Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:28]=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[C:30]=1[OH:31])[C:8]([O:10][C:11]1[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][C:12]=1[C:24]([CH3:27])([CH3:26])[CH3:25])=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:36]([NH2:54])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:36]([NH:54][C:15](=[O:16])[C:14]1[CH:18]=[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:11]([O:10][C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:30]([OH:31])=[C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:28]=2)=[C:12]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:13]=1)[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH3:53]
Reactant: CC(C)(C)c1cc(C(=O)Oc2c(C(C)(C)C)cc(C(=O)Cl)cc2C(C)(C)C)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCCCCCCCN
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCNC(=O)c1cc(C(C)(C)C)c(OC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c(C(C)(C)C)c1

Procedure:
10.10 grams of 4-(3,5-di-tert.butyl-4-hydroxybenzoyloxy)-3,5-di-tert-butylbenzoyl chloride 5.4 grams of n-octadecylamine and 2.0 grams of triethylamine were heated together in about 100 ml of toluene for about 5 hours at 90° to 98°C. The precipitated triethylamine hydrochloride was filtered. The filtrate was washed with water and dried over anhydrous sodium sulfate. The dried toluene solution was concentrated to remove toluene under reduced pressure yielding 14.5 grams of the product. The product was crystallized twice from acetonitrile and melted at 139° to 140°C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]1.[Br:14]N1C(=O)CCC1=O>C1COCC1>[Br:14][CH:9]1[C:10](=[O:12])[CH2:11][CH:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)[CH2:7][C:8]1=[O:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1CC(=O)CC(c2ccco2)C1
Solvent: C1CCOC1
Product: O=C1CC(c2ccco2)CC(=O)C1Br
Temperature: 85 °C
Yield: 69.5 %

Procedure:
To a stirred solution of 5-(2-furyl)cyclohexane-1,3-dione (1 g, 5.6 mmol) in THF (50 mL) was added N-bromosuccinimide (1 g, 5.6 mmol). The reaction mixture was heated to 85° C. for 12 h and on completion was filtered. The filtrate was concentrated in vacuo to give the title compound (1.0 g, 69%) as a white solid. LCMS (ES+) 256.8 (M+H)+.
Reaction SMILES: Cl[CH2:2][P:3]([OH:6])(=[O:5])[OH:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12]>O>[OH2:4].[NH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:2][P:3]([OH:6])(=[O:5])[OH:4]
Reactant: O=P(O)(O)CCl
Reactant: NCCCCN
Solvent: O
Product: NCCCCNCP(=O)(O)O

Procedure:
Chloromethanephosphonic acid (7.0 g, 53.6 mmoles) and 1,4-diaminobutane (30.0 g, 340 mmoles) were heated under reflux in water (200 cm3) for 20 hours. The water was then distilled off and acetone (110 cm3) was added. The phosphonic acid was filtered off and dried. The crude yield was 9.8 g (91%). A sample was purified by recrystallization from water/ethanol to give N-(4-aminobutyl)-aminomethanephosphonic acid monohydrate as a fine white crystalline solid having a melting point of 258° C.
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(Cl)Cl>[N:12]1([C:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]2[C:10]([OH:9])=[O:11])=[O:8])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Solvent: ClCCl
Product: O=C(O)C1CCCCC1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.4 %

Procedure:
To a solution of cis-1,2-cyclohexane dicarboxylic anhydride (1.0 g, 6.49 mmol) in CH2Cl2 (16 mL) was added morpholine (0.56 g, 6.49 mmol) at 0° C., the resulting mixture was allowed to stir at room temperature overnight (20 h). When complete the reaction mixture was washed with HCl (1.0 N, 20 mL) then with H2O (2×20 mL). The combined aqueous layers were extracted with CH2Cl2 (3×10 mL), and the combined organic layers were dried over MgSO4, the solvent was evaporated in vacuo to give the title compound (1.4 g, 90%/) as a white solid which was used later without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C1(N=C=NC2CCCCC2)CCCCC1.[CH2:33](O)[C:34]([F:37])([F:36])[F:35]>C(Cl)Cl.N1C=CC=CC=1>[CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7](=[O:9])[O:8][CH2:33][C:34]([F:37])([F:36])[F:35])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)O)C1(C)C
Reactant: OCC(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1[C@H](C#CC(=O)OCC(F)(F)F)C1(C)C
Reaction time: 1 h
Yield: 65.1 %

