Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:19][NH2:20]>>[O:11]([C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:19][NH2:20])=[O:2])[CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccccc2)CC1
Reactant: NN
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](Oc2ccccc2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-phenoxy-cyclohexanecarboxylic acid methyl ester (1.07 g, 4.57 mmol) and hydrazine hydrate (0.22 g, 4.48 mmol) was heated at 120° C. for 4 h. After cooling to room temperature the reaction mixture was concentrated in vacuo to give the crude title compound as white solid in quantitative yield, which was used in the next step without further purification.
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][CH2:16][CH2:17][N:18]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([O:28][C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][CH:30]=4)[CH2:24][CH2:23]3)[CH3:19])OCC[O:11]2)=[CH:6][CH:5]=1.Cl.C(=O)(O)[O-].[Na+]>CO>[ClH:1].[ClH:1].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:11])[CH2:15][CH2:16][CH2:17][N:18]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([C:35]([F:36])([F:37])[F:38])=[CH:33][CH:34]=3)[CH2:26][CH2:27]2)[CH3:19])=[CH:6][CH:5]=1
Reactant: CN(CCCC1(c2ccc(F)cc2)OCCO1)CCN1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CN(CCCC(=O)c1ccc(F)cc1)CCN1CCC(Oc2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
A solution of 3.75 g (6.38 mmol) of 1-{2-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylamino}ethyl}-4-(4-trifluoromethylphenoxy)piperidine dihydrochloride, 55 ml of methanol, and 22.5 ml of 3N HCl was heated at reflux under nitrogen for 3 hours. The reaction mixture was allowed to cool to room temperature and was subsequently neutralized with sodium bicarbonate. The methanol was evaporated and the residue made basic with sodium carbonate. The mixture was extracted with ether, washed with saturated sodium chloride and dried over potassium carbonate. Filtration followed by evaporation of the solvent provided an oil. The dihydrochloride was recrystallized from acetonitrile to provide 1.75 g (50%) of 1-{2-{N-[4-(4-fluorophenyl)-4-oxobutyl]-N-methylamino}ethyl}-4-(4-trifluoromethyl-phenoxy)piperidine dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][N:9]([CH2:20][C:21]2[CH:22]=[C:23]([CH:35]=[CH:36][CH:37]=2)[CH2:24][N:25]2[CH:29]([C:30](O)=[O:31])[CH2:28][CH2:27][S:26]2(=[O:34])=[O:33])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[C:6]([F:38])[C:5]([O:39][CH3:40])=[CH:4][CH:3]=1.[C:41]12([NH2:51])[CH2:50][CH:45]3[CH2:46][CH:47]([CH2:49][CH:43]([CH2:44]3)[CH2:42]1)[CH2:48]2>>[C:41]12([NH:51][C:30]([C@H:29]3[CH2:28][CH2:27][S:26](=[O:33])(=[O:34])[N:25]3[CH2:24][C:23]3[CH:35]=[CH:36][CH:37]=[C:21]([CH2:20][N:9]([CH2:8][C:7]4[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]([O:39][CH3:40])[C:6]=4[F:38])[C@H:10]([CH2:16][N:17]([CH3:19])[CH3:18])[CH2:11][C:12]([CH3:14])([CH3:15])[CH3:13])[CH:22]=3)=[O:31])[CH2:48][CH:47]3[CH2:46][CH:45]([CH2:44][CH:43]([CH2:49]3)[CH2:42]1)[CH2:50]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: COc1ccc(Cl)c(CN(Cc2cccc(CN3C(C(=O)O)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Product: COc1ccc(Cl)c(CN(Cc2cccc(CN3[C@@H](C(=O)NC45CC6CC(CC(C6)C4)C5)CCS3(=O)=O)c2)[C@H](CN(C)C)CC(C)(C)C)c1F
Yield: 61.8 %

Procedure:
