Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].CC1(C)C(C)(C)OB([C:30]2[CH:31]=[N:32][C:33]([NH2:36])=[N:34][CH:35]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1>[NH2:36][C:33]1[N:34]=[CH:35][C:30]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=2)[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:31][N:32]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(Br)c1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1ncc(-c2cncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)c2)cn1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
5-Bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 61.1, 181 mg, 0.5 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (133 mg, 0.6 mmol), PdCl2(dppf)-(CH2Cl2) (20.42 mg, 0.025 mmol), K2CO3 (138 mg, 1 mmol), water (2 mL) and dioxane (10 mL) were added to a vial, which was sealed, evacuated/purged with argon and the RM was stirred at 90° C. for 24 h. The solvent was evaporated off under reduced pressure and the residue was treated with water and extracted with EtOAc. The combined extracts were dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the product which was recrystallized from hot EtOAc to afford the title compound as a beige powder. UPLC-MS (Condition 2) tR 0.89 min, m/z=376.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 6.98 (s, 2H) 7.41 (d, J=8.99 Hz, 2H) 7.90 (d, J=8.99 Hz, 2H) 8.50-8.55 (m, 1H) 8.76 (s, 2H) 9.00 (d, J=1.95 Hz, 1H) 9.06 (d, J=1.96 Hz, 1H) 10.62 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:18](O)=[O:19])=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=2[F:15])=[C:4]([F:21])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)[N:40]=[N:39]C=2C=1.NN.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:18]([NH:39][NH2:40])=[O:19])=[CH:11][N:12]([CH3:17])[C:13](=[O:16])[C:14]=2[F:15])=[C:4]([F:21])[CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)c(F)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: NN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(C(=O)NN)c(Nc2ccc(Br)cc2F)c(F)c1=O
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (70 mg, 0.195 mmol), EDCI (112 mg, 0.585 mmol), and HOBt (79 mg, 0.585 mmol) in DMF (3 mL) was stirred for 30 minutes. Hydrazine (19 mg, 0.585 mmol) was added followed by Et3N (0.082 mL, 0.585 mmol). After 3 hours, the reaction mixture was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated to yield 64 mg (89%) desired product.
Reaction SMILES: C[O-:2].[Mg+2].C[O-].C[C:7]1[O:14][C:12](=O)[CH:11]([C:15]([CH3:17])=[O:16])[C:9](=[O:10])[CH:8]=1>CO>[O:10]=[C:9]([CH2:11][C:15](=[O:16])[CH3:17])[CH2:8][C:7]([O:14][CH3:12])=[O:2]
Reactant: C[O-]
Reactant: CC(=O)C1C(=O)C=C(C)OC1=O
Agent: [Mg+2]
Solvent: CO
Product: COC(=O)CC(=O)CC(C)=O
Reaction time: 5 h

Procedure:
Magnesium methoxide (6% in MeOH, 530 mL) was added to a suspension of dehydroacetic acid (31 g) in methanol (600 mL) at room temperature. The reaction mixture was refluxed and stirred for 5 h. The solvent was removed and the residue dissolved in HCl 1M (1.5 L). The aqueous phase was extracted with EtOAc (2×750 mL) and then the solvent was evaporated under reduced pressure to give a yellow oil, which was filtered on a silica cartridge using dichloromethane as eluent. After the solvent removal, methyl 3,5-dioxohexanoate was obtained as a light yellow oil (19.9 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:21]([OH:22])=[CH:20][C:7]2[CH2:8][N:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1.[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][N:24]1[C:33]([Cl:35])=[O:34].C(N(CC)CC)C>C(Cl)(Cl)Cl.ClCCl>[ClH:35].[CH3:2][O:3][C:4]1[C:21]([O:22][C:33]([N:24]2[CH2:25][CH2:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23]2)=[O:34])=[CH:20][C:7]2[CH2:8][N:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1
