Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(O[C:16]2[C@H:17]([CH3:40])[C@@H:18]3[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]3[C:20]=2[C:21]([O:23]CC2C=CC([N+]([O-])=O)=CC=2)=[O:22])(C2C=CC=CC=2)=O)C=CC=CC=1.[SH:41][C@@H:42]1[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]2[CH2:55][CH2:54][N:53]([C:56](=[NH:72])[N:57](C)[C:58](OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:52][CH2:51]2)=[O:49])[CH2:43]1>>[OH:38][C@@H:36]([C@H:35]1[C:34](=[O:39])[N:19]2[C:20]([C:21]([OH:23])=[O:22])=[C:16]([S:41][C@@H:42]3[CH2:46][N:45]([CH3:47])[C@H:44]([C:48]([N:50]4[CH2:55][CH2:54][N:53]([C:56](=[NH:72])[NH:57][CH3:58])[CH2:52][CH2:51]4)=[O:49])[CH2:43]3)[C@H:17]([CH3:40])[C@H:18]12)[CH3:37]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: CN(C(=N)N1CCN(C(=O)[C@@H]2C[C@H](S)CN2C)CC1)C(=O)OCc1ccc([N+](=O)[O-])cc1
Product: CNC(=N)N1CCN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C)CC1

Procedure:
A procedure similar to that described in Example 101 was repeated, but using 4-nitrobenzyl (1R,5R,6S)-2-(diphenylphosphoryloxy)-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (prepared as described in Preparation 123) and (2S,4S)-4-mercapto-1-methyl-2-[4-(methyl-4-nitrobenzyloxycarbonylamidino)piperazin-1-yl-carbonyl]pyrrolidine (prepared as described in Preparation 105) as starting materials, in relative proportions similar to those used in that Example, to obtain the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]1[S:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([NH:20][CH:21]3[CH2:23][CH2:22]3)[N:17]3[N:24]=[CH:25][C:26]([CH:27]=[O:28])=[C:16]3[N:15]=2)[CH:10]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.O>CN(C=O)C>[CH:21]1([NH:20][C:18]2[N:17]3[N:24]=[CH:25][C:26]([CH:27]=[O:28])=[C:16]3[N:15]=[C:14]([C:11]3[CH:10]=[C:9]([CH2:8][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[S:13][CH:12]=3)[CH:19]=2)[CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3csc(CBr)c3)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cnn2c(NC3CC3)cc(-c3csc(CN4CCCC4)c3)nc12
Temperature: 50 °C
Yield: 50.5 %

Procedure:
Potassium carbonate (30 mg, 0.20 mmol) was added to 5-(5-(bromomethyl)thiophen-3-yl)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (25 mg, 0.07 mmol) dissolved in DMF (0.7 mL). Pyrrolidine (6 μL, 0.07 mmol) was added and the reaction was heated to 50° C. for 1.25 h. Water (3 mL) was added and the orange precipitate was filtered and dried in vacuo to give 7-(cyclopropylamino)-5-(5-(pyrrolidin-1-ylmethyl)thiophen-3-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (13 mg, 54%) which was used without further purification. LCMS (ES): >85% pure, m/z 368 [M+1]+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1([OH:15])[CH2:9][CH2:8][N:7](C(OCC)=O)[CH2:6]1)[CH3:2]>O>[CH2:1]([NH:3][CH2:4][C:5]1([OH:15])[CH2:9][CH2:8][NH:7][CH2:6]1)[CH3:2]
Reactant: CCNCC1(O)CCN(C(=O)OCC)C1
Solvent: O
Product: CCNCC1(O)CCNC1

Procedure:
7.7 g (35.6 mmol) of ethyl 3-ethylaminomethyl-3-hydroxypyrrolidine-1-carboxylate are heated under reflux overnight with 22 g of Ba(OH)2 . 8H2O in 220 ml of water. The mixture is filtered off with suction from BaCO3 and concentrated. The residue is boiled five times using 100 ml of dioxane each time, and the dioxane solution is concentrated and distilled.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH3:12])=[C:7]([N+:13]([O-])=O)[CH:6]=1)(=[O:4])=[O:3]>[Pd]>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH2:13])[C:8]([NH:11][CH3:12])=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CNc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CNc1ccc(S(C)(=O)=O)cc1N
Yield: 76 %

