Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[CH2:11][CH2:10][C:9]3([CH2:16][O:15]C(C)(C)[O:13][CH2:12]3)[C:8]2([CH2:20][N:21]2[CH:25]=[N:24][CH:23]=[N:22]2)[OH:19])=[CH:4][CH:3]=1.N1C=CC=C1>CO.Cl>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][CH:7]2[C:8]([CH2:20][N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)([OH:19])[C:9]([CH2:12][OH:13])([CH2:16][OH:15])[CH2:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OCC2(CCC(Cc3ccc(Cl)cc3)C2(O)Cn2cncn2)CO1
Agent: Cl
Solvent: CO
Solvent: c1cc[nH]c1
Product: OCC1(CO)CCC(Cc2ccc(Cl)cc2)C1(O)Cn1cncn1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
(cis, trans mixture)-2-(4-chlorobenzyl)-8,8-dimethyl-1-[1,2,4]triazole-1-ylmethyl7,9-dioxaspiro[4,5]decane-1-ol (azole derivative (V′), R6═CH3, R7═CH3, Xm=4-Cl, A=N) (359 mg) was dissolved in a 10% hydrogen chloride methanol solution, and was stirred at a room temperature for 23 hours. After the reaction, a solvent was distilled off, and water was added to a residue. A 2 mol/L sodium hydroxide aqueous solution was added to this suspension, and the resultant mixture was stirred at a room temperature for 15 minutes. The mixture was filtered to obtain a crystal, and the crystal was dried in vacuum to obtain 271.1 mg of (1SR,5RS)-5-(4-chlorobenzyl)-2,2-bishydroxymethyl-1-[1,2,4]triazole-1-ylmethylcyclopentanol(azole derivative (IV′), Xm=4-Cl, A=N).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:14]1[C:22]2[C:17](=[C:18]([CH2:23][S:24][CH3:25])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH2:10][CH2:11][C:12]#[N:13].ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:14]1[C:22]2[C:17](=[C:18]([CH2:23][S:24]([CH3:25])=[O:37])[CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)[CH2:10][CH2:11][C:12]#[N:13]
Reactant: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3Cl)c[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(CCC#N)c3ccc(Cl)cc3Cl)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
200 mg (0.51 mmol) of the compound from Example 41 were introduced into 30 ml of dichloromethane at 0° C., 127 mg (0.51 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT overnight. 2 ml of methanol were added, and the residue after concentration was taken up in dichloromethane, washed twice with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 99 mg (48% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:6]=1[CH3:13])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:6]=1[CH3:13]
Reactant: CC(=O)Oc1ccc(C#N)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc(C#N)ccc1O
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
A stirred solution of 4-cyano-2-methylphenyl acetate (5.2 g, 29.7 mmol) in 75 mL of methanol was treated with a solution of potassium carbonate (30 mmol, 4.15 g) in 25 mL of water at room temperature. After 30 minutes, the mixture was concentrated in vacuo and treated with 1 N sulfuric acid. The resulting precipitate was filtered, washed with water, and dried to give 3.1 g of 4-hydroxy-3-methylbenzonitrile as a white solid (78% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][C:14]#[N:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][C:24]([O:27][CH2:28][CH2:29]Cl)([CH3:26])[CH3:25]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]3([C:14]#[N:15])[CH2:29][CH2:28][O:27][C:24]([CH3:26])([CH3:25])[CH2:23]3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: N#CCc1nc(-c2ccc(F)cc2)cs1
Reactant: CC(C)(CCl)OCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)CC(C#N)(c2nc(-c3ccc(F)cc3)cs2)CCO1
Yield: 48 %

