Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20]>>[CH:22]1([O:21][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)OC4CCCC4)cc23)CC1
Yield: 93 %

Procedure:
Beginning with 13 mg (0.0567 mMol) 5-amino-3-(1-methyl-piperidin-4-yl)-1H-indole and 9.27 mg (0.062 mMol) cyclopentyl chloroformate, 18.1 mg (93% of the title compound were recovered.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:59])[C:5]([C@@:7]1([CH3:58])[CH:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6].[C:60](OCC)(=[O:62])[CH3:61]>>[CH3:1][C:2]1[C@@H:19]([O:20][C:21]([C@H:23]([OH:40])[C@@H:24]([NH:31][C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)=[O:33])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:22])[CH2:18][C@:14]2([OH:41])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:59][C:60]([CH3:61])=[O:62])[C:5]([C@@:7]1([CH3:58])[C@H:12]([C@@H:13]2[O:42][C:43]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)=[O:44])[C@:11]2([O:53][C:54]([CH3:56])=[O:55])[CH2:51][O:52][C@@H:10]2[CH2:9][C@@H:8]1[OH:57])=[O:6]
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C[C@@](O)([C@@H](OC(=O)c4ccccc4)C12)C3(C)C
Reactant: CCOC(C)=O
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Reaction time: 24 h
Yield: 100 %

Procedure:
After 19 hrs of reaction, 0.36% of 7-TES-taxol remained in this mixture. After 24 hrs, 7-TES-taxol and 10-desacetyl-taxol were not present (impurity index II<0.04%) in the reaction mixture. The solution was then diluted with ethyl acetate (1 L) and washed with 1N HCl (800 ml×2). The combined aqueous layer was extracted with ethyl acetate (400 ml×1). The organic layers were combined and washed with saturated aqueous sodium bicarbonate solution (800 ml×5), brine (300 ml×1), dried over sodium sulfate, filtered and concentrated to give 17.46 g (˜100%) of crude taxol as a white solid. The HPLC HI for the crude taxol obtained above was 98.7%. The yield is uncorrected.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([NH:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5[N:26]=[CH:27][N:28](C(C6C=CC=CC=6)(C6C=CC=CC=6)C6C=CC=CC=6)[CH:29]=5)[CH:20]=4)=[O:17])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.CO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:28]1[CH:29]=[C:25]([C:21]2[CH:20]=[C:19]([NH:18][C:16]([C:13]3[CH:12]=[CH:11][C:10]4[CH:9]=[C:8]5[C:2](=[O:1])[NH:3][CH2:4][CH2:5][CH2:6][N:7]5[C:15]=4[CH:14]=3)=[O:17])[CH:24]=[CH:23][CH:22]=2)[N:26]=[CH:27]1
Reactant: O=C(Nc1cccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)c1)c1ccc2cc3n(c2c1)CCCNC3=O
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(-c2c[nH]cn2)c1)c1ccc2cc3n(c2c1)CCCNC3=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a solution of the crude 1-oxo-N-[3-(1-trityl-1H-imidazol-4-yl)phenyl]-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxamide from the preceding step in CH2Cl2 (1.5 mL) and methanol (1.5 mL) is added TFA (1.0 mL). The reaction is stirred for 16 h at room temperature. The solvents are evaporated and the crude material is purified by preparative HPLC using 10-80% acetonitrile/water with 0.1% TFA to afford the title compound (43 mg, 35% for 2 steps). LCMS (ESMS): m/z 386.20 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[CH2:26][CH2:25][NH:24][C:14]=3[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[N:17]=2)[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[C:42](Cl)(=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>O.C(#N)C>[C:1]([O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:13]3[CH2:26][CH2:25][N:24]([C:42]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[O:49])[C:14]=3[N:15]=[C:16]([N:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[N:17]=2)[CH:9]=[CH:10][CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3)c1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccccn1
Solvent: O
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)(C)Oc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 90.2 %