(R)-2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1 dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid (Intermediate 7 (Epimer 2), 0.044 g, 0.073 mmol) was reacted with 1-adamantanamine (0.013 g, 0.089 mmol) to form (R)-2-(3-{[(6-Chloro-2-fluoro-3-methoxy-benzyl)-((S)-1-dimethylaminomethyl-3,3-dimethyl-butyl)-amino]-methyl}-benzyl)-1,1-dioxo-1λ6-isothiazolidine-3-carboxylic acid adamantan-1-ylamide (Epimer 2) (0.033 g, 61%). m/z=731 (M+1); HRMS: calcd for C39H57ClFN4O4S. Calc [M+H+] 731.3768. found 731.3767.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[Cl:34][CH2:35][CH2:36][O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=O)=[CH:40][CH:39]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:42][C:41]1[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH2:35][Cl:34])=[CH:46][CH:45]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(OCCCl)cc1
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc(OCCCl)cc3)c3c(Cl)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 1-(3) and 4-(2-chloroethyloxy)benzoyl chloride were treated in a manner similar to Example 3 to give the titled compound as a colorless powder. APCI-Mass m/Z 499/501 (M+NH4). 1H-NMR (DMSO-d6) δ 3.24 (td, J=9.2, 4.1 Hz, 1H), 3.39 (td, J=8.7, 5.2 Hz, 1H), 3.43-3.47 (m, 2H), 3.62-3.69 (m, 2H), 3.91-3.93 (m, 2H), 4.19-4.21 (m, 4H), 4.53 (t, J=4.9 Hz, 1H), 5.09 (d, J=4.8 Hz, 1H), 5.15 (d, J=4.7 Hz, 1H), 5.21 (d, J=5.3 Hz, 1H), 5.39 (d, J=9.2 Hz, 1H), 6.87 (d, J=8.5 Hz, 2H), 7.02 (d, J=7.5 Hz, 1H), 7.09 (t, J=7.9 Hz, 1H), 7.15 (d, J=8.7 Hz, 2H), 7.22 (s, 1H), 7.53 (d, J=8.2 Hz, 1H).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:11]([CH2:12][CH2:13][C:14]3[C:15]4[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=32)[C@@H:18]([C@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][OH:23])[CH2:17][CH:16]=4)[C:10]1([CH3:35])[CH3:34])(C(C)(C)C)(C)C.[H-].[Na+].[CH3:38]I>CN(C=O)C>[CH3:35][C:10]1([CH3:34])[C@@H:9]([OH:8])[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@H:11]1[CH2:12][CH2:13][C:14]1[C:15]3[C@:25]([CH3:33])([CH2:26][CH2:27][C:28]=12)[C@@H:18]([C@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][O:23][CH3:38])[CH2:17][CH:16]=3
Reactant: C[C@H](CCCO)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)[C@@H]1CC3
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCC[C@@H](C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
3β-tert-Butyldimethylsilyloxy-4,4-dimethyl-5α-chola-8,14-dien-24-ol (100 mg) is methylated with sodium hydride 60% (16 mg) and methyl iodine (0.125 ml) in 1 ml of DMF. The protecting tert-butyldimethylsilyl group is split of by treatment with HCl/ethanol. After aqueous work-up and crystallisation from methanol/water, the title compound (5 mg) is isolated.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]([F:26])([F:25])[F:24])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO.O>CO.C(Cl)Cl>[F:24][C:23]([F:25])([F:26])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:27]
Reactant: CCOC(=O)C1(NC(=O)c2ccccc2C(F)(F)F)Cc2ccccc2C1
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: O=C(NC1(C(=O)O)Cc2ccccc2C1)c1ccccc1C(F)(F)F
Reaction time: 110 h
Yield: 97336.5 %

Procedure:
A 100 mL flask containing 2-(2-trifluoromethyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (324, 0.57 g, 1.5 μmol) is charged with 1,4-dioxane (9 mL) and MeOH (9 mL). A stirring bar is added and stirring is initiated. After dissolution, water (4.5 mL) is added followed by the LiOH monohydrate (160 mg, 3.81 mmol). After 110 h, tlc analysis (silica, 10% MeOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 2 by slowly adding dilute aqueous HCl (3%, ˜9 mL). The contents of the flask are poured into a separatory funnel which contains EtOAc (40 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic phases are washed with water (20 mL) and brine (20 mL), and then dried over MgSO4, filtered and concentrated by pumping to constant weight yields off white solid (0.51 g, 97%).
