Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][CH:22]=2)([CH3:20])[CH3:19])[CH3:16])=[CH:11][CH:10]=1>CC(C)=O>[CH3:16][C:15]([C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])=[CH:14][CH:13]=1)=[CH:17][C:18]([CH3:20])([CH3:19])[C:21]1[CH:22]=[CH:23][C:24]([NH:27][C:1](=[O:7])/[CH:2]=[CH:3]\[C:4]([OH:6])=[O:5])=[CH:25][CH:26]=1
Reactant: O=C1C=CC(=O)O1
Reactant: CC(=CC(C)(C)c1ccc(N)cc1)c1ccc(N)cc1
Solvent: CC(C)=O
Product: CC(=CC(C)(C)c1ccc(NC(=O)/C=C\C(=O)O)cc1)c1ccc(NC(=O)/C=C\C(=O)O)cc1

Procedure:
Maleic anhydride (43 g) was dissolved in 250 ml of acetone. While this solution was being kept at 18° C., 53 g of 2,4-di(p-amino-phenyl)-4-methyl-2-pentene was slowly added thereto with stirring. The resulting reaction mixture was stirred at 18° C. for 21/2 hours to form N,N'-(1-methyl-3,3-dimethyl-1-propenylenedi-p-phenylene)bismaleamic acid having the formula ##STR20## At this time, the reaction mixture was a yellow slurry. Then, 0.5 g of cobalt acetate tetrahydrate, 10 g of triethylamine, and 50 g of acetic anhydride were added, with stirring, to the above slurry. After completion of the addition, the slurry was heated to 61° C. and stirred at that temperature for 8 hours, so that it became a clear brown solution. This solution was cooled to room temperature and, thereafter, worked up in the same manner as described in Example 1. However, the amount of methyl alcohol added to the solution was 80 ml and the amount of water into which the solution was poured was 7,000 ml. As a result, there was obtained 80 g of product melting at 99°-110° C. Its yield was 94% based on the amount of diamine used as the starting material. It was confirmed by infrared absorption spectroscopy, nuclear magnetic resonance spectroscopy, and elemental analysis that the product was N,N'-(1-methyl-3,3-dimethyl-1-propenylenedi-p-phenylene)bismaleimide having the formula ##STR21##
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)=[CH:6][C:5]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:27]=2)=[O:24])=[C:4]([F:40])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:47]([NH2:49])=[O:48].CCOC(C)=O>O1CCOCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:40])[C:5]([NH:22][C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[C:28]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:27]=2)=[O:24])=[CH:6][C:7]=1[C:8]1[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]2[C:16]([CH:17]=1)=[CH:15][N:14]=[C:13]([NH:49][CH:47]=[O:48])[CH:12]=2
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccc(F)c(CN4CCOCC4)c3)c(F)cc2Cl)cc2cnc(Cl)cc21
Reactant: NC=O
Agent: Cl[Pd+]
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: NCCc1[c-]cccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccc(F)c(CN4CCOCC4)c3)c(F)cc2Cl)cc2cnc(NC=O)cc21
Temperature: 100 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
A mixture of 1-(4-chloro-5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluorophenyl)-3-(4-fluoro-3-(morpholinomethyl)phenyl)urea (155 mg, 0.263 mmol), K2CO3 (73 mg, 0.570 mmol) and formamide (59 mg, 1.317 mmol) in dioxane (3 mL) was sparged with Ar, treated with BrettPhos Palladacycle (10 mg, 13 μmol) and heated at 100° C. for 2 h. The mixture was cooled to RT, treated with EtOAc, DMF and 50% satd. NaHCO3 and the solid collected via filtration. The layers of the filtrate were separated, the organics layer washed with brine, dried over Na2SO4, concentrated to dryness, combined with the isolated solid and purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue treated with satd. NaHCO3 and stirred for 1 h. The resulting solid was collected via filtration, dried and re-purified via reverse-phase chromatography (MeCN/H2O with 0.1% TFA). The organics were removed under reduced pressure, the aqueous residue treated with satd. NaHCO3 and extracted with EtOAc (3×). The combined organics were dried over Na2SO4 and concentrated to dryness to afford N-(3-(2-chloro-4-fluoro-5-(3-(4-fluoro-3-(morpholinomethyl)phenyl)ureido)phenyl)-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-7-yl)formamide (33 mg, 20% yield). MS (ESI) m/z: 597.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5].[Br:16]N1C(=O)CCC1=O.O>C(Cl)Cl>[OH:1][C:2]1[C:9]([Br:16])=[C:8]([O:10][CH3:11])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(O)c(C=O)cc1C(C)(C)C
Solvent: ClCCl
Solvent: O
Product: COc1c(C(C)(C)C)cc(C=O)c(O)c1Br
Yield: 69.3 %

