Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C@@H:7]2[CH2:11][C@H:10]([S:12][C:13]3[CH2:19][C@H:18]4[N:15]([C:16](=[O:36])[C@@H:17]4[C@H:20]([O:22]C(OCC4C=CC([N+]([O-])=O)=CC=4)=O)[CH3:21])[C:14]=3[C:37]([O:39]CC3C=CC([N+]([O-])=O)=CC=3)=[O:38])[CH2:9][N:8]2C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[N:6]=1.P([O-])([O-])([O-])=O.[H][H]>[OH-].[OH-].[Pd+2].O1CCCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C@@H:7]2[CH2:11][C@H:10]([S:12][C:13]3[CH2:19][C@H:18]4[N:15]([C:16](=[O:36])[C@@H:17]4[C@H:20]([OH:22])[CH3:21])[C:14]=3[C:37]([OH:39])=[O:38])[CH2:9][NH:8]2)[N:6]=1
Reactant: [H][H]
Reactant: C[C@@H](OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](c4csc(N)n4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)C[C@H]12
Agent: [Pd+2]
Agent: O=P([O-])([O-])[O-]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](c4csc(N)n4)C3)C[C@H]12
Yield: 65.5 %

Procedure:
A mixture of 4-nitrobenzyl (5R,6S)-3-[(2S,4S)-2-(2-aminothiazol-4-yl)-1-(4-nitrobenzyloxycarbonyl) pyrrolidin-4-ylthio]-6-[(1R)-1-(4-nitrobenzyloxycarbonyloxy) ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (1.85 g), 20% palladium hydroxide on carbon (500 mg), 0.05M phosphate buffer (pH 6.5, 30 ml) and tetrahydrofuran (50 ml) was stirred at room temperature for 4 hours under atmospheric pressure of hydrogen. After the catalyst was filtered off, the filtrate was concentrated to remove the organic solvent. The residue was washed with ethyl acetate, adjusted to pH 6.2 with aqueous potassium carbonate and concentrated to remove the organic solvent. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, made by Mitsubishi Chemical Industries) (60 ml) eluting in turn with water (300 ml) and 5% aqueous acetone (200 ml). The fractions containing the desired compound were collected and lyophilized to give (5 R,6S)-3-[(2S,4S)-2-(2-aminothiazol-4-yl) pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid (540 mg).
Reaction SMILES: [C:1]1([N:7]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:10](=O)[C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2>>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([N:18]=[C:10]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:8]3=[O:9])=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: O=C1C(=O)N(c2ccccc2)c2ccccc21
Reactant: Nc1ccc2[nH]ccc2c1
Product: O=C1C(=Nc2ccc3[nH]ccc3c2)c2ccccc2N1c1ccccc1
Temperature: 140 °C
Yield: 13.9 %

Procedure:
1-phenylisatin (51.8 mg, 0.23 mmol) and 5-aminoindole (31 mg, 0.23 mmol) were mixed and heated at 140° C. for 2 h. The resulting crude product was purified by preparative TLC using ethyl acetate/hexane (6:4) as the eluent, giving the desired product as a yellow solid (10.8 mg, 14%). 1H NMR (400 MHz): δ 8.28 (s, 1H), 7.57 (t, J=7.7, 2H), 7.49-7.40 (m, 6H), 7.29-7.23 (m, 1H), 7.03 (dd, J=8.5, 1.7, 1H), 6.98 (d, J=7.6, 1H), 61.83 (d, J=8.0, 1H), 6.74, J=7.6, 1H), 6.59 (s, 1H); ESI-MS m/z found 338 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]2[O:9][C:10]3[C:15]([C:16]([O:18][CH2:19][C:4]=2[CH:3]=1)=[O:17])=[C:14]([O:20][CH3:21])[C:13]([C@@H:22]([OH:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:12][CH:11]=3.[CH:28](I)([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:27][CH:22]([C:13]1[CH:12]=[CH:11][C:10]2[O:9][C:5]3[C:6]([O:8][CH:28]([CH3:30])[CH3:29])=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=3[CH2:19][O:18][C:16](=[O:17])[C:15]=2[C:14]=1[O:20][CH3:21])[CH2:23][CH:24]([CH3:25])[CH3:26]
Reactant: COc1c([C@@H](O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(O)c1O2
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1c(C(O)CC(C)C)ccc2c1C(=O)OCc1cc(C)cc(OC(C)C)c1O2

