Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9](Br)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:30]1[CH:35]=[N:34][CH:33]=[CH:32][N:31]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(Br)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ncc2c(cc(-c3cnccn3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 49 %

Procedure:
A mixture of 1-benzyl-3-bromo-5-hydroxy-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (80 mg, 0.21 mmol), 2-tributylstannanyl-pyrazine (0.078 mL, 0.25 mmol), and PdCl2(PPh3)2 (29 mg, 0.041 mmol) in DMF (4 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., brine (10 mL) and EtOAc (20 mL) were added. 1 M HCl was added with stirring until pH was about 3-4, and the organic layer was washed with water and brine, and dried over MgSO4. After evaporating the solvent, the crude product was purified by silica gel chromatography (20-100% EtOAc/hexanes+2% AcOH) to give 40 mg of the title compound as a light yellow solid. MS: (+) m/z 389.27 (M+1).
Reaction SMILES: Br[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][C:7]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]([CH3:20])[CH:14]=3)([OH:12])[C:6]=2[CH:5]=[N:4][CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)#[N:22]>>[CH3:20][C:15]1[CH:14]=[C:13]([C:7]2([OH:12])[C:6]3[CH:5]=[N:4][CH:3]=[C:2]([C:26]4[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[CH:24][CH:25]=4)[C:11]=3[CH2:10][CH2:9][CH2:8]2)[CH:18]=[CH:17][C:16]=1[CH3:19]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Cc1ccc(C2(O)CCCc3c(Br)cncc32)cc1C
Product: Cc1ccc(C2(O)CCCc3c(-c4ccc(C#N)cc4)cncc32)cc1C
Yield: 79 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-4-bromo-8-(3,4-dimethylphenyl)-5,6,7,8-tetrahydroisoquinolin-8-ol (intermediate A-3) was reacted with 4-cyanophenylboronic acid to give the title compound as white powder in 79% yield. MS: 355.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:3]=1.[CH3:24]I>>[CH3:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH3:24])[C:6]=2[C:5]([S:15][CH3:16])=[C:4]([CH2:17][C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH:3]=1
Reactant: CSc1c(CC(=O)OC(C)C)cc(C)c2c1[nH]c1ccccc12
Reactant: CI
Product: CSc1c(CC(=O)OC(C)C)cc(C)c2c3ccccc3n(C)c12
Yield: 80 %

Procedure:
Following a procedure and using relative proportions of starting materials similar to those described in Example 4, but using isopropyl (4-methyl-1-methylthiocarbazol-2-yl)acetate and methyl iodide as starting materials, the title compound was obtained in a yield of 80% as an oil.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH:11][NH2:12])=[S:10].[F:13][C:14]([F:24])([F:23])[C:15]1[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=1>>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[NH:8][C:9](=[S:10])[NH:11][N:12]=[CH:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:23])[F:24])=[CH:20][CH:19]=1
Reactant: NNC(=S)NC1CC2C=CC1C2
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(C=NNC(=S)NC2CC3C=CC2C3)cc1

Procedure:
The title compound was prepared from a mixture of N1-bicyclo[2.2.1]hept-5-en-2-ylhydrazine-1-carbothioamide (100 mg, 0.56 mmol) and α,α,α-trifluoro-p-tolualdehyde (76 μL, 0.56 mmol) similar to Example 3 and isolated as a white solid (60 mg, 32%). 1H NMR (CDCl3): 9.14 (s, 1H), 7.78 (s, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.67 (d, J=8.7 Hz, 2H), 7.46 (d, J=7.2 Hz, 1H), 6.25-6.14 (m, 2H), 4.30-4.26 (m, 1H), 3.07 (s, 1H), 2.98 (s, 1H), 1.96-1.88 (m, 1H), 1.69 (d, J=9.0 Hz, 1H), 1.51 (d, J=8.7 Hz, 1H), 1.46-1.40(m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:11][S-:12].[Na+]>CN(C)C=O>[CH3:11][S:12][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc2nccn12
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1cccc2nccn12
Temperature: 20 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
Into 100 ml of dimethylformamide are suspended 5 g of 5-chloroimidazo[1,2-a]pyridine and 5 g of sodium methanethiolate and the mixture is stirred at 20° C. for 1 hour. The solvent is evaporated off under reduced pressure and the residue is dissolved in 200 ml of dichloromethane. The mixture is washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate and purified by silica-gel column chromatography to give 3 g of the above-identified compound as an oil.
Reaction SMILES: [O-]CC.[Na+].[Na].[Cl:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13](=[O:16])[C:12]2=NN>C(O)C>[Cl:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13](=[O:16])[CH2:12]2
Reactant: NN=C1C(=O)Nc2c(Cl)cccc21
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: O=C1Cc2cccc(Cl)c2N1
Temperature: 70 °C