Reactant: COc1cc2c(cc1O)CN(Nc1ccncc1)CCC2
Reactant: O=C(Cl)N1CCc2ccccc2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1OC(=O)N1CCc3ccccc3C1)CN(Nc1ccncc1)CCC2
Temperature: 25 °C
Yield: 30.8 %

Procedure:
To a solution of [7-methoxy-8-hydroxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-pyridin-4-yl amine hydrochloride (500 mg) in chloroform (10 mL) was added 1,2,3,4-tetrahydroisoquinoline-2-yl carbonyl chloride (362 mg) followed by triethylamine (0.75 mL). The reaction mixture was heated under reflux for 3 hrs, cooled to ambient temperature, diluted with dichloromethane (200 mL), and the mixture was washed with saturated sodium bicarbonate solution. The organic phase was separated, dried under anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was flash chromatographed over silica gel, eluting with chloroform:methanol (9:1). The appropriate fractions were collected and evaporated. The residue was dissolved in methanol and conc hydrochloric acid was added. The precipitate was collected and crystallized from ethyl acetate-petroleum ether to give 230 mg of product, mp >100° C. (dec).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]2[S:19][C:12]3=[N:13][C:14]([OH:18])=[CH:15][C:16](=[O:17])[N:11]3[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:20]([O-])([OH:22])=[O:21]>C(O)(=O)C>[CH:1]1([CH2:7][CH2:8][C:9]2[S:19][C:12]3=[N:13][C:14]([OH:18])=[C:15]([N+:20]([O-:22])=[O:21])[C:16](=[O:17])[N:11]3[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)nc2sc(CCC3CCCCC3)nn12
Solvent: CC(=O)O
Product: O=c1c([N+](=O)[O-])c(O)nc2sc(CCC3CCCCC3)nn12
Reaction time: 2.5 h

Procedure:
In 125 ml of acetic acid was suspended 9.77 g of 2-(2-cyclohexylethyl)-7-hydroxy-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one, and 3.5 ml of fuming nitric acid was added thereto dropwise while stirring under ice-cooling. The stirring was continued at room temperature for an additional 2.5 hours, and the precipitate formed was collected by filtration and washed successively with water, isopropanol, and diethyl ether to obtain 10.3 g of 2-(2-cyclohexylethyl)-7-hydroxy-6-nitro-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one as a pale yellow crystal.
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Br)[CH:16]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([NH:13][C@@H:4]([CH2:5][C:6]3[CH:11]=[CH:10][C:9]([C:29]4[CH:30]=[CH:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=4)=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:23])=[O:22])[CH:16]=2)=[CH:28][CH:27]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cccc(Br)c1
Product: COc1ccc(-c2ccc(C[C@H](NC(=O)c3cccc(-c4ccc(OC)cc4)c3)C(=O)O)cc2)cc1
Yield: 85 %

Procedure:
(2S)-(3-Bromo-benzoyl-amino)-3-(4-bromo-phenyl)-propionic acid methyl ester (100 mg, 0.22 mmol) was reacted with 4-methoxy-phenyl-boronic acid (204 mg, 1.4 mmol) according to general procedure D yielding the title compound (90 mg, 83%) as a white solid.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:23])[CH2:6][NH:7][C:8](=[O:22])[CH2:9][NH:10][C:11](=[O:21])[C@H:12]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[NH2:13])[CH3:3].C(N(CC)C(C)C)(C)C.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39].CO>C(Cl)Cl>[CH2:2]([O:4][C:5](=[O:23])[CH2:6][NH:7][C:8](=[O:22])[CH2:9][NH:10][C:11](=[O:21])[C@H:12]([CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[NH:13][C:38]([C:34]1[O:33][CH:37]=[CH:36][CH:35]=1)=[O:39])[CH3:3]