Procedure:
4-Methanesulfonyl-N1-methyl-benzene-1,2-diamine (76 mg) was prepared by following General Procedure B starting from (4-methanesulfonyl-2-nitro-phenyl)-methyl-amine (115 mg) and Pd/C (10% by weight, 10 mg). The crude product was used in the next step without further purification.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=1)[NH2:4].Cl.N([O-])=O.[Na+].[F:23][C:24]1[CH:30]=[CH:29][C:27](N)=[CH:26][C:25]=1[CH3:31]>O1CCOCC1.O.C(O)C>[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH:4][C:3]([C:5]2[C:9]([NH:10][CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:8][O:7][N:6]=2)=[N:2][OH:1])=[CH:26][C:25]=1[CH3:31]
Reactant: CS(=O)(=O)NCCNc1nonc1C(N)=NO
Reactant: Cc1cc(N)ccc1F
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(NC(=NO)c2nonc2NCCNS(C)(=O)=O)ccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
N′-Hydroxy-4-({2-[(methylsulfonyl)amino]ethyl}amino)-1,2,5-oxadiazole-3-carboximidamide (35 mg, 0.13 mmol) was stirred in 1,4-dioxane (2 mL) and 6 N hydrogen chloride solution (4 mL) was added. The solution was cooled to 0° C. and a solution of sodium nitrite (11 mg, 0.16 mmol) in water (3 mL) was slowly added. The mixture was stirred for 1 hour at 0° C. and evaporated. Dry 1,4-dioxane (2 mL) was added and the mixture evaporated two more times. A solution of 4-fluoro-3-methylaniline [Aldrich, product #559415] (25 mg, 0.20 mmol) in ethanol (2 mL) was added and the mixture was stirred for 1 hour. Purification by preparative LCMS (pH 2) gave the desired compound (17 mg, 27%). LCMS calculated for C13H15FN6O4S (M+H)+: m/z=373.1. 1H NMR (400 MHz, DMSO-d6): δ 11.25 (s, 1H), 8.61 (s, 1H), 7.18 (m, 1H), 6.91 (m, 1H), 6.72 (m, 1H), 6.58 (m, 1H), 6.24 (s, 1H), 3.32 (m, 2H), 3.11 (m, 2H), 2.89 (s, 3H), 2.05 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH:12]([CH3:14])[CH3:13])[NH:5]C(OCCBr)=O.C=C>CO.[Co].[Li].C1C=CC2C(=C3N=C4N=C(C5C=CC=CC=54)N=C4NC(C5C=CC=CC=54)=NC4=NC(C5C=CC=CC=54)=NC=2N3)C=1>[CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH:12]([CH3:14])[CH3:13])[NH2:5]
Reactant: COC(=O)[C@@H](NC(=O)OCCBr)C(C)C
Agent: [Co]
Agent: C=C
Agent: [Li]
Solvent: CO
Product: COC(=O)[C@@H](N)C(C)C
Yield: 76.2 %

Procedure:
7.7 g (8.5 mmols) of lithium cobalt-phthalocyanine in 50 ml of methanol are stirred with 846 mg (3.0 mmols) of 2-bromoethoxycarbonyl-L-valine methyl ester for 2 hours at 20° C (end of the evolution of ethylene) and the mixture is worked up as described in Example 56. 300 mg (76%) of L-valine methyl ester are obtained. Boiling point10 = 53° C. [α]D25 = +42.2° (c = 0.7 in ethanol).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[CH3:23])[CH:19]=[CH:18][C:17]=2[O:26][CH3:27])[C@@H:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=O)(C)(C)C.FC(C1C=CC(OC(F)(F)F)=C(C=1)CN[C@H]1CCCN[C@H]1C1C=CC=CC=1)(F)C>>[F:24][C:22]([C:20]1[CH:19]=[CH:18][C:17]([O:26][CH3:27])=[C:16]([CH:21]=1)[CH2:15][NH:14][C@H:10]1[CH2:11][CH2:12][CH2:13][NH:8][C@H:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([F:25])[CH3:23]
Reactant: COc1ccc(C(C)(F)F)cc1CN[C@H]1CCCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Agent: CC(F)(F)c1ccc(OC(F)(F)F)c(CN[C@H]2CCCN[C@H]2c2ccccc2)c1
Product: COc1ccc(C(C)(F)F)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 35 in the same manner of Compound 27
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][CH:15]([C:17]([OH:19])=[O:18])[CH2:16][C:11]=3[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH:20]([N-]C(C)C)(C)[CH3:21].[Li+].C([Li])CCC.C(NC(C)C)(C)C.C(I)C.Cl>O1CCCC1.CCCCCC.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]3[CH2:13][CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[C@H:16]([CH2:20][CH3:21])[C:11]=3[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)[N-]C(C)C
Reactant: O=C(O)C1CCc2c(-c3ccc(Cl)cc3)noc2C1
Agent: Cl
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCI
Solvent: C1CCOC1
Product: CC[C@@H]1c2onc(-c3ccc(Cl)cc3)c2CC[C@H]1C(=O)O
Reaction time: 0.25 h