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[BH4-].[Na+].[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C@H:7]([O:8][C:35]([CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[O:41])[O:9][C@@H:10]4[O:16]3)[CH2:4][CH2:3]1
Reactant: O=C1CCC(=O)O1
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Agent: O=C([O-])O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [BH4-]
Solvent: C1COCCO1
Product: C[C@H]1[C@H](OC(=O)CCC(=O)O)O[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Artemisinin (500 mg) and polyhydroxy compound (dextrose, 2 g) are stirred in dioxan (15 ml) for 5 minutes. Sodium borohydride (2.4 gm) is added slowly and the reaction mixture is stirred for 2 hours at room temperature (20-30 degree C.). After completion of the reduction step succinic anhydride (250 mg) and sodium bicarbonate (3.5 g) are added and the reaction mixture is further stirred for 2 hours. After usual workup and purification of impure reaction product (650 mg), 89.6% w/w pure artesunic acid is obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11]1[N:12]([CH3:16])[N:13]=[CH:14][N:15]=1.[Li+].[BH4-]>C1COCC1>[F:10][C:8]1[CH:7]=[CH:6][C:5]([C:11]2[N:12]([CH3:16])[N:13]=[CH:14][N:15]=2)=[C:4]([CH2:3][OH:2])[CH:9]=1
Reactant: COC(=O)c1cc(F)ccc1-c1ncnn1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cn1ncnc1-c1ccc(F)cc1CO
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of 5-fluoro-2-(2-methyl-2H-1,2,4-triazol-3-yl)-benzoic acid methyl ester plus regioisomer (1.5 g, 6.38 mmol) in THF (50.0 mL) is added a solution of 2 M LiBH4 in THF (10.0 mL, 20 mmol). The reaction mixture is stirred at room temperature for 16 hours and is then quenched with 4 M HCl in dioxane to give an acidic solution and concentrated under reduced pressure. The resulting residue is diluted with 1 M aqueous NaOH (100 mL), extracted with EtOAc (10 mL×3) and the combined organic layers are dried with Na2SO4 and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 6% MeOH in CH2Cl2 as the eluent to afford [5-fluoro-2-(2-methyl-2H-1,2,4-triazol-3-yl)-phenyl]-methanol plus regiosiomer (1.0 g, 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:13]3[CH2:20][CH2:19][CH2:18][C:14]=3[S:15][C:16]=2[NH2:17])=O)=[CH:6][CH:5]=1.[CH:22]1([C:25](=[O:30])[CH2:26][C:27](=O)[CH3:28])[CH2:24][CH2:23]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:26]([C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:30])=[C:27]([CH3:28])[N:17]=[C:16]3[S:15][C:14]4[CH2:18][CH2:19][CH2:20][C:13]=4[C:12]=23)=[CH:6][CH:5]=1
Reactant: CC(=O)CC(=O)C1CC1
Reactant: COC(=O)c1ccc(C(=O)c2c(N)sc3c2CCC3)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2c(C(=O)C3CC3)c(C)nc3sc4c(c23)CCC4)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 28.1 %

Procedure:
To a stirred solution of 60 mg (0.20 mmol) 4-(2-amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carbonyl)-benzoic acid methyl ester in 2 ml acetic acid was added 33 mg (0.26 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 22 mg (28%) 4-(3-cyclopropanecarbonyl-2-methyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-4-yl)-benzoic acid methyl ester as a light brown oil. ES-MS m/e (%): 392 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1/[C:8](/[CH2:31][CH3:32])=[C:9](\[C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=1)/[C:10]1[CH:11]=[C:12]2[C:16](=[C:17]([F:19])[CH:18]=1)[NH:15][N:14]=[CH:13]2.C1C=C(Cl)C=C(C(OO)=[O:41])C=1>ClCCl>[C:28](/[CH:27]=[CH:26]/[C:23]1[CH:24]=[CH:25][C:20](/[C:9](/[C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([F:19])[CH:18]=2)[NH:15][N:14]=[CH:13]3)=[C:8](\[C:7]2[CH:6]=[CH:5][N+:4]([O-:41])=[CH:3][C:2]=2[Cl:1])/[CH2:31][CH3:32])=[CH:21][CH:22]=1)([OH:30])=[O:29]