Procedure:
To a solution of sodium ethoxide prepared by heating 5.5 g. of sodium in 200 ml. of ethanol at 70° C. is added 17 g. of 7-chloro-3-hydrazono-oxindole over a period of 3.5 hours, and the resulting solution is heated at 70° C. for 24 hours. The solvent is evaporated in vacuo, the residue dissolved in water, acidified with 6 N. hydrochloric acid and the resulting precipitate recovered by filtering, washed three times with water, dried by suction and crystallized from methylene chloride/ether to obtain 7-chlorooxindole, 218°-220° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li+].CCC[CH2-].[Cl:13][C:14]1[CH:30]=[CH:29][C:17]2[C:18](=[O:28])[C:19]3[N:20]([CH3:27])[C:21]([CH3:26])=[CH:22][C:23]=3[CH2:24][O:25][C:16]=2[CH:15]=1.C[O:32][C:33](=O)[O:34]C>O1CCCC1>[Cl:13][C:14]1[CH:30]=[CH:29][C:17]2[C:18](=[O:28])[C:19]3[N:20]([CH3:27])[C:21]([CH2:26][C:33]([OH:34])=[O:32])=[CH:22][C:23]=3[CH2:24][O:25][C:16]=2[CH:15]=1
Reactant: COC(=O)OC
Reactant: Cc1cc2c(n1C)C(=O)c1ccc(Cl)cc1OC2
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cn1c(CC(=O)O)cc2c1C(=O)c1ccc(Cl)cc1OC2
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a stirred, cooled (0° C.) solution of diisopropylamine (12.5 g, 0.124 m) in dry tetrahydrofuran (40 ml) under a nitrogen atmosphere is added N-butyllithium (0.124 m) and the solution stirred for 10 minutes followed by cooling to -78° C. A mixture of 7-chloro-1,2-dimethyl-4,10-dihydro-10-oxo-1H[1]benzoxepino[4,3-b]pyrrole (31.3 g, 0.12 m), dimethylcarbonate (11.7 g, 0.13 m) and tetrahydrofuran (50 ml) is then added dropwise over 10 min. The bath is then removed and the mixture allowed to warm to room temperature and is stirred for four hours. Water (50 ml) is added and the reaction mixture is further stirred overnight. Aqueous sodium hydroxide is then added and the mixture is filtered. The filtrate is acidified to yield 7-chloro-4,10-dihydro-1-methyl-10-oxo-1H[1]benzoxepino[4,3-b]pyrrole-2-acetic acid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[N:3]=1.[Cl:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:21][CH2:22][N:23]([S:30]([CH2:29][CH2:28][CH2:27][Cl:26])(=[O:32])=[O:31])[CH2:24][CH2:25]2)[N:3]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: O=S(=O)(Cl)CCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Temperature: 5 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (290 mg, 0.72 mmol, Example 59 and 3-chloropropanesulfonyl chloride (165 mg, 0.93 mmol, Aldrich) was treated with diisopropylethyl amine (102 mg, 102 mmol, Aldrich) in methylene chloride (200 mL). This was stirred for 1 hour at 5° C. The reaction was washed with 5% aqueous sodium bicarbonate, dried (MgSO4), and the solvent concentrated in vacuum. This solid was dissolved in tetrahydrofuran, filtered through celite, reduced in volume and triturated with ether to give 300 mg (82%) of [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone as a white solid. HRMS, observed: 486.1375; Calcd for (M+H)+: 486.1373
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:29])=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[C:13]([N+:26]([O-])=O)[CH:12]=3)=[N:8][C:5]2=[N:6][CH:7]=1.[Cl-].[Cl-].[Ca+2]>CCO.[Zn]>[Cl:1][C:2]1[C:3]([Cl:29])=[C:4]2[NH:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[C:13]([CH:12]=3)[NH2:26])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(-c2nc3ncc(Cl)c(Cl)c3[nH]2)ccc1OCCN1CCOCC1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: CCO
Product: Nc1cc(-c2nc3ncc(Cl)c(Cl)c3[nH]2)ccc1OCCN1CCOCC1
Temperature: 70 °C
Yield: 1.1 %