Procedure:
2-(4-(4-Fluorophenyl)thiazol-2-yl)acetonitrile (325 mg, 1.5 mmol), potassium carbonate (617 mg, 4.47 mmol), and 1-chloro-2-(2-chloroethoxy)-2-methylpropane (254 mg, 1.5 mmol) in DMF (5 mL) were microwaved at 160° C. for 5 min then 20 min. A second addition of potassium carbonate and 1-chloro-2-(2-chloroethoxy)-2-methylpropane was made and then the reaction was microwaved again for 30 min two times. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and purified on silica using a gradient of 0-30% ethyl acetate/hexanes to afford 4-(4-(4-Fluorophenyl)thiazol-2-yl)-2,2-dimethyltetrahydro-2H-pyran-4-carbonitrile (228 mg, 48% yield). MS (ESI) m/z: Calculated for C17H17FN2OS: 316.10. found: 317.1 (M+H)+.
Reaction SMILES: Cl.C([N:9]1[CH2:17][C:16]2[C:15]([Cl:18])=[N:14][C:13]([Cl:19])=[N:12][C:11]=2[CH2:10]1)C1C=CC=CC=1.C(N(CC)CC)C.ClC(OC(Cl)C)=O.O>ClCCCl>[ClH:18].[Cl:19][C:13]1[N:14]=[C:15]([Cl:18])[C:16]2[CH2:17][NH:9][CH2:10][C:11]=2[N:12]=1
Reactant: Clc1nc(Cl)c2c(n1)CN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Clc1nc(Cl)c2c(n1)CNC2
Yield: 54 %

Procedure:
6-Benzyl-2,4-dichloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride (0.500 g, 0.00158 mol) prepared according to Process Step 2 was dissolved in 1,2-dichloroethane (15 mL), and the solution was mixed with triethylamine (0.160 g, 0.00158 mol) added dropwise under ice-cooling. The resulting solution was mixed with 1-chloroethyl chloroformate (0.680 g, 0.00478 mol) added dropwise at room temperature, followed by stirring under reflux for three hours. The reaction mixture was mixed with water (20 mL), followed by shaking and separation. The organic layer was dried over anhydrous magnesium sulfate, and was concentrated under reduced pressure. The residue was dissolved in methanol (15 mL), followed by reflux of the solution for one hour. After standing the reaction mixture to cool, methanol was distilled off under reduced pressure, to thereby yield 2,4-dichloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidine hydrochloride (0.19 g, in a yield of 54%).
Reaction SMILES: [H-].[Li+].C(S)CC.[CH3:7][C:8]([CH3:28])([O:10][C:11](=[O:27])[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([CH2:25][CH3:26])[C:21]([O:23]C)=[O:22])[CH3:9]>CN(C)P(N(C)C)(N(C)C)=O>[CH3:28][C:8]([CH3:9])([O:10][C:11](=[O:27])[CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH:20]([CH2:25][CH3:26])[C:21]([OH:23])=[O:22])[CH3:7]
Reactant: CCC(C(=O)OC)c1ccccc1SCC(=O)OC(C)(C)C
Agent: CCCS
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(C(=O)O)c1ccccc1SCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Suspend lithium hydride (1.01 g, 126.4 mmol) in hexamethylphosphoramide (50 mL) and treat with 1-propanethiol (11.5 mL, 126.4 mmol). Stir for 1.5 hours and add to a solution of 4-[[2-(1,1-dimethylethoxy)-2-oxoethyl]thio-alpha-ethyl-benzeneacetic acid, methyl ester (5.85 g, 18.06 mmol) in hexamethylphosphoramide (50 mL) under a nitrogen atmosphere. Stir for 20 hours and pour into ice cold 5% hydrochloric acid (500 mL). Extract into ethyl ether (4×300 mL), wash with water (500 mL) and dry (MgSO4). Evaporate the solvent in vacuo and purify by flash chromatography to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:48]2[CH:53]=[CH:52][C:51](Cl)=[CH:50][CH:49]=2)([OH:47])[CH2:9][NH:10][C:11]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][C@@H:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:27])[CH2:21]3)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:35]2[CH2:39][C@H:38]([NH:40][C:41](=[O:44])[CH2:42][OH:43])[C@@H:37]([OH:45])[C@H:36]2[OH:46])=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[OH:45][C@H:37]1[C@@H:36]([OH:46])[C@H:35]([N:15]2[CH:14]=[N:13][C:12]3[C:16]2=[N:17][C:18]([N:20]2[CH2:24][CH2:23][C@@H:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:27])[CH2:21]2)=[N:19][C:11]=3[NH:10][CH2:9][C:8]([OH:47])([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[CH2:39][C@@H:38]1[NH:40][C:41](=[O:44])[CH2:42][OH:43]
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccccc4)c4ccccc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To a stirred solution of N-((1S,2R,3S,4R)-4-{6-[2,2-Bis-(4-chloro-phenyl)-2-hydroxy-ethylamino]-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-2,3-dihydroxy-cyclopentyl)-2-hydroxy-acetamide in ethanol is added 10 equivalents of ammonium formate and 20 mol % of 10% palladium on carbon. The mixture is stirred at 80° C. for five hours, allowed to cool and filtered through Celite™. Removal of the solvent under reduced pressure affords the title compound.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@H:13]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[O:12][C@@H:11]([N:23]2[C:31]3[CH:30]=[CH:29][N:28]=[C:27](Cl)[C:26]=3[CH:25]=[CH:24]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.O1CCOCC1>[CH2:33]([NH:40][C:27]1[C:26]2[CH:25]=[CH:24][N:23]([C@@H:11]3[O:12][C@H:13]([CH2:14][OH:15])[C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3])[CH2:10]3)[C:31]=2[CH:30]=[CH:29][N:28]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2ccc3c(Cl)nccc32)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(NCc4ccccc4)nccc32)O[C@@H]1CO
Temperature: 95 °C
Yield: 100 %

