Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].C(NC1C=CC(S([N:21]=[N+:22]=[N-])(=O)=O)=CC=1)(=O)C.C(N(CC)CC)C>C(#N)C>[N+:21](=[C:4]([C:5](=[O:7])[CH3:6])[C:1](=[O:3])[CH3:2])=[N-:22]
Reactant: CC(=O)CC(C)=O
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)C(=[N+]=[N-])C(C)=O
Temperature: 0 °C

Procedure:
A 1-L round-bottomed flask was charged with acetylacetone (S1) (10.25 mL, 100 mmol, 1.0 equiv) and acetonitrile (600 mL). p-Acetamidobenzene sulfonyl azide (p-ABSA)(J. S. Baum et al., Synth. Commun. 17, 1709 (1987) (24.0 g, 100 mmol, 1.0 equiv) was added and the reaction was cooled to 0° C. Triethylamine (NEt3) (41.8 mL, 300 mmol, 3 equiv) was added dropwise and the reaction was warmed to rt for 1 hour. The resulting suspension was filtered through a fitted funnel and concentrated. The obtained residue was triturated with 1:1 ether:petroleum ether and the precipitated white solids were removed via filtration. Solvents were removed in vacuo providing analytically pure S2 as a yellow oil in quantitative yield. Spectral data matched those reported in the literature (Z.-B. Chem et al., J. Org. Chem. 74, 903 (2009)).
Reaction SMILES: [CH:1]([CH:4]1[NH:8][C:7](=[O:9])[NH:6][C:5]1=[O:10])([CH3:3])[CH3:2].[CH3:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>>[CH:1]([CH:4]1[NH:8][C:7](=[O:9])[N:6]([CH2:17][C:16]2[CH:19]=[CH:20][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[C:5]1=[O:10])([CH3:3])[CH3:2]
Reactant: CC(C)C1NC(=O)NC1=O
Reactant: COc1ccc(CCl)cc1
Product: COc1ccc(CN2C(=O)NC(C(C)C)C2=O)cc1

Procedure:
Using 5-isopropylimidazolidine-2,4-dione (2.00 g) and 4-methoxybenzyl chloride (2.29 mL) and by the reaction and treatment in the same manner as in Preparation Example 51, the title compound (2.72 g) was obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li])CCC.Br[CH2:20][CH2:21][CH2:22][C:23]#[N:24]>C1COCC1>[CH:1]1[C:13]2[CH:12]([CH2:20][CH2:21][CH2:22][C:23]#[N:24])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Reactant: N#CCCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCCCC1c2ccccc2-c2ccccc21
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
A solution of fluorene (5.04 g; 30.32 mmol) in THF (50 mL) was cooled to 0° C. and treated with n-butyllithium (12.13 mL of a 2.5M solution in hexanes; 30.32 mmol). After stirring the red anion mixture for 15 minutes, 4-bromobutyronitrile (4.86 g; 31.84 mmol) in 20 mL of THF was added via syringe, and the mixture was stirred overnight. It was quenched with 100 mL of saturated ammonium chloride and extracted into ethyl acetate (2×75 mL); the organic portions were washed with brine, dried and concentrated. The crude product was purified on a silica gel column, eluted with 20% ethyl acetate in hexane, to afford 4.91 g (70%) of the product as an orange oil. 1H NMR (CDCl3): δ 1.38 (m, 4H); 2.18, 2.29 (m, 2H each); 4.10 (m, 1H); 7.37 (m, 4H); 7.45 (d, 2H); 7.75 (d, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=1)[NH2:5].Cl[S:17]([C:20]1[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18].O.[Cl-].[NH4+]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:5][S:17]([C:20]2[CH:29]=[CH:28][CH:27]=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])(=[O:19])=[O:18])[CH:6]=[C:7]([O:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:8]=1
Reactant: Nc1cc(F)cc(Oc2cccnc2)c1
Reactant: COC(=O)c1ccccc1S(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccccc1S(=O)(=O)Nc1cc(F)cc(Oc2cccnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-5-(pyridin-3-yloxy)aniline (1.10 g) in pyridine (22 ml), 1.92 g of methyl 2-(chlorosulfonyl)benzoate was added, and the reaction solution was stirred overnight at room temperature. Water and a saturated aqueous ammonium chloride solution were added to the reaction solution, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a 1N aqueous hydrochloric acid solution and a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resultant residue was purified by silica gel chromatography to yield the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:11][CH2:10]1)=[O:5].[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40]>O1CCCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:20]2[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=[C:16]2[NH:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:36][CH:35]=[C:34]([S:37][CH3:38])[CH:33]=4)[NH:1][C:39]3=[O:40])[CH2:14][CH2:13]2)=[CH:23][CH:24]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CSc1ccc(N)c(C(=O)NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)c1
Solvent: C1CCOC1
Product: CSc1ccc2[nH]c(=O)n(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)c(=O)c2c1
Yield: 85 %

