Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([CH3:30])[C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[O:10][C:9]([C:18]1[N:19]=[CH:20][C:21]3[C:26]([CH:27]=1)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8][C:7]2=[N:6][OH:5]
Reactant: CNC
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Product: CN(C)c1ccc2oc(-c3cc4ccccc4cn3)cc(=NO)c2c1

Procedure:
6-dimethylamino-2-isoquinolin-3-yl-chromen-4-one oxime was prepared in 51% overall yield following the method described in example 35, starting from 6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime and dimethylamine (2.0 M in tetrahydrofuran). The title compound was isolated as a pale yellow solid after purification by flash chromatography over silica gel (cyclohexane/ethyl acetate: 0-60%).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]2[CH2:11][O:10]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([O:30][CH3:31])[CH:29]=1)[CH2:25][NH2:26]>CC#N>[CH:1]1([CH2:7][C@H:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C@H:9]([OH:10])[CH2:11][NH:26][CH2:25][C:24]2[CH:27]=[C:28]([O:30][CH3:31])[CH:29]=[C:22]([O:21][CH3:20])[CH:23]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(CN)cc(OC)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H]1CO1
Solvent: CC#N
Product: COc1cc(CNC[C@@H](O)[C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)cc(OC)c1
Yield: 60.9 %

Procedure:
To a solution of tert-butyl (S)-2-cyclohexyl-1-((S)-oxiran-2-yl)ethylcarbamate (67.3 mg, 0.25 mmol) in CH3CN (8 mL) was added 3,5-dimethoxybenzylamine (50 mg, 0.3 mmol) and the mixture was heated under reflux overnight. The solvent was removed in vacuo and the residue was purified by the preparative HPLC to give tert-butyl (2S,3R)-1-cyclohexyl-4-(3,5-dimethoxybenzylamino)-3-hydroxybutan-2-ylcarbamate (66.5 mg, 61%). 1H NMR: 0.82 (m, 1H), 0.95 (m, 1H), 1.10-1.48 (m, 6H), 1.42 (s, 9H), 1.65 (m, 4H), 1.80 (m, 1H), 2.67 (m, 2H), 3.46 (m, 1H), 3.64 (m, 1H), 3.72 (d, 2H), 3.79 (s, 6H), 6.35 (m, 1H). MS (E/Z): 437 (M+H+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>ClCCl>[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([B:9]3[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]3)=[CH:5][CH:4]=2)[CH2:21][CH2:20]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: CN1CCNCC1
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Temperature: 25 °C

Procedure:
A solution of 2-(4-Bromomethyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (60 mg, 212 mmol) in N-methyl piperazine (0.5 mL) was heated at 70-75° C. for 3 h. The reaction mixture was cooled down to RT, diluted with dichloromethane (6 mL), washed with water (2×2 mL), brine (2 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to yield 1-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxborolan-2-yl)-benzyl]-piperazine in reasonably good purity. This boronate ester was used for Suzuki coupling reaction with 3-(4-Iodo-benzyl)-5-(R)-phenyl)-oxazolidin-2-one (40 mg, 105 mmol), without any purification, as described in General Procedure (5). The desired product was isolated as a white solid (28 mg, 60%) by silica gel column chromatography. 1H NMR (300 MHz, CDCl3): δ 7.56 (m, 4H), 7.38 (m, 9H), 5.52 (t, 1H), 4.61 (d, 1H), 4.46 (d, 1H), 3.83 (t, 1H), 3.57 (s, 2H), 3.37 (dd, 1H), 2.53 (bs, 8H), 2.32 (s, 3H). (Note: where N-Boc protected piperazine was used as the base, the final product was obtained by cleaving off the Boc group using trifluoro acetic acid in dichloromethane.)
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[Si:60]([O:67][CH2:68][C:69](OCC#N)=[O:70])([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61]>O.O1CCCC1>[Si:60]([O:67][CH2:68][C:69]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:70])([C:63]([CH3:66])([CH3:65])[CH3:64])([CH3:62])[CH3:61]
Reactant: CC(C)(C)[Si](C)(C)OCC(=O)OCC#N
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.9 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (144 mg, 0.227 mmol) in water (1 ml) and a solution of cyanomethyl 2-(tert-butyldimethylsilyloxy)acetate (Compound 21) (104 mg, 0.453 mmol) in tetrahydrofuran (1 ml) were added to buffer A (30 mL), and the mixture was stirred at room temperature for 2 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (2R,3S,4R,5R)-2-((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-(phosphonooxymethyl)tetrahydrofuran-3-yloxy)(hydroxy)phosphoryloxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-(tert-butyldimethylsilyloxy)acetate (Compound 22) (104.5 mg, 57%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([S:17][CH3:18])=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:30])C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([S:17]([CH3:18])=[O:30])=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2ccc(-c3cccc(Cl)c3)n2n1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(-c3cccc(Cl)c3)n2n1
Temperature: 25 °C