Procedure:
200 mg (0.54 mmol) of penicillide (Ib) in 2 ml of dimethylformamide are stirred under argon at 25° C. for 12 h with 0.5 ml (50 mmol) of isopropyl iodide and 160 mg (1.14 mmol) of anhydrous potassium carbonate. After evaporating in vacuo, the residue is taken up with 1 N aqueous hydrochloric acid and the mixture is exhaustively extracted with diethyl ether. After drying the organic phase, the evaporation residue is chromatographed on silica using petroleum ether/ether =1/1. Fractions which are pure by thin layer chromatography are combined and evaporated.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[CH:9][O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C([Li])CCC.[CH3:17][Sn:18](Cl)([CH3:20])[CH3:19].O>C1COCC1>[CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([Sn:18]([CH3:20])([CH3:19])[CH3:17])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2occc12
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2oc([Sn](C)(C)C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 111.7 %

Procedure:
To a solution of 4-methoxybenzo(b)furan (2.50 g) in THF (50 ml) was added n-butyllithium (1.54 M hexane solution) (16.5 ml) at −78° C. and the mixture was stirred at the same temperature for 20 min. To this solution was added trimethyltin chloride (5.00 g) and the mixture was further stirred at the same temperature for 1 hr. The reaction mixture was warmed to room temperature and water (200 ml) was added. The mixture was extracted with ethyl acetate, and the obtained organic layer was washed with water and saturated brine and dried over magnesium sulfate. This solution was concentrated under reduced pressure to give the title compound (5.86 g) as pale-yellow crystals.
Reaction SMILES: [OH-].[K+].S(O)(O)(=O)=O.[C:8]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(=[NH:10])[NH2:9].[C:24]([CH:27]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:28](OCC)=[O:29])(=O)[CH3:25]>C(O)C.C1(C)C=CC=CC=1>[CH2:17]([N:14]1[CH2:15][CH2:16][N:11]([C:8]2[N:9]=[C:28]([OH:29])[C:27]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:24]([CH3:25])[N:10]=2)[CH2:12][CH2:13]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: N=C(N)N1CCN(Cc2ccccc2)CC1
Reactant: CCOC(=O)CC(C(C)=O)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)Cc1c(C)nc(N2CCN(Cc3ccccc3)CC2)nc1O
Reaction time: 0.5 h
Yield: 17.6 %

Procedure:
Potassium hydroxide (3.1 g) was added to 200 ml of ethanol, and the mixture was stirred for 30 minutes. Then, 12.4 g of 1-amidino-4-benzylpiperazine sulfate was added. The mixture was stirred at room temperature for 10 minutes. To the solution was added 12.4 g of diethyl acetylsuccinate. The mixture was refluxed for 2 hours. Then, 200 ml of toluene was added, and the mixture was refluxed for 3 hours. After the reaction, ethanol was evaporated, and the residue was poured into 50 ml of an aqueous solution of hydrochloric acid. NaHCO3 was added to the solution to neutralize it. The precipitated solid was washed with water and dried over P2O5 to give 2.55 g (yield 15%) of 2-(4-benzylpiperazino)-5-ethoxycarbonylmethyl-4-hydroxy-6-methylpyrimidine as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([CH2:51][N:52]=[S:53]([CH3:58])([N:55]([CH3:57])[CH3:56])=[O:54])=[CH:47][CH:46]=1>O1CCOCC1>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:50]=[CH:49][C:48]([CH2:51][N:52]=[S:53]([CH3:58])([N:55]([CH3:57])[CH3:56])=[O:54])=[CH:47][CH:46]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CN(C)S(C)(=O)=NCc1ccc(Br)cc1
Solvent: C1COCCO1
Product: CN(C)S(C)(=O)=NCc1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N′-[(4-bromophenyl)methyl]-N,N-dimethyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3) using 1,4-dioxane as a solvent. LC (method 1): tR=1.04 min; Mass spectrum (ESI+): m/z=714 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].C([O-])(=O)C.[Na+].Cl.[NH:34]1[CH2:42][CH2:41][CH2:40][C@H:35]1[C:36]([O:38]C)=[O:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCl.C(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH2:26][CH3:27])=[C:19]([CH2:23][CH2:24][N:34]4[CH2:42][CH2:41][CH2:40][C@H:35]4[C:36]([OH:38])=[O:37])[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CCc1c(CC=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: CCc1c(CCN2CCC[C@H]2C(=O)O)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 40.9 %

