Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]([C:7]2[N:16]=[CH:15][C:14]3[N:13]([CH3:17])[C:12](=[O:18])[C@@H:11]([CH2:19][CH3:20])[N:10]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:9]=3[N:8]=2)[CH:4]=[CH:5][N:6]=1.[CH3:26][S:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28].[OH-].[Na+]>COCCOC.O.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>[CH:21]1([N:10]2[C:9]3[N:8]=[C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[C:33]4[CH:34]=[CH:35][C:30]([S:27]([CH3:26])(=[O:29])=[O:28])=[CH:31][CH:32]=4)[N:16]=[CH:15][C:14]=3[N:13]([CH3:17])[C:12](=[O:18])[C@H:11]2[CH2:19][CH3:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3Br)nc2N1C1CCCC1
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCOC
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3ccnc3-c3ccc(S(C)(=O)=O)cc3)nc2N1C1CCCC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 2.1 %

Procedure:
(R)-2-(2-bromo-1H-imidazol-1-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 65, 0.15 g, 0.37 mmol), 4-(methylsulfonyl)phenylboronic acid (0.148 g, 0.74 mmol), aqueous sodium hydroxide (240 μL of 3N) and Pd(PPh3)4 (42 mg, 0.037 mmol) were dissolved in 1.2 mL of DME/H2O (5/1, v/v) and a stream of nitrogen was bubbled through the mixture for 2 minutes. The resulting solution was stirred at 90° C. for 18 h. The reaction mixture was diluted with brine, extracted with EtOAc, dried with Na2SO4 then purified by silica gel column chromatography and preparative HPLC to give to give the title compound (3.8 mg). LCMS: 481.2 m/z (M+H)+; ret. Time: 6.19 min (Analytical Method C).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:14])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=[CH:25][C:24]=1[N+:33]([O-:35])=[O:34]>ClCCl>[OH:14][C:3]1([CH2:2][NH:1][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]=[CH:25][C:24]=2[N+:33]([O-:35])=[O:34])[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:7][CH2:8]1
Reactant: CCOC(=O)N1CCC(O)(CN)CC1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(O)(CNc2c([N+](=O)[O-])cnc3ccccc23)CC1
Reaction time: 18 h
Yield: 68 %

Procedure:
To a solution of ethyl 4-(aminomethyl)-4-hydroxypiperidine-1-carboxylate (22.4 mmol, prepared as described above) in dichloromethane (90 mL) was added triethylamine (3.12 mL, 22.4 mmol) and 4-chloro-3-nitroquinoline (3.71 g, 17.8 mmol). The mixture was sonicated and more dichloromethane (10 mL) was added in order to dissolve the 4-chloro-3-nitroquinoline. The solution was allowed to stand at rt for 18 h, then was poured into a reparatory funnel and washed with 1 M NaOH (25 mL), water (2×30 mL), and brine (30 mL). The organic layer was dried over MgSO4, filtered, and concentrated to yield a yellow foam that was crystallized from isopropanol. The solid was isolated by filtration and dried to afford ethyl 4-hydroxy-4-{[(3-nitroquinolin-4-yl)amino]methyl}piperidine-1-carboxylate as yellow crystals (4.53 g, 54%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][S:18](Cl)(=[O:20])=[O:19])=[CH:13][CH:12]=1)([O-:10])=[O:9]>C(Cl)Cl>[OH:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][NH:1][S:18]([CH2:17][C:14]1[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:16][CH:15]=1)(=[O:19])=[O:20]
Reactant: O=[N+]([O-])c1ccc(CS(=O)(=O)Cl)cc1
Reactant: CC(C)(CN)CO
Solvent: ClCCl
Product: CC(C)(CO)CNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.2 %