Procedure:
6,7-Dichloro-2-{4-[2-(4-morpholinyl)ethoxy]-3-nitrophenyl}-1H-imidazo[4,5-b]pyridine (Example 246) (200 mg), zinc powder (200 mg) and anhydrous CaCl2 (500 mg) were mixed in 95% EtOH (20 ml) and heated (70° C., 4 h). The reaction mixture was allowed to cool and then filtered and evaporated in vacuo. The residue was dissolved in acetonitrile and subjected to semi-preparative HPLC-C18. The appropriate fraction was evaporated in vacuo and the residue dissolved in EtOAc (5 ml). This solution was washed with saturated aqueous NaHCO3 (5 ml) and brine (2 ml). The organic phase was dried (MgSO4) and evaporated in vacuo to afford the pure product (2 mg, 1%).
Reaction SMILES: Cl.[NH2:2][C@:3]12[CH2:39][CH2:38][C@@H:37]([C:40]([CH3:42])=[CH2:41])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:36])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[C:27]([F:35])[CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1.Cl.Cl[CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1.P(=O)(O)(O)O.[K].[I-].[K+]>C(#N)C>[F:35][C:27]1[CH:26]=[C:25]([C:12]2[C:13]([CH3:23])([CH3:24])[C@H:14]3[C@:9]([CH3:36])([CH2:10][CH:11]=2)[C@@H:8]2[C@:17]([CH3:22])([C@@:18]4([CH3:21])[C@H:5]([CH2:6][CH2:7]2)[C@H:4]2[C@H:37]([C:40]([CH3:42])=[CH2:41])[CH2:38][CH2:39][C@:3]2([NH:2][CH2:45][CH2:46][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:34]=[CH:33][C:28]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=P(O)(O)O
Agent: [I-]
Solvent: CC#N
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 120 °C
Yield: 68.3 %

Procedure:
To a sealable flask containing methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)-2-fluorobenzoate hydrochloride (0.1 g, 0.167 mmol) was added 4-(2-chloroethyl)morpholine hydrochloride (0.093 g, 0.501 mmol), phosphoric acid, potassium salt (0.156 g, 0.735 mmol) and potassium iodide (0.075 g, 0.451 mmol). The mixture was diluted with acetonitrile (3 mL), was flushed with nitrogen, then the vial was sealed and heated to 120° C. After heating the mixture for 16 h, the mixture was cooled to rt. The crude product was adsorbed to silica gel then was purified by flash chromatography using a Thomson 12 g silica gel column and a 0-5% methanol in dichloromethane gradient. The fractions containing the expected product were combined and concentrated under reduced pressure to give methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(2-morpholinoethylamino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (77 mg, 0.114 mmol, 68.3% yield) as an off-white foam. LCMS: m/e 675.5 (M+H)+, 1.91 min (method 2).
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:15](OC)(=[O:21])[CH2:16][C:17]([O:19][CH3:20])=[O:18].C[O-].[Na+]>CO>[CH2:11]([NH:10][C:8]([C:7]1[CH:6]=[CH:5][C:4]([N:1]2[C:15]([OH:21])=[C:16]([C:17]([O:19][CH3:20])=[O:18])[N:3]=[N:2]2)=[CH:14][CH:13]=1)=[O:9])[CH3:12]
Reactant: COC(=O)CC(=O)OC
Reactant: CCNC(=O)c1ccc(N=[N+]=[N-])cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)OC)c2O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.1 %