Procedure:
To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]acetaldehyde (D52) (110 mg, 0.274 mmol) in Dichloromethane (DCM) (10 mL) was added sodium acetate (33.8 mg, 0.412 mmol) and hydrogen chloride-methyl L-prolinate (1:1) (68.2 mg, 0.412 mmol). After 5 minutes, sodium triacetoxyborohydride (87 mg, 0.412 mmol) was added and the reaction solution was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was hydrolized by NaOH (2.74 mL, 1.372 mmol) in isopropanol/water (10 mL, 1:1). The residue was purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-ethylphenyl]ethyl}-L-proline (E65) (56 mg) as a TFA salt.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][C:9]([C:15]1[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=1)=[CH:8]2.[NH2:22][NH2:23]>CO>[CH3:20][N:18]1[CH:19]=[C:15]([C:9]2[CH:10]=[N:11][C:12]3[C:7]([CH:8]=2)=[CH:6][C:5]([CH2:4][C:3]([NH:22][NH2:23])=[O:2])=[CH:14][CH:13]=3)[CH:16]=[N:17]1
Reactant: NN
Reactant: COC(=O)Cc1ccc2ncc(-c3cnn(C)c3)cc2c1
Solvent: CO
Product: Cn1cc(-c2cnc3ccc(CC(=O)NN)cc3c2)cn1
Temperature: 55 °C

Procedure:
A solution of [3-(1-Methyl-1H-pyrazol-4-yl)-quinolin-6-yl]-acetic acid methyl ester (8.6 mmols) and hydrazine (80.6 mmols) in methanol (75 mL) was heated at 55° C. for an hour before a second addition of hydrazine (80.6 mmol) was added and the reaction heated 55° C. for a further 16 hours After such time the mixture was cooled to 0° C. and the resulting precipitate collected via filtration and washed with cold methanol and dried to return the title compound as a white solid (1.74 g, 70%). 1H NMR 500 MHz (DMSO-d6): ES-MS m/z: 282 (M+H+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:32]=[CH:31][C:15]([O:16][C:17]2[C:18]([C:23]3[CH2:28][CH2:27][N:26]([CH3:29])[C:25](=[O:30])[CH:24]=3)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1)=[O:11]>[Pd].CCO.O1CCOCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[C:18]([CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[C:25](=[O:30])[CH2:24]3)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:31][CH:32]=1)=[O:11]
Reactant: CN1CCC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)=CC1=O
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CN1CCC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1=O
Yield: 38.1 %