Procedure:
To an acetonitrile solution (2 ml) of 4-(3-t-butoxyphenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (36 mg), an acetonitrile solution (1 ml) of pyridine (25 μl, 3 equivalents), dimethylaminopyridine (ca. 2 mg, catalytic amount) and benzoyl chloride (28 mg, 2 equivalents) was added under ice cooling, followed by stirring at room temperature for 10 hours. To the reaction mixture, water (20 ml) was added, followed by extraction with ethyl acetate (10 ml×2). The organic layer was washed with aqueous ammonium chloride solution and brine, and subsequently dried over sodium sulfate. After filtering off the drying agent, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative TLC (n-hexane/ethyl acetate=2/1), to obtain the desired compound as a colorless powder (42 mg, 90%).
Reaction SMILES: [SH:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][N:3]=1.CN(C)P(=O)(N(C)C)N(C)C.C[Si](C)(C)N[Si](C)(C)C.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1>[CH2:28]([S:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][N:3]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: BrCc1ccccc1
Reactant: Cc1nnc(S)s1
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1nnc(SCc2ccccc2)s1
Reaction time: 0.17 h

Procedure:
2.0 mg (0.004 mmoles) of di-4-nitrophenyl N-(4-toluenesulfonyl)phosphoramidate were added to a solution of 264 mg (2 mmoles) of 5-mercapto-2-methyl-1,3,4-thiadiazole in 5 ml of toluene and 1.06 ml (6.1 mmoles) of hexamethylphosphoric triamide and then while refluxing, 0.50 ml (2.4 mmoles) of hexamethyldisilazane were added. After refluxing for 1.5 hours, the solution was evaporated to dryness and the residue was dissolved in 4 ml of acetonitrile. 0.28 (2.3 mmoles) of benzyl bromide were added to the solution and it was established that the conversion was complete after stirring for 10 minutes. HPLC analysis of the reaction mixture indicated a quantitative yield of 5-benzylthio-2-methyl-1,3,4-thiadiazole.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].[F:24][C:25]([F:45])([F:44])[C:26]([C:29]1[O:33][N:32]=[C:31]([NH:34][C:35](=O)[O:36]C2C=CC=CC=2)[CH:30]=1)([CH3:28])[CH3:27]>C1COCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:35]([NH:34][C:31]2[CH:30]=[C:29]([C:26]([CH3:28])([CH3:27])[C:25]([F:45])([F:44])[F:24])[O:33][N:32]=2)=[O:36])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: CC(C)(c1cc(NC(=O)Oc2ccccc2)no1)C(F)(F)F
Reactant: COc1cc2ncnc(Oc3cc(N)ccc3F)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)ccc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 15 h
Yield: 14 %

Procedure:
To a stirred solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluoroaniline from the previous step (150 mg, 0.476 mmol) and phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 260A (179 mg, 0.571 mmol) in anhydrous THF (5 mL), was added 4-(dimethylamino)pyridine (6 mg, 0.0492 mmol) and the mixture was stirred at rt for 15 h. Concentration in vacuo followed by purification via silica gel column chromatography (eluted with a gradient of 20% ethyl acetate in hexanes to 100% ethyl acetate), afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)-4-fluorophenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (35 mg, 14%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 9.79 (brs, 1H), 9.01 (s, 1H), 8.58 (s, 1H), 7.70 (m, 1H), 7.58 (s, 1H), 7.30-7.42 (m, 3H), 6.86 (s, 1H), 4.00 (s, 6H), 1.54 (s, 6H); LC-MS (ESI) m/z 536 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[Si]([O:28][CH2:29][CH:30]1[CH:34]([CH2:35][O:36][Si](C(C)(C)C)(C)C)[CH2:33][C:32]([CH2:44]Br)=[CH:31]1)(C(C)(C)C)(C)C>>[OH:28][CH2:29][CH:30]1[CH:34]([CH2:35][OH:36])[CH2:33][C:32]([CH2:44][N:8]2[C:9]([O:10][C:11]3[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]2=[O:19])=[CH:31]1
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CC(C)(C)[Si](C)(C)OCC1C=C(CBr)CC1CO[Si](C)(C)C(C)(C)C
Product: Cc1cc(C)cc(Oc2c(C(C)C)c(=O)[nH]c(=O)n2CC2=CC(CO)C(CO)C2)c1
Yield: 17.5 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and [3,4-di(t-butyldimethylsilyloxymethyl)cyclopent-1-en-1-yl]methyl bromide were reacted by the same method with example 28 to obtain the titled compound (48 mg).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH:24]C(=O)C(Cl)(Cl)Cl)[C:14]=2[N:13]=[C:12]1[CH2:31][CH2:32][CH2:33][CH3:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:23]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:24])[C:14]=2[N:13]=[C:12]1[CH2:31][CH2:32][CH2:33][CH3:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCc1nc2c(NC(=O)C(Cl)(Cl)Cl)nc3ccccc3c2n1CCOCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCOCc1ccccc1
Yield: 7.3 %