Procedure:
To a solution of 4-azido-N-ethylbenzamide (3.8 g, 20 mmol) obtained in Example 43a) in methanol (200 ml) was added dimethyl malonate (3.96 g, 30 mmol) at 0-5° C., and then 28% sodium methoxide in methanol solution (5.79 g, 30 mmol) was added. The mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated, and the residue was dissolved in water (50 ml) and adjusted to pH 2-3 with 1N hydrochloric acid. The precipitated crystals were filtered off, and the filtrate was neutralized with 6% aqueous sodium hydrogen carbonate solution. The mixture was concentrated to dryness, methanol (100 ml) was added to the residue, and the insoluble material was filtered off. The filtrate was concentrated to dryness. Ethanol (50 ml) was added to the residue and the precipitated crystals were collected by filtration, and dried to give the title compound as a white powder (2.5 g, 43%).
Reaction SMILES: CCN(C(C)C)C(C)C.[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.Cl[C:32]1[N:40]=[CH:39][N:38]=[C:37]2[C:33]=1[N:34]=[CH:35][NH:36]2>C(O)CCC.CCOC(C)=O>[NH2:10][C:11]1([C:17]([NH:19][C@H:20]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:21][CH2:22][OH:23])=[O:18])[CH2:16][CH2:15][N:14]([C:32]2[N:40]=[CH:39][N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][NH:36]3)[CH2:13][CH2:12]1
Reactant: Clc1ncnc2[nH]cnc12
Reactant: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: NC1(C(=O)N[C@@H](CCO)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]cnc23)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
DIPEA (0.335 mL, 1.92 mmol) was added to (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)piperidine-4-carboxamide (Intermediate 49) (200 mg, 0.64 mmol) and 6-chloro-9H-purine (99 mg, 0.64 mmol) in butan-1-ol (4 mL). The resulting solution was stirred at 60° C. for 18 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (25 mL) and saturated brine (25 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 6% MeOH with ammonia in DCM. Pure fractions were evaporated to dryness to afford (S)-4-amino-N-(1-(4-chlorophenyl)-3-hydroxypropyl)-1-(9H-purin-6-yl)piperidine-4-carboxamide (141 mg, 51.1%) as a white solid.
Reaction SMILES: C[C:2](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:3].[NH2:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([O:34][CH3:35])=[O:33])[CH:27]=1>C(O)=O>[CH:2]([NH:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([O:34][CH3:35])=[O:33])[CH:27]=1)=[O:3]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: COC(=O)c1cc(N)ccn1
Solvent: O=CO
Product: COC(=O)c1cc(NC=O)ccn1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of formic acid (20 g.) and acetic anhyride (41.3 g.) was stirred for 30 minutes at 50° C. and thereto was added methyl 4-amino-2-pyridinecarboxylate (11 g.) at ambient temperature, and then the mixture was stirred for 2 hours at 70°-75° C. After the removal of the solvent from the reaction mixture, the residue was recrystallized from ethanol (160 ml.) to give a pale yellow powder of methyl 4-formamido-2-pyridinecarboxylate (8.3 g.), mp. 185° to 186.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>ClCCl>[C:31]([NH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(NC(=O)c4ccccc4)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
To a solution of methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (300 mg) in dichloromethane (3 ml) was added triethylamine (110 mg). Benzoyl chloride (134 mg) was added under ice-cooling and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane was added to the residue for crystallization, and the crystals were collected by filtration and dried under reduced pressure to give the objective compound (317 mg) as colorless crystals.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][NH:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)C(C)C)(C)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(#N)C>[CH2:2]([O:4][C:5]([C@@H:7]1[C@@H:11]([C:12](=[O:21])[NH:13][C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:10][N:9]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:8]1)=[O:6])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)[C@H]1CNC[C@@H]1C(=O)Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CN(S(C)(=O)=O)C[C@@H]1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 39c (1.44 g; 4.32 mmol) is dissolved in acetonitrile (10 ml) under addition of N,N-diisopropyl ethyl amine (2200 μl; 12.96 mmol). Methanesulfonylchloride (990 mg; 8.64 mmol) is added and the mixture is stirred for 18 h at 25° C. The reaction mixture is evaporated to dryness and purified with silica gel chromatography. Yield: 0.895 g (55.3%), ESI-MS: m/z=375 [M+H]+, Cl-pattern
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][CH2:5][O:4][C:3]1([OH:13])[CH2:7][N:8]1[CH:12]=[N:11][CH:10]=[N:9]1.[OH-].[K+].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1>CS(C)=O.O>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][CH:7]([C:3]2([OH:13])[C:2]([CH3:14])([CH3:1])[CH2:6][CH2:5][O:4]2)[N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:20][CH:19]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: CC1(C)CCOC1(O)Cn1cncn1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)CCOC1(O)C(Cc1ccc(Cl)cc1)n1cncn1
Yield: 39.4 %