Procedure:
A mixture of 6 parts of 2-amino-N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-5-(methylthio)benzamide, 1.78 parts of 1,1'-carbonylbis[1H-imidazole] and 90 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 5.2 parts (85%) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-6-(methylthio)-2,4(1H,3H)-quinazolinedione; mp. 238° C. (compound 126).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([Cl:24])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:15][CH3:16])=[C:9]([S:11](Cl)(=[O:13])=[O:12])[CH:10]=1.C(N(CC)CC)C.[CH:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[CH:32]1([NH:36][S:11]([C:9]2[CH:10]=[C:5]([O:4][C:3]3[C:2]([Cl:1])=[CH:20][C:19]([N+:21]([O-:23])=[O:22])=[CH:18][C:17]=3[Cl:24])[CH:6]=[CH:7][C:8]=2[O:15][CH3:16])(=[O:13])=[O:12])[CH2:35][CH2:34][CH2:33]1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)Cl
Reactant: NC1CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)NC1CCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
To a solution of 5-(2,6-Dichloro-4-nitro-phenoxy)-2-methoxy-benzenesulfonyl chloride (1.3 grams, 3.2 mmol) in methylene chloride (30 mL) at 0° C. was added triethylamine (0.58 mL, 4.1 mmol) followed by cyclobutylamine (0.27 mL, 3.2 mmol). After stirring at room temperature for 2 hours, the reaction mixture was quenched with 1N hydrochloric acid (25 mL) and extracted with methylene chloride (3 times 15 mL). The combined organic extracts were washed with 1N HCl (20 mL), saturated aqueous NaHCO3 (2 times 20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (30% ethyl acetate in hexane) to afford the title compound (531 mg). 1H NMR (400 MHz, CDCl3) δ8.28 (s, 2H), 7.28 (d, 1H), 7.07-7.04 (dd, 1H), 6.98 (d, 1H), 5.26 (d, 1H), 3.96 (s, 3H), 3.71-3.69 (m, 1H), 1.99-1.92 (m, 2H), 1.74-1.68 (m, 2H), 1.57-1.48 (m, 2H). MS (APCI−) Calc: 446.1, Found: 445.2 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:17]([CH3:19])[N:18]=2)[CH:12]=[C:13]([CH3:25])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cc(Br)cn12
Reactant: CB1OB(C)OB(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)nc2c(OCc3ccccc3)cc(C)cn12
Temperature: 25 °C

Procedure:
Under argon, 105 g (270 mmol) of ethyl 8-(benzyloxy)-6-bromo-2-methylimidazo[1,2-a]pyridine-3-carboxylate Example 85A were suspended in 4.2 l of 1,4-dioxane, 135.4 g (539 mmol, purity 50%) of trimethylboroxine, 31.2 g (27 mmol) of tetrakis(triphenylphosphine)palladium(0) and 78.3 g (566 mmol) of potassium carbonate were added in succession and the mixture was stirred under reflux for 8 h. The reaction mixture was cooled to RT, the precipitate was filtered off over silica gel and the filtrate was concentrated. The residue was dissolved in dichloromethane and purified by silica gel chromatography (dichloromethane:ethyl acetate=9:1). This gave 74 g (84.6% of theory; purity 100%) of the target compound.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[F:47][C:48]1[CH:53]=[CH:52][C:51](B(O)O)=[CH:50][CH:49]=1.CO.[CH2:59]([N:66]1[CH2:70][CH:69]=[C:68]([C:71](=[O:73])[CH3:72])[CH2:67]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1>O>[CH2:59]([N:66]1[CH2:70][C@H:69]([C:51]2[CH:52]=[CH:53][C:48]([F:47])=[CH:49][CH:50]=2)[C@@H:68]([C:71](=[O:73])[CH3:72])[CH2:67]1)[C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(=O)C1=CCN(Cc2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Solvent: O
Product: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)cc1
Temperature: 60 °C
Yield: 9.7 %