Reactant: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1cc(F)c2[nH]ncc2c1)c1ccncc1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1cc(F)c2[nH]ncc2c1)c1cc[n+]([O-])cc1Cl
Reaction time: 15 h

Procedure:
A mixture of (E)-3-(4-((E)-2-(3-chloropyridin-4-yl)-1-(7-fluoro-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylic acid (14.1 mg, 0.031 mmol, Compound 245), mCPBA (11 mg, 0.048 mmol), and dichloromethane (0.5 mL) was stirred vigorously for 15 h. Additional starting material (20 mg, 0.045 mmol) and mCPBA (15 mg, 0.065 mmol) were added and stirring was continued for 3 d. The reaction was concentrated and then purified by reverse-phase HPLC(CH3CN, H2O, TFA) to give 4-((E)-1-(4-((E)-2-carboxyvinyl)phenyl)-1-(7-fluoro-1H-indazol-5-yl)but-1-en-2-yl)-3-chloropyridine-1-oxide. 1H NMR (400 MHz, DMSO-d6): δ 8.44 (d, 1H), 8.25 (d, 1H), 8.16 (dd, 2H), 7.56 (s, 1H), 7.50-7.42 (m, 4H), 7.05-6.96 (m, 3H), 6.43 (d, 1H), 2.41 (q, 2H), 0.94 (t, 3H); LCMS: 464.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C@@H:6]([N:13]1[C:17]2=[N:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=[C:16]2[NH:15][C:14]1=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2].[I-].[CH3:27][N:28]1[C:36]2[C:31](=[C:32]([CH3:37])[CH:33]=[CH:34][CH:35]=2)[C:30]([CH2:38][N+](C)(C)C)=[CH:29]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C@@H:6]([N:13]1[C:17]2=[N:18][C:19]([C:22]#[N:23])=[CH:20][CH:21]=[C:16]2[N:15]([CH2:38][C:30]2[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][C:32]=3[CH3:37])[N:28]([CH3:27])[CH:29]=2)[C:14]1=[O:24])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: Cc1cccc2c1c(C[N+](C)(C)C)cn2C
Reactant: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)[nH]c2ccc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@H](c1ccccc1)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2ccc(C#N)nc21
Temperature: 60 °C
Yield: 78.8 %

Procedure:
To a solution of (R)-3-(5-cyano-2-oxo-1,2-dihydro-imidazo[4,5-b]pyridin-3-yl)-3-phenyl-propionic acid ethyl ester (60 mg, 0.18 mmol) in DMF (5 ml) were added (1,4-dimethyl-1H-indol-3-ylmethyl)-trimethyl-ammonium iodide (74 mg, 0.21 mmol) and K2CO3 (30 mg, 0.21 mmol) at room temperature under nitrogen atmosphere. The solution was heated at 60° C. for 18 hours. The solution was cooled and poured into water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (1×). The combined organics were dried (MgSO4), filtered and concentrated. The remaining residue was purified via silica gel flash column chromatography (Companion, 12 g silica gel, 30-50% EtOAc/hexanes) to give 70 mg (80%) of the title compound as foam.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[CH:8]=1)#[N:2].Cl.[OH-:20].[Na+]>>[C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[CH:8]=1)(=[O:20])[NH2:2]
Reactant: [OH-]
Reactant: Cc1cccc(C)c1-n1cc(C#N)c(=O)[nH]c1=O
Agent: Cl
Agent: [Na+]
Product: Cc1cccc(C)c1-n1cc(C(N)=O)c(=O)[nH]c1=O

Procedure:
A mixture of 5-cyano-1-(2,6-dimethylphenyl)uracil (0.01 mol) and 50 ml of NaOH (2.5 N) is heated for 2 hours at about 90°. After cooling, a small amount of dilute HCl is added to precipitate product. The mixture is filtered to the collected precipitate washed with water to yield 5-carbamoyl-1-(2,6-dimethylphenyl)uracil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([NH2:9])=[N:7][CH:8]=1)#[CH:2].I[C:11]1[CH:12]=[C:13]([CH:27]=[CH:28][C:29]=1[CH3:30])[C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[O:15].CC#N>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCN(CC)CC>[NH2:9][C:6]1[N:7]=[CH:8][C:3]([C:1]#[C:2][C:28]2[CH:27]=[C:13]([CH:12]=[CH:11][C:29]=2[CH3:30])[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=2)=[O:15])=[CH:4][N:5]=1
Reactant: C#Cc1cnc(N)nc1
Reactant: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2cccc(C(F)(F)F)c2)cc1C#Cc1cnc(N)nc1
Temperature: 90 °C

Procedure:
To a sealable tube containing 5-ethynylpyrimidin-2-amine (172 mg, 1.44 mmol), PdCl2(PPh3)2 (25 mg, 0.036 mmol), 3-iodo-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide (292 mg, 0.72 mmol) was added MeCN (10 mL) and Et3N (3 mL) followed by CuI (6.8 mg, 0.036 mmol). The tube was sealed and heated at 90° C. for 1 h. The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The resulting brown solid was reconstituted in MeOH:CH2Cl2 (1:1, 10 mL) and silica gel was added and reconcentrated. The silica-gel combined crude mixture was purified via automated flash chromatography (silica gel, 0 to 5% MeOH in CH2Cl2, gradient elution) to afford 3-(2-(2-aminopyrimidin-5-yl)ethynyl)-4-methyl-N-(3-(trifluoromethyl)phenyl)benzamide. MS m/z=397 [M+H]+. Calc'd for C21H15F3N4O: 396
Reaction SMILES: C([N:8]1[C@@H:13]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH3:19])(OC(C)(C)C)=O>FC(F)(F)C(O)=O.ClCCl>[CH3:19][C@H:9]1[CH2:10][CH2:11][CH2:12][C@H:13]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[NH:8]1
Reactant: CC(C)CC[C@H]1CCC[C@H](C)N1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC[C@H]1CCC[C@H](C)N1

Procedure:
To a stirred solution of trans-N-Boc-2-methyl-6-isopentylpiperidine (1.5 g, 5.56 mmol) in 15% trifloroacetic acid (35 mL) in dichloromethane was stirred for 2 h at room temperature, and the reaction mixture was quenched with 90 mL saturated NaHCO3 solution. The mixture was extracted with ether *5 and the combined extracts were dried over K2CO3 and then concentrated to give trans-2-methyl-6-isopentylpiperidine as an oil. The crude oil was immediately dissolved in a small amount of ether, and ether saturated with HCl (g) was added slowly via pipette. This solution was allowed to stand for 10 minutes, and the solvent was evaporated. More ether was added and the flask was swirled constantly until crystallization occurred. The solid was collected via filtration, and dried in vacuo to give the piperidinium hydrochloride as a white solid. mp 134.1-134.7° C.; 1H NMR (250 MHz) δ 9.36 (s, 2H), 3.53 (s, 1H), 3.25 (s, 1H), 1.96-1.1 (m, 14H), 0.88-0.82 (d, 6H); 13C NMR (62.7 MHz) δ 51.9 (s), 47.8 (s), 34.7 (s), 28.9 (s), 28.4 (s), 27.8 (s), 26.0 (s), 22.7 (s), 22.1 (s), 17.3 (s), 16.9 (s). FT-IR (neat): 3422, 2949, 1636, 1602, 1587, 1500, 1422, 1384, 1230, 1105, 1030, 998, 895. Elemental Analysis for C, H24NCl: C, 64.20%; H, 11.78%; N, 6.80%. Found: C, 64.08%; H, 11.72%; N, 6.78%.
