Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[C:19](OCC)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.C(O)(=O)C>[C:20]1([C:19]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[O:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccccn1
Reactant: CCOC(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.1 %

Procedure:
To a solution of 2-methylpyridine (9.31 g) in tetrahydrofuran (200 ml) was added a 1.5 M hexane solution of n-butyllithium (73.3 ml) at -20° C. The resulting solution was stirred for 30 minutes at room temperature and added to a solution of ethyl benzoate (15.02 g) in tetrahydrofuran (100 ml) at -60° C. After stirring for 2 hours at -60° C, acetic acid (15 ml) was added and the resulting mixture was allowed to warm to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water. The aqueous layer was reextracted with ethyl acetate and the combined extracts were washed with water, 10% aqueous solution of sodium hydrogen carbonate, and saturated aqueous sodium chloride. After drying over magnesium sulfate, the ethyl acetate extracts were filtered and evaporated. The residue (20.5 g) was chromatographed on silica gel (Merck 70-230 mesh, 308 g) eluting with chloroform to give 2-pyridylmethyl phenyl ketone (10.86 g) as an oil.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:30]=[CH:31][C:24]=34)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([O:16]C)=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].O.[OH-].[Li+].Cl>CO.C1COCC1.O>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[N:29]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:37])([CH3:39])[CH3:38])[CH:30]=[CH:31][C:24]=34)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2]
Reactant: COC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5c4ccn5COCC[Si](C)(C)C)cn3)C2)cn1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)O)cn5)C4)c3)ccnc21
Temperature: 40 °C
Reaction time: 3 h
Yield: 78.5 %

Procedure:
A reaction mixture of methyl 5-{3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylate (0.13 g, 0.24 mmol), lithium hydroxide monohydrate (0.025 g, 0.60 mmol) in methanol (4.0 mL), THF (2.0 mL) and water (1.0 mL) was stirred at 40° C. for 3 h. The mixture was adjusted to pH=4 with 2.0 N HCl aqueous solution, and concentrated under reduced pressure to remove MeOH and THF. The precipitate formed was filtered, washed with water and ether, and dried in vacuum to afford the desired product (0.100 g, 79%). LCMS (M+H)+: m/z=531.4.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:8][CH:9]=2)[N:4]([CH3:20])[N:3]=1.[C:21]([O:25][C:26](=[O:44])[NH:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][C:29]=1[CH3:43])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:44])[NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[N:8][CH:9]=3)[N:4]([CH3:20])[N:3]=2)=[CH:30][C:29]=1[CH3:43])([CH3:24])([CH3:23])[CH3:22]
Reactant: Cn1nc(Cl)c2cnc(NCCN3CCOCC3)nc21
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Product: Cc1cc(-c2nn(C)c3nc(NCCN4CCOCC4)ncc23)ccc1NC(=O)OC(C)(C)C

Procedure:
Prepared as described above in Example 15 starting from (3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-(2-morpholin-4-yl-ethyl)-amine and [2-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-carbamic acid tert-butyl ester to give the title compound {2-methyl-4-[1-methyl-6-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-phenyl}-carbamic acid tert-butyl ester; LC/MS (m/e)=468.2 (MH+), Rt=1.40 min
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4](C)[C:3]=1C=C.S([O-])([O-])=[O:16].[Na+].[Na+].[C:21]([OH:25])(C)([CH3:23])[CH3:22]>ClCCl.O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:3])[C:22]=1[CH:21]([OH:25])[CH2:23][OH:16]
Reactant: O=S([O-])[O-]
Reactant: C=Cc1c(C)cc2ccccc2c1Cl
Reactant: CC(C)(C)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1cc2ccccc2c(Cl)c1C(O)CO
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A biphasic mixture of AD mix-α (6.907 g) in tert-butanol (24.5 mL)/H2O (24.5 mL) was cooled to 0° C. and 1-chloro-3-methyl-2-vinyl-naphthalene (1.00 g, 4.93 mmol) was added. The reaction mixture was stirred for 8 h at 0° C. Sodium sulfite (7.4 g) was added at 0° C. and the reaction was stirred for 40 minutes to give a white mixture. The mixture was diluted with dichloromethane and H2O. The mixture was extracted with dichloromethane (3×) and the combined organic layer was dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give 1-(1-chloro-3-methyl-naphthalen-2-yl)-ethane-1,2-diol. 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=8.2 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.57 (s, 1H), 7.56-7.47 (m, 2H), 5.70 (dd, J=9.4, 3.9 Hz, 1H), 4.11 (dd, J=10.5, 10.5 Hz, 1H), 3.80 (dd, J=11.6, 3.9 Hz, 1H), 2.66 (s, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@H:10]3[CH2:12][C@H:11]3NC)[C:4]=2[CH2:3][CH2:2]1.[CH2:15]([N:17](CC)CC)C.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C@H:10]3[CH2:12][C@H:11]3[CH2:15][NH:17][C:25]([CH:22]3[CH2:24][CH2:23]3)=[O:26])[C:4]=2[CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: CN[C@@H]1C[C@@H]1c1cccc2c1CCO2
Reactant: O=C(Cl)C1CC1
Product: O=C(NC[C@@H]1C[C@@H]1c1cccc2c1CCO2)C1CC1
Yield: 43.3 %

