Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH:17]([OH:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][CH:17]([OH:19])[CH3:18])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 80 °C
Yield: 79.9 %

Procedure:
A mixture of 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.58 mmoles, 1.0 equiv.), 1-bromopropan-2-ol (358 mg, 2.58 mmoles, 1.0 equiv.), and cesium carbonate (1010 mg, 3.09 mmoles, 1.20 equiv.) in DMF (10 mL) was heated in an oil bath at 80° C. for 16 hours. LCMS indicated the reaction complete. The reaction was filtered and concentrated to dryness under high vacuum to give the desired product (520 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH:15]=2)[CH:10]=[N:9][CH:8]=1)(=O)=O.[C:28]([N:31]1[CH2:36][CH2:35][C:34]([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)([OH:37])[CH2:33][CH2:32]1)(=[O:30])[CH3:29]>>[C:28]([N:31]1[CH2:36][CH2:35][C:34]([C:38]2[CH:43]=[CH:42][C:41]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH:15]=4)[CH:10]=[N:9][CH:8]=3)=[CH:40][CH:39]=2)([OH:37])[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: CC(=O)N1CCC(O)(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2cncc(OS(=O)(=O)C(F)(F)F)c2c1
Product: CC(=O)N1CCC(O)(c2ccc(-c3cncc4ccc(C(=O)OCC[Si](C)(C)C)cc34)cc2)CC1
Yield: 99.9 %

Procedure:
Using 2-(trimethylsilyl)ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-6-carboxylate (800 mg, 1.90 mmol) and 1-acetyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidin-4-ol (983 mg, 2.85 mmol) synthesized in Reference Example 10, the desired title compound (931 mg, yield 100%) was obtained by the same method as in Reference Example 4 (4a).
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[O:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH:33]=[C:32]1B(O)O>>[O:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH:33]=[C:32]1[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: OB(O)c1cc2ccccc2o1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1cc2ccccc2o1
Yield: 58 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and benzofuran-2-ylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a yellow solid (58% yield); 1H-NMR (d6-DMSO) 1.08 (9H, s), 3.70 (2H, m), 4.18 (3H, m), 6.68 (1H, s), 6.77 (1H, s), 7.18-7.25 (2H, m), 7.48-7.56 (2H, m); 13C-NMR (CDCl3) 27.7, 41.3, 67.2, 100.7, 110.6, 120.4, 122.8, 123.4, 134.2; MS ES(+) 246.1 (M+-tBu); Anal. Calcd for C17H19NO4: C, 67.76; H, 6.35; N, 4.65. Found: C, 67.34; H, 6.38; N, 4.68. IR λmax=1690 cm−1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:9][C:10]1[C:11]([N+:17]([O-:19])=[O:18])=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:9][C:10]1[C:11]([N+:17]([O-:19])=[O:18])=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:16][CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: ClCCN1CCCC1
Reactant: Cc1cccc(O)c1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Product: Cc1cccc(OCCN2CCCC2)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 63 %