Procedure:
A solution of 3.16 g (30.6 mmol) of 3-amino-2,2-dimethylpropanol in 10 mL of CH2Cl2 was added at once to a solution of 2.40 g (10.2 mmol) of 4-nitrophenylmethanesulphonyl chloride (Lee, et al., Journal of the American Chemical Society 1987, 109, 7472-7; Macor, et al., Tetrahedron Letters 1992, 33, 8011-4) in 40 mL of CH2Cl2. The mixture was stirred at rt for 15 min, the solvent was removed in vacuo and the residue was redissolved in 50 mL of EtOAc. The solution was washed with three 50-mL portions of 1.0 N HCl and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (hexane/EtOAc 1:1) afforded N-(3-hydroxy-2,2-dimethyl-propyl)-(4-nitrophenyl)-methanesulfonamide as a white solid (0.84 g, 27%): 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.78 (d, J=6.4 Hz, 2H), 3.11 (d, J=5.3 Hz, 2H), 4.47 (t, J=5.3 Hz, 1H), 4.52 (s, 2H), 7.02 (t, J=6.4 Hz, 1H), 7.65 (d, J=8.8 Hz, 2H), 8.25 (d, J=8.8 Hz, 2H); APCI−MS: m/z 301 (M−H)−. A mixture of 0.66 g (2.2 mmol) of N-(3-hydroxy-2,2-dimethyl-propyl)-(4-nitro-phenyl)-methanesulfonamide and ˜0.06 g Pd/C 10% in 50 mL of MeOH was shaken on a Parr hydrogenator for 3.5 h. The catalyst was removed via filtration, and 0.273 mL (3.28 mmol) of conc. HCl was added. The solvent was removed in vacuo, and the solid residue was redissolved in 20 mL of EtOH and added to 0.486 g (1.98 mmol) of 8-dimethylaminomethylene-6,8-dihydro-1-thia-3,6-diaza-as-indacen-7-one. The mixture was heated to reflux for 4.5 h and cooled to ambient temperature. The solid was collected by vacuum filtration, washed with water, and dried in a vacuum oven at 70° C. to afford the title compound as a yellow solid (0.66 g, 70%): mp 229-230° C. (dec); 1H NMR (DMSO-d6): δ 0.74 (s, 6H), 2.73 (d, J=6.4 Hz, 2H), 3.08 (d, J=5.3 Hz, 2H), 4.27 (s, 2H), 4.43 (t, J=5.3 Hz, 1H), 6.84 (t, J=6.4 Hz, 1H), 7.09 (d, J=8.3 Hz, 1H), 7.37 (d, J=8.5 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 8.03 (d, J=12.3 Hz, 1H), 9.24 (s,1 H), 10.84 (s, 1H), 11.04 (d, J=12.3 Hz, 1H); ESI−MS: m/z 471 (M−H)−. Anal. Calcd for C22H24N4O4S2.0.5 H2O: C, 54.87; H, 5.23; N, 11.63; S, 13.32. Found: C, 54.90; H, 5.26; N, 11.68; S, 13.25.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19]([OH:21])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][C@@H:15]([CH3:17])[C@H:14]([CH2:18][C:19](=[O:21])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: Nc1ccccc1
Reactant: C[C@@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)O
Product: C[C@@H]1Cc2cc(Br)cc3[nH]c(=O)c(=O)n(c23)[C@H]1CC(=O)Nc1ccccc1
Yield: 92.4 %

Procedure:
A procedure similar to that described in Example 5 was carried out with trans-9-bromo-5-carboxymethyl-6-methyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (100 mg, 0.283 mmol) and aniline (28 mL, 0.311 mmol) to give 112 mg of the title compound (92%): mp>300° C.; 1H NMR (270 MHz, DMSO-d6) δ12.08 (s, 1H), 9.99 (s, 1H), 7.55 (d, 2H, J=7.6 Hz), 7.30 (t, 2H, J=7.6 Hz), 7.21 (s, 1H), 7.17 (s, 1H), 7.05 (t, 1H, J=7.6 Hz), 4.92~5.02 (m, 1H), 3.25 (dd, 1H, J=17.8, 5.9 Hz), 2.50~2.66 (m, 3H), 2.28~2.42 (m, 1H), 0.86 (d, 3H, J=6.9 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[C:19]([O:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(O)c(C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(C)cc1C(=O)O
Temperature: 23 °C
Reaction time: 1 h