Procedure:
A flame dried Schlenk flask was charged with 1-[(2R,4S,5R)-4-{[tert-butyl(dimethyl)silyl]oxy}-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)tetrahydrofuran-2-yl]-4-chloro-1H-pyrrolo[3,2-c]pyridine (0.343 g, 0.690 mmol), 1,4 dioxane (1.40 mL), benzylamine (0.226 mL, 2.07 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.0126 g, 0.0138 mmol), 2-(dicyclohexylphosphino)biphenyl (0.00686 g, 0.0196 mmol), and sodium tert-butoxide (0.186 g, 1.93 mmol). The tube purged with N2 (3×), sealed and the mixture was heated at 95° C. overnight. The reaction mixture was cooled to r.t., diluted with CH2Cl2 (20 mL) and washed with water (20 mL). The aq layer was extracted with CH2Cl2 (3×20 mL) and the combined organics were dried (Na2SO4), filtered, and concentrated. The crude oil was purified by flash chromatography (10 to 40% EtOAc/hexanes) to give the title compound as a light yellow foam (0.313 g, 28%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:34][CH2:33][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][N:13]([CH2:22][C:23]3[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=3)[C:26]([OH:28])=[O:27])[C:12]2=[O:32])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.O[CH2:51][CH2:52][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>CN(C)C1C=CN=CC=1.ClCCl>[O:56]1[CH2:57][CH2:58][N:53]([CH2:52][CH2:51][O:27][C:26]([C:25]2[CH:24]=[C:23]([CH:31]=[CH:30][CH:29]=2)[CH2:22][N:13]2[C:12](=[O:32])[C:11]3([CH2:33][CH2:34][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14]2)=[O:28])[CH2:54][CH2:55]1
Reactant: OCCN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)O)c1)CN2c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1cccc(C(=O)OCCN3CCOCC3)c1)CN2c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 118.8 %