Procedure:
4 g of the product of Step A and 3.5 g of dicyclohexylcarbodiimide were added to a solution of 20 ml of methylene chloride and 1 ml of pyridine and the reaction mixture was stirred for 1 hour. 2.15 g of trifluoroethanol and 5 ml of methylene chloride were then added to the mixture which was stirred at 20° C. for 16 hours and was filtered. The filtrate was rinsed with methylene chloride and the filtrate was evaporated to dryness. The residue was taken up in ether and the solution was washed with N hydrochloric acid, then with water and dried and evaporated to dryness. The 5 g of residue was chromatographed over silica gel and was eluted with a 95-5 benzene-ethyl acetate mixture to obtain 3.5 g of 1,1-dimethylethyl (1R,cis) 2,2-dimethyl-3-[3-oxo-3-(2,2,2-trifluoroethoxy)-1-propynyl]-cyclopropane-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]([OH:8])[C:6](=[O:9])[CH:5]=[CH:4][N:3]=1.Br[CH2:11]Br.[H-].[Na+]>CS(C)=O.[Cl-].[Na+].O>[CH3:1][C:2]1[C:7]2[O:8][CH2:11][O:9][C:6]=2[CH:5]=[CH:4][N:3]=1
Reactant: CC1=NC=CC(=O)C1O
Reactant: BrCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nccc2c1OCO2
Reaction time: 72 h

Procedure:
2-Methyl-3-hydroxy-4-pyridone (1.25 g, 10 mmol) was dissolved in dry DMSO (20 ml). Dibromomethane (3.5 g, 20 mmol) was added followed by sodium hydride (1 g, >20 mmol, 50-60% in oil). The mixture was left at ambient temperature under stirring for 3 days whereupon it was poured into brine (50 ml). The water-DMSO solution was extracted with methylene chloride (3×50 ml) and the collected extracts were used directly in the next step. A sample for NMR analysis was withdrawn.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:21]=[N:22][CH:23]=[N:24][CH:25]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].Br[CH2:35][CH:36]1[CH:40]([CH3:41])[O:39][C:38](=[O:42])[O:37]1.C(OCC)(=O)C>CN(C)C(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:31]/[OH:32])/[C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH2:35][CH:36]4[CH:40]([CH3:41])[O:39][C:38](=[O:42])[O:37]4)=[O:27])=[C:15](/[CH:18]=[CH:19]\[C:20]4[CH:25]=[N:24][CH:23]=[N:22][CH:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(=O)[O-])=C(/C=C\c4cncnc4)CS[C@H]23)cs1
Reactant: CC1OC(=O)OC1CBr
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC1OC(=O)OC1COC(=O)C1=C(/C=C\c2cncnc2)CS[C@@H]2[C@H](NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12

Procedure:
The compound (100 mg) of Example 16 was dissolved in N,N-dimethylacetamide (2 ml), followed by the addition of 4-bromomethyl-5-methyl-1,3-dioxolan-2-one (50 mg). They were reacted for 1 hour. Ethyl acetate (50 ml) was added. The resulting mixture was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure. Ether was added to the residue and the resulting solid was collected by filtration, whereby the title compound (15 mg) was obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].CS(C)=O>O>[CH3:17][O:18][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1
Reactant: C[O-]
Reactant: Clc1ccc(-c2nc3ccccc3o2)cc1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(-c2nc3ccccc3o2)cc1
Yield: 88.8 %

Procedure:
A mixture of 1.15 g (5 mmoles) of 2-(p-chloro-phenyl)benzoxazole, 2.5 g of sodium methoxide and 10 ml of dimethyl sulfoxide is heated at 80° C.-90° C. under nitrogen atmosphere for one hour. The mixture is cooled and diluted with 100 ml of water. The title compound (1 g, 87 percent yield) precipitates and is recovered. It has a melting point of 99.5° C.-101.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-])=O>[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(-c2cccnc2)cc1
Agent: [Pd]
Product: Nc1ccc(-c2cccnc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.2 %

