Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:20]=[CH:19][C:11]([CH:12]([CH3:18])[C:13](OCC)=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH:22][NH2:23].[OH-].[K+]>CO>[C:1]1([C:6]([C:8]2[CH:20]=[CH:19][C:11]([CH:12]([CH3:18])[C:13]([NH:23][OH:22])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C(=O)NO)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 12.6 parts of ethyl p-(2-thenoyl)-hydratropate in 35 parts of methanol is added successively and while cooling, first a solution of 6.05 parts of hydroxyl amine hydrochloride in 35 parts of methanol and then a solution of 7.3 parts of potassium hydroxide in 35 parts of methanol. Upon completion, the whole is stirred for 30 minutes. The mixture is filtered and the filtrate is stirred for 3 days at room temperature. The reaction mixture is evaporated and the residue is taken up in water. The aqueous solution is acidified with hydrochloric acid solution and the product is extracted with ether. The extract is washed with water, dried, filtered and evaporated. The residue is taken up in water, alkalized with sodium hydroxide solution, washed with ether and the aqueous phase is acidified with concentrated hydrochloric acid solution. The product is extracted with ether. The latter is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silicagel, using a mixture of chloroform and 10% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in a mixture of petroleumether and diisopropylether. The solid product is filtered off and crystallized from 2-propanol, yielding p-(2-thenoyl)hydratropohydroxamic acid; m.p. 143.5° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1.[O:22]=[C:23]1[CH2:26][N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([F:21])=[CH:4][C:5]2[CH:11]3[CH2:10][CH:9]([CH2:12]3)[N:8]3[C:13]([C:23]4([OH:22])[CH2:24][N:25]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH2:26]4)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=[C:7]3[C:6]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: COC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Product: COC(=O)c1nc2n(c1C1(O)CN(C(=O)OC(C)(C)C)C1)C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
Methyl 10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate (0.3 g) was reacted with tert-butyl 3-oxoazetidine-1-carboxylate similar to as described in example 8 with non-critical modifications to produce methyl 10-bromo-3-(1-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate. This crude intermediate was reacted via General Procedure L then deprotected with 4N HCl in dioxane (5 eq) at room temperature to provide 10-bromo-9-fluoro-3-(3-hydroxyazetidin-3-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. 10-bromo-9-fluoro-3-(3-hydroxyazetidin-3-yl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with cyclopropane carboxylic acid similar to as described in Example 2 with non-critical modifications to afford crude 10-bromo-3-(1-(cyclopropanecarbonyl)-3-hydroxyazetidin-3-yl)-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was then reacted with 2-Methyl-3-butyne-ol via General Procedure F to afford 7.9 mg (71.8%) 3-[1-(cyclopropanecarbonyl)-3-hydroxy-azetidin-3-yl]-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[CH2:14]([N:21]1[CH:25]=[C:24]([CH2:26][NH:27][C:28]2[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[CH:23]=[N:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([N:21]1[CH:25]=[C:24]([CH2:26][N:27]([C:28]2[CH:29]=[CH:30][C:31]([CH:34]([CH3:36])[CH3:35])=[CH:32][CH:33]=2)[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])[CH:23]=[N:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)c1ccc(NCc2cnn(Cc3ccccc3)c2)cc1
Reactant: O=C(O)C1CCCc2ccccc21
Product: CC(C)c1ccc(N(Cc2cnn(Cc3ccccc3)c2)C(=O)C2CCCc3ccccc32)cc1
Yield: 80.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.26 g) and [(1-benzylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.46 g) as starting materials, N-[(1-benzylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.55 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=S)[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][CH:37]([CH3:43])[CH2:38][C:39]([NH:41][NH2:42])=O>CC1C=CC(C)=CC=1>[CH2:38]([C:39]1[N:26]2[C:21]3[CH:20]=[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:18]([C:15]4[CH:16]=[CH:17][C:12]([C:8]5([NH:7][C:6](=[O:35])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:11][CH2:10][CH2:9]5)=[CH:13][CH:14]=4)=[N:28][C:22]=3[O:23][CH2:24][C:25]2=[N:42][N:41]=1)[CH:37]([CH3:43])[CH3:36]
Reactant: CC(C)CC(=O)NN
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=S)CO4)cc2)CCC1
Solvent: Cc1ccc(C)cc1
Product: CC(C)Cc1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Temperature: 150 °C
Yield: 6.6 %