Procedure:
Into a 100 mL round bottom flask, [7-(3-Chloro-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (1.60 g, 0.00580 mol) was dissolved in Methylene chloride (60 mL, 1 mol) and the mixture was treated with m-Chloroperbenzoic acid (1.35 g, 0.00783 mol). The reaction was allowed to stir at room temperature until HPLC showed consumption of starting material. The reaction was partitioned between sodium bicarbinate and DCM. The organic layer was separated, washed with water subsequently with Brine and dried over sodium sulfate. The solution was filtered and reduced. The solid was then triturated with ether to afford 7-(3-Chloro-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid. The product was used as is with mixture of sulfone by-product.
Reaction SMILES: [C:1]([CH2:9][N:10]1[C:15]2[C:16](=[O:25])[N:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:18][C:14]=2[C:13](=[O:26])[N:12]2[N:27]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:29]=[C:11]12)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:37][OH:38].N1C=CC=CC=1>C(O)C>[CH:19]1([N:17]2[CH2:18][C:14]3[C:13](=[O:26])[N:12]4[N:27]=[C:28]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:29]=[C:11]4[N:10]([CH2:9][C:1](=[N:37][OH:38])[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[C:15]=3[C:16]2=[O:25])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(Cn1c2c(c(=O)n3nc(-c4ccccc4)cc13)CN(C1CCCCC1)C2=O)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1c2c(c(=O)n3nc(-c4ccccc4)cc3n2CC(=NO)c2ccccc2)CN1C1CCCCC1
Temperature: 25 °C
Yield: 60 %