Reactant: CCOC(=O)CNC(=O)CNC(=O)[C@@H](N)CC1CCCCC1
Reactant: O=C(Cl)c1ccco1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)CNC(=O)[C@H](CC1CCCCC1)NC(=O)c1ccco1
Yield: 98.2 %

Procedure:
To a solution of 90.1 mg (0.258 mmol) of β-cyclohexyl-L-alanyl-glycyl-glycine ethyl ester hydrochloride in methylenechloride (1 mL), 100.0 mg (0.774 mmol) of N,N-diisopropylethylamine and 37.2 mg (0.285 mmol) of 2-furoyl chloride were added with stirring under ice cooling and the reaction mixture was stirred for 0.5 hour. Methanol (0.2 mL) was added and the reaction mixture was stirred at room temperature, and then concentrated under reduced pressure. Chloroform (25 mL) was added to the residue, and then the mixture was washed with 0.5M hydrochloric acid (3×5 mL) and 5% aqueous sodium hydrogencarbonate solution (3×5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure, whereby 127 mg of the crude product was obtained. The crude product was purified by silica gel column chromatography [silica gel 7.5 g, chloroform, methanol-chloroform (1:100)], to give 103.2 mg of 2-furoyl-β-cyclohexyl-L-alanyl-glycyl-glycine ethyl ester as a colorless oil (yield 98%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH2:16][C:17]#[N:18])[CH3:15])[CH2:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[C@@H:7]([CH2:13][N:14]([CH3:15])[CH2:16][CH2:17][NH2:18])[CH2:6]2
Reactant: COc1cc2c(cc1OC)[C@@H](CN(C)CC#N)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1OC)[C@@H](CN(C)CCN)C2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 1.1 g (4.5 mmol) of the compound of Step 1 in 10 mL of THF is poured dropwise into 0.21 g (5.4 mmol) lithium aluminium hydride suspended in 5 mL of THF, at ambient temperature, and is then stirred at ambient temperature for 5 hours. Cooling to about 0° C. is carried out and there are then added, cautiously, in succession, 0.14 mL of water, 0.11 mL of 20% aqueous sodium hydroxide solution and 0.51 mL of water. Stirring is carried out overnight at ambient temperature, and then the salts are filtered off over a frit and rinsed with THF. The combined filtrates are concentrated to yield the desired product.
Reaction SMILES: C([O-])(=O)C.[Na+].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15]([CH:17]2[CH2:19][CH2:18]2)=[O:16])=[C:9]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:8]=1.Cl.[NH2:30]O>C(O)C>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:14]2[CH:20]=[N:30][O:16][C:15]=2[CH:17]2[CH2:19][CH2:18]2)=[O:24])=[C:9]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:8]=1
Reactant: CCOC=C(C(=O)c1ccc(Cl)cc1S(C)(=O)=O)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CS(=O)(=O)c1cc(Cl)ccc1C(=O)c1cnoc1C1CC1

Procedure:
Sodium acetate (1.93 g) was added to a mixture of 1-(4-chloro-2-methylsulphonylphenyl)-3-cyclopropyl-2-ethoxymethylenepropan-1,3-dione (8.4 g) and hydroxylamine hydrochloride (1.64 g) in ethanol with stirring. The mixture was stirred at room temperature overnight. It was evaporated and the residue was dissolved in ethyl acetate, washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue was recrystallized from ether to give 4-(4-chloro-2-methylsulphonylbenzoyl)-5-cyclopropylisoxazole, compound 260 (4.4 g) as an off-white solid, m.p. 183°-185° C.