Procedure:
10.3 g (0.052 mole) of 3,3-dimethyl-2-hydroxy-2-(1,2,4-triazol-1-yl-methyl)-tetrahydrofuran, 2.9 g (0.052 mole) of potassium hydroxide and 8.4 g (0.052 mole) of 4-chlorobenzyl chloride are stirred in a mixture of 100 ml of dimethylsulphoxide and 6 ml of water at 30° C. for 2 hours. The reaction solution is then poured onto water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate and concentrated. After trituration in n-hexane, the residue crystallizes. 6.6 g (39.5% of theory) of 1-(4-chlorophenyl)-2-(3,3-dimethyl-2-hydroxy-tetrahydrofuran-2-yl)-2-(1,2,4-triazol-1-yl)-ethane of melting point 98° C. are obtained. ##STR98##
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([O:13][CH3:14])=[O:12].[O:15]=[C:16]1[CH2:20][CH2:19][C:18](=[O:21])[N:17]1[O:22][C:23](ON1C(=O)CCC1=O)=[O:24]>C(#N)C>[O:15]=[C:16]1[CH2:20][CH2:19][C:18](=[O:21])[N:17]1[O:22][C:23]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[C:11]([O:13][CH3:14])=[O:12])=[O:24]
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Reactant: COC(=O)n1ncc2c(N)cccc21
Solvent: CC#N
Product: COC(=O)n1ncc2c(NC(=O)ON3C(=O)CCC3=O)cccc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl 4-amino-1H-indazole-1-carboxylate (1.9 g, 10 mmol) and 1-({[(2,5-dioxo-1-pyrrolidinyl)oxy]carbonyl}oxy)-2,5-pyrrolidinedione (2.8 g, 11 mmol) were combined in acetonitrile (100 mL), stirred for 48 hours at ambient temperature, and filtered. The filter cake was washed with acetonitrile (10 mL) and dried under reduced pressure at ambient temperature to provide the title compound.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[CH2:8][CH:7](O)[C:6]2[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:16]([C:3]1([CH2:1][CH3:2])[CH:8]=[CH:7][C:6]2[CH:10]=[C:11]([C:14]#[N:15])[CH:12]=[CH:13][C:5]=2[O:4]1)[CH3:17]
Reactant: CCC1(CC)CC(O)c2cc(C#N)ccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(CC)C=Cc2cc(C#N)ccc2O1
Yield: 69.9 %

Procedure:
A mixture of 2,2-diethyl-3,4-dihydro-4-hydroxy-2H-1-benzopyran-6-carbonitrile (2.28 g) and p-toluenesulfonic acid hydrate (0.19 g) in toluene was refluxed for an hour and 20 minutes with azeotropic removal of the formed water. The reaction mixture was diluted with ethyl acetate, and then washed with water and brine successively. The extract was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified with silica gel column chromatography using a mixture of methylene chloride and n-hexane (1:5) as an eluent to give 2,2-diethyl-2H-1-benzopyran-6-carbonitrile (1.47 g).