Procedure:
A mixture of 4-(benzoylmethyl)-6-cyclohexyl-6,7-dihydro-2-phenyl-4H-pyrazolo[1,5-a]pyrrolo[3,4-d]pyrimidine-5,8-dione (see Example 4), (1.00 g.; 2.15 mmoles) and hydroxylamine hydrochloride (225 mg.; 3.23 mmole), in 4.5 ml of absolute ethanol and 1.5 of pyridine was heated to reflux, becoming homogenous. The solution deposited a precipitate with time, so another 2 ml. of ethanol was added to aid stirring. After a total of eight hours at reflux, the mixture was cooled and diluted with 15 ml. of ethanol. The mixture was suction filtered through a medium glass frit and the collected solid was washed with ethanol and dried in vacuo. The crude solid was suspended in boiling 95% ethanol (400 ml.), and chloroform was added until dissolution was achieved (70 ml.). About 50 ml. of the resulting solvent mixture was then boiled off before cooling to room temperature. This procedure afforded 624 mg. (60% yield) of the titled compound, m.p. >280° C. The NMR spectral analysis of a sample of this material indicated that a 1:1 mixture of the titled oxime isomers had been obtained. 1H NMR (DMSO d6, δ) (mixture of oxime isomers) 12.14 (s, 1H, OH), 11.12 (s, 1H, OH), 8.01 [d, 2H, J=7 Hz, 2-phenyl-H (ortho)], 7.89 (d, 2H, J=7 Hz, oxime-phenyl-H (ortho)], 7.2-7.7 (m, 17H, phenyl-H and pyrazole-H of one isomer), 6.76 (s, 1H, pyrazole-H), 6.12 (bs, 2H, (C(NOH)CH2), 5.72 (bs, 2H, C(NOH)CH2), 4.41 (s, 2H, NCH2), 4.30 (s, 2H, NCH2), 4.0 (m, 2H, cyclohexyl CH of both isomers), 1.1-1.9 (m, 20H, cyclohexyl CH2 of both isomers).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8]CC[N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.Cl.COC[C@H]1CCN1>>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:9][CH2:8][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:25])=[O:26])[CH:20]=[CH:21][CH:22]=2)[N:11]=1
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Agent: COC[C@H]1CCN1
Agent: Cl
Agent: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: COC[C@H]1CCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B35 was prepared following the general procedure reported for B4 using A1 and A6 and obtained as white crystals; yield: 85 mg (26%). MS (ES) C15H20N6O3S requires: 364. found: 365 (M+H)+.
Reaction SMILES: [O:1]1[CH2:3][CH2:2]1.[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:7][CH:6]=1>CO>[F:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:3][CH2:2][OH:1])[CH2:26][CH2:27]2)=[CH:7][CH:6]=1
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: C1CO1
Solvent: CO
Product: OCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 9 parts of oxirane, 3.24 parts of 1-(4-fluorophenyl-methyl)-N-(4-piperidinyl)-1H-benzimidazol-2-amine and 400 parts of methanol was stirred first overnight at room temperature and further for 4 hours at 50° C. The reaction mixture was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 15 parts of 4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2ylamino]-1-piperidineethanol; mp. 138.7° C. (intermediate 93).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:28]=[CH:27][C:13]3[N:14]4[CH:19]=[C:18]([C:20]5[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=5)[N:17]=[C:15]4[S:16][C:12]=3[CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:29]([C:33]1[O:37][N:36]=[C:35]([NH:38][C:39](=O)[O-:40])[CH:34]=1)([CH3:32])([CH3:31])[CH3:30]>>[C:29]([C:33]1[O:37][N:36]=[C:35]([NH:38][C:39]([NH:26][C:23]2[CH:22]=[CH:21][C:20]([C:18]3[N:17]=[C:15]4[N:14]([CH:19]=3)[C:13]3[CH:27]=[CH:28][C:10]([O:9][CH2:8][CH2:7][N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:11][C:12]=3[S:16]4)=[CH:25][CH:24]=2)=[O:40])[CH:34]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)c1cc(NC(=O)[O-])no1
Reactant: Nc1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1
Product: CC(C)(C)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1

Procedure:
reacting 7-(2-morpholin-4-yl-ethoxy)-2-(4-aminophenyl)imidazo[2,1-b]benzothiazole (VIII) with a 5-tert-butylisoxazol-3-ylcarbamate derivative (X) to yield N-(5-tert-butyl-isoxazol-3-yl)-N′-{4-[7-(2-morpholin-4-yl-ethoxy)imidazo[2,1-b][1,3]benzo-thiazol-2-yl]phenyl}urea (I); and
Reaction SMILES: [OH-].[Ca+2:2].[OH-].[CH3:4][C:5]1[C:9]2[C:10](=[O:15])[NH:11][S:12](=[O:14])(=[O:13])[C:8]=2[S:7][C:6]=1[CH3:16]>O>[Ca:2].[CH3:4][C:5]1[C:9]2[C:10](=[O:15])[NH:11][S:12](=[O:14])(=[O:13])[C:8]=2[S:7][C:6]=1[CH3:16]
Reactant: [Ca+2]
Agent: Cc1sc2c(c1C)C(=O)NS2(=O)=O
Agent: [OH-]
Solvent: O
Product: [Ca]