Reaction SMILES: [ClH:1].[C:2]1([N:8]([CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][S:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:16][C:15]=3[CH:30]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[ClH:1].[C:2]1([N:8]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[S:18][C:17]([CH2:19][S:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH2:29])=[CH:23][CH:22]=4)=[N:16][C:15]=3[CH:30]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc2sc(CSc3ccc(C(=N)N)cc3)nc2c1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N=C(N)c1ccc(SCc2nc3cc(C(=O)N(CCC(=O)O)c4ccccc4)ccc3s2)cc1
Yield: 95 %

Procedure:
Prepared analogously to Example 10 from 2-[(4-amidinophenyl)thiomethyl]benzothiazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide hydrochloride and sodium hydroxide solution. Yield: 95% of theory, C25H22N4O3S2 (490.61); Rf value: 0.25 (Merck RP-8, methanol/5% NaCl solution=6:4); EKA mass spectrum: (M+H)+=491; (M+Na)+=513.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[Br:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]([OH:35])=O)[CH:28]=[N:29][CH:30]=1.[CH:36]1([O:41][C:42]2[CH:43]=[C:44]([CH:50]3[N:54]([CH3:55])[NH:53][C:52](=[O:56])[CH2:51]3)[CH:45]=[CH:46][C:47]=2[O:48][CH3:49])[CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)Cl>[Br:24][C:25]1[CH:26]=[C:27](/[CH:31]=[CH:32]/[C:33]([N:53]2[C:52](=[O:56])[CH2:51][CH:50]([C:44]3[CH:45]=[CH:46][C:47]([O:48][CH3:49])=[C:42]([O:41][CH:36]4[CH2:37][CH2:38][CH2:39][CH2:40]4)[CH:43]=3)[N:54]2[CH3:55])=[O:35])[CH:28]=[N:29][CH:30]=1
Reactant: O=C(O)C=Cc1cncc(Br)c1
Reactant: COc1ccc(C2CC(=O)NN2C)cc1OC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2CC(=O)N(C(=O)/C=C/c3cncc(Br)c3)N2C)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.20 mmol, 0.230 g), 1-hydroxybenzotriazole hydrate (1.20 mmol, 0.162 g) and 3-(5-bromo-3-pyridyl)propenoic acid (1.20 mmol, 0.274 g [see Nishikawa, et al, J Med Chem, 32, 583 (1989)] is suspended in dry methylene chloride (20 mL) at room temperature and stirred for 2 hours. To the suspension is added a solution of 5-[3(cyclopentyloxy)-4-methoxyphenyl]-1-methyl-3-pyrazolidinone (1.20 mmol, 0.340 g) in dry methylene chloride (10 mL) and the resulting mixture is stirred at room temperature overnight followed by reflux for 24 hours. The homogenous solution is cooled to room temperature and the volatiles are removed in vacuo. The residue is partitioned between ethyl acetate (50 mL) and 1N NaOH (50 mL), the aqueous phase extracted with ethyl acetate (50 mL) and the combined organics are washed with water (50 mL) and dried (Na2SO4). Concentration in vacuo affords a white foam, which is purified via flash chromatography (SiO2 : concentration gradient ranging from 5% ethyl acetate/methylene chloride to 15% ethyl acetate/methylene chloride) to give the title compound as a white solid which is triturated with ether and hexane and dried in vacuo at 50° C. to provide analytically-pure material (0.52 mmol, 0.260 g, 52%). H-NMR (DMSO-d6, 400 MHz) δ8.82 (d, 1H, J=1.7 Hz); 8.66 (d, 1H, J=1.7 Hz); 8.41 (t, 1H); 7.71 (d, 2H, J=2.4 Hz,); 6.98 (d, 1H, J=1.5 Hz); 6.89 (m, 2H); 4.70 (m, 1H); 4.47 (dd, 1H, J=0.6, 1.7 Hz); 3.70 (s, 3H); 3.65 (m, 1H); 2.84 (s, 3H); 2.77 (m, 1H); 1.80 (m, 2H); 1.62 (m, 4H); 1.49 (m, 2H). IR (KBr, cm-1) 3460, 2940, 2860, 1748, 1660, 1623, 1515, 1445, 1435, 1425, 1326, 1260, 1235, 1208, 1150, 1130, 1015, 990, 962, 848, 680.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C@H:11]2[CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH3:10])[C:5]2[N:17]([CH:20]([F:22])[F:21])[CH:18]=[N:19][C:4]=2[CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[CH:27][C:26]=1[N:40]1[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[F:21][CH:20]([F:22])[N:17]1[C:5]2[C:6]([O:8][C@@H:9]([C@@H:11]3[CH2:12][C:13](=[O:16])[NH:14][CH2:15]3)[CH3:10])=[N:7][C:2]([C:29]3[CH:28]=[CH:27][C:26]([N:40]4[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[O:47])[CH2:42][CH2:41]4)=[C:25]([O:24][CH3:23])[CH:30]=3)=[CH:3][C:4]=2[N:19]=[CH:18]1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: C[C@@H](Oc1nc(Cl)cc2ncn(C(F)F)c12)[C@H]1CNC(=O)C1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cc3ncn(C(F)F)c3c(O[C@H](C)[C@H]3CNC(=O)C3)n2)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C