Procedure:
A solution of 4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-1-methyl-5,6-dihydropyridin-2(1H)-one (0.0687 g, 0.161 mmol) (Step 7, Example 252) in 1:1 EtOH-dioxane (8 mL) was added palladium, 10% wt. on activated carbon (0.007 g, 6.58 μmol) and hydrogenated (double-walled balloon pressure) at room temperature for 24 h. The reaction mixture was filtered via a pad of Celite, and the filtrate was concentrated in vacuo and purified via flash column chromatography (20% to 80% Teac (10% MeOH)/Hexanes) to give 4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-1-methylpiperidin-2-one (0.0262 g, 38.0% yield) as a light yellow amorphous solid. MS (ESI, pos. ion) m/z: 428.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[N:26]=[C:27]([CH3:30])[S:28][CH:29]=4)[CH2:23][CH2:22][C:21]([C:31]([OH:33])=O)=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Cl.Cl.[CH3:37][N:38]([CH2:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[CH:48][CH:47]=1)[CH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[N:26]=[C:27]([CH3:30])[S:28][CH:29]=4)[CH2:23][CH2:22][C:21]([C:31]([NH:50][C:49]4[CH:51]=[CH:52][C:46]([CH2:45][N:38]([CH3:37])[CH:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[CH:47][CH:48]=4)=[O:33])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2csc(C)n2)cc1
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3c2csc(C)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
In DMF (20 ml) were suspended 7-[4-(2-butoxyethoxy)phenyl]-1-(2-methylthiazol-4-yl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.13 g), 4-[N-methyl-N-(tetrahydro-2H-pyran-4-yl)aminomethyl]aniline dihydrochloride (0.1 g) and 1-hydroxybenzotriazole (0.06 g). Under ice-cooling, to the suspension were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g), triethylamine (0.18 ml) and 4-dimethylaminopyridine (catalytic amount), and the mixture was stirred at room temperature overnight, which was poured into water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified with silica gel column (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethyl acetate-diethyl ether-hexane to give 7-[4-(2-butoxyethoxy)phenyl]-1-(2-methylthiazol-4-yl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 45) (0.087 g) as pale yellow crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].N1C=CC=CC=1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl.CN(C)C1C=CN=CC=1>[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: COc1ccccc1CCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccccc1CCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The solution of 7.50 g of 2-[2-(2-methoxyphenyl)ethoxy]ethanol in 75 ml of dichloromethane is admixed successively with 8.5 ml of pyridine, 0.519 g of 4-dimethylaminopyridine and 9.10 g of p-toluenesulphonyl chloride, and stirred at room temperature over 16 hours. The reaction mixture is washed with brine (2×200 ml). The organic phase is dried with sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.26 (1:2 EtOAc-heptane); Rt=5.02.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:72]=[C:71]([CH3:73])[CH:70]=[CH:69][N:68]=2)[C:56]=1[CH3:74].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:38]1([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:72]=[C:71]([CH3:73])[CH:70]=[CH:69][N:68]=4)[C:56]=3[CH3:74])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:39][CH2:40][O:35][CH2:36][CH2:37]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)c1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.025 g, 0.053 mmol), 2,5-dimorpholinopyridin-3-amine (0.104 g, 0.39 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (0.1 g, 0.33 mmol) and Pd2dba3 (0.012 g, 0.013 mmol) in toluene (3.28 mL) was added sodium t-butoxide (0.079 g, 0.820 mmol). The reaction mixture was heated to 120° C. and stirring continued for 2.5 h. The reaction was then cooled to rt and diluted with water (15 mL). The mixture was extracted with EtOAc (2×15 mL) and DCM (1×15 mL). The organic layers were combined and washed with brine (1×20 mL) and dried over magnesium sulfate. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-di(4-morpholinyl)-3-pyridinyl)-5,7-difluoro-3-methyl-2-(4-methyl-2-pyridinyl)-4-quinolinamine. 1H NMR (400 MHz, CDCl3) δ ppm 8.53 (1H, d, J=2.2 Hz), 7.81 (1H, d, J=7.8 Hz), 7.71 (2H, dd, J=7.6, 2.0 Hz), 7.63 (2H, d, J=2.5 Hz), 6.96-7.06 (1H, m), 6.45 (1H, br. s.), 3.92 (4H, br. s.), 3.78-3.87 (4H, m), 3.23 (4H, br. s.), 3.03-3.12 (4H, m), 2.45 (3H, s), 2.22 (3H, s). Mass Spectrum (ESI) m/e=533.2 (M+1).
Reaction SMILES: CSC.S([O:9][CH3:10])(OC)(=O)=O.[CH2:11]([S:14][C:15]1([C:18]([CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])=O)[CH2:17][CH2:16]1)[CH2:12][CH3:13].[OH-].[K+].OO>C(O)(C)(C)C>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[CH:21]=[CH:20][C:18]1([C:15]2([S:14][CH2:11][CH2:12][CH3:13])[CH2:16][CH2:17]2)[CH2:10][O:9]1
Reactant: COS(=O)(=O)OC
Reactant: CCCSC1(C(=O)C=Cc2ccc(Cl)cc2Cl)CC1
Agent: OO
Agent: [K+]
Agent: [OH-]
Solvent: CSC
Solvent: CC(C)(C)O
Product: CCCSC1(C2(C=Cc3ccc(Cl)cc3Cl)CO2)CC1
Reaction time: 14 h
Yield: 89.2 %