Procedure:
1 g of 5-methylsalicylic acid (6.58 mmol) and 1.83 ml of tri-ethylamine (2 equivalents) were dissolved in 80 ml of ethyl acetate. At 0° C., 0.94 ml of acetyl chloride (2 equivalents) was added dropwise, and the mixture was then stirred at 23° C. for 1 h. The precipitated salts are [sic] filtered off. 100 ml of 1M HCl were added to the filtrate, which was then stirred overnight. A homogeneous solution formed, and it was adjusted to about pH 4 with saturated NaHCO3 solution. It was then extracted with chloroform, and the organic phase was washed with a little water and dried over MgSO4. The solvent was substantially removed, and the crude product was recrystallized from hexane/ethyl acetate.
Reaction SMILES: [CH2:1]([O:8]CCOC1C=C(C2OC(=O)NCC2)C=CC=1OC)C1C=CC=CC=1.[CH3:27][C:28]([CH3:51])([CH:31]([OH:50])[C:32]1[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH:41]2[CH2:49][C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:42]2)[CH:33]=1)[C:29]#[N:30]>>[CH3:27][C:28]1([CH3:51])[CH:31]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[C:34]([O:40][CH:41]3[CH2:49][C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH2:42]3)[CH:33]=2)[O:50][C:1](=[O:8])[NH:30][CH2:29]1
Reactant: COc1ccc(C(O)C(C)(C)C#N)cc1OC1Cc2ccccc2C1
Reactant: COc1ccc(C2CCNC(=O)O2)cc1OCCOCc1ccccc1
Product: COc1ccc(C2OC(=O)NCC2(C)C)cc1OC1Cc2ccccc2C1
Yield: 75.9 %

Procedure:
According to the same procedure as in Example 1(2) to (3), using 2,2-dimethyl-3-hydroxy-3-[3-(2-indanyloxy)-4-methoxyphenyl]propiononitrile instead of 3-(3,4-dimethoxyphenyl)-3-hydroxypropiononitrile, the above-described compound (yield 75.9%) was obtained as an off white solid.
Reaction SMILES: CS(Cl)(=O)=O.O[C@@H:7]1[C@H:13]2[C@H:14]3[C@H:23]([CH2:24][CH2:25][C@:10]2([CH2:11][CH3:12])[C:9](=[O:27])[CH2:8]1)[C@@H:22]1[C:17](=[CH:18][C:19](=[O:26])[CH2:20][CH2:21]1)[CH2:16][CH2:15]3.CN(C)C=O.C([O-])(=O)C.[Na+]>N1C=CC=CC=1>[CH3:12][CH2:11][C@:10]12[CH2:25][CH2:24][C@H:23]3[C@@H:14]([CH2:15][CH2:16][C:17]4[C@@H:22]3[CH2:21][CH2:20][C:19](=[O:26])[CH:18]=4)[C@@H:13]1[CH:7]=[CH:8][C:9]2=[O:27]
Reactant: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1[C@@H](O)CC2=O
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1C=CC2=O
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
At 0° C., 77.5 ml of methanesulfonyl chloride is added dropwise within 10 minutes to 250 g of 15α-hydroxy-18-methyl-4-estrene-3,17-dione in 704 ml of pyridine. After 3.5 hours, 350 ml of dimethylformamide and 283 g of anhydrous sodium acetate are added, the mixture is stirred under argon for 20 hours at room temperature, and the reaction mixture is introduced into ice water. The thus-precipitated product is suctioned off, washed with water, and dried under vacuum. For purposes of purification, the crude product (212 g) is treated with 21 g of active carbon in 1,500 ml of ethyl acetate and 0.4 ml of pyridine. After concentrating the solution to 420 ml, 188 g of 18-methyl-4,15-estradiene-3,17-dione is crystallized at 0° C. Melting point 156.9° C. (from acetone/hexane).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([P:8]([O:13][CH2:14][CH3:15])(=[O:12])[O:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:28])C>>[CH:1]([C:2]1[CH:3]=[CH:4][C:5]([P:8]([O:13][CH2:14][CH3:15])(=[O:12])[O:9][CH2:10][CH3:11])=[CH:6][CH:7]=1)=[O:28]
Reactant: CC(=O)O
Reactant: CCOP(=O)(OCC)c1ccc(C)cc1
Agent: C1N2CN3CN1CN(C2)C3
Product: CCOP(=O)(OCC)c1ccc(C=O)cc1

Procedure:
Diethyl 4-formyl-benzenephosphonate was prepared in a known manner by bromination of diethyl 4-methyl-benzenephosphonate and subsequent reaction of the product with hexamethylenetetramine in acetic acid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][OH:11])=[CH:5][CH:4]=1)#[N:2].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][O:11][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CCO)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCc2ccc(C#N)cc2)cc1
Yield: 67 %