Procedure:
37 mgm (0.5 millimols) of calcium hydroxide and 217 mgm (1 millimol) of 4,5-dimethyl-thieno[3,2-d]isothiazole-3-(2H)-one-1,1-dioxide were added to 50 ml of boiling water. The virtually clear resulting solution was filtered and evaporated to 1 ml. 180 mg (76% of theory) of 4,5-dimethyl-thieno[3,2-d]-isothiazole-3(2H)-one-1,1-dioxide calcium salt crystallized out.
Reaction SMILES: [CH3:1][C@@:2]12[C@@H:10](O)[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH2:13][C:14]3[C@@H:20]([C@H:5]1[CH2:4][CH2:3]2)[CH2:19][CH2:18][C:16](=[O:17])[CH:15]=3.C([O-])(=[O:23])C.CC(OC(C)=O)=O.N#N>C1(C)C=CC=CC=1.C(Cl)Cl.N1C=CC=CC=1>[CH3:1][C@:2]12[CH2:3][CH2:4][C@H:5]3[C@@H:6]([CH2:12][CH:13]([OH:23])[C:14]4[CH:15]=[C:16]([OH:17])[CH:18]=[CH:19][C:20]=43)[C@@H:7]1[CH2:8][CH:9]=[CH:10]2
Reactant: CC(=O)[O-]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Agent: N#N
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C[C@@]12C=CC[C@H]1[C@@H]1CC(O)c3cc(O)ccc3[C@H]1CC2
Yield: 28 %

Procedure:
This synthesis is depicted in FIG. 11. 19-Nortestosterone (XIX) is commercially available, e.g., from Chemical Dynamics Corp. It provides the starting material for 19-Nor-16-androstene derivatives D 19-Nortestosterone (XIX) was converted into the acetate (Hartman, J. A. et al., J. Am. Chem. Soc. (1956) 78:5662) with acetanhydride and pyridine (a) D A solution of this acetate (4.8 g, 15.17 mmol) in toluene (10 ml) was pyrolyzed (b) at 540° (200 Torr, slow N2 -stream) in a glass tube packed with quartz pieces. Chromatography of the crude pyrolysate (3.1 g) on silica gel (150 g) with CH2Cl2 gave 1.1 g (28%) of the homogenous oily ketone 9; +57.9° (C 1) ((27!: m.p. 71°-73°). - IR. (CHCl3): 1660s, 1615m, 1585w, -1 H-NMR. (90 MHz): 0.84 (s, 3 H); 5.82 (m, 2 H); 5.87 (br. s, 1 H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH:16]=[C:15]([CH3:22])[C:14]=2[C:13]=1[C:23]([O:25]C)=[O:24])(=[O:10])=[O:9].[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH2:31]>C(#N)C.C(N(CC)CC)C>[CH3:27][N:28]([CH3:32])[CH2:29][CH2:30][NH:31][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH:16]=[C:15]([CH3:22])[C:14]=2[C:13]=1[C:23]([OH:25])=[O:24])(=[O:9])=[O:10]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1C(C)=CCC2
Reactant: CN(C)CCN
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC1=CCCc2ccc(NS(=O)(=O)c3ccccc3NCCN(C)C)c(C(=O)O)c21
Yield: 103.3 %

