Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:10](=[N:23][NH2:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:11]1([C:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:23][NH:24][C:2]2[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(Br)cn1
Reactant: NN=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(NN=C(c2ccccc2)c2ccccc2)cn1
Temperature: 120 °C
Yield: 67.7 %

Procedure:
5-Bromo-2-methoxy-pyridine (1.1 g, 5.85 mmol) in 15 mL dry toluene was treated with benzophenone hydrazone (1.25 g, 6.45 mmol), (2-Biphenyl)ditert-butylphosphine (55 mg, 0.18 mmol), sodium tert-butoxide (845 mg, 8.80 mmol), and Pd2(dba)3 (55 mg, 0.06 mmol). Heated to 120° C. in the microwave for five minutes. Extracted using EtOAc/H2O (3×100 mL EtOAc, 1×100 mL H2O, 1×100 mL brine). Dried using Na2SO4 and then purified by flash chromatography (silica, 2-10% MeOH/DCM) to afford 5-(2-(diphenylmethylene)hydrazinyl)-2-methoxypyridine (1.20 g, 3.96 mmol, 68%). 1H NMR (300 MHz, DMSO-d6) δ 8.83 (s, 1H), 8.09 (s, 1H), 7.67-7.29 (m, 11H), 6.70 (d, 1H), 3.77 (s, 3H); LC-MS (ESI) m/z 304 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:6](=[O:12])[CH:7]=[CH:8][C:9](=[O:11])[CH:10]=1)[CH:2]=[CH2:3].[CH3:13][C:14]1([CH3:22])[C:19]([CH:20]=[CH2:21])=[CH:18][CH2:17][CH2:16][CH2:15]1>CO>[CH2:1]([O:4][C:5]1[C:6](=[O:12])[C:7]2[C:8](=[CH:21][CH:20]=[C:19]3[C:18]=2[CH2:17][CH2:16][CH2:15][C:14]3([CH3:22])[CH3:13])[C:9](=[O:11])[CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCOC1=CC(=O)C=CC1=O
Reactant: C=CC1=CCCCC1(C)C
Solvent: CO
Product: C=CCOC1=CC(=O)c2ccc3c(c2C1=O)CCCC3(C)C
Yield: 36 %

Procedure:
2-Allyloxy-1,4-benzoquinone (10.0 g, 60.9 mM) and 6,6-Dimethyl-1-Vinylcyclohexene (19.8 g, 183 mM) were dissolved in 100 ml of MeOH, and refluxed for 3 hours. 3-Allyloxy-8,8-dimethyl-5,6,7,8-tetrahydro-1,4-phenanthrenequinone (6.5 g, 22.0 mM) was obtained in the same manner as in Example 1.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[C:5]([C:12]2[O:16][CH:15]=[N:14][CH:13]=2)[CH:4]=1.[H-].[Na+].[CH:21]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.[Cl-].[NH4+]>CN(C=O)C>[CH:21]1([C:24]([N:9]2[C:10]3[C:6](=[C:5]([C:12]4[O:16][CH:15]=[N:14][CH:13]=4)[CH:4]=[C:3]([C:2]([F:17])([F:1])[F:18])[CH:11]=3)[CH:7]=[CH:8]2)=[O:25])[CH2:23][CH2:22]1
Reactant: O=C(Cl)C1CC1
Reactant: FC(F)(F)c1cc(-c2cnco2)c2cc[nH]c2c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: O=C(C1CC1)n1ccc2c(-c3cnco3)cc(C(F)(F)F)cc21
Reaction time: 0.33 h

Procedure:
To a solution of 5-(6-(trifluoromethyl)-1H-indol-4-yl)oxazole (50.0 mg) in DMF (1 mL) was added 60% sodium hydride (9.52 mg) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added cyclopropanecarbonyl chloride (22 μL) at 0° C., and the mixture was stirred for 3 hr, saturated aqueous ammonium chloride solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (30.0 mg).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2C)[CH2:12][CH2:11]1.[C:25]([O:28]CC)(=[O:27])C.Cl>C(O)C>[O:2]=[C:3]1[CH:8]=[CH:7][NH:6][CH:5]=[C:4]1[CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]3[O:27][CH2:25][O:28][C:19]=23)[CH2:12][CH2:11]1
Reactant: COc1ccncc1CN1CCC(CCc2ccccc2C)CC1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCO
Product: O=c1cc[nH]cc1CN1CCC(CCc2cccc3c2OCO3)CC1