Procedure:
2-(4-Cyanophenyl)ethanol (1.46 g; 9.9 mmol) and 4-toluenesulfonyl chloride (1.9 g; 10 mmol) were stirred in pyridine (20 mL) at 5° C. for 3 hours. Work-up was performed by removing the solvent, addition of 2M aqueous HCl and extraction with EtOAc. The organic phase was washed with aqueous citric acid, then passed through a short plug of silica gel with Et2O. Removal of the solvent in vacuo afforded a colourless oil, containing ca. 30% of unreacted 2-(4-cyanophenyl)ethanol according to 1H NMR. The oil was further subjected to the reaction conditions above for 2 hours. Work-up as above afforded 2.0 g (66%) of the sub-title compound as a yellow solid.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].Br[C:16]1[CH:17]=[CH:18][C:19]([CH3:22])=[N:20][CH:21]=1>>[CH3:22][C:19]1[N:20]=[CH:21][C:16]([N:5]2[CH2:6][C@@H:1]3[CH2:7][C@H:4]2[CH2:3][N:2]3[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:17][CH:18]=1
Reactant: Cc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Product: Cc1ccc(N2C[C@@H]3C[C@H]2CN3C(=O)OC(C)(C)C)cn1

Procedure:
tert-Butyl (1S,4S)-2,5-diazabicyclo [2.2.1]heptane-2-carboxylate, prepared as described in (J. Med. Chem., (1988) 31, 1598-1611), and 5-bromo-2-methyl-pyridine (purchased from Emka Chemie) were coupled according to the procedure described in Example 1A to provide the title product. MS (DCI/NH3) m/z 290 (M+H)+.
Reaction SMILES: CC(C)C[N:4]1[CH2:8][C:7](=[O:9])[NH:6]C1C1C=CC=CC=1.[OH:17][CH:18]([CH3:23])[CH2:19][C:20]([O-:22])=O>CS(C)=O.O>[CH2:19]1[C:20](=[O:22])[N:4]([CH2:8][C:7]([NH2:6])=[O:9])[CH2:23][CH:18]1[OH:17]
Reactant: CC(C)CN1CC(=O)NC1c1ccccc1
Reactant: CC(O)CC(=O)[O-]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)CN1CC(O)CC1=O

Procedure:
A solution of 0.65 g 2-methylpropyl 2-phenyl-4-oxoimidazolidine-β-hydroxybutanoate in 1.5 ml dimethyl sulfoxide and 0.5 ml water is heated at reflux for 16 h. After evaporating, the residue is chromatographed on silica, eluting with 7:3 ethyl acetate/methanol. Oxiracetam is obtained as a white powder, m.p. 167°-70° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH3:11]O>CC#N.C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CO
Solvent: CC#N
Solvent: ClCCl
Product: COC(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 6-aminonicotinic acid (1.00 g, 7.24 mmol) in MeOH (20 ml) and MeCN (10 ml) was added 10% solution of trimethylsilyldiazolmethane in CH2Cl2 (25 ml) at room temperature. After stirring at room temperature for 0.5 h, the solvent was evaporated to give crude methyl 6-aminonicotinate as a yellow solid. Title compound was prepared from this crude methyl 6-aminonicotinate in 17% yield according to a procedure similar to that described in Preparation 6.
Reaction SMILES: [CH:1]1([C:4]2[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=[C:6]([CH:16]=O)[CH:5]=2)[CH2:3][CH2:2]1.[CH3:18][NH:19][C:20](=[O:33])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH:1]1([C:4]2[C:9]3[O:10][CH:11]([CH3:15])[C:12](=[O:14])[NH:13][C:8]=3[CH:7]=[C:6]([CH2:16][N:30]3[CH2:29][CH2:28][N:27]([C:24]4[CH:23]=[CH:22][C:21]([C:20]([NH:19][CH3:18])=[O:33])=[CH:26][CH:25]=4)[CH2:32][CH2:31]3)[CH:5]=2)[CH2:2][CH2:3]1
Reactant: CNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC1Oc2c(cc(C=O)cc2C2CC2)NC1=O
Product: CNC(=O)c1ccc(N2CCN(Cc3cc4c(c(C5CC5)c3)OC(C)C(=O)N4)CC2)cc1