Procedure:
To a solution of 3-((8-(tert-butoxycarbonyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoic acid (0.3 g, 0.65 mmol), dicyclohexylcarbodiimide (0.16 g, 0.78 mmol) and 4-(dimethylamino)pyridine (0.01 g, 0.078 mmol) in dichloromethane (10 mL), was added hydroxyethyl morpholine (0.037 g, 0.32 mmol, d=1.072). After stirring at room temperature for 18 hours, the reaction mixture was filtered, concentrated in vacuo and isolated by preparatory TLC (5% methanol/dichloromethane) to obtain the title compound (0.22 g, 59%); 1H NMR (DMSO-d6): δ 1.45 (s, 9H), 1.59-1.66 (m, 4H), 2.43-2.48 (m, 4H), 2.66 (t, 2H, J=5.6 Hz), 3.32-3.51 (m, 4H), 3.89 (br, 2H), 3.90 (br, 2H), 4.37 (t, 2H, J=5.6 Hz), 4.62-4.65 (m, 4H), 6.68 (d, 2H, J=8.4 Hz), 6.77 (t, 1H, J=7.2 Hz), 7.17 (t, 2H, J=8.8 Hz), 7.53-7.61 (m, 2H), 7.86-7.90 (m, 2H); MS for C32H42N4O6 m/z 579.09 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]CC)=[O:9])[N:5]=[C:4]([C:13](=O)[CH2:14]Br)[CH:3]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23]([NH2:25])=[S:24])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[S:24][CH:14]=[C:13]([C:4]3[CH:3]=[C:2]([OH:1])[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=3)[N:25]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: CCOC(=O)c1cc(O)cc(C(=O)CBr)n1
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Product: CCOc1ccc(-c2nc(-c3cc(O)cc(C(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 4-hydroxy-6-ethoxycarbonyl-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide. Then, hydrolysis was conducted in the same manner as in Example 2 to obtain 2-(3,4-diethoxyphenyl)-4-(4-hydroxy-6-carboxy-2-pyridyl)thiazole.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][NH:9][C:10](=[O:14])[O:11][CH2:12][CH3:13])(=[O:4])=[O:3]
Reactant: CCOC(=O)NCCO
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)NCCOS(C)(=O)=O
Reaction time: 16 h

Procedure:
60 g of methanesulfonyl chloride are metered over approximately 30 minutes at 0° to +5° C. to a solution of 66.5 g of ethyl 2-hydroxyethylcarbamate, 43.5 g of pyridine and 1.9 g of 4-dimethylaminopyridine in 150 ml of methylene chloride, with stirring, and the mixture is stirred for 2 more hours at +5° C. and then for 16 hours at room temperature. The reaction mixture is filtered, the residue is washed with a small quantity of ethyl acetate, and the combined filtrates are washed with dilute hydrochloric acid and water. After the mixture has been dried over magnesium sulfate, the solvent mixture is removed completely by distillation in vacuo, which gives ethyl 2-methylsulfonyloxyethylcarbamate, nD20 1.4450.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C:12]([CH3:16])([CH3:15])[C:13]#[CH:14])(=O)C.CCN(CC)CC>C1COCC1.Cl[Cu]>[CH3:15][C:12]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:16])[C:13]#[CH:14]
Reactant: Nc1ccccc1
Reactant: C#CC(C)(C)OC(C)=O
Agent: Cl[Cu]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CC(C)(C)Nc1ccccc1
Yield: 65.9 %