Procedure:
259 mg of 1-[(4-methoxy-3-pyridinyl)methyl]-4-[2-(2-methylphenyl)ethyl]piperidine was dissolved in 5 ml of ethanol. To the mixture was added 1.91 ml of a hydrogen chloride-ethyl acetate solution, followed by heating under reflux overnight. The solvent was evaporated, and to the residue was added a 2N hydrochloric acid (15 ml), followed by heating under reflux for further 7 hours. A sodium carbonate aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The crude product was purified by NH-silica gel column chromatography (n-hexane:ethyl acetate=2:1), to give 42 mg of the title compound as a white powder.
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:30]([C:33]2[C:34]([CH3:39])=[N:35][O:36][C:37]=2[CH3:38])(=[O:32])=[O:31])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:48]>O1CCOCC1>[ClH:48].[CH3:39][C:34]1[C:33]([S:30]([N:16]([CH2:15][C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][CH2:7][C:6]([OH:40])=[O:5])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:22][CH:23]=2)(=[O:31])=[O:32])=[C:37]([CH3:38])[O:36][N:35]=1
Reactant: Cc1noc(C)c1S(=O)(=O)N(Cc1ccc(-c2ncccn2)cc1)Cc1cccc(OCC(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: Cc1noc(C)c1S(=O)(=O)N(Cc1ccc(-c2ncccn2)cc1)Cc1cccc(OCC(=O)O)c1

Procedure:
The title compound was prepared following the method described in Example 3, Step C from (3-{[(3,5-dimethyl-isoxazole-4-sulfonyl)-(4-pyrimidin-2-yl-benzyl)-amino]-methyl}-phenoxy)-acetic acid tert-butyl ester of Step A. The HCl salt was prepared by treating the TFA salt with HCl in dioxane (4M) as described in Step C of Example 13i. 1H NMR (400 MHz, CDCl3) δ 8.92 (d, 1H, J=4.1 Hz), 8.25 (d, 1H, J=2.9 Hz), 7.55 -6.71 (m, 8H), 6.62 (m, 1H), 4.55 (s, 2H), 4.52 (s, 2H), 4.45 (s, 2H), 2.62 (s, 3H), 2.43 (s, 3H); MS 507 (M−1).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([CH2:11][C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1.CN(C)CCN(C)C.ICCCCI.[Cl-].[NH4+]>O1CCCC1>[Br:6][C:7]1[CH:15]=[C:14]2[C:10]([C:11]3([CH2:4][CH2:3][CH2:2][CH2:1]3)[C:12](=[O:16])[NH:13]2)=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: O=C1Cc2ccc(Br)cc2N1
Agent: CN(C)CCN(C)C
Agent: ICCCCI
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C1Nc2cc(Br)ccc2C12CCCC2
Temperature: -20 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
n-Butyl lithium (2.5 M in hexanes, 3.8 mL, 9.5 mmol) was added dropwise over 30 minutes to a stirred suspension of 6-bromoindolin-2-one (preparation 1, 1.00 g, 4.7 mmol) and N,N,N′,N′-tetramethylethylenediamine (1.42 mL, 9.4 mmol) in tetrahydrofuran (20 mL) at −78° C. The mixture was stirred for 1 hour, then 1,4-diiodobutane (3.11 mL, 23.6 mmol) was added dropwise over 5 minutes. The mixture was warmed to −20° C. over a 1 hour period, was stirred for a further hour at this temperature and was then warmed to room temperature. After 3 hours stirring at room temperature, saturated aqueous ammonium chloride solution was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (10:1 hexanes/ethyl acetate) gave the title compound (0.57 g, 45%) as a pale pink solid.
Reaction SMILES: CN1CCOCC1.Cl[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:10].[NH2:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:25][C:26]([NH:28][CH:29]([CH3:40])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=1)=[O:27].O>C(Cl)Cl>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:9]([NH:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH:21]2[CH2:25][C:26]([NH:28][CH:29]([CH3:40])[CH2:30][O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)=[O:27])=[O:10])=[CH:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CC(COc1ccc(C#N)cc1)NC(=O)CC1CCCC1N
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CC(COc1ccc(C#N)cc1)NC(=O)CC1CCCC1NC(=O)Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 33.1 %