Procedure:
2.64 (102 mg, 0.308 mmol), tert-butyl 4-(2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine-1-carboxylate 7.08 (160 mg, 0.38 mmol), K3PO4 (191 mg, 0.9 mmol) and Bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]dichloropalladium (II) (7.2 mg, 0.01 mmol) were taken up in 1,4-dioxane (4.4 mL) and water (0.44 mL). The stirred reaction mixture was heated to 100° C. for 1.5 h and was then cooled and partitioned between EtOAc, water and brine. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (0-15% MeOH in DCM) to provide tert-butyl 4-(4-(3-(difluoromethyl)-4-((R)-1-((R)-5-oxopyrrolidin-3-yl)ethoxy)-3H-imidazo[4,5-c]pyridin-6-yl)-2-methoxyphenyl)piperazine-1-carboxylate. LCMS-ESI+ (m/z): [M+H]+ calcd for C29H37F2N6O5: 587.3; found: 587.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([NH:10]C(=O)OC(C)(C)C)[CH:5]=[CH:4][N:3]=1.[O:18]1[CH2:22][CH2:21][O:20][CH:19]1[C:23]1[CH:28]=[CH:27][C:26]([C:29](=O)[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:7]=1[CH:8]=[C:30]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:29]([C:26]1[CH:27]=[CH:28][C:23]([CH:19]3[O:20][CH2:21][CH2:22][O:18]3)=[CH:24][CH:25]=1)=[N:10]2
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1C=O
Reactant: O=C(Cc1ccccc1)c1ccc(C2OCCO2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Clc1nccc2nc(-c3ccc(C4OCCO4)cc3)c(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (2-chloro-3-formylpyridin-4-yl)carbamate (3-1, 30.5 g, 118.9 mmol) and 1-[4-(1,3-dioxolan-2-yl)phenyl]-2-phenylethanone (3-2, 29.0 g, 108.1 mmol) in anhydrous THF (300 mL) at room temperature was added LHMDS (1M in THF, 248 mL) in a stream. The reaction mixture was stirred at room temperature overnight and then it was refluxed for 24 hr. It was cooled and concentrated to a syrup and treated with NaHCO3 (saturated, 50 mL) and water (300 mL) to form a solid which was collected via filtration. The solid was dried, washed with ether and further dried with toluene azeotropically to give the title compound. LRMS m/z (M+1) Calcd: 389.1. Found 389.1.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][CH3:14])[CH:8]=2)[N:5]=[C:4]([CH3:15])[CH:3]=1.[F:16][C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:36])[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[C:30](I)[CH:29]=2)[CH:23]=[N:24][CH:25]=1)([CH3:19])[CH3:18].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:16][C:17]([C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:36])[C:28]2[CH:29]=[CH:30][C:31]([CH3:34])=[C:32]([NH:1][C:2]3[N:6]([C:7]4[CH:8]=[C:9]([NH:13][CH3:14])[N:10]=[CH:11][N:12]=4)[N:5]=[C:4]([CH3:15])[CH:3]=3)[CH:33]=2)[CH:23]=[N:24][CH:25]=1)([CH3:19])[CH3:18]
Reactant: Cc1ccc(C(=O)Nc2cncc(C(C)(C)F)c2)cc1I
Reactant: CNc1cc(-n2nc(C)cc2N)ncn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CNc1cc(-n2nc(C)cc2Nc2cc(C(=O)Nc3cncc(C(C)(C)F)c3)ccc2C)ncn1
Temperature: 150 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
A suspension of [6-(5-amino-3-methyl-pyrazol-1-yl)-pyrimidin-4-yl]-methyl-amine (17 mg, 0.083 mmol), N-[5-(1-fluoro-1-methyl-ethyl)-pyridin-3-yl]-3-iodo-4-methyl-benzamide (41 mg, 0.104 mmol), Pd(OAc)2 (2 mg, 0.009 mmol), Xantphos (9 mg, 0.0166 mmol) and Cs2CO3 (54 mg, 0.166 mmol) in anhydrous 1,4-dioxane (2 mL) in a pressure vial was degassed by a stream of argon and sealed. The reaction was stirred at 150° C. for 1 hour. LCMS showed completion of the reaction. A solution of 5% diethyl dithiocarbomic acid sodium salt (3 mL) was added to the reaction. A light yellow precipitate was collected by filtration, washed with water and dried. The crude was purified by column (SiO2, EtOAc/hexanes: 30 to 100%) to give a white solid (25 mg, 64%): m/z 475.2 (M+1).