Procedure:
Using 346A and N-methyl-4-(piperazin-1-yl)benzamide 282 in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.60-0.71 (m, 2H) 0.87-0.95 (m, 2H) 1.43 (d, J=6.82 Hz, 3H) 2.04-2.12 (m, 1H) 2.40-2.48 (m, 4 H) 2.73 (d, J=4.55 Hz, 3H) 3.18-3.26 (m, 4H) 3.36 (s, 2H) 4.61-4.67 (m, 1H) 6.41 (d, J=1.77 Hz, 1H) 6.69 (d, J=1.77 Hz, 1H) 6.93 (m, 2H) 7.69 (m, 2H) 8.14 (q, J=4.21 Hz, 1H) 10.55 (s, 1H). ESI-MS: m/z 435.4 (M+H)+. mp=256.1-258.6° C.
Reaction SMILES: [C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2[C:12]([O:14]CC)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:1]1([C:7]2[S:11][CH:10]=[N:9][C:8]=2[C:12]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:14])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: CCOC(=O)c1ncsc1-c1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NCCNC(=O)c1ncsc1-c1ccccc1
Yield: 60.1 %

Procedure:
4.8 g (20.58 mmol) of ethyl 5-phenyl-4-thiazolecarboxylate and 4.0 g (25.0 mmol) of t-butyl (2-aminoethyl)carbamate were heated under reduced pressure for 21 hours at a bath temperature of 100°, whereby the ethanol formed was distilled off continuously. Subsequently, the mixture was cooled, dissolved in 50 ml of methylene chloride and chromatographed on 150 g of silica gel. Elution was first carried out with methylene chloride, then with a 9:1, 8:2 and finally 7:3 mixture of methylene chloride and ethyl acetate. The fractions which were pure according to the thin-layer chromatogram were combined and recrystallized from ethyl acetate/hexane. In this manner there were obtained 4.3 g (60.1% of t-butyl [2-(5-phenyl-4-thiazolecarboxamido)ethyl]carbamate as white crystals, melting point 139°-140°.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[N+:24]([C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:35]=1[NH:34][N:33]=[CH:32]2)([O-:26])=[O:25]>CN(C=O)C>[F:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:34]3[C:35]4[C:31](=[CH:30][CH:29]=[CH:28][C:27]=4[N+:24]([O-:26])=[O:25])[CH:32]=[N:33]3)[CH2:6][CH2:7]2)=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1cccc2cn[nH]c12
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Cn1ncc2cccc([N+](=O)[O-])c21)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone (0.834 g, 3.3 mmol) was taken in dry DMF (15 mL) and dry potassium carbonate (1.6 g, 11.6 mmol) was added to it and the reaction mixture stirred at room temperature for 1 h under nitrogen. 7-Nitro-1H-indazole (0.5 g, 2.9 mmol) in DMF (2 mL) was then added to the mixture through a syringe. The reaction was then heated at 70° C. for 14 h, cooled and then quenched with water and extracted with ethyl acetate. Drying of the organic layer with Na2SO4 followed by concentration afforded material that was purified on neutral alumina column (pet ether/ethyl acetate). The resulting solid was recrystallized from DCM/pet ether to obtain pure product as a pale yellow solid.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[CH2:16]([O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O)[CH2:17][CH2:18][CH3:19]>>[CH2:16]([O:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOc1cc(F)ccc1B(O)O
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Product: CCCCOc1cc(F)ccc1-c1c(-c2cc(C#N)ccn2)ncn1C

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile (PREPARATION 2) and 2-butoxy-4-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C20H19FN4O, 351. Found, 351.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[N:4]=[C:5]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[C:6]2[CH:11]=[CH:10][N:9](COCC[Si](C)(C)C)[C:7]=2[N:8]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[CH3:1][N:2]([CH3:25])[C:3]1[NH:8][C:7]2=[N:9][CH:10]=[CH:11][C:6]2=[C:5]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[N:4]=1
Reactant: CN(C)c1nc(-c2ccco2)c2ccn(COCC[Si](C)(C)C)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1nc(-c2ccco2)c2ccnc-2[nH]1
Yield: 21.2 %