Procedure:
0.4 g of N-methylmorpholine, and subsequently 0.8 g of 4-chlorophenyl chloroformate were added to a suspension containing 1.2 g of 2-amino-N-[2-(4-cyanophenoxy)-1-methylethyl]cyclopentylacetic acid amide suspended in 40 ml of methylene chloride at -15° C. The mixture was allowed to sit and warm naturally to room temperature and stirred for 15 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed with water, the organic layer was dried over anhydrous magnesium sulfate and then the methylene chloride was removed under reduced pressure. The residue was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of colorless grains (yield: 30%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]=O)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][OH:13].C([O-])(=O)C.[NH4+]>CO.O>[Cl:1][C:2]1[C:7]([F:8])=[C:6]([CH:9]=[N:12][OH:13])[CH:5]=[CH:4][N:3]=1
Reactant: NO
Reactant: O=Cc1ccnc(Cl)c1F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: ON=Cc1ccnc(Cl)c1F
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-3-fluoro-pyridine-4-carbaldehyde (1.20 g, 5.64 mmol) in MeOH (48 mL) and water (8 mL) were added hydroxylamine hydrochloride (0.59 g, 8.46 mmol) and ammonium acetate (1.30 g, 16.9 mmol), and stirring was continued at RT overnight. The reaction mixture was concentrated in vacuo, and the residue was suspended in CH2Cl2/MeOH 9:1. The precipitate was filtered off, washed with CH2Cl2 and dried to afford the title compound as a white solid. MS (LC/MS): 175.0 [M+H]+; tR (HPLC conditions b): 2.78 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:28])[N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].BrN1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.ClC1C=CC=C(Cl)C=1N1C2C(=C(C3C=CC(F)=CC=3F)C=C(OC)C=2)C=CC1=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[C:14]2[C:9]=1[CH:10]=[CH:11][C:12](=[O:28])[N:13]2[C:20]1[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)CC2
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: COc1cc(-c2ccc(F)cc2F)c2ccc(=O)n(-c3c(Cl)cccc3Cl)c2c1
Agent: O=C1CCC(=O)N1Br
Product: COc1cc(-c2ccccc2Cl)c2ccc(=O)n(-c3c(Cl)cccc3Cl)c2c1

Procedure:
5-(2-Chlorophenyl)-1-(2,6-dichlorophenyl)-7-methoxy-2(1H)-quinolinone was prepared from 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3,4-dihydro-7-methoxy-2(1H)-quinolinone (INTERMEDIATE 6), N-bromosuccinimide, and 2,2′-azobis(2-methylpropionitrile) by a procedure analogous to that described in INTERMEDIATE 4. Mass spectrum (ESI) 430.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 7.53-7.62 (m, 3H); 7.30-7.49 (m, 5H); 6.77 (d, J=2.0 Hz, 1H); 6.61 (d, J=9.5 Hz, 1H); 6.03 (d, J=2.5 Hz, 1H); 3.74 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[C:15]([N:22]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CCOCC>[OH:27][C:24]1([C:2]2[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:25][CH2:26][N:22]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: COc1ccc(Br)cn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: COc1ccc(C2(O)CCN(C(=O)OC(C)(C)C)C2)cn1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
5-bromo-2-methoxypyridine (324 μL, 2.50 mmol) was added dropwise to a stirred suspension of n-butyllithium (1.72 mL of a 1.6 M hexanes solution, 2.75 mmol) in ether (10.0 mL) at −78° C. After 10 min, a solution of N-Boc-3-pyrrolidinone (463 mg, 2.50 mmol) in ether (2.00 mL) was added dropwise, and the reaction mixture was allowed to stir at −78° C. After 2 h, the reaction was quenched with satd. aq. NH4Cl and extracted with EtOAc. The combined organics were washed with brine, dried (sodium sulfate) and concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 10%-80% EtOAc/hexanes as eluent) afforded the title compound i-6a. m/z (ES) 295 (MH)+. 1HNMR (500 MHz, CDCl3): δ 831 (s, 1H), 7.71 (d, 1H, J=7.1 Hz), 6.79 (dd, 1H, J=12, 8.6 Hz), 3.97 (s, 3H), 3.40-3.80 (m, 4H), 2.25 (m, 2H), 1.51 (s, 9H).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11]>C(Cl)Cl.O>[CH2:1]([NH:8][S:10]([CH3:9])(=[O:12])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccccc1