Procedure:
A solution of 1.73 g (0.00625 mol) of 3-(4-chlorophenyl)-4,5,6,7-tetrahydro-1,2-benzisoxazole-6-carboxylic acid in 30 ml of dry tetrahydrofuran was added slowly at -70° C. to a solution of lithium diisopropylamide prepared by adding 5.25 ml of a 2.5M solution of n-butyllithium in hexane to 1.32 g (0.013 mol) of diisopropylamine in 20 ml of dry tetrahydrofuran at -70° C. After 0.25 hour a deep red color had developed. 1.05 g (0.0067 mol) of ethyl iodide in 5 ml of dry tetrahydrofuran were added and the temperature was allowed to rise to -20° C. over a period of 1.25 hours. The resulting light brown solution was poured into an excess of water and acidified with 2N hydrochloric acid. The mixture was extracted four times with diethyl ether and the combined ether extracts were washed with sodium chloride solution, dried over magnesium sulfate and evaporated. The residue was crystallized twice from glacial acetic acid and there was obtained 0.36 g of trans-3-(4-chlorophenyl)-7-ethyl-4,5,6,7-tetrahydro-1,2-benzisoxazole-6-carboxylic acid of melting point 162°-163° C.
Reaction SMILES: COC1C=CC(CN2CCN(C)CC2)=CC=1N.[NH2:18][C:19]1[CH:20]=[C:21]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=O)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[CH3:26][O:25][C:24]1[CH:23]=[CH:22][C:21]([CH2:27][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:20][C:19]=1[NH2:18]
Reactant: COc1ccc(C(=O)N2CCOCC2)cc1N
Agent: COc1ccc(CN2CCN(C)CC2)cc1N
Product: COc1ccc(CN2CCOCC2)cc1N

Procedure:
2-Methoxy-5-morpholin-4-ylmethyl-phenylamine was prepared in an analogous fashion to 2-Methoxy-5-(4-methyl-piperazin-1-ylmethyl)-phenylamine of Example 495a replacing (3-Amino-4-methoxy-phenyl)-(4-methyl-piperazin-1-yl)-methanone with (3-Amino-4-methoxy-phenyl)-morpholin-4-yl-methanone (1.31 g, 73%). LC/MS (E/I+) 223.05 (M+H).
Reaction SMILES: [Na].C(OP([CH:10]([Cl:19])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=O)OCC)C.[CH3:20][C:21]([CH3:25])=[CH:22][CH:23]=O.O>C(O)C.O1CCCC1>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([Cl:19])=[CH:23][CH:22]=[C:21]([CH3:25])[CH3:20])=[CH:16][CH:15]=1
Reactant: CCOP(=O)(OCC)C(Cl)c1ccc(OC)cc1
Reactant: CC(C)=CC=O
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(Cl)=CC=C(C)C)cc1
Reaction time: 1 h
Yield: 56.1 %