Procedure:
Potassium carbonate (34.9 g., 252 mmol) and sodium iodide (1.0 g., 6.5 mmol) were added to a solution of 3-methyl-2-nitrophenol (10 g., 65.3 mmol). With stirring, 1-(2-chloroethyl)-pyrrolidine hydrochloride (16.65 g., 98 mmol) was added portion-wise to the solution. The reaction mixture was refluxed for 15 hours, at which time 1-(2-chloroethyl)-pyrrolidine hydrochloride (8.5 g., 50 mmol) and potassium carbonate (18 g., 130 mmol) were added. After an additional hour of reflux, the reaction mixture was allowed to cool to room temperature and was washed with sequentially with water (1×100 mL) and brine (1×100 mL.) The combined organic fractions spontaneously crystallized, and the solid was purified by flash chromatography (5% MeOH in CH2Cl2) to give 1-[2-(3-Methyl-2-nitrophenoxy)-ethyl]-pyrrolidine (10.291 g., 69%). MS: 251 (M+H)+
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]3)[CH:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1.ClC(OCC(C)C)=O.C[N:44]1CCOCC1.N>O1CCCC1>[F:34][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([C:27]([NH2:44])=[O:28])[CH2:25][CH2:26]3)[CH:9]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1
Reactant: O=C(O)[C@H]1CC[C@H](Nc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Product: NC(=O)[C@H]1CC[C@H](Nc2cc(-n3c(C(F)F)nc4ccccc43)nc(N3CCOCC3)n2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
trans-4-({6-[2-(Difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)cyclohexanecarboxylic acid (232 mg) was dissolved in tetrahydrofuran (2.3 mL), and isobutyl chloroformate (70 μL) and 4-methylmorpholine (60 μL) were added thereto at 0° C., followed by stirring at 0° C. for 30 minutes and at room temperature for 2 hours. Subsequently, 28% aqueous ammonia (300 μL) was added thereto at 0° C., followed by stirring for 2 hours. The solvent was evaporated under reduced pressure and purified by silica gel chromatography (hexane:ethyl acetate=40:60-0:100 and chloroform:methanol-100:0-95:5) to obtain trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}amino)cyclohexanecarboxamide (230 mg).
Reaction SMILES: [C:1]([C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7](Cl)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C(C#N)=C[CH:19]=[C:18]([C:24]([CH3:27])([CH3:26])[CH3:25])N=1>>[C:1]([C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:19]#[C:18][C:24]([CH3:27])([CH3:26])[CH3:25])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C#N)c(Cl)nc1C(C)(C)C
Reactant: CC(C)(C)c1ccc(C#N)c(Cl)n1
Product: Cc1cc(C#N)c(C#CC(C)(C)C)nc1C(C)(C)C

Procedure:
Procedure analogous to 31, using 62.6 g (300 mmol) of 6-tert-butyl-2-chloro-5-methylnicotinonitrile, S79, instead of 194.7 g (1 mol) of 2-chloro-3-cyano-6-tert-butylpyridine, S28, and scaling the remaining reagents correspondingly on a molar level. Yield: 68.9 g (271 mmol), 90%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([N:48]2[N:52]=[CH:51][CH:50]=[N:49]2)[C:40]=1[C:41](O)=[O:42].