Procedure:
Using the general method of example 1 Part D, N-{1-[2-(benzyloxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-yl}-2,2,2-trichloroacetamide (3.3 g, 6.39 mmol) was hydrolyzed with sodium methoxide (5 mL of 25% in methanol). The resulting tan solid was purified by chromatography over silica gel (98/2 dichloromethane/methanol), recrystallized from methanol and dried under vacuum at 60° C. for 18 hours to provide 0.174 g of 1-[2-(benzyloxy)ethyl]-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 133-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([CH:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([N:19]4[C:23]5[CH2:24][CH2:25][CH2:26][C:22]=5[C:21]([C:27]([O:29]CC)=O)=[N:20]4)=[C:15]([C:32]([F:35])([F:34])[F:33])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.[NH3:39].Cl>CO>[NH2:39][C:27]([C:21]1[C:22]2[CH2:26][CH2:25][CH2:24][C:23]=2[N:19]([C:16]2[CH:17]=[CH:18][C:13]([C:12]([NH:11][CH:9]([C:7]3[NH:6][C:5]4[CH:37]=[CH:38][C:2]([Cl:1])=[CH:3][C:4]=4[N:8]=3)[CH3:10])=[O:36])=[CH:14][C:15]=2[C:32]([F:35])([F:34])[F:33])[N:20]=1)=[O:29]
Reactant: CCOC(=O)c1nn(-c2ccc(C(=O)NC(C)c3nc4cc(Cl)ccc4[nH]3)cc2C(F)(F)F)c2c1CCC2
Reactant: N
Agent: Cl
Solvent: CO
Product: CC(NC(=O)c1ccc(-n2nc(C(N)=O)c3c2CCC3)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Temperature: 65 °C
Reaction time: 17 h

Procedure:
130 mg (0.19 mmol) of rac.-N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-4-[3-(ethoxycarbonyl)-5,6-dihydro-4H-cyclopentapyrazol-1-yl]-3-trifluoromethylbenzamide is dissolved in 5 mL of methanol, combined with 6 mL of concentrated ammonia solution, and stirred for 17 hours at 65° C. in a Schlenk flask. The cooled reaction solution is poured onto ice water, adjusted to pH 7.5 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phases are dried and concentrated by evaporation. The residue is chromatographed on silica gel, eluting with ethyl acetate/ethanol (0%-5%). Yield: 50 mg (51%); Rf value: 0.38 (silica gel; ethyl acetate/ethanol=9:1); C24H20ClF3N6O2 (516.91); mass spectrum: (M−H)−=515/517 (chlorine isotope).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=3)[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C@@H:20]([C:24]1[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1)[CH2:21][CH2:22][OH:23].C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:30][C:27]1[N:26]=[CH:25][C:24]([C@H:20]([NH:19][C:2]2[C:3]3[CH2:11][N:10]([C:12]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=4)[CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:21][CH2:22][OH:23])=[CH:29][CH:28]=1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)nc1
Reactant: Cc1ccc([C@H](N)CCO)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CCO)c4ccc(C)nc4)c3C2)nc1

