Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:7][C:8]([NH2:12])=[N:9][C:10]=1[CH3:11].[CH:19]([C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:23][CH:22]=1)=O.C(O)(=O)C.[BH4-].[Na+]>C1COCC1.CO>[NH2:12][C:8]1[N:9]=[C:10]([CH3:11])[C:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:19][C:21]2[CH:22]=[CH:23][C:24]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:25][CH:26]=2)=[C:6]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[N:7]=1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: CCCCCNc1nc(N)nc(C)c1CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCCNc1nc(N)nc(C)c1CCCNCc1ccc(CC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.8 %

Procedure:
The product from Example 1 step (v) (0.3 g) and methyl 2-(4-formylphenyl)acetate (0.213 g) were combined in THF (20 mL), acetic acid (0.072 g) was added and the reaction mixture stirred at rt for 16 h. Sodium borohydride (0.0677 g) and MeOH (3 drops) were added and the reaction mixture stirred for 72 h. The solvents were evaporated and the product dissolved in MeOH and purified by RPHPLC to give the title compound 0.3 g.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=2)=[O:21])[C:5](=[O:19])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:7]=1[CH3:8].[CH3:34][C:35]1[C:39]([Sn](CCCC)(CCCC)CCCC)=[CH:38][O:37][N:36]=1.C(OCC)(=O)C.O>COCCOC.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>[CH3:8][C:7]1[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:5](=[O:19])[C:4]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][CH:25]=2)=[O:21])=[CH:3][C:2]=1[C:39]1[C:35]([CH3:34])=[N:36][O:37][CH:38]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1conc1C
Reactant: Cc1c(I)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1nocc1-c1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 100 °C
Reaction time: 24 h

Procedure:
5-Iodo-6-methyl-N-[4-(methylsulfonyl)benzyl]-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (25 mg, 0.042 mmol), tetrakis(triphenylphosphine)palladium (2.5 mg, 0.0022 mmol) and 3-methyl-4-(tributylstannyl)isoxazole [synthesized as described by D. Uchiyama in Heterocycles, 43, 6, 1301, 1996] (32 mg, 0.086 mmol) were mixed in DME (0.45 ml) in an argon filled vial. The vial was closed and heated with stirring at 100° C. for 24 h. The reaction mixture was poured into a mixture of ethyl acetate and water. The mixture was shaken, the water phase was removed and the organic phase was dried over sodium sulphate. The product was purified by preparative HPLC. Yield: 12 mg, 0.022 mmol (52%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](=[NH:36])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:36]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:16]=2)[CH2:10][C@@H:9]1[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: C[C@H]1C[C@@H](Oc2cccc(Br)c2)CCN1C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: C[C@H]1C[C@@H](Oc2cccc(N=C(c3ccccc3)c3ccccc3)c2)CCN1C(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
Heat a mixture of 4-(3-bromo-phenoxy)-cis-2-methyl-piperidine-1-carboxylic acid tert-butyl ester isomer 2 (preparation 23, 0.759 g), benzhydrylideneamine (0.446 g), racemic-2,2′-bis(diphenylphosphino)-1,1′ binaphthyl (50 mg) and sodium t-butoxide (0.269 g) in toluene (20 mL) at 100° C. After 10 min., add tris(dibenzylidineacetone)-dipalladium(0) (37 mg) and heat at 100° C. After 2.5 hr., partition between ethyl acetate-hexane (1:4) and saturated aqueous NaCl, dry over anhydrous sodium sulfate, evaporate and purify on a 35 g silica gel column eluting with dichloromethane-2M NH3 in methanol gradient to give the crude title compound (0.74 g). Mass spectrum (electrospray) m/z 471 (M+1).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[N:8]=1.N.S(=O)(=O)(O)[OH:23]>>[F:20][C:2]([F:1])([F:19])[CH2:3][N:4]=[C:5]([NH2:18])[NH:6][C:7]1[N:11]=[CH:10][N:9]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH2:17])=[O:23])[N:8]=1
Reactant: O=S(=O)(O)O
Reactant: N#CCCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Agent: N
Product: NC(=O)CCCCn1cnc(NC(N)=NCC(F)(F)F)n1
Yield: 54 %