Procedure:
The title compound was prepared by the general procedure described in Example 1 using (cis)-2-(2,3-dihydrobenzofuran-4-yl)cycloprop-1-yl methyl amine (0.79 mmol), triethylamine (2.37 mmol) and cyclopropane carbonyl chloride (0.95 mmol). Purification by silica gel column chromatography (Hex:EtOAc, 2:1) provided 88 mg of the desired product (43%) as a white wax. HPLC purity=92%.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([O:28][CH3:29])[C:22]([CH3:31])([CH3:30])[CH2:21]1.N1C=CC=CC=1.CO>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([O:19][CH:20]1[CH2:25][C:24]([CH3:26])([CH3:27])[N:23]([O:28][CH3:29])[C:22]([CH3:31])([CH3:30])[CH2:21]1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)Cl)cc(C(C)(C)C)c1O
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: CO
Product: CON1C(C)(C)CC(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC1(C)C
Reaction time: 1 h
Yield: 61 %

Procedure:
A solution of 7.6 g (28.3 mmol) of 3,5-di-t-butyl-4-hydroxybenzoyl chloride in toluene (35 ml) is added dropwise over 20 minutes to a solution of 5.3 g (28.3 mmol) of 4-hydroxy-1-methoxy-2,2,6,6-tetramethylpiperidine and 2.46 g (31.1 mmol) of pyridine in toluene (30 ml). The reaction temperature is kept below 60° C. during the addition and the reaction mixture is stirred for one hour at 55°-60° C. after the addition and then filtered. The filtrate is washed with 1N HCl (2×50 ml), water (100 ml), saturated NaHCO3 (100 ml), dried (magnesium sulfate), and concentrated. The crude oil is chromatographed on silica gel (9:1 hexane:ethyl acetate) to obtain 7.3 g (61% yield of a white crystalline solid, m.p. 126°-8° C. (methanol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[P:9]([O-:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].C(N(CC)CC)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>[CH2:11]([O:10][P:9]([C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1)(=[O:16])[O:13][CH2:14][CH3:15])[CH3:12]
Reactant: Fc1ccc(Br)cc1
Reactant: CCOP([O-])OCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1ccc(F)cc1
Temperature: 90 °C
Yield: 61.7 %