Procedure:
A reaction mixture of 4-chloro-5,6,7,8-tetrahydro-6-(5-methylpyridin-2-yl)pyrido[4,3-d]pyrimidine (35 mg, 0.14 mmol) and (R)-3-amino-3-(6-methylpyridin-3-yl)propan-1-ol (15 mg, 0.090 mmol) in acetonitrile (1.5 mL) and N,N-diisopropylethylamine (31 μL, 0.18 mmol) was subjected to microwave irradiation at 180° C. for 2 h. The reaction mixture was concentrated and purified by semi-prep HPLC ((100×20.2 mm, C18 column; 30-60% CH3CN-water [10 mM Et2NH]) to give a light yellow foam. LC-MS: 391.4 [M+H]+.
Reaction SMILES: [C:1]([CH:6]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:3][CH2:4][CH3:5])=[O:2].[CH:26]1([OH:35])[CH:34]2[CH:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:28]O1>C(#N)C>[OH:35][CH2:26][CH:34]1[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]1/[CH:28]=[CH:6]/[C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: OC1OCC2CCCCC21
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: CCOC(=O)/C=C/C1CCCCC1CO
Temperature: 85 °C
Reaction time: 2 h

Procedure:
DIBAL-H (1M in toluene) (35.2 mmol, 35.2 mL) was added dropwise to a solution of hexahydroisobenzofuran-1(3H)-one (33.5 mol, 4.7 g) in anhydrous ether (100 mL) at −10° C. under argon. The resulting mixture was stirred at −10° C. for 30 min under argon and quenched with MeOH (30 mL). The mixture was stirred at rt for overnight and the resulting suspension was added saturated Rochelle's salt aqueous solution and stirred for additional 30 min at rt. The organic layer was separated and washed with saturated Rochelle's salt aqueous solution. The combined aqueous layer was extracted with ether (3×). The organic layer were combined, dried with dried with MgSO4 and concentrated in vacuo to give lactol octahydroisobenzofuran-1-ol which was used for next step without further purification. (Carbethoxymethylene)triphenylphosphorane (17.7 g, 50.7 mmol) was added to a solution of the above described octahydroisobenzofuran-1-ol in acetonitrile (100 mL) and the resulting mixture was refluxed at 85° C. overnight. Acetonitrile was removed in vacuo and the resulting residue was diluted with ether which was stirred at rt for 2 h. The white precipitate was filtered off and washed with cold ether. All ether portion was combined and concentrated in vacuo to give crude product which was purified by chromatograph to afford desired (E)-ethyl 3-(2-(hydroxymethyl)cyclohexyl)acrylate as colorless oil (Y: 78.9% over two steps). 1H NMR (CDCl3, 400 MHz) δ 7.12-7.05 (m, 1H), 5.80 (d, 1H), 4.15-4.09 (m, 2H), 3.40-3.37 (m, 2H), 2.63-2.59 (m, 1H), 1.80-1.29 (m, 9H), 1.25-1.19 (m, 3H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.N([O-])=O.[Na+].C(OCC)C.[F:21][B-](F)(F)F.[H+]>>[F:21][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: F[B-](F)(F)F
Reactant: Nc1ccc2ncccc2c1
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: CCOCC
Product: Fc1ccc2ncccc2c1
Reaction time: 1 h