Procedure:
A solution of 2.56 g (12.3 mmol) of 2-hydroxy 4-methoxy-5-(1,1-dimethylethyl)benzaldehyde and 2.19 g (12.3 mmol) of N-bromosuccinimide in 20 ml of methylene chloride was stirred for 6 hours. Water (50 ml) was added. The organic phase was dried and evaporated. The residue was chromatographed on silica gel (36 g) using 2:98 (v/v) ether/hexane as eluent. There was obtained 2.45 g (8.53 mmol, 69%) of 2-hydroxy-3-bromo-4-methoxy-(1,1-dimethylethyl)benzaldehyde as white crystals after crystallization from cyclohexane; mp 123°-124° C.
Reaction SMILES: C1(N)N=C(N)N=C(N)N=1.COCC(O)C.C1(N(C2C=CC=C(O)C=2)[C:23]2[C:28](N(C3C=CC=CC=3)C3C=CC=C(O)C=3)=[CH:27][CH:26]=[CH:25][C:24]=2[C:43]2[C:44]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[CH:45][CH:46]=[CH:47][CH:48]=2)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>[C:49]1([C:44]2[C:43]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:23]=3)=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: Oc1cccc(N(c2ccccc2)c2cccc(-c3ccccc3-c3ccccc3)c2N(c2ccccc2)c2cccc(O)c2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Nc1nc(N)nc(N)n1
Solvent: COCC(C)O
Solvent: c1ccncc1
Product: c1ccc(-c2ccccc2-c2ccccc2)cc1
Temperature: 40 °C

Procedure:
A coating composition is formed containing 2.5 grams Joncryl 587 (acrylated polyol from Johnson Polymers Inc.), 3.5 grams Cymel 303, 27 grams 1-methoxy-2-propanol (Dowanol PM), and 3.0 grams N,N′-diphenyl-N,N′-di[3-hydroxyphenyl]-terphenyl-diamine in a 1 ounce bottle. The components are mixed and the temperature is raised to about 40° C. until a complete solution is achieved. Next, 0.9 grams of p-toluenesulfonic acid/pyridine (8% acid/pyridine complex in 1-methoxy-2-propanol) (0.072 grams acid, 0.75% by weight) as catalyst is added.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:16][CH:15]3[N:17](C)[CH:11]([CH2:12][CH2:13][CH2:14]3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC(Cl)(Cl)COC(Cl)=O.[OH-].[Na+].N.Cl>C(OCC)C.[Zn].CO.ClCCl.O.C(O)(=O)C.C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:16][CH:15]3[NH:17][CH:11]([CH2:12][CH2:13][CH2:14]3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN1C2CCCC1CN(c1ccc(Cl)c(Cl)c1)C2
Agent: Cl
Agent: N
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: Clc1ccc(N2CC3CCCC(C2)N3)cc1Cl