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:20][N:19]([CH3:21])[C:11]1[N:10]=[C:9]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][N:3]([C:41]([C:40]4[C:44]([N:48]5[N:52]=[CH:51][CH:50]=[N:49]5)=[CH:45][CH:46]=[CH:47][C:39]=4[F:38])=[O:42])[CH2:2]3)[CH2:7]2)[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[N:12]=1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: CN(C)c1nc(N2C[C@@H]3CCNC[C@@H]32)cc(C(F)(F)F)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: CN(C)c1nc(N2C[C@@H]3CCN(C(=O)c4c(F)cccc4-n4nccn4)C[C@@H]32)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[4-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-6-trifluoromethyl-pyrimidin-2-yl]-dimethyl-amine (Intermediate 11) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 6-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C22H22F4N8O, 490.46; m/z found 491.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.98-7.73 (m, 2H), 7.52-7.28 (m, 2H), 7.19-6.73 (m, 1H), 5.88-5.43 (m, 1H), 4.50-4.24 (m, 1H), 4.21-3.85 (m, 5H), 3.82-3.40 (m, 2H), 3.24-2.77 (m, 6H), 2.31-1.91 (m, 2H).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[CH2:21]([NH2:27])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[CH2:21]([NH:27][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Reactant: CCCCCCN
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCCCCNC1CCc2cc(Oc3ccc(C(N)=O)cn3)ccc21
Yield: 33.8 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 1.11 g, 4.14 mmol), n-hexylamine (502 mg, 4.96 mmol), Ti(iPrO)4 (2.35 g, 8.27 mmol), TiCl4 (1.0M/DCM, 8.27 ml, 8.27 mmol), and NaBH3CN (520 mg, 8.27 mmol) gives the title compound (495 mg) as a tan solid. Mass spectrum (ion spray): m/z=354 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.16 (d, 1H), 7.38 (d, 1H), 6.99 (s, 1H), 6.96 (d, 1H), 6.94 (d, 1H), 5.92 (br. s, 2H), 4.24 (t, 1H), 3.01 (m, 1H), 2.83 (m, 1H), 2.73 (t, 2H), 2.45 (m, 1H), 1.88 (m, 1H), 1.53 (m, 3H), 1.32 (m, 5H), 0.89 (t, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][NH:16][C:17]2[N:22]=[C:21]3[NH:23][N:24]=[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=5)[N:27]=4)[C:20]3=[CH:19][N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>CCO>[Cl:40][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][CH:37]=1)[CH2:33][NH:32][C:28]1[N:27]=[C:26]([C:25]2[C:20]3[C:21](=[N:22][C:17]([NH:16][CH2:15][CH2:14][N:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[N:18][CH:19]=3)[NH:23][N:24]=2)[CH:31]=[CH:30][N:29]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCNc2ncc3c(-c4ccnc(NCc5cccc(Cl)c5)n4)n[nH]c3n2)CC1
Agent: Cl
Solvent: CCO
Product: Clc1cccc(CNc2nccc(-c3n[nH]c4nc(NCCN5CCNCC5)ncc34)n2)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 4-(2-{3-[2-(3-chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino}-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (90 mg, 0.16 mmol) in EtOH (10 mL) was added conc. HCl (5 mL). The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed to afford {3-[2-(3-Chloro-benzylamino)-pyrimidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-(2-piperazin-1-yl-ethyl)-amine; hydrochloride. (Yield 46 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[N:8][CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:3]=1[C:4]#[N:5].ClC1C=CC=C(C(OO)=[O:26])C=1>ClCCl>[Cl:1][C:2]1[CH:9]=[N+:8]([O-:26])[CH:7]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[C:3]=1[C:4]#[N:5]
Reactant: COc1cccc(-c2cncc(Cl)c2C#N)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1cccc(-c2c[n+]([O-])cc(Cl)c2C#N)c1
Yield: 93.9 %