Procedure:
4-Bromo-fluorobenzene (10.95 g, 62.57 mmol) was added to diethyl phosphite (8.86 mL, 68.8 mmol) at ambient temperature, followed by the addition of triethylamine (9.6 mL, 68.8 mmol). The resulting solution was degassed with nitrogen followed by the addition of tetrakis(triphenylphosphine)-palladium (3.0 g, 2.6 mmol). The resulting mixture was heated at 90° C. overnight. The reaction mixture was allowed to cool to ambient temperature and then ethyl acetate (350 mL) was added. The solution was washed with saturated sodium bicarbonate (350 mL) and then with saturated brine (2×350 mL). The crude product was purified by vacuum distillation (ca. 98° C., 0.6 Torr) to yield 8.956 g of 4-fluorophenyl-phosphonic acid diethyl ester (38.6 mmol, 94% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.88-7.80 (m, 2H); 7.20-7.14 (m 2H); 4.22-4.04 (m, 4H); 1.36-1.32 (t, 6H); ESMS (m/z): (M+1)+ found, 233.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C:5]([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C:6]([O:8]CC)=O)#[N:2]>N.CO.CO.[Ni]>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:5]2([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[CH2:4][CH2:3][CH2:1][NH:2][C:6]2=[O:8])=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(CCC#N)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Product: O=C1NCCCC1(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product from Example 23A (560 mg, 1.700 mmol) as a solution in 7 M ammonia/methanol (20 mL) was added to solvent-washed Raney®-nickel (2800 mg, 47.7 mmol) in a 250 mL stainless steel pressure bottle and stirred at room temperature for 24 hours under hydrogen (30 pounds per square inch). The mixture was filtered through a nylon membrane and was concentrated. The residue was dissolved in methanol/dichloromethane (1:1), filtered and concentrated to give a solid which was slurried in methanol, filtered and dried to give the title compound. MS (DCI) m/z 288 (M+H)+.
Reaction SMILES: NN1CN=CS1.C(N(CC)CC)C.ClS([N:18]=[C:19]=O)(=O)=O.[F-].[CH2:22]([N+:26](CCCC)([CH2:31]CCC)[CH2:27]CCC)[CH2:23][CH2:24][CH3:25].O1CCCC1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:27][N:26]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:19][N:18]=1)[CH3:31]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: O=C=NS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: NN1CN=CS1
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)c1ccccn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
2-Amino-1,2,4 thiadiazole (0.006 g, 0.06 mmol) and triethylamine (0.0376 mL, 0.27 mmol) were added to 1 mL dichloromethane and cooled to 0° C. To this was slowly added chlorosulfonylisocyanate (0.007 mL, 0.08 mmol) at 0° C. Stirred thirty minutes until starting material consumed. Simultaneously, in a separate flask trimethylsilylethyl ether 44 was dissolved in 0.5 mL tetrahydrofuran. To this was added triethylamine (0.0376 mL, 0.27 mmol) and 1M tetrabutylammonium fluoride in tetrahydrofuran (0.135, 0.135 mmol) and stirred at room temperature. After 20 minutes, diluted with dichloromethane, washed with 1M HCl solution and brine, concentrated to give crude. At 0° C., dissolved in 0.5 mL dichloromethane and added to the solution prepared in situ above. Stirred at 0° C. for Sminutes, catalytic DMAP added, then stirred for one hour at room temperature. Diluted with dichloromethane, washed with 1M HCl solution, brine, concentrated to give crude. Chromatographed (5 to 30% methanol/dichloromethane) to give dimethylaminopyridine adduct 227 (0.033 g, 0.046 mmol, 68%.) 1H NMR (CDCl3) δ 8.97 (dd, 1H), 8.54 (d, 2H), 8.19 (d, 1H), 8.00 (s, 1H), 7.72 (d, 4H), 7.42 (dd, 1H), 7.26-7.14 (m, 7H), 7.02 (dd, 2H), 6.52 (d, 2H), 4.74 (s, 2H), 4.17 (s, 2H), 3.22 (s, 6H.) MS: 718 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:17]3=[N:18][C:19](S(C)=O)=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:25]3[C:30]([F:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[F:36])[C:13]2=[O:37])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:38][NH2:39].O1CCCC1>O1CCOCC1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:17]3=[N:18][C:19]([NH:39][CH3:38])=[N:20][CH:21]=[C:16]3[CH2:15][N:14]([C:25]3[C:30]([F:31])=[C:29]([O:32][CH3:33])[CH:28]=[C:27]([O:34][CH3:35])[C:26]=3[F:36])[C:13]2=[O:37])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CN
Reactant: CCOC(=O)C1CCC(N2C(=O)N(c3c(F)c(OC)cc(OC)c3F)Cc3cnc(S(C)=O)nc32)CC1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CCOC(=O)C1CCC(N2C(=O)N(c3c(F)c(OC)cc(OC)c3F)Cc3cnc(NC)nc32)CC1

Procedure:
To a 100-mL round-bottomed flask was added Ethyl-4-[3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylsulfinyl-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-cyclohexanecarboxylate (820 mg, 1.52 mmol), dioxane(60 mL), then a 2 M solution of methylamine in tetrahydrofuran (7.6 mL, 15.2 mmol), and the solution was heated to 60° C. under an atmosphere of nitrogen for 5 hours. The solution was then concentrated in vacuo, and reacted further without purification: LRMS: 506.2 (M+H).
Reaction SMILES: CO[C:3]([CH:5]1[CH2:9][CH:8]([OH:10])[CH:7]([CH2:11][NH:12][C:13]([C:15]2[S:16][C:17]([Cl:20])=[CH:18][CH:19]=2)=[O:14])[CH2:6]1)=[O:4].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][C:29]2=[O:34])=[CH:24][CH:23]=1>>[OH:10][CH:8]1[CH2:9][CH:5]([C:3](=[O:4])[NH:21][C:22]2[CH:23]=[CH:24][C:25]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][C:29]3=[O:34])=[CH:26][CH:27]=2)[CH2:6][CH:7]1[CH2:11][NH:12][C:13]([C:15]1[S:16][C:17]([Cl:20])=[CH:18][CH:19]=1)=[O:14]
Reactant: COC(=O)C1CC(O)C(CNC(=O)c2ccc(Cl)s2)C1
Reactant: Nc1ccc(N2CCOCC2=O)cc1
Product: O=C(NCC1CC(C(=O)Nc2ccc(N3CCOCC3=O)cc2)CC1O)c1ccc(Cl)s1