Procedure:
A solution of 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeronitrile (0.15 g.) in concentrated sulphuric acid (3 ml.) was stirred for 1.5 hours at room temperature then poured onto ice and basified with concentrated aqueous ammonia. Extraction with EtOAc gave 0.12 g. of a white solid which was triturated with ether to give 5-[3-(2-[2,2,2-trifluoroethyl]guanidino)-1,2,4-triazol-1-yl]valeramide (0.085 g., 54%), m.p. 162°-164°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH2:18])[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)[CH3:6].[F:21][C:22]1[CH:23]=[C:24]2[C:29](=[C:30]([F:32])[CH:31]=1)[CH2:28][C:27](=O)[CH2:26][CH2:25]2>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][CH:5]([N:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:19])[CH:14]([NH:18][CH:27]2[CH2:26][CH2:25][C:24]3[C:29](=[C:30]([F:32])[CH:31]=[C:22]([F:21])[CH:23]=3)[CH2:28]2)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]1)[CH3:6]
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Reactant: CCCC(N)C(=O)Nc1cn(C(C)CC(=O)OC)cn1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)CC(=O)OC)cn1

Procedure:
3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-butyric acid methyl ester was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: MS m/z 449.3 (M+1).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([CH3:19])[O:7][C@@H:6]1[N:20]=[N+]=[N-])(=[O:3])[CH3:2]>CCOC(C)=O.[Pd]>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([CH3:19])[O:7][C@@H:6]1[NH2:20])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](N=[N+]=[N-])[C@H]1OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)O[C@H](N)[C@H]1OC(C)=O
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 2,3,4-Tri-O-acetyl-beta-L-fucopyranosyl azide (Acros) (750 mg, 2.38 mmol) in 40 mL of EtOAc was added 120 mg of 10% Pd/C. This solution was stirred under an atmosphere of hydrogen gas (1 atm) for 3 hours. The mixture was filtered through a pad of Celite® and the pad was washed with EtOAc (25 mL). The solution was evaporated to afford the desired amine 148 (688 mg, 100%).
Reaction SMILES: [CH2:1]([S:11][CH2:12][CH2:13][OH:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)C(C)C)(C)C>CS(C)=O.C(Cl)Cl>[CH2:1]([S:11][CH2:12][CH:13]=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCSCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCCCCCCCCCSCC=O
Temperature: -40 °C
Reaction time: 0.25 h