Procedure:
A solution of 3-chloro-5-(3-methoxyphenyl)isonicotinonitrile (1.60 g, 6.54 mmol) and 77% 3-chloroperbenzoic acid (5.86 g, 26.2 mmol) in dichloromethane (60 mL) was stirred at room temperature for 16 h. The mixture was diluted with dichloromethane (100 mL), washed with 1 M sodium sulfite (25 mL), 1 N NaOH (2×25 mL), brined (25 mL), dried (MgSO4) and concentrated to give crude 3-chloro-4-cyano-5-(3-methoxyphenyl)pyridine 1-oxide as white solid (1.60 g). The crude material was used in the next step without purification. MS (ES+) m/z: 261 (M+H); LC retention time: 2.933 min (analytical HPLC Method A).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[N:33]1([CH2:39][CH2:40][C:41](O)=[O:42])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:41](=[O:42])[CH2:40][CH2:39][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)[CH2:31][CH2:32]2)[N:10]=1
Reactant: O=C(O)CCN1CCCCC1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(C(=O)CCN3CCCCC3)CC2)nc1N

Procedure:
The same procedure as described in Example 81 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and 1-piperidine propionic acid (Aldrich) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-3-piperidin-1-yl-propan-1-one. MS (M+H)+: 485.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([N:13]2[C:17]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[CH:16][C:15]([C:23]([F:26])([F:25])[F:24])=[N:14]2)[CH:8]=1)(=O)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C=O)C>[N:27]([CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([N:13]2[C:17]([C:18]3[O:19][CH:20]=[CH:21][CH:22]=3)=[CH:16][C:15]([C:23]([F:26])([F:25])[F:24])=[N:14]2)[CH:8]=1)=[N+:28]=[N-:29]
Reactant: CS(=O)(=O)OCc1ccnc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccnc(-n2nc(C(F)(F)F)cc2-c2ccco2)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To a stirred solution of 38 (0.695 mmol) in DMF (4.6 mL) at room temperature was added sodium azide (136 mg, 2.085 mmol) drop wise. The resulting solution was allowed to stir for 1 h at 60° C. The mixture was quenched with water and extracted with ethyl acetate, washed with brine (two times), dried (MgSO4) filtered and concentrated. Compound 39 (205 mg, 88%) was isolated as a brown oil and used as is for the next step. LRMS (ESI): calc. 334.1; found 335.1 (MH)+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH3:8][CH:9]([CH:11]([OH:16])[CH2:12][C:13]([CH3:15])=[CH2:14])[CH3:10].[N+]([C:20]1[CH:27]=[CH:26][CH:25]=[C:22]([C:23]#[N:24])[C:21]=1[C:28]#[N:29])([O-])=O>C1(C)C=CC=CC=1.O>[CH3:8][CH:9]([CH:11]([O:16][C:20]1[CH:27]=[CH:26][CH:25]=[C:22]([C:23]#[N:24])[C:21]=1[C:28]#[N:29])[CH2:12][C:13]([CH3:15])=[CH2:14])[CH3:10]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Reactant: C=C(C)CC(O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)CC(Oc1cccc(C#N)c1C#N)C(C)C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
9.6 g (0.24 mol) of 60% sodium hydride and 150 ml of N,N-dimethylformamide were placed in a container equipped with a stirrer, a reflux condenser and a nitrogen-introducing tube, and the solution was then stirred under the feed of nitrogen. Afterward, 32 g (0.25 mol) of 2,5-dimethyl-5-hexene-3-ol was added dropwise thereto at 20°-30° C. over 1 hour, and the solution was then stirred at the same temperature for 3 hours to prepare a sodium alcoholate solution. Next, 34.6 g (0.2 mol) of 3-nitrophthalonitrile and 150 ml of N,N-dimethylformamide were placed in a container equipped with a stirrer, and the above-mentioned sodium alcoholate solution was then added dropwise at 0° C. or less over 5 hours. After completion of the addition, the temperature of the solution was raised up to a level of 20°-30° C., and the solution was then stirred for 2 hours to bring reaction to an end. The thus obtained reaction solution was poured into 3 l of water and then stirred for 30 minutes, and 500 ml of toluene were added. After stirring for 30 minutes, the solution was allowed to stand to separate a toluene layer. After toluene was distilled off under reduced pressure, recrystallization was carried out from 500 ml of n-hexane to obtain 43.7 g of 3-(2,5-dimethyl-5-hexene-3-oxy)phthalonitrile (yield =86.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:17]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[S:20][C:18]=2[N:19]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(Cl)nc2s1
Product: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1OC

Procedure:
Following the procedure of Example 1, the reaction of 3,4-dimethoxybenzylamine with 2,4dichloro-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-chloro-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([C:3]1[C:4]([N:10]=[CH:11][N:12](C)C)=[N:5][C:6]([CH3:9])=[CH:7][CH:8]=1)#[N:2].[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([S:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:20](N)[CH:21]=1>C(O)(=O)C>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([S:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[C:20]([NH:2][C:1]2[C:3]3[CH:8]=[CH:7][C:6]([CH3:9])=[N:5][C:4]=3[N:10]=[CH:11][N:12]=2)[CH:21]=1
Reactant: Cc1ccc(Sc2ccccc2)c(N)c1
Reactant: Cc1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: Cc1ccc(Sc2ccccc2)c(Nc2ncnc3nc(C)ccc23)c1
Temperature: 25 °C