Procedure:
A solution of aniline (19 mL, 0.20 mol), 3-acetoxy-3-methyl-1-butyne (26 g, 0.20 mol), CuCl (1.0 g, 10 mmol) and Et3N (28 mL, 0.20 mol) in THF (120 mL) was heated at reflux for 5 h and was filtered through a pad of Celite™. Removal of solvent and chromatography of the crude mixture (silica gel, EtOAc/hexane, 3/7) afforded 21 g (67%) of 3-methyl-3-phenylamino-1-butyne. Treatment of the aminobutyne with CuCl (0.70 mg, 7.0 mmol) in THF (200 mL ) at 70° C. for 16 h followed by chromatography (silica gel, EtOAc/hexane, 3/7) afforded 13 g (60%) of 1,2-dihydro-2,2-dimethylquinoline (structure 75A of Scheme LII, where R1 =H, R2-3 =methyl). Treatment of the quinoline with di-tert-butyl dicarbonate (22 g, 0.10 mol) and DMAP (12 g, 0.10 mol) in THF (100 mL ) for 16 h followed by chromatography (silica gel, EtOAc/hexane, 2/8) afforded 15 g (71%) of 1-tert-butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline. 1-tert-Butoxycarbonyl-1,2-dihydro-2,2-dimethylquinoline (3.0 g, 11 mmol) in THF (30 mL ) was treated with 1.0M BH3 -THF in THF (29 mL, 29 mmol) at rt for 3 h and was quenched with 3M KOH (20 mL). To the above solution 30% H2O2 (5 mL) was added and the mixture was stirred for 60 min, then 5 mL of water was introduced. The mixture was extracted, washed with brine and concentrated. Chromatography of the crude mixture on a silica gel column using a 10-30% mixture of EtOAc/Hexane as eluents afforded a 2:1 mixture of two isomers (0.87 g, 3.1 mmol), which was oxidized with PCC (2.5 g, 11 mmol) in 60 mL of methylene chloride at rt for 60 min. Removal of solvent and chromatography of the black oil on a silica gel column using a 20% mixture of EtOAc and hexane as solvent afforded 0.58 g (68%) of 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone as a white solid. Data for 1-tert-butoxycarbonyl-1,2,3,4-tetrahydro-2,2-dimethyl-4-quinolinone: 1H NMR (400 MHz, CDCl3) 7.93 (d, J=7.8, 1H), 7.42 (t, J=7.8, 1H), 7.31 (d, J=7.8, 1H), 7.02 (t, J=7.8, 1H), 2.73 (s, 2H), 1.56 (s, 9H), 1.49 (s, 6H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[CH:10]([C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:15]=2[N:14]=1)([CH3:12])[CH3:11].[OH-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>>[CH:10]([C:13]1[N:17]([CH3:18])[C:16]2[CH:19]=[C:20]([N+:1]([O-:4])=[O:2])[C:21]([C:23]([F:25])([F:26])[F:24])=[CH:22][C:15]=2[N:14]=1)([CH3:12])[CH3:11]
Reactant: CC(C)c1nc2cc(C(F)(F)F)ccc2n1C
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)c1nc2cc(C(F)(F)F)c([N+](=O)[O-])cc2n1C
Temperature: 0 °C

Procedure:
Slowly add 1.01 g. of 90% nitric acid dissolved in 2.2 ml. of concentrated sulfuric acid to a stirred solution of 3.00 g. of 2-isopropyl-1-methyl-5-trifluoromethylbenzimidazole in 13.2 ml. of concentrated sulfuric at about 5° C. Maintain the reaction at about 5° C for 2 hours. Pour the reaction mixture into 300 ml. of ice water and basify with 26 ml. of 50% sodium hydroxide followed by sodium carbonate. Extract with ether, dry over sodium sulfate and evaporate to dryness. Recrystallize from dichloromethane-hexane, obtaining the product of this example.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:4]([CH2:5][CH:6]2[CH2:10][CH2:9][CH2:8][CH2:7]2)[C:3]([OH:21])=[O:2])=[CH:12][C:13]=1[N+:18]([O-:20])=[O:19]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 97.9 %

Procedure:
A solution of 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid methyl ester (260 mg, 0.834 mmol) in tetrahydrofuran (3 mL) was treated with a 0.8M aqueous lithium hydroxide solution (1.25 mL, 1.00 mmol). The reaction mixture was stirred at 25° C. for 15 h. The resulting reaction mixture was partitioned between water (50 mL) and ethyl acetate (50 mL) and then treated with a 1N aqueous hydrochloric acid solution (10 mL). The layers were shaken and separated. The aqueous layer was further extracted with ethyl acetate (50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 2-(4-chloro-3-nitro-phenyl)-3-cyclopentyl-propionic acid (243 mg, 98%) as a yellow solid which was used without further purification: mp 112–115° C.; FAB-HRMS m/e calcd for C14H16ClNO4 (M+H)+ 298.0847, found 298.0851.
Reaction SMILES: CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH3:32][C:33]([CH3:49])([O:35][C:36]([NH:38][C:39]1[CH:47]=[CH:46][CH:45]=[C:44]([CH3:48])[C:40]=1[C:41]([OH:43])=O)=[O:37])[CH3:34].[NH2:50][C:51]1[CH:56]=[CH:55][C:54]([CH3:57])=[CH:53][CH:52]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:57][C:54]1[CH:55]=[CH:56][C:51]([NH:50][C:41](=[O:43])[C:40]2[C:44]([CH3:48])=[CH:45][CH:46]=[CH:47][C:39]=2[NH:38][C:36]([O:35][C:33]([CH3:32])([CH3:34])[CH3:49])=[O:37])=[CH:52][CH:53]=1
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1C(=O)O
Reactant: Cc1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1ccc(NC(=O)c2c(C)cccc2NC(=O)OC(C)(C)C)cc1
Temperature: 18 °C
Reaction time: 16 h