Procedure:
In a flame-dried r.b. flask equipped with a magnetic stirring bar was dissolved 3-(4-nitrophenyl)pyridine (131 mg, 0.655 mmol) and 10% Pd on C (10 mg) in anhydrous CH2C12 (3 mL) was added. The flask was repeatedly evacuated and filled with N2 to remove any residual O2, and then H2 gas was introduced. The solution was stirred at rt for 18 h, filtered though a Celite™ plug and concentrated int vacuo to give the desired amine (105 mg, 95%) as an off-white solid. Data for 3-(4-aminophenyl)pyridine: Rf=0.17 (silica gel, methanol/CHCl3, 5/95); 1H NMR (400 MHz, acetone-d6) 8.77 (d, J=2.3, 1H), 8.42 (dd, J=6.4, 1.6, 1H), 7.88 (m, 1H), 7.41 (d, J=8.5, 2H), 7.33 (m, 1H), 6.78 (d, J=8.5, 2H), 4.86 (br s, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:24]=3[CH3:30])[CH2:19][CH2:18]2)=[O:16])=[C:11]([S:31]([CH3:34])(=[O:33])=[O:32])[CH:10]=1>>[CH3:30][C:24]1[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=1[N:20]1[CH2:19][CH2:18][N:17]([C:15]([C:12]2[CH:13]=[CH:14][C:9]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][C:2]3=[O:7])=[CH:10][C:11]=2[S:31]([CH3:34])(=[O:33])=[O:32])=[O:16])[CH2:22][CH2:21]1
Reactant: O=C1CCCCN1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCCC4=O)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 62.4 %

Procedure:
Using piperidin-2-one (104 mg) and (4-bromo-2-methanesulfonylphenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (451 mg) described in Preparation Example 110 and by the reaction and treatment in the same manner as in Example 1, the title compound (293 mg) was obtained.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=2[O:32][CH3:33])=[CH:11][C:10]=1[C:34]1[N:38]([CH2:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:37]=[N:36][N:35]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH:29]([C:27]1[CH:26]=[CH:25][C:24]([O:32][CH3:33])=[C:23]([C:12]2[C:13]([OH:15])=[CH:14][C:9]([OH:8])=[C:10]([C:34]3[N:38]([CH2:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[N:37]=[N:36][N:35]=3)[CH:11]=2)[CH:28]=1)([CH3:31])[CH3:30]
Reactant: COc1ccc(C(C)C)cc1-c1cc(-c2nnnn2CCc2ccccc2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C(C)C)cc1-c1cc(-c2nnnn2CCc2ccccc2)c(O)cc1O
Reaction time: 8 h
Yield: 63.9 %

Procedure:
5% Pd/C (30 mg) was wetted carefully with methanol under nitrogen in a 25 ml round flask, then a solution of 5-(4,6-bis-benzyloxy-5′-isopropyl-2′-methoxy-biphenyl-3-yl)-1-phenethyl-1H-tetrazole (100 mg, 0.16 mmol) in methanol (10 ml) was added. The reaction flask was vacuumed and filled with hydrogen three times. The reaction was then stiffed under hydrogen at r.t. overnight. After filtering the catalyst over celite, the filtrate was concentrated to give 5′-isopropyl-2′-methoxy-5-(1-phenethyl-1H-tetrazol-5-yl)-biphenyl-2,4-diol (44 mg, 63%). M.p.: 206-209° C.; 400 MHz 1H NMR (DMSO-d) δ: 10.22 (s, 1H), 9.64 (s, 1H), 7.19-7.08 (m, 4H), 7.02-6.97 (m, 3H), 6.94 (d, J=8.4 Hz, 1H), 6.75 (s, 1H), 6.61 (s, 1H), 4.55 (t, J=7.2 Hz, 2H), 3.66 (s, 3H), 3.11 (t, J=7.2 Hz, 2H), 2.90-2.81 (m, 1H), 1.20 (d, J=7.2 Hz, 6H); LCMS: 431 [M+H].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][CH2:12][O:13][CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:21]([S:28][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][CH2:12][O:13][CH3:14])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: SCc1ccccc1
Reactant: COCCc1cc([N+](=O)[O-])ccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCc1cc([N+](=O)[O-])ccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.9 %