Procedure:
A two necked flask was charged under argon with rhodium(acac)bis ethylene (185 mg, 0.05 eq.), (R)-BINAP (442 mg, 0.05 eq.) and 4-fluoro-phenylboronic acid (4.87 g, 2.5 eq.). 300 mL of MeOH and 30 mL of H2O were added followed by 1-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)-ethanone (2.8 g). The reaction mixture was heated at 60° C. for 8 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO2, EtOAc/Heptane 2/1) afforded 0.40 g (10%) of the title product as a light yellow oil. ES-MS m/e: 298.2 (M+H+).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[C:9]([O:13][C:14]([NH:16][C@H:17]([C:28]([OH:30])=[O:29])[CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>CN(C=O)C>[CH3:1][O:29][C:28](=[O:30])[C@H:17]([CH2:18][CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:16][C:14]([O:13][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:15]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCOCc1ccccc1)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](CCOCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.6 %

Procedure:
Potassium carbonate (2.07 g), methyl iodide (1.25 mL) were added to a solution of N-tert-butoxycarbonyl-O-benzyl-L-homoserine (3.10 g) in DMF (15 mL). After stirring at room temperature for 5 hr, the solvent was removed in vacuo. Ethyl acetate and water were added to the residue. The separated organic layer was washed with brine, dried over sodium sulfate, and evaporated in vacuo to give the title compound (3.13 g) as a pale yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.44 (m, 9H), 1.95-2.15 (m, 2H), 3.55 (m, 2H), 3.68 (s, 3H), 4.44 (m, 1H), 4.45 (d, J=11.6 Hz, 1H), 4.49 (d, J=11.7 Hz, 1H), 5.47 (m, 1H), and 7.27-7.37 (m, 5H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH2:13][CH2:14][OH:15])[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5]1.[O:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23]Cl)[CH2:18][CH2:17]1.Cl>O.C1C=CC=CC=1>[CH3:3][C:4]1([CH2:13][CH2:14][O:15][CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[O:8]1
Reactant: ClCCN1CCOCC1
Reactant: CC1(CCO)Oc2ccccc2O1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC1(CCOCCN2CCOCC2)Oc2ccccc2O1

Procedure:
3.2 g. of 80% NaH are added a little at a time, with cooling, to 10 g. of 2-methyl-2-(β-hydroxyethyl)-1,3-benzodioxole dissolved in 180 cc. of anhydrous benzene. The mixture is refluxed for one hour and cooled. 15 g. of morpholino-ethyl chloride are added drop by drop, and the mixture is refluxed for three hours. The solvent is eliminated under vacuum, and the residue is dissolved in water, acidified with dilute HCl and extracted with ether. The aqueous phase is made alkaline, and again extracted with ether. The organic phase is separated, dried over Na2SO4, and evaporated.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:17][C:18]=2[CH3:19])[CH:11]=1)[CH2:7]O)[CH3:2].S(Cl)([Cl:28])=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:28][CH2:7][C:6]1[CH:9]=[C:10]([CH:11]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[O:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:17][C:18]=1[CH3:19]
Reactant: CCOc1cc(CO)cc(OCc2nc(-c3ccccc3)oc2C)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1cc(CCl)cc(OCc2nc(-c3ccccc3)oc2C)c1
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a solution of 3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl alcohol (4.38 g) in toluene (80 ml) was added dropwise thionyl chloride (1.69 g) at room temperature. After stirring for 90 min, ethyl acetate (100 ml) was added to the reaction mixture and the mixture was washed with aqueous sodium bicarbonate and then with water. The organic layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the crystals obtained from the fraction eluted with ethyl acetate-hexane (1:4, volume ratio) were recrystallized from ethyl acetate-hexane to give 4-(3-chloromethyl-5-ethoxyphenoxymethyl)-5-methyl-2-phenyloxazole (4.25 g, 92%) as colorless prism crystals. melting point: 86–87° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:47]=[CH:48][CH:49]=1)[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:36][CH:35]=1)=[O:32].CS(C)=O>CO>[O:40]([C:37]1[CH:36]=[CH:35][C:34]([NH:33][C:31](=[O:32])[C:30]2[CH:47]=[CH:48][CH:49]=[C:28]([NH:27][C:2]3[C:7]([C:8]4[N:9]=[C:10]([NH:14][C:15]5[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=5)[N:11]=[CH:12][N:13]=4)=[CH:6][CH:5]=[CH:4][N:3]=3)[CH:29]=2)=[CH:39][CH:38]=1)[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: Nc1cccc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1
Reactant: COc1cc(Nc2ncnc(-c3cccnc3Cl)n2)cc(OC)c1OC
Solvent: CO
Solvent: CS(C)=O
Product: COc1cc(Nc2ncnc(-c3cccnc3Nc3cccc(C(=O)Nc4ccc(Oc5ccccc5)cc4)c3)n2)cc(OC)c1OC
Temperature: 90 °C