Procedure:
4.6 g (0.2 mol) of sodium were dissolved incrementally in 100 ml of dry ethanol. When all the sodium had dissolved, 100 ml of anhydrous tetrahydrofuran were added and 58.4 g (0.2 mol) of 4-methoxy-α-chloro-benzyl-phosphonic acid diethyl ester, dissolved in 50 ml of anhydrous tetrahydrofuran, were added dropwise at 0° C., while stirring. After stirring had been continued at 0°-10° C. for a further 1 hour, 16.8 g (0.2 mol) of β,β-dimethylacrolein, dissolved in 30 ml of anhydrous tetrahydrofuran, were added dropwise, while stirring. Stirring was then continued at room temperature for a further 12 hours. 600 ml of water were then added to the reaction mixture and the mixture was extracted twice with 300 ml of methylene chloride each time. The organic phase was separated off and dried over magnesium sulphate, the solvent was distilled off under a waterpump vacuum and the residue was distilled in vacuo. 25 g of 1-(4'-methoxyphenyl)-1-chloro-4,4-dimethyl-1,3-butadiene (isomer mixture) were obtained as a yellow oil which had a boiling point of 130°-145° C./2 mm Hg and partially crystallized after some time.
Reaction SMILES: CN.[CH3:3][N:4]([CH3:54])[CH2:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:52][CH3:53])=[C:14]([NH:17][C:18]3[N:19]=[C:20]([NH:37][C:38]4[C:39]([C:48]([NH:50][CH3:51])=[O:49])=[CH:40][C:41]5[C:46]([CH:47]=4)=[CH:45][CH:44]=[CH:43][CH:42]=5)[C:21]4[CH:26]=[CH:25][N:24](S(C5C=CC(C)=CC=5)(=O)=O)[C:22]=4[N:23]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7].C[O-].[Na+].[Na+].[Cl-]>O1CCCC1.CO.C1COCC1.C(OCC)(=O)C>[CH3:54][N:4]([CH3:3])[CH2:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:52][CH3:53])=[C:14]([NH:17][C:18]3[NH:23][C:22]4=[N:24][CH:25]=[CH:26][C:21]4=[C:20]([NH:37][C:38]4[C:39]([C:48]([NH:50][CH3:51])=[O:49])=[CH:40][C:41]5[C:46]([CH:47]=4)=[CH:45][CH:44]=[CH:43][CH:42]=5)[N:19]=3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7]
Reactant: CNC(=O)c1cc2ccccc2cc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: CN
Agent: C[O-]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CNC(=O)c1cc2ccccc2cc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)[nH]c2nccc1-2
Temperature: 80 °C
Reaction time: 12 h
Yield: 70.1 %

Procedure:
Filtrates containing 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-3,14-dihydro-7H-6I5-benzo[g]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7-one (generated above) were taken to a residue under reduced pressure, redissolved in tetrahydrofuran, and 2.0M methyl amine in tetrahydrofuran (5 mL) was added. The solution was stirred for 12 hours and all solids were evaporated under reduced pressure to generate crude 3-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-N-methyl-2-naphthalenecarboxamide of sufficient purity for direct use in the subsequent transformations. To a solution of 3-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-N-methyl-2-naphthalenecarboxamide (100 mg, 0.139 mmol) in MeOH/THF (1:1, 10 mL) was added sodium methoxide (113 mg, 2.087 mmol). The resulting solution was warmed to 80° C. for 45 minutes, cooled to room temperature, and poured into saturated aqueous NaCl (50 mL) and diluted with ethyl acetate (25 mL). The organic layer was dried over solid sodium sulfate, filtered, stripped onto celite, and purified by chromatography on SiO2 to give 3-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-N-methyl-2-naphthalenecarboxamide as a yellow solid (0.055 g); 1H NMR (400 MHz, DMSO-d6) δ ppm 11.42 (s, 1H), 11.20 (s, 1H), 9.22 (s, 1H), 8.89-9.00 (m, 1H), 8.58 (s, 1H), 8.26 (s, 1H), 7.78 (d, J=8.06 Hz, 1H), 7.66 (s, 1H), 7.46-7.54 (m, 1H), 7.40-7.46 (m, 1H), 7.34 (t, J=7.42 Hz, 1H), 6.98 (s, 1H), 6.90-6.95 (m, 1H), 6.28 (dd, J=3.02, 1.74 Hz, 1H), 4.16 (t, J=8.33 Hz, 2H), 3.74 (s, 3H), 3.16 (t, J=8.42 Hz, 2H), 2.97 (s, 2H), 2.85 (d, J=4.58 Hz, 3H), 2.00 (s, 6H). ESIMS (M+H)+=565.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([CH3:10])([CH3:9])[C:5](OC)=[O:6].[C:11](#[N:13])[CH3:12].Cl>C1COCC1.O>[F:3][C:4]([CH3:10])([CH3:9])[C:5](=[O:6])[CH2:12][C:11]#[N:13]
Reactant: COC(=O)C(C)(C)F
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(F)C(=O)CC#N
Temperature: 70 °C
Yield: 69.7 %