Procedure:
To a solution of 1-bromo-2-(2-methoxyethyl)-4-nitrobenzene (7.8 g, 30 mmol) and Cs2CO3 (14.66 g, 45 mmol) in DMF (100 mL) was added BnSH (4.1 g, 33 mmol) slowly, followed by stirring at room temperature for three hours. Water was added, the precipitate was filtered, washed by water and petroleum to give benzyl(2-(2-methoxyethyl)-4-nitrophenyl)sulfane (8 g, yield 88%). 1H NMR: 400 MHz CDCl3 δ 8.05 (s, 1H), 8.01-7.98 (m, 1H), 7.38-7.28 (m, 6H), 4.23 (s, 2H), 3.64-3.61 (m, 2H), 3.34 (s, 3H), 3.03-2.99 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:10]3[CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=[CH:22][C:9]2=3)[CH2:4][CH2:3]1.[CH2:26]([NH:28]CC)[CH3:27]>>[CH2:26]([NH:28][C:23]([C:20]1[CH:21]=[CH:22][C:9]2[C:8](=[C:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][O:11][C:10]=2[CH:19]=1)=[O:24])[CH3:27]
Reactant: CCNCC
Reactant: CN1CCC(=C2c3ccccc3COc3cc(C(=O)O)ccc32)CC1
Product: CCNC(=O)c1ccc2c(c1)OCc1ccccc1C2=C1CCN(C)CC1

Procedure:
The title compound was synthesized from compound 4d using an adaptation of Procedure 6, substituting ethylamine for diethylamine. MS m/z (MH+) 363.0.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH:28]2[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]2)=[CH:23][C:22]=1[CH3:39])=[O:19])=[O:12].Cl>C(OCC)(=O)C.O1CCOCC1>[NH:30]1[CH2:31][CH:28]([O:27][C:24]2[CH:25]=[CH:26][C:21]([NH:20][C:18]([C:17]3[NH:16][CH:15]=[N:14][C:13]=3[C:11]([NH:10][C:2]3[NH:1][C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)=[O:12])=[O:19])=[C:22]([CH3:39])[CH:23]=2)[CH2:29]1
Reactant: Cc1cc(OC2CN(C(=O)OC(C)(C)C)C2)ccc1NC(=O)c1[nH]cnc1C(=O)Nc1nc2ccccc2[nH]1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(OC2CNC2)ccc1NC(=O)c1[nH]cnc1C(=O)Nc1nc2ccccc2[nH]1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
1,1-dimethylethyl 3-({4-[({4-[(1H-benzimidazol-2-ylamino)carbonyl]-1H-imidazol-5-yl}carbonyl)amino]-3-methylphenyl}oxy)azetidine-1-carboxylate (155.0 mg, 0.29 mmol) was suspended in 5 mL of ethyl acetate, which was cooled with an ice-water bath. 3 mL of 4 N HCl in dioxane was added dropwise. The reaction mixture was stirred overnight. The suspension was filtered and the solid was washed with 5 mL of ethyl acetate, dried under vacuum to afford the desired product (102 mg, 0.22 mmol) as the hydrochloride salt. 1H-NMR (400 MHz, DMSO-d6): δ=10.9 (br, 1H), 9.85 (br, 2H), 8.32 (s, 1H), 7.63 (m, 2H), 7.38 (m, 3H), 6.84 (m, 1H), 6.78 (m, 1H), 5.05 (m, 1H), 4.43 (m, 2H), 3.94 (m, 2H), 2.25 (s, 3H). MS: 432 (M++1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:13])([CH3:12])[C:9]([CH3:15])([CH3:14])[O:8]2)=[C:5]([CH3:16])[NH:4][N:3]=1.[H-].[Na+].Cl[CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[CH3:1][C:2]1[C:6]([B:7]2[O:11][C:10]([CH3:12])([CH3:13])[C:9]([CH3:15])([CH3:14])[O:8]2)=[C:5]([CH3:16])[N:4]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:3]=1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nn(COCC[Si](C)(C)C)c(C)c1B1OC(C)(C)C(C)(C)O1
Reaction time: 1.5 h
Yield: 86 %