Procedure:
To [4-(2-chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine (Example 2, Step 4)(103 mg, 0.275 mmol) was added 3-amino-N-(4-phenoxyphenyl)-benzamide (297 mg, 0.975 mmol) and DMSO (150 ml), and the mixture was heated overnight at 90° C. The residue was treated with IpOH and MeOH, triturated, sonicated, and filtered to obtain N-(4-phenoxy-phenyl)-3-{3-[4-(3,4,5-trimethoxy-phenylamino)-[1,3,5]triazin-2-yl]-pyridin-2-ylamino}benzamide as a yellow solid: MS m/z 642.5=[M+H]+. Calc'd for C36H31N7O5: 641.24.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[O:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][C:19]=2[NH2:21])[CH:14]=[CH:13]1.NC1N=CC(C2SC(CN3CCCCC3)=CC=2)=CC=1C(NC1C=CN=CC=1)=O>>[NH2:1][C:2]1[C:7]([C:8]([NH:21][C:19]2[CH:18]=[CH:17][N:16]=[C:15]3[CH:14]=[CH:13][O:12][C:20]=23)=[O:10])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: Nc1ccnc2ccoc12
Agent: Nc1ncc(-c2ccc(CN3CCCCC3)s2)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(Br)cc1C(=O)Nc1ccnc2ccoc12

Procedure:
7.1 Reaction of 2-amino-5-bromo-pyridine-3-carboxylic acid with furo[3,2-b]pyridin-7-amine according to the synthesis described for “A1” step 1, gives 2-Amino-5-bromo-N-furo[3,2-b]pyridin-7-yl-pyridine-3-carboxamide.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6](F)[CH:5]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([OH:22])[CH:21]=1)[CH:17]=[O:18].Cl>CN(C=O)C.O>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([O:13][C:14]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:16]([CH:17]=[O:18])[CH:15]=2)[CH:5]=1
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: N#Cc1ccc(Cl)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cl)cc1Oc1cc(O)cc(C=O)c1
Temperature: 80 °C
Yield: 23.1 %

Procedure:
Sodium hydride (502 mg, 60% in mineral oil) was added portionwise to 4-chloro-2-fluorobenzonitrile (2.04 g) and 3,5-dihydroxybenzaldehyde (1.81 g) in DMF and the solution heated to 80° C. for 16 h. The cooled solution was diluted with water, acidified with concentrated hydrochloric acid, extracted twice with ethyl acetate, the extracts dried over sodium sulphate and evaporated. Purification by chromatography gave the sub-title compound as a white solid (0.83 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:27])[C:25]=4[NH2:26])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:28]1([C:34]2[S:35][C:36]([CH:39]=O)=[CH:37][N:38]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[N:23][N:24]([CH3:27])[C:25]=4[NH:26][CH2:39][C:36]4[S:35][C:34]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=5)=[N:38][CH:37]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4N)cc3)cc2)CC1
Reactant: O=Cc1cnc(-c2ccccc2)s1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4NCc4cnc(-c5ccccc5)s4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 21, Step 5, using the following starting materials: 1-[4′-(5-amino-1-methyl-1H-pyrazol-4-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-phenyl-thiazole-5-carbaldehyde.
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([F:24])[CH:18]=1>C(O)CCC.O1CCOCC1>[Br:16][C:17]1[CH:23]=[CH:22][C:20]([NH:21][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=3[N:6]=2)=[C:19]([F:24])[CH:18]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Solvent: C1COCCO1
Solvent: CCCCO
Product: Fc1cc(Br)ccc1Nc1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 90 °C
Yield: 58.1 %