Procedure:
A mixture of 3-(3,4-dichloro-phenyl)-9-methyl-3,9-diaza-bicyclo[3.3.1]nonane (0.50 g, 1.75 mmol), 2,2,2-trichloroethylchloroformate (1.11 g, 5.26 mmol) and toluene (30 ml) was stirred at reflux for 15 h. Water (30 ml) was added and the phases were separated. The organic phase was evaporated. Acetic acid (10 ml) and water (10 ml) and zinc powder (0.57 g, 8.8 mmol) was added. The mixture was stirred for 15 h. Aqueous sodium hydroxide (20 ml, 1 M) was added followed by extraction with dichloromethane (3×10 ml). The crude product was purified by silica get column chromatography using a solvent mixture of dichloromethane, methanol and aqueous ammonia (9:1:1%). Yield 150 mg (32%). The corresponding salt was obtained by addition a mixture of hydrogen chloride solved in diethylether (1 ml, 2 M). Mp 295.4° C. LC-ESI-HRMS of [M+H]+ shows 271.0769 Da. Calc. 271.076879 Da, dev. 0.1 ppm.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[C:26]12([NH2:36])[CH2:35][CH:30]3[CH2:31][CH:32]([CH2:34][CH:28]([CH2:29]3)[CH2:27]1)[CH2:33]2>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:36][C:26]34[CH2:27][CH:28]5[CH2:34][CH:32]([CH2:31][CH:30]([CH2:29]5)[CH2:35]3)[CH2:33]4)[N:7]=[CH:6][N:5]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2cc(NC34CC5CC(CC(C5)C3)C4)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.078 mmol) in 1.5 mL of ethanol is added 10 μL of triethylamine and 1-Adamantanamine (12 mg, 0.078 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture can then be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]2[O:10][CH:9]=[CH:8][CH:7]([C:11]([OH:13])=[O:12])[C:6]=2[CH:14]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([Cl:15])=[CH:4][C:5]2[O:10][CH:9]=[CH:8][CH:7]([C:11]([O:13][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:12])[C:6]=2[CH:14]=1
Reactant: O=C(O)C1C=COc2cc(Cl)c(Cl)cc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)C1C=COc2cc(Cl)c(Cl)cc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 6,7-dichloro-4H-1-benzopyran-4-carboxylic acid (16.8 gm), tetra (N-butyl)ammonium hydrogensulfate (23 gm), benzyl bromide (9.7 mL), saturated sodium bicarbonate (100 mL) and dichloromethane (100 mL) were stirred vigorously at room temperature for 14 hours, then diluted with dichloromethane, and the organic layer separated, washed with saturated sodium bicarbonate, water, brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (2:1 dichloromethane/hexanes, SiO2) to afford the title compound (11.8 gm, Rf=0.3 (2:1 dichloromethane/hexanes, SiO2).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][CH:10]2[CH2:15][CH:14]([C:16]([O:18]C)=[O:17])[CH2:13][CH2:12][N:11]2[C:20]([O:22][CH3:23])=[O:21])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[Br-].[Li+].C(N(CC)CC)C.CC(OC)(C)C>C(#N)C.O>[CH3:23][O:22][C:20]([N:11]1[CH2:12][CH2:13][CH:14]([C:16]([OH:18])=[O:17])[CH2:15][CH:10]1[CH2:9][C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:25][CH:24]=1)=[O:21]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2ccc(S(C)(=O)=O)cc2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: CC#N
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1ccc(S(C)(=O)=O)cc1
Yield: 79.4 %

Procedure:
Dimethyl 2-(4-(methylsulfonyl)benzyl)piperidine-1,4-dicarboxylate (5.5 g, 14.89 mmol) was dissolved in acetonitrile (50 mL) and water (1 mL), then lithium bromide (10.34 g, 119.10 mmol) and triethylamine (8.25 mL, 59.55 mmol) were added and the resulting suspension was heated at reflux for 2 h. Water and MTBE were added. The organic phase was extracted with water (×2). To the pooled aqueous layer was added ethyl acetate and the solution was acidified to pH 1 with HCl and then extracted with ethyl acetate twice. The organic layer was dried (Na2SO4), filtered through celite and evaporated to yield 1-(methoxycarbonyl)-2-(4-(methylsulfonyl)benzyl)piperidine-4-carboxylic acid (4.2 g, 79%). MS m/z 354 (M−H)−
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][C:20]3[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:22][C:21]=3[F:34])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:35][CH3:36])C1C=CC=CC=1>C(O)C.[Pd]>[F:34][C:21]1[CH:22]=[C:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH:24]=[CH:25][C:20]=1[O:19][C:13]1[C:12]2[C:17](=[CH:18][C:9]([OH:8])=[C:10]([O:35][CH3:36])[CH:11]=2)[N:16]=[CH:15][CH:14]=1
Reactant: COc1cc2c(Oc3ccc(NC(=O)OC(C)(C)C)cc3F)ccnc2cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(Oc3ccc(NC(=O)OC(C)(C)C)cc3F)ccnc2cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.5 %