Procedure:
In analogy to example 15C, (1SR,3RS,4SR)-3-{[(5-chloro-thiophene-2-carbonyl)-amino]-methyl}-4-hydroxy-cyclopentanecarboxylic acid methyl ester was reacted with 4-(4-amino-phenyl)-morpholin-3-one (CAS 438056-69-0) to give 5-chloro-thiophene-2-carboxylic acid {(1RS,2SR,4SR)-2-hydroxy-4-[4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-cyclopentylmethyl}-amide. Orange solid. MS: 478.3 ([M+H]+).
Reaction SMILES: [O:1]([C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)[C:2]([CH3:4])=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:39]([O:41][C:42]([C:44]1([NH2:53])[CH2:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45]1)=[O:43])[CH3:40].CCN(C(C)C)C(C)C>CC(O)C.C(Cl)Cl.C(Cl)Cl>[CH2:39]([O:41][C:42]([C:44]1([NH:53][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:5]=2[O:1][C:2](=[O:3])[CH3:4])[CH2:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45]1)=[O:43])[CH3:40]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: CC(=O)Oc1c(C)cccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)=O)Cc2ccccc2C1
Reaction time: 0.08 h
Yield: 161.5 %

Procedure:
A 40 mL vial containing a stirring bar is charged with 2-acetoxyl-3-methyl-benzoic acid (1 g, 4.87 mmol) and dry DCM (14 mL), and stirring is initiated. After dissolution is complete, HBTU (1.85 g, 4.87 mmoles) is added. After 5 min, 2-amino-indane-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) is added followed by DIPEA (2.1 mL, 12.18 mmol). The reaction is allowed to stir for 110 h. Analysis by tlc of the reaction mixture (silica, 5% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a reparatory funnel and diluted with EtOAc (100 mL). This is washed consecutively with dilute aqueous HCl (3%, 40 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 3 g of a light orange solid. This material is dissolved in 15 mL of DCM. This material is purified utilizing an ISCO Companion with an 80 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 50% EtOAc over 12 column volumes. Fractions 19 through 27 are combined and evaporated in vacuo to give 1.38 g of white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH:11]=O)[N:10]=2)[CH:7]=1.C(C1NC(C=O)=C(C)N=1)C.[CH:23]1([C:28]2([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]4([C:49]#[N:50])[CH2:48][CH2:47][CH2:46][CH2:45]4)=[C:40]([F:51])[CH:39]=3)[CH2:33][C:32](=[O:34])[CH2:31][C:30](=[O:35])[O:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1.C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(O)=CC(=O)O2)CCCC1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([CH2:11][C:31]3[C:30](=[O:35])[O:29][C:28]([CH2:36][CH2:37][C:38]4[CH:43]=[CH:42][C:41]([C:44]5([C:49]#[N:50])[CH2:45][CH2:46][CH2:47][CH2:48]5)=[C:40]([F:51])[CH:39]=4)([CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:33][C:32]=3[OH:34])[N:10]=2)[CH:7]=1
Reactant: O=Cc1nc2ncc(Cl)cn2n1
Reactant: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CCCC1
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(O)=CC(=O)O2)cc1F
Agent: CCc1nc(C)c(C=O)[nH]1
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(O)=C(Cc4nc5ncc(Cl)cn5n4)C(=O)O3)cc2F)CCCC1