Procedure:
To a stirred suspension of 60% NaH/mineral oil (12.48 g, 0.31 mol) in dry THF at 75° C. was added dropwise methyl 2-fluoro-2-methylpropanoate (24 g, 0.2 mol) in dry acetonitrile (16 mL, 0.31 mol) over the course of 45 min. The resulting pale yellow suspension was heated at 70° C. overnight, whereupon analysis by TLC indicated a single new product. After cooling to rt, the mixture was poured into water, acidified to pH˜2 with 2N HCl, and extracted with diethyl ether (1 L). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-30% EtOAc in petroleum ether to afford 4-fluoro-4-methyl-3-oxopentanenitrile as a colorless oil (18 g, 72% yield). LC-MS (ESI) m/z 128 (M−H)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([O:12][CH3:13])[CH:6]=1)[CH3:4].[F:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](F)[N:16]=1>CS(C)=O>[CH2:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[N:16]=2)=[C:7]([O:12][CH3:13])[CH:6]=1)[CH3:4]
Reactant: CCc1ccc(O)c(OC)c1
Reactant: Fc1cccc(F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCc1ccc(Oc2cccc(F)n2)c(OC)c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of NaH (1.2 mmol; 50 mg) in anhydrous DMSO (1 mL) under argon, was added 4-ethyl-2-methoxyphenol (1 mmol; 152.2 mg) followed by 2,6-difluoropyridine (1 mmol; 0.1 ml). The reaction mixture was stirred at 120° C. overnight. After quenching with NaOH (0.1N; 3 mL), the mixture was extracted with dichloromethane (3*5 mL). Combined organic phases were dried over Na2SO4, concentrated in vacuo, to give the title compound as a light yellow oil (250 mg; 1 mmol; 100%), used without further purification.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[Cl:13][C:14]1[C:23]([NH2:24])=[C:22]([NH:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.N1C=CC=CC=1.C(OCC)C>C1COCC1>[Cl:13][C:14]1[C:23]2[N:24]=[C:1]([OH:2])[N:25]([CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: Nc1c(Cl)nc2ccccc2c1NCc1cccnc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Oc1nc2c(Cl)nc3ccccc3c2n1Cc1cccnc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
1,1′-Carbonyldiimidazole (3.20 g, 19.7 mmol) was added to 2-chloro-N4-(pyridin-3-ylmethyl)quinoline-3,4-diamine (5.09 g, 17.9 mmol) in THF (100 mL), and the resulting suspension was heated at 80° C. for three days. An analysis by LC/MS indicated the presence of starting material, and pyridine (100 mL) and additional 1,1′-carbonyldiimidazole (1 equivalent) were added. The reaction was stirred for two hours at 80° C., and additional 1,1′-carbonyldiimidazole (1 equivalent) was added. The reaction was stirred overnight at 80° C. and allowed to cool; a solid was present. Diethyl ether (50 mL) was added, and the solid was isolated by filtration and dried under vacuum to provide 4.2 g of 4-chloro-1-(pyridin-3-ylmethyl)-1H-imidazo[4,5-c]quinolin-2-ol as a gray solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2=[O:14])=[CH:7][CH:6]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C1(C)C=CC=CC=1.C(OCC)C.C(=O)(O)[O-].[Na+].C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][C:11]2=[O:14])=[CH:7][CH:6]=1
Reactant: O=C1CCc2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C1C=Cc2ccc(Oc3ccc(C(F)(F)F)cc3Cl)cc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 6-[2-chloro-4-(trifluoromethyl)phenoxy]indan-1-one (200 mg, 0.612 mmol) in toluene (5.0 mL) at 0° C. under nitrogen was added triethylamine (0.104 mL, 0.734 mmol) followed by trimethylsilyl trifluoromethanesulfonate (0.140 g, 0.612 mmol). The reaction warmed to room temperature and stirred for 10 min, then was diluted with diethyl ether and saturated sodium bicarbonate. The aqueous layer was extracted with diethyl ether and the combined organic layers were washed with brine, dried with magnesium sulfate, filtered and concentrated. The resulting residue was dissolved in dichloromethane (1.0 mL) and added via canula at room temperature in the dark to a suspension of Pd(OAc)2 (134 mg, 0.60 mmol) in acetonitrile (4.0 mL). The resulting reaction mixture stirred 1.25 h, then was diluted with diethyl ether, filtered through celite and concentrated to provide the final product as yellow oil which was carried forward without further purification.
Reaction SMILES: [S:1]=[C:2](C(S)C(OCC)=O)[CH3:3].[NH:11]([C:13]([O:15][CH3:16])=[O:14])[NH2:12].C(Cl)(Cl)Cl.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>ClCCl>[S:1]=[C:2]([NH:12][NH:11][C:13]([O:15][CH3:16])=[O:14])[CH3:3]
Reactant: CCOC(=O)C(S)C(C)=S
Reactant: COC(=O)NN
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)NNC(C)=S
Yield: 65.3 %