Procedure:
Under nitrogen, 2-(decylthio)ethanol (50 g, 230 mmol), N,N-diisopropylethylamine (128 ml, 730 mmol) and methylene chloride (400 ml) were cooled to −40° C. To this solution was added, over 15 minutes, a solution of sulfur trioxide pyridine complex (116 g, 730 mmol) in dimethyl sulfoxide (600 ml) and methylene chloride (200 ml). After addition, the mixture was stirred a further 15 minutes at −40° C., then 600 ml ice water as added. The mixture was removed from the cooling bath, 1 L water was added, and the liquids partitioned. The organic phase was washed with 1 L of 1 N hydrochloric acid, and dried over magnesium sulfate. Filtration gave 600 ml liquid, which was diluted with 600 ml hexane and passed through 200 ml silica. The silica was washed with 100 ml 50% methylene chloride/hexane, then 300 ml methylene chloride. The combined organics were concentrated in vacuo to give 2-decylthio)acetaldehyde (48 g, 220 mmol) as a colorless liquid that was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[CH2:3]1.[H-].[Na+].F[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>CN(C=O)C>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH2:3]1
Reactant: N#Cc1cccc(F)c1
Reactant: CN1CCC(CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCC(COc2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(1-Methylpyrrolidin-3-yl)methanol (0.500 g, 4.34 mmol) was dissolved in dry DMF (8 mL), cooled (<0° C.), NaH (0.260 g, 6.51 mmol, 55% in oil) added and stirred for 30 minutes. 3-Fluorobenzonitrile (0.552 g, 4.56 mmol) was added and the reaction mixture allowed to warm to r.t. over 1 h. Due to excessive foaming the reaction mixture was diluted with dry DMF to 20 mL and stirred over night at r.t. The reaction was quenched by addition of water portionwise, and the mixture was extracted with DCM. The organic phase was dried over a phase separator and concentrated in vacuo. The product was purified by flash chromatography using a step gradient of EtOAc:MeOH:TEA (100:10:2) in EtOAc to give the title compound as an oil. Yield: 0.573 g (58%). 1H NMR (400 MHz, CDCl3) δ 7.30-7.35 (m, 1H), 7.18-7.22 (m, 1H), 7.09-7.12 (m, 1H), 7.07-7.09 (m, 1H), 3.86 (d, 2H, J=6.95 Hz), 2.54-2.67 (m, 3H), 2.40-2.51 (m, 2H), 2.33 (s, 3H), 2.00-2.10 (m, 1H), 1.51-1.61 (m, 1H).
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[N:15]([CH3:53])[C:16]([CH2:18][O:19][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[N:27](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:26]4=[O:50])=[CH:22][CH:21]=3)=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CO>[OH:8][C:9]1[N:14]=[C:13]2[N:15]([CH3:53])[C:16]([CH2:18][O:19][C:20]3[CH:52]=[CH:51][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[NH:27][C:26]4=[O:50])=[CH:22][CH:21]=3)=[N:17][C:12]2=[CH:11][CH:10]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(OCc3ccccc3)nc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(O)nc21
Yield: 15.5 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 1.20 g of 5-{4-(5-benzyloxy-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 95), 1.80 g of 10% w/w palladium-on-charcoal and 50 ml of methanol were used, and that the product was purified by column chromatography through silica gel, using a gradient elution method, with mixtures of ethyl acetate and methanol in ratios ranging from 1:0 to 10:1 by volume as the eluent, to give 0.10 g of the title compound, melting at 240°-242° C.
Reaction SMILES: [Br:1][C:2]1[S:12][C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([NH2:10])[C:4]=2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.CC(C)([O-])C.[Na+].[CH:27]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28]1.CN(C=O)C>C1COCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[S:12][C:5]2=[N:6][C:7]([CH3:11])=[CH:8][C:9]([NH:10][S:30]([CH:27]3[CH2:29][CH2:28]3)(=[O:32])=[O:31])=[C:4]2[C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(N)c23)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)C4CC4)c23)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 32.3 %

Procedure:
To a stirred solution of 2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-amine (Description 17) (303 mg, 0.868 mmol) in THF (5 mL) at RT, was added sodium tert-butoxide (214 mg, 2.227 mmol). The reaction mixture was stirred at RT for 15 min, followed by the addition of cyclopropanesulfonyl chloride (0.16 mL, 1.74 mmol). The reaction mixture was stirred at RT for 1.5 h, followed by the sequential of addition of DMF (2.5 mL), sodium tert-butoxide (202 mg) and cyclopropanesulfonyl chloride (0.16 mL, 1.741 mmol). The reaction mixture was stirred at RT for another 1.5 h, followed by the addition of water (25 mL) and ethyl acetate (25 mL). The aqueous layer was separated and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed with water (15 mL), dried (phase separating column) and concentrated to give a residue, which was purified on silica, eluting with a gradient of 0-75% ethyl acetate in cyclohexane, to give a residue (127 mg). Ca. 45 mg of this material was purified further by MDAP (acidic conditions) followed by trituration with diethyl ether, to give the title compound (9 mg). LCMS (A) m/z: 453/455 [M+1]+, Rt 1.50 min (acidic).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH2:26][CH3:27])=[CH:20][C:21](OCC)=[O:22])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:21](=[O:22])[CH:20]=[C:19]([CH2:26][CH3:27])[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C=C(CC)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: [Na]
Solvent: CC(C)O
Product: CCc1cc(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)[nH]1