Procedure:
30 ml (0.41 mol) of dimethyl sulphide and 43.5 g (0.35 mol) of dimethyl sulphate are added to 60 ml of tert.-butanol and allowed to stand at room temperature for 14 hours. A solution of 40 g (0.13 mol) of 2,4-dichlorophenyl-ethenyl 1-propylmercaptocyclopropyl ketone in 120 ml of tert.-butanol is initially added dropwise to the reaction mixture with stirring and then 39.1 g of potassium hydroxide powder is introduced, the temperature of the reaction mixture being held at 20° to 30° C. The mixture is stirred for a further 3 hours at 30° C., then the dimethyl sulphide is stripped off under reduced pressure and the reaction mixture is then poured into 70 ml of a 1% strength aqueous hydrogen peroxide solution. The mixture is extracted with ethyl acetate. The organic phase is washed using water and concentrated by stripping off the solvent under reduced pressure after drying over sodium sulphate. In this manner, 38.2 g (91% of theory) of 2-(2,4-dichlorophenylethenyl)-2-(1-propylmercaptocyclopropyl)-oxirane are obtained in the form of an oily product, which is further reacted without additional purification. ##STR77##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][CH:22]([F:34])[CH2:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](O)=[O:32])=[N:29][CH:30]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31]([C:28]3[CH:27]=[CH:26][C:25]([O:24][CH2:23][CH:22]([F:34])[F:21])=[CH:30][N:29]=3)=[O:32])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: O=C(O)c1ccc(OCC(F)F)cn1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ccc(OCC(F)F)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-(2,2-difluoro-ethoxy)-pyridine-2-carboxylic acid (CAS1097730-45-4, WO2009091016) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=473.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH2:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C:8]1[C:9]([NH:22][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ncc(-c3ccc(OC)cc3)nc2Cc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 17 h
Yield: 80.8 %

Procedure:
To a solution of 3-benzyl-5-(4-methoxyphenyl)pyrazin-2-amine (12) (synthesized by the process of M. Adamczyk, et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (500 mg, 1.72 mmol) in pyridine (5 mL) were successively added 4-(dimethylamino)pyridine (21.0 mg, 172 μmol) and 4-methoxybenzoyl chloride (17) (587 mg, 3.44 mmol) at room temperature, and the mixture was heated with stirring at 50° C. for 17 hours. After cooling to room temperature, to the mixture was added water and the product was extracted with dichloromethane (×3). The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residual pyridine was azeotropically removed with toluene (×3). The residue was purified by column chromatography (silica gel 50 g, dichloromethane/ethyl acetate=9/1). The residue was further recrystallized from ethyl acetate to give Compound 11x (592 mg, 1.39 mmol, 80.8%) as a colorless solid. Rf=0.63 (dichloromethane/ethyl acetate=9/1); 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 3H), 3.85 (s, 3H), 4.17 (s, 2H), 7.04-7.11 (m, 4H), 7.14-7.26 (m, 5H), 7.93-7.98 (AA′BB′, 2H), 8.05-8.11 (AA′BB′, 2H), 8.96 (s, 1H), 10.63 (s, 1H); 13C NMR (67.8 MHz, DMSO+CDCl3) 40.3, 54.7, 54.8, 112.9 (2C), 113.7 (2C), 125.4, 125.7, 127.4 (2C), 127.7 (2C), 128.0, 128.5 (2C), 129.4 (2C), 136.2, 137.6, 143.6, 148.2, 150.4, 160.1, 162.0, 165.5; IR (KBr, cm−1) 700, 743, 843, 1030, 1159, 1177, 1258, 1290, 1452, 1485, 1514, 1535, 1580, 1609, 1643, 3242; Anal. Calcd. For C26H23N3O3: C, 73.39; H, 5.45; N, 9.88. Found: C, 73.48; H, 5.40; N, 9.94.