Procedure:
The title compound was prepared analogously to Example A(97) where 6-Chloro-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde was substituted in place of 2-ethyl-4-methyl-1H-imidazole-5-carbaldehyde and 1-{4-[2-(2-Cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopentanecarbonitrile (Example A(189) (was substituted in place of 2-{4-[2-(2-cyclopentyl-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile. 1H NMR (400 MHz, CDCl3) δ: 1.41-1.98 (m, 17H), 2.30-2.68 (m, 6H), 3.62 (d, J=16 Hz, 1H), 3.71 (d, J=16 Hz, 1H), 6.99-7.03 (m, 2H), 7.21-7.25 (m, 1H), 8.74 (s, 1H), 9.45 (s, 1H), 10.8 (s, 1H). Anal. Calcd. For C30H31ClFN5O3: C, 63.88; H, 5.54; N, 12.42. Found: C, 63.73; H, 5.71; N, 12.17. MS (ESI): 564 (M+H)+.
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[NH2:48][CH2:49][C:50]1[C:51]([OH:58])=[N:52][C:53]([CH3:57])=[CH:54][C:55]=1[CH3:56]>ClCCl.O>[OH:58][C:51]1[C:50]([CH2:49][NH:48][C:4](=[O:6])[C:3]2[CH:2]=[CH:10][C:9]([CH2:11][O:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][CH:7]=2)=[C:55]([CH3:56])[CH:54]=[C:53]([CH3:57])[N:52]=1
Reactant: Cc1cc(COc2ccccc2)ccc1C(=O)O
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(COc3ccccc3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A mixture of methyl 4-(phenoxymethyl)benzoic acid (420 mg, 1.84 mmol), 1-hydroxybenzotriazole (373 mg, 2.75 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (530 mg, 2.75 mmol), triethylamine (0.8 mL, 5.7 mmol) were dissolved in dichloromethane (20 mL). The mixture was stirred at room temperature for 0.5 hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (280 mg, 1.84 mmol) was added to the solution. The mixture was stirred at room temperature for 12 hours. To the resultant mixture, water (10 mL) was added and then extracted with dichloromethane (10 mL×3). The combined organic phase was separated, dried over sodium sulfate, filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:4) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(phenoxymethyl)benzamide (Compound I-11) as a white solid (300 mg, 45%). LRMS (M+H+) m/z: calcd 362.16. found 362. HPLC purity (214 nm): 98%. 1H NMR (300 MHz, d6-DMSO): δ 11.49 (s, 1H), 8.37 (t, J=5.1 Hz, 1H), 7.87 (d, J=8.4 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.31 (t, J=7.8 Hz, 2H), 7.04-6.96 (m, 3H), 5.88 (s, 1H), 5.17 (s, 2H), 4.32 (d, J=5.1 Hz, 2H), 2.20 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](OC)(OC)(OC)[CH3:21]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH3:20][C:21]1[N:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: COC(C)(OC)OC
Reactant: CCOC(=O)CCNc1c(N)cnc2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCOC(=O)CCn1c(C)nc2cnc3ccccc3c21
Yield: 85.5 %

Procedure:
Ethyl N-(3-aminoquinolin-4-yl)-β-alaninate (15.0 g, 57.8 mmol) was treated with trimethyl orthoacetate (10.3 mL, 81.0 mmol) and pyridinium p-toluenesulfonate (0.200 g) according to the method described in Part A of Example 10 to provide 14.0 g of ethyl 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate as a brown solid.
Reaction SMILES: BrC1C=C(C)C(C(N2CCC(N3CCCC3)CC2)=O)=C(C)C=1.BrC1C=C(C)C(C(N2CCC(N3CCC[C@H]3CO)CC2)=O)=C(C)C=1.[CH3:47][C:48]1[C:53]([C:54](O)=[O:55])=[C:52]([CH3:57])[N:51]=[C:50]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=2)[N:49]=1.[NH:68]1[CH2:73][CH2:72][CH:71]([N:74]2[CH2:78][CH2:77][CH2:76][C@H:75]2[CH2:79][O:80][C:81](=[O:88])[C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[CH2:70][CH2:69]1>>[CH3:57][C:52]1[C:53]([C:54]([N:68]2[CH2:73][CH2:72][CH:71]([N:74]3[CH2:78][CH2:77][CH2:76][C@H:75]3[CH2:79][O:80][C:81](=[O:88])[C:82]3[CH:83]=[CH:84][CH:85]=[CH:86][CH:87]=3)[CH2:70][CH2:69]2)=[O:55])=[C:48]([CH3:47])[N:49]=[C:50]([C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([C:64]([F:67])([F:66])[F:65])[CH:59]=2)[N:51]=1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)O
Reactant: O=C(OC[C@@H]1CCCN1C1CCNCC1)c1ccccc1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCC[C@H]2CO)CC1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1

Procedure:
In analogy to the procedures described for intermediate 1 and for intermediate 4 B), 4,6-dimethyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid (intermediate 5) was converted into its acid chloride and subsequently reacted with benzoic acid (S)-1-piperidin-4-yl-pyrrolidin-2-ylmethyl ester (intermediate 3) to give benzoic acid (S)-1-{1-[4,6-dimethyl-2-(3-trifluoromethyl-phenyl)-pyrimidine-5-carbonyl]-piperidin-4-yl}-pyrrolidin-2-ylmethyl ester, which was subsequently saponified to give the title compound as colorless solid. MS: 463.2 (MH+).