Procedure:
A mixture of Example 275E (50 mg, 0.133 mmol), N,N-dimethylethylenediamine (117 μl, 1.06 mmol), and triethylamine (56 mL, 0.4 μmol) in 0.5 mL of acetonitrile was heated to 200° C. for 1200 seconds in a microwave oven. The obtained reaction mixture containing a crude product was purified by reverse phase column chromatography to provide 59 mg of the desired product. MS (ESI(+)) m/e 430 (M+H)+; MS (ESI(−)) m/e 428 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 7.48 (dd, 1H), 7.42 (d, 1H), 7.06 (d, 1H), 6.93 (d, 1H), 6.66-6.76 (m, 2H), 6.10 (t, 1H), 5.99 (t, 1H), 5.75 (s, 3H), 3.59-3.64 (m, 2H), 3.25-3.30 (m, 2H), 2.85 (m, 6H), 2.54-2.56 (m, 2H), 1.96-2.09 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH:16]1([C:19](=[S:21])[NH2:20])[CH2:18][CH2:17]1>>[CH3:1][O:2][C:3]([C:4]1[N:20]=[C:19]([CH:16]2[CH2:18][CH2:17]2)[S:21][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:15]
Reactant: NC(=S)C1CC1
Reactant: COC(=O)C(=O)C(Cl)c1ccc(F)cc1
Product: COC(=O)c1nc(C2CC2)sc1-c1ccc(F)cc1

Procedure:
prepared by reaction of 3-chloro-3-(4-fluoro-phenyl)-2-oxo-propionic acid methyl ester with cyclopropanecarbothioic acid amide. LC-MS: tR=1.01 min; [M+H]+=278.3.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Cl[C:22]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[C:23]([C:26]#[N:27])[C:24]#[N:25]>CCO>[C:26]([C:23]([C:24]#[N:25])=[C:22]([N:18]1[CH2:17][CH2:16][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CC(C#N)=C(Cl)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(C(=C(C#N)C#N)c2ccccc2)CC1
Reaction time: 16 h

Procedure:
Triethyl amine (1 ml) was added into a solution of N-Boc piperazine (1 g) and 2-(chloro(phenyl)methylene)malononitrile (1 g) in EtOH (20 ml). After 16 hours at 115° C., the reaction mixture was cooled down and some of desired product, tert-butyl 4-(2,2-dicyano-1-phenylvinyl)piperazine-1-carboxylate, precipitated out from the solution. After filteration, the mother solution was concentrated to offer a residue which was purified using silica gel chromatography to afford more tert-butyl 4-(2,2-dicyano-1-phenylvinyl)piperazine-1-carboxylate. 1H NMR (500 MHz, DMSO-d6) □7.53 (m, 5H), 3.93 (b, 2H), 3.61 (b, 2H), 3.36 (b, 2H), 3.15 (b, 2H), 1.39(s, 9H); 13C NMR(125 MHz, DMSO-d6) □170.9, 153.6, 132.6, 131.7, 129.1, 129.0, 117.4, 116.7, 79.4, 51.5, 50.33, 42.9, 27.9. MS m/z: (M+H)+ calcd for C19H23N4O2 339.18, found 339.17. Retention time 1.46 min (column A).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)[OH:25])[CH:21]=[CH:22][CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]([O:25][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Reactant: Cc1cccc(C(O)c2cccc(F)c2)c1
Product: Cc1cccc(C(OC(=O)O[C@H]2CN3CCC2CC3)c2cccc(F)c2)c1

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3-fluoro-phenyl)-m-tolyl-methanol.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[Br:13]N1C(=O)CCC1=O.[Br:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[C:27]([CH3:32])[CH:26]=[CH:25]2>C(Cl)(Cl)(Cl)Cl>[Br:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[C:27]([CH2:32][Br:13])[CH:26]=[CH:25]2
Reactant: Cc1ccc2cc(Br)ccc2n1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1ccc2cc(Br)ccc2n1