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-ethylvinyl]ureido}-benzoate with sodium isopropylate in isopropanol there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-ethyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 121°-124° C.,
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][O:34][C:35]([C:37]1[CH:42]=[CH:41][C:40](B(O)O)=[CH:39][CH:38]=1)=[O:36].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:33][O:34][C:35](=[O:36])[C:37]1[CH:42]=[CH:41][C:40]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([C:12]([N:9]4[CH2:8][CH2:7][N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[CH2:11][CH2:10]4)=[O:13])=[CH:22][CH:21]=3)[CH:17]=[C:18]2[C:23]([N:25]2[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]2)=[O:24])=[CH:39][CH:38]=1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)cc1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 4-methoxycarbonylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (67%).
Reaction SMILES: [O-2].[Mg+2].[CH:3](O)=[O:4].C(OC(=O)C)(=O)C.[NH2:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][C:16]([OH:18])=O>>[CH:3]([NH:13][C@@H:14]1[C:19](=[O:20])[O:21][C:16](=[O:18])[CH2:15]1)=[O:4]
Reactant: O=CO
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(=O)OC(C)=O
Product: O=CN[C@H]1CC(=O)OC1=O
Reaction time: 0.21 h

Procedure:
Magnesium oxide (0.121 grams; 0.003 mole) was dissolved in 19.3 grams (0.4 mole) of 95% formic acid under nitrogen. Acetic anhydride (69.3 grams; 0.655 mole) was then added to the solution which was stirred for 10-15 minutes. The temperature of the mixture rose to 40° C. L-aspartic acid (39.93 grams; 0.30 mole) was added to the mixture and the resulting slurry was stirred at about 50° C. for about 6 hours. N-formyl-L-aspartic anhydride was formed at this point as shown by high performance liquid chromatography (HPLC). The mixture was then filtered and washed with 30 grams of acetic acid in order to isolate the N-formyl-L-aspartic anhydride. The yield of the N-formyl-L-aspartic anhydride from the L-aspartic acid was 80%. The N-formyl-L-aspartic anhydride will include some acetic acid, which remains for use as a solvent in the coupling step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:10]2[N:15]=[C:14]([O:16][CH3:17])[N:13]=[C:12]([NH:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[F:31])[CH:11]=2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[F:31][C:22]1[CH:23]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][NH:18][C:12]1[N:13]=[C:14]([O:16][CH3:17])[N:15]=[C:10]([C:6]2[CH:5]=[C:4]([CH2:3][CH2:2][NH:1][C:39](=[O:41])[CH3:40])[CH:9]=[CH:8][CH:7]=2)[CH:11]=1
Reactant: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(CCN)c2)n1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(CCNC(C)=O)c2)n1
Reaction time: 0.17 h

Procedure:
A solution of {6-[3-(2-amino-ethyl)-phenyl]-2-methoxy-pyrimidin-4-yl}-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine [150 mg, 0.35 mmol, see Example 64, step 2] and triethylamine (0.24 mL, 1.73 mmol) in DCM (5 mL) is treated with acetyl chloride (54 mg, 0.69 mmol) at 10° C. After 10 min at 10° C., the mixture is quenched with aqueous NaHCO3 solution (8 mL), and filtered through Chem-Elut with CH2Cl2 washing (10 mL). The filtrate is concentrated, and subjected to chromatography on silica gel eluting with 80% EtOAc in Heptane to 5% MeOH in CH2Cl2 to give N-[2-(3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-ethyl]-acetamide, which is treated with saturated solution of hydrogen chloride in EtOAc followed by lyophilization to afford N-[2-(3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-ethyl]-acetamide hydrochloride [70 mg, Example 65]. LCMS: RT=2.2 minutes, MS: 477 (M+H); 1H NMR (300 MHz, CDCl3) □9.1 (1H, s), 7.95 (1H, brs), 7.7-7.4 (7H, m), 6.65 (1H, s), 4 (3H, s), 3.8-3.75 (2H, m), 3.3 (2H, q, J=6.9 Hz), 3.04 (2H, t, J=6.6 Hz), 2.78 (2H, t, J=7.5 Hz), 2.49 (3H, s). IC50=37 nM
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16](B4OC(C)(C)C(C)(C)O4)[C:15]=3[CH3:29])[CH2:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:31]1[CH:32]=[C:33]([NH:46][C:47]2[CH:51]=[C:50]([CH:52]3[CH2:54][CH2:53]3)[NH:49][N:48]=2)[C:34](=[O:45])[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:36]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([C:5]1[S:6][C:7]2[C:12](=[O:13])[N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:31]4[CH:32]=[C:33]([NH:46][C:47]5[CH:51]=[C:50]([CH:52]6[CH2:53][CH2:54]6)[NH:49][N:48]=5)[C:34](=[O:45])[N:35]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[N:36]=4)[C:15]=3[CH3:29])[CH2:10][C:8]=2[N:9]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Reactant: C[Si](C)(C)CCOCn1nc(Cl)cc(Nc2cc(C3CC3)[nH]n2)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2cc(Nc3cc(C4CC4)[nH]n3)c(=O)n(COCC[Si](C)(C)C)n2)cccc1N1Cc2nc(C(C)(C)C)sc2C1=O
Yield: 68.1 %