Procedure:
To a solution of 6-aminoquinoline (1.0 g) in 42% tetrafluoroboric acid (5 ml), sodium nitrite (527 mg) was added under ice cooling and stirred at the same temperature for 1 hour. After addition of diethyl ether:ethyl acetate=1:1 (10 ml), the reaction mixture was decanted and the precipitate was dried. To the dried product, toluene (20 ml) was added and heated under reflux for 2 hours. The reaction mixture was decanted, and the resulting residue was dissolved in 1M aqueous hydrochloric acid and alkalized with saturated aqueous sodium carbonate. Insoluble materials were filtered off and the filtrate was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:diethyl ether=4:1 to 1:1) to give 6-fluoroquinoline (273 mg) as an orange-colored oil. To a solution of 6-fluoroquinoline thus obtained (273 mg) in methanol (50 ml), 10% palladium on activated carbon (50 mg) was added and stirred overnight under a hydrogen atmosphere (60 psi) at room temperature. After the reaction mixture was filtered, the solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (eluting solvent: n-hexane:ethyl acetate=10:1 to 4:1) to give the titled compound, i.e., 6-fluoro-1,2,3,4-tetrahydroquinoline (172 mg) as a light-brown oil.
Reaction SMILES: [O-2].[Zn+2:2].[C:3]1([P:9](=[O:12])([OH:11])[OH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O>[O-2:10].[Zn+2:2].[C:3]1([P:9](=[O:10])([O-:12])[O-:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Zn+2:2]
Reactant: O=P(O)(O)c1ccccc1
Agent: [O-2]
Agent: [Zn+2]
Solvent: O
Product: O=P([O-])([O-])c1ccccc1

Procedure:
An aqueous slurry of zinc oxide was prepared by charging a 300 mL reaction flask equipped with a stirrer with 10.0 g (123 mmol) of zinc oxide (JIS grade 2, available from HakusuiTech Ltd.) and 90.0 g of water. An aqueous solution of 19.4 g (123 mmol) of phenylphosphonic acid (Nissan Chemical Industries, Ltd.) dissolved in 110.0 g of water was gradually added dropwise at room temperature (about 25° C.) to this slurry with stirring, thereby effecting a reaction for five hours. The slurry was then filtered and the wet cake was thoroughly rinsed with water. The wet cake was subsequently dried at 120° C. for at least 12 hours, yielding a white powder of zinc phenylphosphonate. FIG. 2 shows a micrograph taken with a field-emission scanning electron microscope (SEM: JSM-7400F, manufactured by JEOL Ltd.) of the white powder of zinc phenylphosphonate thus obtained.
Reaction SMILES: C(OC([N:8]([C@@H:16]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[CH2:19][N:18]([CH2:31][C:32]([OH:35])([CH3:34])[CH3:33])[C:17]1=[O:36])C(OC(C)(C)C)=O)=O)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[NH2:8][C@@H:16]1[CH2:22][CH2:21][C@@H:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[CH2:19][N:18]([CH2:31][C:32]([OH:35])([CH3:33])[CH3:34])[C:17]1=[O:36].[C:39]([OH:41])([C:38]([F:43])([F:42])[F:37])=[O:40]
Reactant: CC(C)(O)CN1C[C@H](c2cccc(F)c2F)CC[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)CN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O

Procedure:
A solution of di-tert-butyl[(3R,6S)-6-(2,3-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)-2-oxoazepan-3-yl]imidodicarbonate (0.095 g, 0.185 mmol) in DCM (10 mL) was treated with trifluoroacetic acid (3 mL). After 1 h the reaction was concentrated to dryness to afford the title compound as a TFA salt. MS 313.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[BH4-].[Na+]>C(O)(=O)C.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=Cc1ccccc1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1CCC(N2C(=O)c3cccc(NCc4ccccc4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 17 h
Yield: 15.6 %