Procedure:
A stirred suspension of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.15 g, 0.68 mmol) in THF (5 mL) was treated with NaH (0.032 g, 60% dispersion in oil, 0.81 mmol) at r.t. After 5 minutes [2-(chloromethoxy)ethyl]-trimethylsilane (0.14 mL, 0.81 mmol) was added and the reaction mixture stirred for 1.5 h. The reaction mixture was quenched with water (5 mL), diluted with EtOAc (20 mL) and the organic fraction separated. The organic fraction was dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 0-40% EtOAc/hexanes) gave the title compound (0.206 g, 86%) as a clear oil. δH (CDCl3) 5.35 (2H, s), 3.60 (2H, m), 2.50 (3H, s), 2.35 (3H, s), 1.35 (12H, s), 0.90 (2H, m), 0.00 (9H, s). LCMS (ES+) 353.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH3:8][NH2:9]>>[CH3:8][NH:9][CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CN
Reactant: C=CC(=O)OCC
Product: CCOC(=O)CCNC
Reaction time: 3 h

Procedure:
At 0° C., a solution of ethyl acrylate in alcohol (2M, 1000 mL, 2 mol) was added drop wise to a solution of MeNH2 in alcohol (33%, 540 mL, 4 mol). The resulting mixture was stirred for 3 h. Upon completion of the reaction, monitored by TLC, the solvent and volatiles were removed under reduced pressure to give ethyl 3-(methylamino)propanoate (250 g, crude) as an oil, which was used in the next step without further purification.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[NH:11][C:12]([CH2:17][OH:18])=[C:13](CO)[N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[CH3:9][C:10]1[NH:11][C:12]([CH2:17][OH:18])=[C:13]([Cl:1])[N:14]=1
Reactant: Cc1nc(CO)c(CO)[nH]1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(Cl)c(CO)[nH]1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
3.86 Grams (28.9 mmol) of the N-chlorosuccinimide was added little by little to a solution consisting of 3.87 g (27.2 mmol) of a 2-methyl-4,5-bis(hydroxymethyl) imidazole and 50 ml of water maintained at room temperature with stirring over a period of about 40 minutes. The mixture was then stirred at the same temperature for 20 hours followed by the addition of sodium carbonate thereto to make the mixture alkaline. Water was then distilled off under reduced pressure. The resulting reaction mixture was extracted with ethanol, and the extract was evaporated dryness under reduced pressure. The resulting solid product was then extracted with acetone and the extract was evaporated under reduced pressure to obtain a yellowish oily product. The oily product was then subjected to the column chromatography (silica gel-acetone) to obtain a yellowish brown crystalline 2-methyl-4-chloro-5-(hydroxymethyl) imidazole in an amount of 2.4 g (yield, 60.2%). By using acetonitrile, the recrystallization was repeated two times to obtain a colorless powdery product in pure form. The TLC and spectra of this compound were the same as the properties exhibited by the above-mentioned 2-methyl-4-chloro-5-(hydroxymethyl) imidazole.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12](/[CH:13]=[CH:14]/[C:15]#[C:16][C:17]2[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=2)=[CH:11][C:10]([CH3:29])([CH3:28])[CH2:9][CH:8]=1)(=O)=O.FC(F)(F)S(O[C:38]1[C:43](/C=C/CCC2C=CC(C(OCC)=O)=CC=2)=[CH:42][C:41](C)([CH3:59])[CH2:40][CH:39]=1)(=O)=O>>[CH3:59][C:41]1[CH:42]=[CH:43][C:38]([C:7]2[C:12](/[CH:13]=[CH:14]/[C:15]#[C:16][C:17]3[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=3)=[CH:11][C:10]([CH3:29])([CH3:28])[CH2:9][CH:8]=2)=[CH:39][CH:40]=1
Reactant: CCOC(=O)c1ccc(C#C/C=C/C2=CC(C)(C)CC=C2OS(=O)(=O)C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(CC/C=C/C2=CC(C)(C)CC=C2OS(=O)(=O)C(F)(F)F)cc1
Product: CCOC(=O)c1ccc(C#C/C=C/C2=CC(C)(C)CC=C2c2ccc(C)cc2)cc1