Procedure:
18.27 g of benzylamine were dissolved in 100 ml of methylene chloride and, while cooling with ice, 6.00 ml of methanesulfonyl chloride were very slowly added dropwise. On completion of addition of the methanesulfonyl chloride, the reaction solution was diluted with 100 ml of water, and the aqueous phase was extracted again with 50 ml of methylene chloride. The combined organic phases were washed with 1 N aqueous hydrochloric acid, dried over MgSO4 and concentrated by rotary evaporation. This gave the product (14.40 g) with a molecular weight of 185.3 g/mol (C8H11NO2S).
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl.Cl[CH2:45][C:46]1[N:50]([CH3:51])[N:49]=[N:48][CH:47]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:45][C:46]3[N:50]([CH3:51])[N:49]=[N:48][CH:47]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Reactant: Cn1nncc1CCl
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Cl
Product: Cn1nncc1Cn1nnc2c(N3CC4(COC4)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-1,2,3-triazole hydrochloride and isolated as white solid. MS(m/e): 370.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:14]=[CH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])=O>>[F:25][C:24]([F:26])([F:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16]1[N:3]2[N:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[N:1]=[CH:14][CH:15]=1
Reactant: CN(C)C=CC(=O)c1ccccc1C(F)(F)F
Reactant: CCOC(=O)c1c[nH]nc1N
Product: CCOC(=O)c1cnn2c(-c3ccccc3C(F)(F)F)ccnc12

Procedure:
As for Example 1, ethyl 3-aminopyrazole-4-carboxylate is reacted with 3-dimethylamino-2'-(trifluoromethyl)acrylophenone to give the product as crystals, m.p. 148°-149° C.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][C:4]([NH:6][C:7]1[C:15]([C:16]2C=NC=[CH:20][CH:21]=2)=[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1)=[O:5].C(/B(O)O)=C\C>>[CH3:1][C:2]([CH3:22])([CH3:23])[CH2:3][C:4]([NH:6][C:7]1[C:15](/[CH:16]=[CH:21]/[CH3:20])=[C:10]2[N:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1)=[O:5]
Reactant: CC(C)(C)CC(=O)Nc1nn2cccnc2c1-c1cccnc1
Agent: C/C=C/B(O)O
Product: C/C=C/c1c(NC(=O)CC(C)(C)C)nn2cccnc12

Procedure:
The product from Example 110B and trans-1-propen-1-ylboronic acid were processed using the method analogous to that described in Example 110C to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.99-10.02 (bs, 1H), 8.99 (dd, J=6.9, 1.7 Hz, 1H), 8.54 (dd, J=4.1, 1.7 Hz, 1H), 7.02 (dd, J=6.9, 4.1 Hz, 1H), 6.63 (dq, J=15.8, 6.6 Hz, 1H), 6.31 (dd, J=15.9, 2.0 Hz, 1H), 2.26 (s, 2H), 1.85 (dd, J=6.6, 1.7 Hz, 3H), 1.06 (s, 9H); MS (ESI) m/z 273 (M+H)+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[C:20]1B(O)O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[S:19]1[C:20]([C:16]2[CH:15]=[CH:14][N:13]=[C:12]([NH:11][C:9]3[CH:8]=[CH:7][C:6]4[O:1][CH2:2][CH2:3][O:4][C:5]=4[CH:10]=3)[CH:17]=2)=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]1=2
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Reactant: OB(O)c1cc2ccccc2s1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: c1ccc2sc(-c3ccnc(Nc4ccc5c(c4)OCCO5)c3)cc2c1
Temperature: 150 °C

Procedure:
Following the same procedure described for Example 401(c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401(b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), benzothiophene-2-boronic acid (Frontier Scientific, Inc.) (45 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150° C. for 10 min and purification on a Biotage 40S column (4:1 hexane:EtOAc), the title compound as a light-yellow solid. MS (ESI, pos. ion) m/z: 361 (M+1). Mp: 154.0-154.1° C.
Reaction SMILES: [N:1]1([C:7](=[O:11])[CH2:8][C:9]#[N:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:12]>[Pt].CO>[ClH:12].[NH2:10][CH2:9][CH2:8][C:7]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:11]
Reactant: N#CCC(=O)N1CCOCC1
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: NCCC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 80.5 %

Procedure:
A nitrogen inerted reactor is charged with 5% Pt-C (43 g; 58% water-wet) followed by 3-morpholin-4-yl-3-oxo-propionitrile (2.8 mol). A solution of MeOH (3.4 L) and 12N HCl (3.08 mol) is added at such a rate as to maintain an internal temperature of ca. 25° C. The vessel and its contents are degassed via three N2 pressure purges (50 psi). The atmosphere is switched to hydrogen via three H2 pressure purges (50 psi), and the reaction is stirred vigorously at ca. 25° C. under a sustained pressure of hydrogen (50 psi) for ca. 24 hours. The H2 pressure is released and replaced with N2. The reaction is passed through filter agent, which is subsequently washed with MeOH (500 mL). The reaction is concentrated in vacuo to a volume of ca. 1.4 L, and IPA (2.2 L) is added. The reaction mixture is cooled to 0° C. and filtered. The filter cake is washed with MtBE (500 mL) and dried under vacuum at ca. 30° C. to provide 3-amino-1-morpholin-4-yl-propan-1-one, hydrochloride as a white solid (439 g). This material is used in subsequent steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH3:12].NC1C=CC(C#N)=C2C=1C=CC(C)(C)O2>>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[NH2:9]
Reactant: Cc1cc(Cl)c(C)c([N+](=O)[O-])c1
Agent: CC1(C)C=Cc2c(N)ccc(C#N)c2O1
Product: Cc1cc(N)c(C)c(Cl)c1
Yield: 94.2 %