Procedure:
To a solution of tert-butyl 4-(7-(benzyloxy)-6-methoxyquinolin-4-yloxy)-3-fluorophenylcarbamate (800 mg, 1.632 mmol) in ethanol (50 mL) was added a catalytic amount of Pd/C. The suspension was stirred at rt under H2 for 3 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound as a light green solid (650 mg, 99%).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C[Si]([C:12]#[C:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[C:17]#[N:18])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:12]#[C:13][C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)[C:17]#[N:18])[CH:3]=1
Reactant: C[Si](C)(C)C#Cc1cccc(C#N)c1
Reactant: Ic1cccnc1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#Cc1cccc(C#Cc2cccnc2)c1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 71 %

Procedure:
Add triethylamine (5 mL) to a stirring mixture of 3-iodopyridine (1.03 g, 5.03 mmol), bis(triphenylphosphine)palladium (II) dichloride (176 mg, 0.252 mmol), copper (I) iodide (96 mg, 0.503 mmol), and 3-trimethylsilanylethynylbenzonitrile, (prepared essentially as described in PREPARATION 5), (1.0 g, 5.03 mmol) at −78° C. After about 3 min, add a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (5.03 mL, 5.03 mmol) in one portion, warm to room temperature and stir overnight. Filter the reaction mixture through fluted filter paper and concentrate. Dissolve the residue in ethyl acetate, wash sequentially with a saturated solution of aqueous sodium bicarbonate, a saturated solution of aqueous sodium chloride, dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 0:100 to 40:60 ethyl acetate:hexanes, followed by a second silica gel chromatography, eluting with 0:100 to 40:60 ethyl acetate:dichloromethane), to give the title product as a yellow solid (730 mg, 71%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20]([N:31]4[CH2:35][CH2:34][CH2:33][C@H:32]4[CH3:36])[N:19]=3)[C@H:14]([CH3:37])[CH2:13]2)[N:6]=1)=[O:4].O.O[Li].O>C1COCC1>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:22]2[N:21]=[C:20]([N:31]3[CH2:35][CH2:34][CH2:33][C@H:32]3[CH3:36])[N:19]=[C:18]([N:15]3[CH2:16][CH2:17][N:12]([C:7]4[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][C:8]=4[CH3:11])[CH2:13][C@H:14]3[CH3:37])[CH:23]=2)=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(C)c(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCC[C@H]4C)n3)[C@H](C)C2)n1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(=O)O)nc1N1CCN(c2cc(-c3ccc(F)cc3)nc(N3CCC[C@H]3C)n2)[C@H](C)C1
Temperature: 50 °C

Procedure:
To a solution of 6-{4-[6-(4-fluoro-phenyl)-2-(2-(R)-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-3-(R)-methyl-piperazin-1-yl}-5-methyl-pyridine-2-carboxylic acid methyl ester (300 mg, 0.595 mmol) in THF, add water dropwise until the cloudiness almost persists. To this mixture add LiOH.H2O (50 mg, 1.2 mmol). Heat the mixture at 50° C. for 2 h, and then concentrate under reduced pressure. Add a small amount of water to the residue. Adjust the final pH to 6 and collect the off-white solid via filtration. Wash the solid with water and dry to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15]C)=[O:14])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO>[OH:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(CO)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(CO)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of methyl 4-(hydroxymethyl)-1-naphthalenecarboxylate (700 mg, 3.24 mmol) in methanol (10 ml) was added 1N aqueous sodium hydroxide solution (3.24 ml, 3.24 mmol) and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to the reaction solution (5 ml) and the mixture was extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 4-(hydroxymethyl)-1-naphthalenecarboxylic acid (570 mg, 87%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:22]=[CH:23][CH:24]([OH:34])[CH2:25][C:26](=[O:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:10]([CH:19]([CH3:21])[CH3:20])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(B(CC)CC)C.[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([CH:22]=[CH:23][CH:24]([OH:34])[CH2:25][CH:26]([OH:33])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:10]([CH:19]([CH3:21])[CH3:20])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)CC(O)C=Cc1c(C(C)C)sc(-c2ccccc2)c1-c1ccc(F)cc1
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)CC(O)C=Cc1c(C(C)C)sc(-c2ccccc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.5 %