Procedure:
A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.0 g, 3.7 mmol) and benzaldehyde (0.4 ml, 3.9 mmol) in acetic acid (20 ml) was stirred at room temperature for 17 h, then was heated to reflux for 3 h. The mixture was cooled to room temperature. To the stirred mixture was added sodium borohydride (140 mg, 3.7 mmol) and kept at room temperature for 18 h. The mixture was then heated to reflux for 2 h. To the mixture was added additional benzaldehyde (0.4 ml, 3.9 mmol) during reflux. After 30 min of reflux the reaction was allowed to cool to room temperature. To the mixture was added sodium borohydride (180 mg, 4.8 mmol) and the mixture stirred at room temperature for 3 days. The solvent was removed in vacuo to yield an oil. The oil was diluted with ethyl acetate (90 ml) and aqueous sodium hydrogen carbonate (sat, 100 ml). The organic layer was separated and was washed with aqueous sodium hydrogen carbonate (sat, 2×100 ml), brine (100 ml) and dried over MgSO4. The solvent was removed in vacuo to give a solid. The solid was purified by column chromatography (Silca Gel, 50% EtOAc:CH2Cl2) to give a yellow solid. The solid was further purified by column chromatography (KP-C18-HS, 35:65 CH3CN:0.1% CF3COOH in water) to give 2-(2,6-dioxo(3-piperidyl))-4-[benzylamino]isoindoline-1,3-dione as a yellow solid (210 mg, 16% yield): mp, 209-211° C.; 1H NMR (DMSO-d6) δ 2.02-2.08 (m, 1H, CHH), 2.46-2.63 (m, 2H, CH2), 2.82-2.97 (m, 1H, CHH), 4.56 (d, J=6.2 Hz, 2H, CH2), 5.07 (dd, J=5.3, 12.4 Hz, 1H, NCH), 6.96 (d, J=8.6 Hz, 1H, Ar), 7.02 (d, J=7.0 Hz, 1H, Ar), 7.19-7.40 (m, 6H, Ar, NH), 7.51 (dd, J=7.5, 8.4 Hz, 1H, Ar), 11.11 (s, 1H, NH); ° C. NMR (DMSO-d6) δ 22.15, 30.99, 45.44, 48.59, 109.58, 110.74, 117.63, 126.95, 126.99, 128.53, 132.21, 136.09, 138.95, 146.09, 167.27, 168.78, 170.07, 172.79; Anal Calcd for C20H17N3O4: C, 66.11; H, 4.72; N, 11.56. Found: C, 65.96; H, 4.60; N, 11.49.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([CH3:26])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:16]=1>>[N:20]1[CH:19]=[CH:18][C:17]([C:15]2[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[C:12]3[CH:25]=[C:24]([CH3:26])[S:23][C:13]=3[N:14]=2)=[CH:22][CH:21]=1
Reactant: NCCc1ccccc1
Reactant: Cc1cc2c(Cl)nc(-c3ccncc3)nc2s1
Product: Cc1cc2c(NCCc3ccccc3)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyridin-4-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-phenethylamino-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15]#[CH:16])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:17])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.CCOC(C)=O.O.[Si]([N:29]=[N+:30]=[N-:31])(C)(C)C>>[CH:1]1([C:5]2[C:14]([C:15]3[CH:16]=[N:31][NH:30][N:29]=3)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:17])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: C#Cc1cc(C(=O)OC)c(C)cc1C1CCC1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(-c2cn[nH]n2)c(C2CCC2)cc1C
Temperature: 170 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
Methyl 4-cyclobutyl-5-ethynyl-2-methylbenzoate (compound 446.2, 180 mg, 0.69 mmol) was dissolved in TMSN3 (1 ml) in sealed tube. The reaction was heated to 170° C. for 24 hours behind a blast shield then cooled down to 0° C. EtOAc (10 ml) and water (20 ml) were added. The resulting mixture was stirred at RT for 1 hr. The organic phase was then washed with brine, dried (MgSO4), and concentrated. The residue was purified by flash chromatography (SiO2; 0-30% EtOAc in Hexane) to give 92 mg (49%) of the title compound as a liquid. m/z (ES+) (272) (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.83 (s, 1H), 7.35 (s, 1H), 3.90 (s, 4H), 2.69 (s, 3H), 2.27-2.15 (m, 2H), 2.13-2.03 (m, 2H), 1.99-1.90 (m, 1H), 1.86-1.76 (m, 1H).