Procedure:
In a 250-mL round-bottom flask, 2-chloro-6-trifluoromethoxy-1,3-benzothiazole (5.36 g, 21.14 mmol) and 4-bromo-2-fluoroaniline (4.82 g, 25.36 mmol) were combined in 100 mL n-butanol containing 1% 4.0 M HCl in dioxane, and heated at 90° C. overnight. The mixture was cooled to rt and the solvent was removed under reduced pressure. Ethyl acetate (50 mL) was added, and the mixture was ultrasonicated by suspending the flask in an ultrasonication bath for 30 minutes. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Acetonitrile (50 mL) was added to the mixture, which was then ultrasonicated for 30 minutes and then filtered to provide the product as a white solid (5 g, 58%). LC-MS m/z 409.1 (MH+), ret. time 4.02 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[CH:13]=[CH:12][S:11]3)=[CH:4][C:3]=1[O:16][CH3:17].[C:18](OC(=O)C)(=[O:20])[CH3:19].S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:18](=[O:20])[CH3:19])[CH:13]=[CH:12][S:11]3)=[CH:4][C:3]=1[O:16][CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(-c2cn3ccsc3n2)ccc1F
Agent: O=S(=O)(O)O
Solvent: O
Product: COc1cc(-c2nc3sccn3c2C(C)=O)ccc1F
Temperature: 140 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
To a mixture of 6-(4-fluoro-3-methoxyphenyl)-imidazo[2,1-b]thiazole (1.0 g, 4.03 mmol) and acetic anhydride (25 ml), heated to 140° C., was added 43 μl of concentrated sulfuric acid. The reaction mixture was heated at 140° C. for 1 hour. The reaction was monitored by HPLC. After one hour, only 10% product was observed. Another 43 μl of concentrated sulfuric acid was added and the mixture was kept at 140° C. for 4 hours. The reaction mixture was then poured onto 50 ml of ice, and diluted with 50 ml of water and the resulting mixture was extracted two times with 100 ml each of ethyl acetate. The combined extracts were washed with two portions of 50 ml of water and two portions of 50 ml of saturated aqueous sodium chloride solution. The organic phase was dried with sodium sulfate, filtered and concentrated in vacuo, to give a brown solid. The product, -[6-(4-fluoro-3-methoxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]ethanone, was purified by flash chromatography (gradient 25%-50% ethyl acetate in hexanes) and obtained as a pale yellow solid (1.12 g, 96%). 400 MHz 1H NMR (DMSO-d6) δ 8.44 (d, J=4.3 Hz, 1H), 7.56 (d, J=4.3 Hz, 1H), 7.43 (dd, J=8.2, 2.0 Hz, 1H), 7.34 (dd, J=11.7, 8.6 Hz, 1H), 7.21 (ddd, J=8.2, 4.3, 2.0 Hz, 1H), 3.89 (s, 3H), 2.14 (s, 3H). LCMS: 291 [M+H].
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH2:7]1[O:9][CH:8]1CO>C1C2NC3C(=CC=CC=3)SC=2C=CC=1.C([O-])(=O)CCCCCCCCCCCCCCCCC.[Ca+2].C([O-])(=O)CCCCCCCCCCCCCCCCC>[C:1]([O:5][CH2:6][CH:8]1[O:9][CH2:7]1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)OC
Reactant: OCC1CO1
Agent: CCCCCCCCCCCCCCCCCC(=O)[O-]
Agent: [Ca+2]
Agent: c1ccc2c(c1)Nc1ccccc1S2
Product: C=CC(=O)OCC1CO1
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To the same apparatus as described in Example 1 were added 2,150 g (25 mol) of methyl acrylate, 370 g (5 mol) of glycide, 1 g of phenothiazine as the polymerization inhibitor and 41.3 g (0.068 mol) of calcium stearate as the catalyst. The resulting mixture was heated at a temperature of 50° to 70° C. under a reduced pressure of 200 to 400 mmHg while introducing a slight amount of air to effect the reaction while distilling off the formed methanol as an azeotropic mixture with methyl acrylate. The reaction was completed in 2 hours. The formation of glycidyl acrylate was 96.5%. 575 g of glycidyl acrylate was obtained by the distillation (purity: 98.1%, yield: 89.7%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4](S(C)(=O)=O)[N:3]=1.[CH:23]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]3[O:12][CH2:13][O:14][C:10]=3[CH:9]=2)[C:5]([C:17]#[N:18])=[C:4]([O:29][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1
Reactant: OC1CCCCC1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccc3c(c2)OCO3)c1C#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OC2CCCCC2)nc(N)nc1-c1ccc2c(c1)OCO2

Procedure:
From 2-amino-4-benzo[1,3]dioxol-5-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, cyclohexanol and DBU in DME. ES-MS m/e (%): 339 (M+H+, 45), 257 (100).