Procedure:
The title compound (1.70 g) was prepared from 21A (2.15 g, 11.6 mmol) in a manner similar to that described in Experiment 6C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([Cl:8])=[N:6][CH:7]=1.[Cl-].[C:11]([O:15][C:16](=[O:19])[CH2:17][Zn+])([CH3:14])([CH3:13])[CH3:12].CCOCC>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].CC(P(C(C)(C)C)[C-]1C=CC=C1)(C)C.C1C=CC([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)=CC=1.[Fe+2].C1COCC1>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([CH2:17][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:19])=[CH:3][C:4]=1[CH3:9]
Reactant: CC(C)(C)OC(=O)C[Zn+]
Reactant: Cc1cc(Br)cnc1Cl
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)cnc1Cl
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a sealed tube was added 5-bromo-2-chloro-3-methylpyridine 86-4 (4.69 g, 22.72 mmol), 0.5 M (2-tert-butoxy-2-oxoethyl) zinc(II) chloride in ether 86-5 (50 mL, 25 mmol), Pd(dba)2 (262 mg, 0.45 mmol), Q-phos (320 mg, 0.45 mmol), and THF (75 mL). The reaction mixture was bubbled with nitrogen for 1 minute and stirred at 70° C. for 4 hours. After cooling to room temperature, all the solvents were evaporated and the residue was redissolved in ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to dryness by rotary evaporation. The crude product was purified by silica gel flash chromatography and eluted with 20% ethyl acetate in hexane to give tert-butyl 2-(6-chloro-5-methylpyridin-3-yl)acetate 86-6 as red oil. MS m/z 242.1 (M+1)
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C@H:6]([C:18]2[CH:23]=[CH:22][C:21](F)=[CH:20][C:19]=2[Cl:25])[N:7]=[C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[NH:9][C:10]=1[CH2:11][Br:12])=[O:4].[C:26](OCC)(=O)CC(C)=O.ClC1C=CC=CC=1C=O.ClC1C=C(F)C=CC=1C=O>>[Br:12][CH2:11][C:10]1[NH:9][C:8]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:7][C@@H:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])[C:5]=1[C:3]([O:2][CH2:1][CH3:26])=[O:4]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: CCOC(=O)CC(C)=O
Agent: O=Cc1ccc(F)cc1Cl
Agent: O=Cc1ccccc1Cl
Product: CCOC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccccc1Cl

Procedure:
The title compounds were prepared in analogy to Example 86 starting from methyl 2-(6-fluoro-3-oxa-9-azabicyclo[3.3.1]nonan-7-yl)acetate 100a (100 mg) and ethyl (4R)-6-(bromomethyl)-4-(2-chloro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 102a (215 mg). The crude product was purified by silica gel chromatography first, and then by preparative HPLC to give Example 102 (27 mg), and Example 103 (21 mg). Ethyl (4R)-6-(bromomethyl)-4-(2-chloro-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidine-5-carboxylate 102a was prepared in analogy to compound C with procedures shown in Example 1 by using ethyl acetoacetate and 2-chloro-benzaldehyde instead of methyl acetoacetate and 2-chloro-4-fluoro-benzaldehyde in the three component reaction.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.[CH3:28][N:29](C)C=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.[C-]#N.[Zn+2].[C-]#N>[C:28]([C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])#[N:29]
Reactant: CCOC(=O)c1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1Cl
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1C#N
Temperature: 150 °C
Reaction time: 4 h

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (691 mg, 0.592 mmol) and zinc cyanide (402 mg, 3.25 mmol) were added to a solution of ethyl 7-chloro-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-carboxylate (1.1 g, 2.96 mmol) in N,N-dimethylformamide (10 mL), followed by stirring at 150° C. for four hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, and the residue was purified by silica gel column chromatography (15% ethyl acetate/hexane), to give the title compound (1 g).