Procedure:
To a solution of 5.5 g of the title product of Step 4, above, in 100 ml of THF was added 12 ml of a 1.0 m solution of triethylborane in THF. After stirring at R.T. for 3 hours, the mixture was cooled to -78°, then 450 mg of sodium borohydride was added. The mixture was stirred at -78° for 24 hours. The reaction was then quenched with saturated aq. ammonium chloride solution, and extracted twice with MTBE. The extracts were combined and solvent was removed under reduced pressure to obtain a residue. The residue dissolved in 100 ml of methanol. After stirring at R.T. for 24 hours, the solvent was removed under reduced pressure and the resulting residue was flash chromatographed using 1% methanol/methylene chloride to elute the product, yielding 2.4 g of the title product of this example. (HPLC indicated an erythro:threo mixture of 82.3:17.7). Recrystallization of the product from cyclohexane increased the ratio to 88.3:11.7; m.p.=123°-125° .
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[F:11][C:12]([F:25])([F:24])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([N:21]2[CH2:22][CH2:23][C@@H:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]([F:11])([F:24])[F:25])[CH2:20]2)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccccc1[C@@H]1CCNC1
Reactant: O=C(O)c1cccc(Br)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cccc(Br)n1)N1CC[C@@H](c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
After 6-bromopicolinic acid (430 mg, 2.13 mmol) was suspended in acetonitrile (25 ml), (S)-3-(2-(trifluoromethyl)phenyl)pyrrolidine (503 mg, 2.34 mmol), N,N-diisopropylethylamine (0.56 ml, 3.20 mmol), and HBTU (969 mg, 2.56 mmol) were sequentially added thereto, and then the resulting mixture was stirred at room temperature under nitrogen stream for 3 hours. The resulting reaction liquid was concentrated under reduced pressure, and then the residue thus obtained was subjected to MPLC (40% EtOAc/Hexanes), to obtain 765 mg of white solid (90%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([CH3:25])([C:17]([NH:19][C:20]1[S:21][CH:22]=[CH:23][N:24]=1)=[O:18])[CH2:5]2.[C:26]1(B(O)O)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:25][C:6]1([C:17]([NH:19][C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[O:18])[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([O:1][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:3]=2)[CH:7]1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC1(C(=O)Nc2nccs2)Cc2cc(O)ccc2C1c1ccccc1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C(=O)Nc2nccs2)Cc2cc(Oc3ccccc3)ccc2C1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of Example 36 (11.3 mg, 0.032 mmol), Cu(OAc)2 (8.9 mg, 1.5 eq), phenylboronic acid (11.3 mg, 2.9 mmol), triethylamine (22.6 μL, 5 eq) and powdered 4 Å molecular sieve (33.7 mg) in CH2Cl2 (2.5 mL) was stirred at room temperature for 16 h while open to the atmosphere. After filtration to remove the molecular sieve, the filtrate was concentrated and purified by reverse-phase HPLC (80-100% solvent B gradient) to give Example 155. (4.9 mg, 36%). MS Found: (M+H)+=427.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([N:6]([CH2:8][CH2:9][C:10]#[N:11])[CH3:7])=[O:5].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([Cl:24])=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[C:10]([CH2:9][CH2:8][N:6]([CH3:7])[C:4](=[O:5])[C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[NH:1][C:19]1[C:20]([Cl:24])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)#[N:11]
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CN(CCC#N)C(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CCC#N)C(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 80 °C
Reaction time: 96 h
Yield: 50.6 %

Procedure:
2-Amino-N-(2-cyano-ethyl)-N-methyl-benzamide (5.73 g, 28.2 mmol) in N,N-Dimethylformamide (50 mL) was treated with 2,4,5-Trichloro-pyrimidine (4.00 mL, 34.9 mmol) and Potassium carbonate (5.8 g, 42 mmol). The mixture was heated at 80° C. for 4 h, then cooled to room temperature and stirred for 4 days. The reaction was diluted with 200 mL water, extracted with DCM (200 mL, then 2×50 mL). The combined organics were washed 1×100 mL brine, dried over sodium sulfate and conc. in vacuo to give an oil, which was chromatographed (ISCO 330 g silica gel, 0-80% EtOAc:Hex). The product eluted with ˜60% EtOAc to afford N-(2-Cyano-ethyl)-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide as an oil (5.0 g, 50%). 1H-NMR (CDCl3): 9.36 (s, 1H), 8.34 (d, 1H, J=8.4 Hz), 8.22 (s, 1H), 7.53 (m, 1H), 7.38 (m, 1H), 7.21 (m, 1H), 3.81 (m, 2H), 3.22 (s, 3H), 2.80 (m, 2H).