Procedure:
To a solution of the product from Example 10B (90 mg, 0.517 mmol) and the product from Example 5I (122 mg, 0.569 mmol) in acetic acid (1 mL) was heated at 130° C. for 1 hour. The mixture was then allowed to cool to room temperature, the resulting solid collected and washed with methanol, then dissolved 50 mg of the material in dioxane (2 mL) and added hydrochloric acid followed by removal of the solvent under vacuum to provide the title compound as a hydrochloride salt. 1H NMR (300 MHz, DMSO-D6) δ ppm: 2.37 (s, 3H), 2.74 (s, 3H), 7.18 (m, 5H), 7.24 (m, 1H), 7.37 (m, 2H), 7.81 (d, J=8.5 Hz, 1H), 8.80 (s, 1H), 8.99 (d, J=8.5 Hz, 1H), 11.82 (bs, 1H); MS (ESI)+ m/z 359 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[CH3:39]C1C=C(CC(=O)C(OCC)=O)C=CC=1.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[C:26]([CH3:39])[CH:25]=[CH:24][CH:23]=2)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Cc1cccc(C)c1
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: CCOC(=O)/C(=C/c1cccc(C)c1)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 19 %

Procedure:
The title compound was prepared as described for C4 using ethyl 3-(3-methylphenyl)-2-oxopropanoate B18 (100 mg, 0.485 mmol), sodium hydride (11.64 mg, 0.485 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-glucose bromide (199 mg, 0.485 mmol). The compound was isolated in the form of white solid in 19% yield.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.O.[CH3:23]O>C1COCC1>[CH3:23][O:20][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)=[CH:14][CH:15]=1)=[O:21]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(-c2ccc(O)cc2)cc1
Yield: 86 %

Procedure:
Concentrated sulfuric acid (approximately 4 ml) was carefully added to a solution of 4'-hydroxy-4-biphenylcarboxylic acid (Aldrich) (8.20 g, 38.3 mmol) in 1 liter of methanol. The reaction mixture was refluxed for three days and the solvent was evaporated. The resulting solid was filtered, washed with water, and recrystallized as follows. The crude solid was dissolved in a minimum amount of hot THF, and approximately three equivalents of methanol was added to the solution. The solution was brought to a boil, and water was added with vigorous stirring until the solution remained cloudy. After cooling, the tan precipitate was filtered, washed with cold ethanol, and air dried to yield 7.57 g (86%) of a tan solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C@@H:16]2[O:30][C:20]3=[C:21]4[C:26](=[CH:27][CH:28]=[C:19]3[O:18][CH2:17]2)[N:25]=[C:24]([CH3:29])[CH:23]=[CH:22]4)=[CH:4][CH:3]=1.[C:31]([BH3-])#N.[Na+].[ClH:35]>C=O.C(O)(=O)C.CO.C(OCC)(=O)C.CCOCC>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH2:13][N:14]([CH3:31])[CH2:15][CH:16]2[O:30][C:20]3=[C:21]4[C:26](=[CH:27][CH:28]=[C:19]3[O:18][CH2:17]2)[N:25]=[C:24]([CH3:29])[CH:23]=[CH:22]4)=[CH:4][CH:3]=1.[ClH:35]
Reactant: [BH3-]C#N
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CNCCCn1ccc2ccc(F)cc21)O3
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN(C)CCCn1ccc2ccc(F)cc21)O3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of [3-(6-fluoro-indol-1-yl)-propyl]-[(2S)-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl]-amine (0.53 g, 1.3 mmol) in 1.05 mL of formaldehyde, 0.11 mL of acetic acid and 20 mL of methanol was added to 95% sodium cyanoborohydride (0.13 g, 1.9 mmole). The mixture was allowed to stir at room temperature under nitrogen overnight. The mixture was partitioned between 400 mL each of methylene chloride and water. The organic portion was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was then column chromatographed on silica gel using 55% ethyl acetate/44% hexane/1% methanol as eluant. The product-containing fractions were concentrated under vacuum to give a yellow oil, which was dissolved in ethyl acetate and treated with excess HCl in ether to give 0.040 g of the (S)-enantiomer of the title compound as a yellow hydrochloride, m.p. 75.9-83.7° C.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH3:27].[C:28]1([OH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH3:27][C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:34][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Oc1ccccc1
Reactant: CCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(Oc2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 13.6 %

Procedure:
A mixture of 4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g), phenol (0.16 g), 8 M potassium hydroxide solution (0.2 mL) and dimethyl sulfoxide (5 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.07 g, 13%).