Reaction SMILES: C1([SiH3])C=CC=CC=1.[C:8]([C:11]1[CH:16]=[CH:15][C:14](/[C:17](/[CH3:22])=[CH:18]/[N+:19]([O-:21])=[O:20])=[CH:13][CH:12]=1)(=[O:10])[CH3:9].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CC(C)([O-])C.[Cu+].C1(C)C=CC=CC=1.C[C@H](P(C1CCCCC1)C1CCCCC1)[C]1[C](P(C2C=CC=CC=2)C2C=CC=CC=2)[CH][CH][CH]1.[CH]1[CH][CH][CH][CH]1.[Fe].O.O1CCCC1>[C:8]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:22])[CH2:18][N+:19]([O-:21])=[O:20])=[CH:13][CH:12]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(/C(C)=C/[N+](=O)[O-])cc1
Agent: [Cu+]
Agent: [Fe]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C(C)C[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
In a 10 mL Schlenk-flask, 6.8 mg of copper (I) tert-butoxide and 55 μmol of (S)—(R)-JOSIPHOS were dissolved in 5 ml of toluene. After stirring for 30 minutes at room temperature to give an asymmetric copper complex. This solution to the amount containing 10 μmol of the asymmetric copper complex were mixed with 4.9 ml of toluene. Further, 185 μL of (1.5 mmol) of phenylsilane and 27 μL (1.5 mmol) of water were added thereto. After stirring for 5 minutes, 1 mmol of (E)-2-(4-acetylphenyl)-1-nitro-1-propene was added, and the mixture was further stirred for 24 hours at room temperature. Four milliliters (4 mL) of a tetrahydrofuran solution of tetrabutylammonium fluoride (1 mol/L) were added to the reaction mixture and stirring was continued for 3 hours. Water was added and the mixture was extracted with diethyl ether (30 mL×2). After drying over sodium sulfate, the solvent was evaporated. The residue was purified by flash chromatography (silica gel, hexane/ethyl acetate) to provide optically active 2-(4-acetylphenyl)-1-nitropropane.
Reaction SMILES: [Li]CCCC.CCCCCC.Br[C:13]1[C:14]([Cl:21])=[N:15][CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.C1COCC1>>[Cl:21][C:14]1[C:13]([B:22]([OH:27])[OH:23])=[CH:18][C:17]([O:19][CH3:20])=[CH:16][N:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1cnc(Cl)c(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cnc(Cl)c(B(O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
2.5 M n-BuLi in hexane (3.7 mL, 9.3 mmol) was added slowly to a stirred premixed solution of 3-bromo-2-chloro-5-methoxypyridine (1.73 g, 7.8 mmol) and triisopropyl borate (2.1 mL, 9.3 mmol) in THF (10.0 mL, 122 mmol) at −78° C., and the resulting deep colored mixture was stirred at the same temperature for 1 h and then allowed to warm up to room temperature over 1 h. The reaction was quenched with 1 N NaOH(aq) and then some EtOAc. The separated aqueous layer was acidified with 5N HCl until pH about 5 and then extracted with EtOAc(×2) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give 2-chloro-5-methoxypyridin-3-ylboronic acid (1.0276 g, 71%) as a brown solid. LCMS (API-ES) m/z 188 (M+H)+.