Reaction SMILES: [Cl-].[NH4+].[OH:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)C=O.C(O[CH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])C>CCO>[CH2:22]([O:21][CH:17]([O:18][CH2:19][CH3:20])[C:12]1[CH:13]=[C:6]([CH2:5][CH2:4][OH:3])[CH:7]=[CH:8][CH:11]=1)[CH3:23]
Reactant: O=Cc1cccc(CCO)c1
Reactant: CCOC(OCC)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(OCC)c1cccc(CCO)c1
Temperature: 70 °C

Procedure:
Ammonium chloride (0.08 g) was added to a solution of 3-(2-hydroxyethyl)benzaldehyde (example 20, step b) (0.45 g) and triethoxymethane (0.55 g) in EtOH (8 mL) and the reaction mixture heated at 70° C. for 3 h. After cooling, the reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The ethyl acetate solution was dried over sodium sulphate, filtered and evaporated in vacuo to give the subtitled compound as a gum. Yield 0.24 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22]([C:26](O)=[O:27])=[CH:21][CH:20]=[CH:19]2.[NH2:29][CH2:30][C:31]1[CH:47]=[CH:46][C:34]([C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][C:39]=2[NH2:45])=[O:36])=[CH:33][CH:32]=1>>[NH2:45][C:39]1[CH:40]=[C:41]([CH3:44])[CH:42]=[CH:43][C:38]=1[NH:37][C:35]([C:34]1[CH:46]=[CH:47][C:31]([CH2:30][NH:29][C:26]([C:22]2[C:23]3[C:18](=[CH:17][C:16]([O:15][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)=[CH:25][CH:24]=3)[CH:19]=[CH:20][CH:21]=2)=[O:27])=[CH:32][CH:33]=1)=[O:36]
Reactant: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Reactant: Cc1ccc(NC(=O)c2ccc(CN)cc2)c(N)c1
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)NCc5ccc(C(=O)Nc6ccc(C)cc6N)cc5)cccc4c3)c2cc1OC
Yield: 85.9 %

Procedure:
The title compound (52.7 mg, 86% yield) was prepared as a brown solid from 6-(6,7-dimethoxyquinazolin-4-yloxy)-1-naphthoic acid (37.6 mg, 0.1 mmol) and 4-(aminomethyl)-N-(2-amino-4-methylphenyl)benzamide (30.6 mg, 0.12 mmol) by an analogous procedure to that described in example 16. LC-MS (m/z) 614 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2.[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(N(CC)CC)C>C(O)C>[CH3:13][C:14]1[N:19]=[C:18]([S:20][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][CH:7]=[N:6]3)[N:17]=[C:16]([OH:21])[CH:15]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1ccc2nccnc2c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1cc(O)nc(SCc2ccc3nccnc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
A mixture of 6-(bromomethyl)quinoxaline (900 mg, 4.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (440 mg, 3.1 mmol), and triethylamine (1.1 mL, 7.8 mmol) in absolute ethanol (20 mL) was stirred at room temperature overnight. The reaction mixture was evaporated and then co-evaporated with EtOAc. The solid residue was treated with water (100 mL). The solid product was recovered by filtration, washed with water (2×20 mL), diethyl ether (3×20 mL), and hexanes (3×20 mL), and then dried in vacuo, affording 6-methyl-2-[(quinoxalin-6-ylmethyl)sulfanyl]pyrimidin-4-ol (658 mg, 75% yield). The product was used without further purification.