Procedure:
Following the procedures of Example 109, 148.4 mg (0.36 mmol) of 2-tert-butyl-5-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 109f, 114.6 mg (0.3 mmol) of 6-chloro-4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one 111a, 27.5 mg (0.03 mmol) of tris(dibenzylideneacetone)dipalladium(0), 29.6 mg (0.072 mmol) of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.596 mmol), 0.71 mL (0.9 mmol) of 1.27 M of potassium phosphate in water, and 10 mL of 1,4-dioxane to afford 129 mg (68%) of 2-tert-butyl-5-(3-(5-(5-cyclopropyl-1H-pyrazol-3-ylamino)-6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,6-dihydropyridazin-3-yl)-2-methylphenyl)-4H-pyrrolo[3,4-d]thiazol-6(5H)-one 111b.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:22](C(OC(C)(C)C)=O)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=O>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:22])[C@H:10]([CH3:14])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: C[C@@H]1CN(Cc2ccccc2)CCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of (R)-1-benzyl-3-methylpiperazine (10 g, 52.6 mmol) in dichloromethane (30 mL) at room temperature was added triethylamine (10.6 g, 106 mmol) and the reaction mixture was stirred for 1 h. To the reaction mixture was added (BOC)2O (13.7 g, 62.8 mmol) and the contents were stirred for further 4 h. The reaction mixture was quenched in water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography eluting with 10% ethyl acetate in n-hexanes to afford 13.0 g of (R)-tert-butyl 4-benzyl-2-methylpiperazine-1-carboxylate.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7]Br)[C:3](Cl)=[O:4].Cl.[NH2:10][CH2:11][C:12]#[N:13].C(N(CC)CC)C.[H-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][CH:2]1[CH2:6][CH2:7][N:13]([CH2:12][C:11]#[N:10])[C:3]1=[O:4]
Reactant: N#CCN
Reactant: O=C(Cl)C(Br)CCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: N#CCN1CCC(Br)C1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.7 %

Procedure:
To a solution of 2,4-dibromobutanoyl chloride (3.6 g, 14 mmol) in DCM (100 mL) and 2-aminoacetonitrile hydrochloride (1.3 g, 14 mmol) was added triethylamine (5.7 mL, 41 mmol) at 0° C. The mixture was stirred at ambient temperature for 24 h. To the resulting material was added methylene chloride and it was washed with water and then brine. The combined organic layers were dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The resulting residue was taken up in toluene (130 mL) and at 0° C. was added sodium hydride (545 mg, 13.6 mmol, 60% in mineral oil) portion-wise over 20 minutes. The reaction was stirred at ambient temperature for 60 h. The mixture was diluted with ethyl acetate and then poured into ice water. The organic layer was separated, washed with brine, dried over sodium sulfate, and purified via flash column chromatography (ethyl acetate:hexane, 0:100 to 100:0) to provide a brown oil (730 mg, 26% yield). 1H NMR (400 MHz, CDCl3) δ 4.37-4.50 (m, 2H), 4.10-4.28 (m, 1H), 3.70 (dq, J=7.6, 2.0 Hz, 1H), 3.51-3.59 (m, 1H), 2.65-2.79 (m, J=7.0 Hz, 1H), 2.33-2.50 (m, 1H).