Procedure:
Firstly N-methylmorpholine (6.15 mL, 5.64 g, 55.8 mmol) and then O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (10.15 g, 26.8 mmol) are added to a stirred mixture of 2-{[(1,1-dimethylethoxy)carbonyl]amino}-6-methylbenzoic acid (5.60 g, 22.3 mmol) and p-toluidine 4.78 g, 44.6 mmol) in dry dimethylformamide (110 mL) under an argon atmosphere, and stirred at 18° C. for 16 hours. The solvent is evaporated off under reduced pressure to give a residue which is treated with aqueous sodium hydrogen carbonate solution (200 mL of 10%) and extracted with dichloromethane (3×100 mL). The combined extracts are washed with aqueous citric acid solution (100 mL of 10%), dried (Na2SO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 20% ethyl acetate in hexane, and recrystallised from tert-butyl-methyl ether-hexane to give the title compound as a colourless crystalline solid, m.p. 250° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12]C)[N:8]=[C:7]([NH:14][C:15]1[CH:26]=[CH:25][C:18]([C:19]([NH:21][CH:22]([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=1)[N:6]=[CH:5]2.C[S-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[N:8]=[C:7]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][CH:22]([CH3:23])[CH3:24])=[O:20])=[CH:25][CH:26]=1)[N:6]=[CH:5]2
Reactant: COc1cc2nc(Nc3ccc(C(=O)NC(C)C)cc3)ncc2cc1Br
Agent: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1ccc(Nc2ncc3cc(Br)c(O)cc3n2)cc1
Yield: 90 %

Procedure:
A 0.15M suspension of 4-(6-bromo-7-methoxyquinazolin-2-ylamino)-N-isopropylbenzamide (1.0 eq) and sodium thiomethoxide (4.0 eq) in DMF was heated to 80° C. in an oil bath for 12 h. The mixture was partitioned between ethyl acetate and water. The pH of aqueous phase was adjusted to 5 by adding saturated ammonium hydrochloride. Aqueous phase was extracted with ethyl acetate, and combined organic phase was washed with brine, dried over sodium sulfate, and concentrated to give desired product in 90% yield. ES/MS m/z 401/403 (MH+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]#[CH:15])(=O)=O)=CC=1.[N:16]1([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:12]([N:19]1[CH2:20][CH2:21][N:16]([C:22]2[N:23]=[CH:24][CH:25]=[CH:26][N:27]=2)[CH2:17][CH2:18]1)[CH2:13][C:14]#[CH:15]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCCN1CCN(c2ncccn2)CC1
Yield: 54.6 %

Procedure:
A solution of but-3-ynyl 4-methylbenzenesulfonate (1.14 g), 2-(piperazin-1-yl)pyrimidine (1.06 g) and diisoproylethylamine (1.24 mL) in 1,2-dichloroethane (6 mL) was heated to reflux overnight. The mixture was concentrated, diluted with sat. aq. NaHCO3 (5 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (EtOAc/hexane 1:1→1:0) afforded 2-(4-(but-3-ynyl)piperazin-1-yl)pyrimidine (0.60 g).