Procedure:
Following General Procedure A, ethyl (E)-4-(4-(2-(trifluoromethanesulfonyl)oxy-5,5-dimethyl-1,3-cyclohexadien-3-yl)but-3-ene-1-yn-1-yl)benzoate (Compound 21, 46 mg, 0.098 mmol) was converted into the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[CH:24]1([C:29](O)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH:17][C:29]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:30])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Reactant: O=C(O)C1CCCC1
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)C3CCCC3)c2c1N

Procedure:
Prepared as in Example 24a from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methyl-quinoline-3-carboxylate (Example 24b) and cyclopentane carboxylic acid as a yellow solid (33%). 1H NMR (400 MHz, DMSO-d6) δ 1.34 (t, J=4.0 Hz, 3H), 1.37 (s, 6H), 1.42-1.53 (m, 6H), 1.64-1.69 (m, 2H), 2.58 (m, 1H), 2.62 (s, 3H), 4.32 (s, 2H), 4.35 (m, 2H), 6.96 (m, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.58 (m, 1H), 7.66 (s, 1H), 8.41 (d, 2H). MS 414 (MH+).
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([NH:16][CH3:17])[N:13]=[CH:12][N:11]=2)[CH:5]=1.ClC1N=CN=C(C2C=[C:28](C=CC=2)[C:29]([OH:31])=[O:30])C=1>CN>[C:4]([O:31][C:29](=[O:30])[CH2:28][C:3]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]2[CH:15]=[C:14]([NH:16][CH3:17])[N:13]=[CH:12][N:11]=2)[CH:5]=1)=[O:18])([CH3:9])([CH3:5])[CH3:3]
Reactant: CNc1cc(-c2cccc(C(=O)OC)c2)ncn1
Reactant: O=C(O)c1cccc(-c2cc(Cl)ncn2)c1
Agent: CN
Product: CNc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ncn1
Temperature: 50 °C
Reaction time: 36 h

Procedure:
The title compound was prepared from 3-[6-methylamino-pyrimidin-4-yl]-benzoic acid methyl ester [prepared by the following procedure: 3-(6-Chloro-pyrimidin-4-yl)-benzoic acid (1.49 g, 6 mmol) was heated in 40% aqueous methylamine (5 ml) to 80° C. for 14 h. The mixture was evaporated in vacuum and the residual oil was stirred in 1N HCl-MeOH (10 ml) for 36 h at 50° C. The crude product was purified by chromatography (silica gel, AcOEt) to give the methyl ester as yellow solid (0.62 g).] (0.60 g, 2.4 mmol) by treatment with lithium tert-butyl acetate according to general procedure K (method b). Obtained as a white solid (0.72 g).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[N:4]1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CN(C=O)C>[C:24]([O:23][C:21](=[O:22])[CH2:20][N:3]1[CH:7]=[CH:6][C:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])=[N:4]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1c2ccccc2C(=O)N1c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1ccc(N2C(=O)c3ccccc3C2=O)n1
Reaction time: 18 h

Procedure:
Sodium hydride (60% in oil, 0.538 g, 13.4 mmol) is added to a stirred solution of 2-(1H-pyrazol-3-yl)-isoindole-1,3-dione (2.39 g, 11.2 mmol) in dry DMF (25 ml) at room temperature. After 10 minutes tert-butyl bromoacetate (1.81 ml, 11.2 mmol) is added and the reaction is stirred for 18 hours. The reaction is quenched with water (1 ml), ethyl acetate (150 ml) is added and the organic phase is washed with water (3×100 ml) followed by brine (1×100 ml). The solvent is removed and the product is purified by chromatography on silica (gradient elution: ethyl acetate—hexane) to give the titled compound.