Procedure:
A mixture of 129 g of 2-(1-thioxoethyl)thioglycolic acid, ethyl ester, 67.5 g of methyl hydrazinocarboxylate and 500 ml of chloroform was heated at reflux for 8 hours, then concentrated in vacuo. The oily residue was concentrated further under high vacuum, giving a yellow oil. This oil was dissolved in 500 ml of dichloromethane and passed through a bed of hydrous magnesium silicate, washing with additional dichloromethane. The resulting light yellow oil was crystallized from toluene-methylcyclohexane, giving 70 g of the desired compound as ivory crystals, mp 99°-100.5° C. Proton nuclear magnetic resonance (δ [ppm], CDCl3) 90 MHz: 2.42 (s, 3H, CH3CS); 3.76 (s, 3H, OCH3); 8.55 (bs, 1H, NH); 9.56 (bs, 1H, NH).
Reaction SMILES: [H-].[Na+].[CH:3]1[CH:8]=CC=C[CH:4]=1.[CH3:9][C:10]12[C:16]([CH3:18])([CH3:17])[CH:13]([CH2:14][CH2:15]1)[CH2:12][C:11]2=[N:19][OH:20].C(Br)C#C>CN(C)C=O.O>[CH2:8]([O:20][N:19]=[C:11]1[CH2:12][CH:13]2[C:16]([CH3:17])([CH3:18])[C:10]1([CH3:9])[CH2:15][CH2:14]2)[C:3]#[CH:4]
Reactant: c1ccccc1
Reactant: CC12CCC(CC1=NO)C2(C)C
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCON=C1CC2CCC1(C)C2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.5 %

Procedure:
4.8 g (0.2 mole) of sodium hydride are added to 150 ml of dry benzene, and a solution of 33.4 g (0.2 mole) of (±)-1,7,7-trimethyl-bicyclo[2,2,1]heptane-2-one-oxime in 50 ml of dimethyl formamide is introduced into the mixture at 50° C. within 0.5 hours. When gas evolution ceases, the mixture is cooled to 25° C., and 23.8 g (0.2 mole) of propargyl bromide are added. The reaction is continued for an additional 2 hours. Thereafter the reaction mixture is shaken with water, the phases are separated, the benzene phase is evaporated, and the residue is subjected to fractional distillation in vacuo. 37.0 g (90.5%) of (±)-2-(propargyloxyimino)-1,7,7-trimethyl-bicyclo[2,2,1]heptane are obtained as a light yellow oil; b.p.: 94°-96° C./1.5 mm Hg, nD20 =1.4953.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl>[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[CH2:38][NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([CH:18]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32]
Reactant: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=Cc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1cc(-c2nn(C3CCN(C4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NCc1ccco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
3-(4-amino-3-methoxyphenyl)-1-[1-(1-methylpiperidin-4-yl)-piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.229 mmol), 2-furaldehyde (0.027 mL, 0.321 mmol), sodium triacetoxyborohydride (193 mg, 0.916 mmol) and glacial acetic acid (55 mg, 0.916 mmol) were mixed with 1,2-dichloroethane (5 mL). The reaction mixture was stirred at room temperature overnight. Saturated sodium bicarbonate solution was added to adjust the pH to about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol/ammonium hydroxide (95:5:0.2) as mobile phase to give 3-{4-[(2-furylmethyl)amino]-3-methoxyphenyl}-1-[1-(1-methylpiperidin-4-yl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (57 mg, 48%). 1H NMR (DMSO-d6) δ 1.45 (m, 2H), 1.71 (m, 2H), 1.87 (m, 4H), 2.14 (s, 3H), 2.28 (m, 5H), 2.80 (m, 2H), 3.01 (m, 2H), 3.86 (s, 1H), 4.37 (d, J=3.13, 1H), 6.76 (d, J=8.62, 1H), 7.07 (m, 2H), 7.57 (s, 1H), 8.19 (s, 1H). LCMS (Finigan-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.0 mL/min.): MH+ 517.3, Rt=2.28 min.