Procedure:
148 mg (1.00 mmol) α,α-azoisobutyronitrile and 8.01 g (45.0 mmol) N-bromosuccinimide are added successively to a solution of 10.0 g (45.0 mmol) 6-bromo-2-methyl-quinoline in 60 mL carbon tetrachloride. The reaction mixture is refluxed for 8 h. It is filtered and the filtrate is washed twice with water. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (PE/EtOAc 4:1).
Reaction SMILES: Cl.Cl.[CH:3]12[NH:10][CH:7]([CH2:8][CH2:9]1)[CH2:6][CH:5]([NH:11][C:12]([N:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][N:21]=3)[CH2:15]1)=[O:13])[CH2:4]2.CCN(C(C)C)C(C)C.[Si]([N:41]=[C:42]=[O:43])(C)(C)C>C(Cl)Cl>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([NH:19][C@@H:16]2[CH2:17][CH2:18][N:14]([C:12]([NH:11][CH:5]3[CH2:6][CH:7]4[N:10]([C:42]([NH2:41])=[O:43])[CH:3]([CH2:9][CH2:8]4)[CH2:4]3)=[O:13])[CH2:15]2)=[N:21][CH:22]=1)#[N:27]
Reactant: N#Cc1ccc(N[C@@H]2CCN(C(=O)NC3CC4CCC(C3)N4)C2)nc1
Reactant: C[Si](C)(C)N=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N[C@@H]2CCN(C(=O)NC3CC4CCC(C3)N4C(N)=O)C2)nc1
Reaction time: 8 h

Procedure:
To a stirred solution of (3R)—N-(8-azabicyclo[3.2.1]octan-3-yl)-3-(5-cyanopyridin-2-ylamino)pyrrolidine-1-carboxamide dihydrochloride salt (17.5 mg, 0.042 mmol) and i-Pr2NEt (0.032 mL, 0.18 mmol) in CH2Cl2 (1 mL) was added Me3SiNCO (0.008 mL, 0.06 mmol). The mixture was stirred at overnight and concentrated. The residue was purified by prep HPLC to give two isomeric products.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:17]
Reactant: Cc1cccnc1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc[n+]([O-])c1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.4 %

Procedure:
A solution of 2-bromo-3-methylpyridine (10.0 mL, 0.0898 mol) in dichloromethane (150 mL) at 0° C. was treated with mCPBA (˜77%, 22.1 g, 0.0987 mol) in three equivalent portions. The mixture was warmed to room temperature, stirred for 18 hours, cooled to 0° C., and treated with 1N NaOH (50 mL). The organic phase was washed with 1N NaOH and saturated NaHCO3, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with ethyl acetate and 9:1 ethyl acetate/methanol to provide 7.83 g (47%) of the desired product. MS (DCI/NH3) m/z 187.9 (M+H)+; 1H NMR (CDCl3) δ 8.28-8.26 (m, 1H), 7.15-7.09 (m, 2H), 2.46 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]2[N:9]=[C:10]([O:31][C@H:32]3[CH2:35][C@H:34]([NH:36]C(=O)OC(C)(C)C)[CH2:33]3)[C:11]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:15][N:14]([CH2:23][O:24]CC[Si](C)(C)C)[C:12]=3[N:13]=2)[CH:4]=[N:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:36][C@H:34]1[CH2:33][C@H:32]([O:31][C:10]2[C:11]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=4)=[CH:15][N:14]([CH2:23][OH:24])[C:12]=3[N:13]=[C:8]([NH:7][C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[N:9]=2)[CH2:35]1
Reactant: Cn1cc(Nc2nc(O[C@H]3C[C@H](NC(=O)OC(C)(C)C)C3)c3c(-c4ccccn4)cn(COCC[Si](C)(C)C)c3n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(Nc2nc(O[C@H]3C[C@H](N)C3)c3c(-c4ccccn4)cn(CO)c3n2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution tert-butyl {trans-3-[(2-[(1-methyl-1H-pyrazol-4-yl)amino]-5-(pyridin-2-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]cyclobutyl}carbamate (359 mg, 0.592 mmol) in DCM (3 mL) was added trifluoroacetic acid (2 mL) and stirred at ambient temperature for 2 hrs. The reaction was concentrated down to a dark oil to give the title compound that was used as is for next step. m/z (ESI+) for C20H22N8O2 407.0 (M+H)+.