Procedure:
A solution of N,N-dimethyl4-(2-furyl)-7-(2-trimethylsilylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-amine (370 mg, 0.97 mmol) in THF (3 mL) was treated with tetrabutylammonium fluoride (1 ml, 1-M in THF, 1 mmol), refluxed for 36 h, poured into water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (EtOAc:Heptane, 1:9, alumina) to give the title compound (47 mg, 21%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:16])=[C:5]2[C:9](=[CH:10][CH:11]=1)/[C:8](=[CH:12]/[C:13]([OH:15])=[O:14])/[CH2:7][CH2:6]2.[CH2:17](N(CC)CC)C.[Si](C=[N+]=[N-])(C)(C)C>CO>[CH3:1][O:2][C:3]1[C:4]([CH3:16])=[C:5]2[C:9](=[CH:10][CH:11]=1)[C@@H:8]([CH2:12][C:13]([O:15][CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: CCN(CC)CC
Reactant: COc1ccc2c(c1C)CC/C2=C\C(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Product: COC(=O)C[C@H]1CCc2c1ccc(OC)c2C
Temperature: 25 °C
Reaction time: 24 h
Yield: 771.6 %

Procedure:
To a solution of (2E-)-(5-methoxy-4-methyl-2,3-dihydro-1H-inden-1-ylidene)acetic acid (1.0 g, 4.58 mmol, from Step F) in methanol (10 mL) was added [(S)-(−)-2,2′bis(diphenylphosphino)-1,1′-binaphthyl]ruthenium (II) (36.0 mg, 0.0458 mmol) and triethylamine (64 μL, 0.458 mmol). The resultant mixture was subjected to 3 atm H2 and was shaken at ambient temperature for 24 hr. The reaction mixture was filtered through Celite®, and concentrated in vacuo. The residue was dissolved in THF (5 mL) and methanol (5 mL) and treated with TMSCHN2 (6.51 mL, 13.0 mmol) at ambient temperature. After 1 hr, the reaction mixture was concentrated in vacuo and purified by flash chromatography (3% EtOAc/hexanes) on SiO2 to give 828 mg of the title compound as a colorless liquid: 1H NMR (500 MHz, CDCl3) δ 1.71-1.78 (m, 1H), 2.15 (s, 3H), 2.37-2.46 (m, 2H), 2.73-2.81 (m, 2H), 2.86-2.92 (m, 1H), 3.53-3.59 (m, 1H), 3.73 (s, 3H), 3.82 (s, 3H), 6.69 (d, 1H, J=8.2 Hz), 6.96 (d, 1H, J=8.2 Hz).
Reaction SMILES: C(O[C:9]([N:11]1C=CC=[C:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:12]1[C:24](=[O:49])[CH:25]([N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48])[CH2:26]NC(OCC1C=CC=CC=1)=O)=O)C1C=CC=CC=1.C=O>CO.[Pd]>[O:49]=[C:24]1[N:12]2[C@@H:13]([C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])[NH:12][CH2:24][CH2:25][CH2:26][N:11]2[CH2:9][CH2:26][C@@H:25]1[N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48]
Reactant: CC(C)(C)OC(=O)C1=CC=CN(C(=O)OCc2ccccc2)N1C(=O)C(CNC(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: [Pd]
Agent: C=O
Solvent: CO
Product: CC(C)(C)OC(=O)[C@H]1NCCCN2CC[C@H](N3C(=O)c4ccccc4C3=O)C(=O)N12
Reaction time: 24 h
Yield: 94.6 %

Procedure:
A solution of ester 267 (50 mg, 0.074 mmol) in methanol (15 ml) was treated with 10% palladium on carbon (50 mg) and hydrogenated at room temperature and atmospheric pressure for 24 h. The mixture was evacuated thoroughly to remove hydrogen then treated with 37% aqueous formaldehyde (18 mg, 0.22 mmol) and stirred under nitrogen for 2 h. The mixture was filtered, evaporated to dryness and the product purified by flash chromatography (4-100% ethyl acetate/dichloromethane) to afford 268 14.5 mg (48%) as an oil: 1H NMR (CDCl3) δ 7.85 (2H, m), 7.71 (2H, m), 5.78 (1H, dd, J=10, 5), 4.99 (1H, dd, J=6.1, 1.5), 4.07 (1H, d, J=10.6), 3.49 (1H, dd, J=14, 5), 3.39 (1H, d, J=10.3), 3.24 (1H, dd, J=14, 10.2), 3.17 (2H, m), 2.39 (1H, m), 1.84-1.46 (3H), 1.51 (9H, s); MS (ES+), 415 (M+1), 437 (M+Na).