title compound as a white solid (1.0 g, 73%).
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[N:20]4[CH:21]=[CH:22][N:23]=[C:19]4[CH:18]=[C:17]([C:24]4[CH:29]=[CH:28][C:27](N5CCOCC5)=[CH:26][CH:25]=4)[N:16]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:36](O)[CH3:37]>>[CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[N:20]4[CH:21]=[CH:22][N:23]=[C:19]4[CH:18]=[C:17]([C:24]4[CH:25]=[CH:26][C:27]([CH:37]5[CH2:36][CH2:15][N:20]([CH3:21])[CH2:19][CH2:18]5)=[CH:28][CH:29]=4)[N:16]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCO
Reactant: N#CCC(C1CCCC1)n1cc(-c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccn23)cn1
Product: CN1CCC(c2ccc(-c3cc4nccn4c(-c4cnn(C(CC#N)C5CCCC5)c4)n3)cc2)CC1
Yield: 40 %

Procedure:
3-Cyclopentyl-3-(4-(7-(4-morpholinophenyl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 113; 0.015 g, 0.032 mmol) was separated by chiral HPLC (Chiral Tech. OD-H, 2.2 cm×250 mm; 220 nm, 21 mL/min; 50% Ethanol: 50% Hexanes). Peak 1 was isolated to afford the single enantiomer 1 of 3-cyclopentyl-3-(4-(7-(4-(1-methylpiperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (6.0 mg, 40% yield). MS (apci) m/z=468.2 (M+H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:21][C:22]1([CH3:30])[CH2:27][C:26]([CH3:29])([CH3:28])[CH2:25][NH:24][CH2:23]1.[Cl-].[NH4+]>C(#N)C>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:24]2[CH2:25][C:26]([CH3:29])([CH3:28])[CH2:27][C:22]([CH3:30])([CH3:21])[CH2:23]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ncnc(Cl)c1F
Reactant: CC1(C)CNCC(C)(C)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: CC#CCOc1ncnc(N2CC(C)(C)CC(C)(C)C2)c1F
Temperature: 70 °C
Reaction time: 4 h
Yield: 72.3 %

Procedure:
Into 2 ml of acetonitrile were added 0.20 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine, 0.54 g of potassium carbonate and 0.30 g of 3,3,5,5-tetramethylpiperidine hydrochloride, and the mixture was stirred for 4 hours at 70° C. The reaction mixture was cooled to near room temperature, a saturated ammonium chloride aqueous solution was added therein, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.22 g of 4-(2-butynyloxy)-5-fluoro-6-(3,3,5,5-tetramethylpiperidino)pyrimidine (hereinafter, referred to as Compound (39)).
Reaction SMILES: NC1C=CC(CC2C=CC(OC)=C(C=2)OC2C=C(C=CC=2)C#N)=CC=1.COC(=O)[O:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[C:33]([O:39]C2C=CC=C(C#N)C=2)[CH:32]=1.CC1(C)C(C)(C)OB(C2C=CC(N)=CC=2)O1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2C=CC=CC=2)CCCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+].CN(C)C=O>[OH:39][C:33]1[CH:32]=[C:31]([CH:36]=[CH:35][C:34]=1[O:37][CH3:38])[CH:30]=[O:29]
Reactant: COC(=O)OCc1ccc(OC)c(Oc2cccc(C#N)c2)c1
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1O
Temperature: 85 °C

Procedure:
3-[5-(4-Amino-benzyl)-2-methoxy-phenoxy]-benzonitrile P-15. In an 8 mL vial equipped with a stir bar was placed (18) (250 mg, 0.798 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (192 mg, 0.878 mmol), potassium carbonate (331 mg, 2.39 mmol), 1,5-bis(diphenylphosphino)pentane (105 mg, 0.239 mmol), and dimethylformamide (4.5 mL). The mixture was degassed with nitrogen for 15 minutes and allylpalladium(II) chloride dimer (43.8 mg, 0.120 mmol) was added. The mixture was heated to 85° C. for 18 hours. The reaction mixture was filtered through celite and to the filtrate were added water (30 mL) and saturated ammonium chloride solution (30 mL). After extractions with ethyl acetate (2×75 mL), the organic portions were combined, washed with brine (50 mL), dried (MgSO4) and concentrated. The crude material was purified by silica gel column chromatography utilizing 50% ethyl acetate/hexanes to produce 118 mg (45% yield) of P-15 as a yellow viscous oil. MS (APCI+): 331.1 (M+1), LC-MS: >99%
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:13]([O-])([O-:15])=[O:14].[K+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Temperature: 12.5 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
To a solution of methyl 2,4-difluorobenzoate (50.0 g, 290.48 mmol, 1.00 equiv) in sulfuric acid (150 ml) was added a solution of potassium nitrate (35.23 g, 348.81 mmol) in sulfuric acid (30 ml) dropwise in an ice-water bath with stirring for 1 h at 0-25° C. The reaction was then quenched by the addition of ice-water. The solids were collected by filtration to afford methyl 2,4-difluoro-5-nitrobenzoate as a white solid (40.0 g, 63%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([NH:12][C:13](=[O:15])[CH3:14])[CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CN(C=O)C.O.CC(OC)(C)C>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([N:12]([C:13](=[O:15])[CH3:14])[CH2:25][CH:24]=[CH2:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(Cl)nc(NC(C)=O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: C=CCN(C(C)=O)c1cc(C(=O)OCC)cc(Cl)n1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A mixture of 6.0 g (25 mmol) 2-acetylamino-6-chloro-isonicotinic acid ethyl ester, 10.36 g (75 mmol) potassium carbonate and 4.23 ml (50 mmol) allyl bromide in 25 ml DMF is stirred at 60° C. for 24 h. The cooled mixture is diluted with water and TBME. The organic phase is washed with water, dried over Na2SO4 and evaporated. The product is purified by chromatography on silica gel (hexane/EtOAc 9/1) to yield the title compound as a yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)=[C:12]([CH3:19])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]3[N:15]=[CH:16][N:17]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=4)[CH:18]=3)=[C:12]([CH3:19])[O:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: Cc1onc(-c2ccc(F)c(F)c2)c1-c1c[nH]cn1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1-c1cn(-c2ccc(C(F)(F)F)cc2)cn1
Yield: 10 %

Procedure:
As described for Example 53, 3-(3,4-difluoro-phenyl)-4-(1H-imidazol-4-yl)-5-methyl-isoxazole (78 mg, 0.3 mmol) using 4-fluorobenzotrifluoride instead of 4-fluoroacetophenone was converted to the title compound (12 mg, 10%) which was obtained as a colourless gum. MS: m/e=406.3 [M+H]+.