Procedure:
A suspension of tert-butyl(1-(4-(7-phenyl-2-thioxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (200 mg, 0.410 mmol) and 3-methylbutanehydrazide (47 mg, 0.410 mmol) in p-xylene (1.5 ml) was heated to 150° C. for 15 minutes under microwave irradiation. The resulting reaction mixture was concentrated to dryness under reduced pressure and purified by Biotage silica gel chromatography (gradient 0% to 20% ethyl acetate in n-hexanes) to give the title compound (15 mg, 5%). LCMS (Method D): RT=1.5687 min, M+1=552. 1H NMR (500 MHz, CDCl3): 7.80 (1H, s), 7.36-7.31 (5H, m), 7.30-7.27 (2H, m), 7.23-7.19 (2H, m), 5.57 (2H, s), 2.98 (2H, d), 2.54-2.41 (4H, m), 2.33-2.24 (1H, m), 2.13-2.01 (1H, m), 1.88-1.76 (1H, m), 1.44-1.26 (9H, bs), 1.11 (6H, d).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]2[N:15]=[C:14]3[C:10]([N:11]=[C:12]([O:23]C)[N:13]3[CH2:16][CH:17]3[CH2:22][CH2:21][CH2:20][O:19][CH2:18]3)=[C:9]([NH2:25])[N:8]=2)[CH2:3][CH2:2]1.Cl.[OH-].[Na+]>CO.O1CCOCC1>[NH2:25][C:9]1[N:8]=[C:7]([NH:6][CH2:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[N:15]=[C:14]2[C:10]=1[NH:11][C:12](=[O:23])[N:13]2[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][O:19][CH2:18]1
Reactant: COc1nc2c(N)nc(NCCC3CC3)nc2n1CC1CCCOC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc(NCCC2CC2)nc2c1[nH]c(=O)n2CC1CCCOC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 59.5 %

Procedure:
To a solution of N2-(2-cyclopropylethyl)-8-(methoxy)-9-(tetrahydro-2H-pyran-3-ylmethyl)-9H-purine-2,6-diamine (198 mg) in methanol (19.1 ml) at room temperature was added 4.0M hydrogen chloride in 1,4-dioxane (3.57 ml) to give a colorless solution. The reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was neutralised with 2M NaOH and concentrated in vacuo. The resulting solid was taken up in water (50 ml) and filtered off to give a white solid. This solid was recrystallised from ethanol:water (1:1) and filtered to afford an off-white crystalline solid (113 mg).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[S:12]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13].[CH2:21]([O:23][P:24]([O:28]CC)[O:25][CH2:26][CH3:27])[CH3:22]>CC1C=CC=CC=1C.C(OCC)(=O)C>[CH2:21]([O:23][P:24]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[S:12]([O:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:14])=[O:13])([O:25][CH2:26][CH3:27])=[O:28])[CH3:22]
Reactant: CC(C)(C)COS(=O)(=O)c1cc([N+](=O)[O-])ccc1CBr
Reactant: CCOP(OCC)OCC
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)OCC(C)(C)C)OCC
Temperature: 25 °C
Yield: 58 %

Procedure:
2-Bromomethyl-5-nitro-benzenesulfonic acid, 2,2-dimethylpropyl ester (Example 44, 2.0 g, 5.46 mmol) was dissolved in 100 mnL of anhydrous o-xylene. To this solution was added triethylphosphite (3.75 mL, 21.84 mmol). A water cooled condenser was attached and the material was heated to exactly 100° C. After six hours the mixture was cooled to room temperature then diluted with with ethyl acetate (400 mL) and washed with brine (2×). After drying over MgSO4 the organic layer was concentrated on a rotovap and then purified by flash column chromatography using 50 to 60% ethyl acetate/hexanes gradient as an eluant to provide 1.34 g of the title compound as a yellow oil.(55%): 1HNMR (CDCl3) δ8.87 (m, 1H), 8.43 (dd, J=9 Hz, 2 Hz, 1H), 8.05 (dd, J=9 Hz, 2 Hz, 1H), 4.12 (m, 4H), 3.81 (s, 2H), 3.77 (d, J=23 Hz, 2H), 1.32 (m, 6H), 0.96 (s, 9H); MS (ES-POS): [M+Na]+ 446; Analytical HPLC determined that this compound was 96.1% pure by C-18 reverse phase.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]#[C:13][CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][O:17]3)=[CH:11][C:6]=2[C:5](=[O:22])[CH2:4][S:3]1(=[O:24])=[O:23].C(N(CC)CC)C.[Cl:32][C:33]1[CH:42]=[CH:41][C:36]([CH2:37][N:38]=[C:39]=[O:40])=[CH:35][CH:34]=1.Cl>CS(C)=O>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]([CH2:37][NH:38][C:39]([C:4]2[S:3](=[O:23])(=[O:24])[N:2]([CH3:1])[C:7]3[CH:8]=[CH:9][C:10]([C:12]#[C:13][CH2:14][O:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][O:17]4)=[CH:11][C:6]=3[C:5]=2[OH:22])=[O:40])=[CH:41][CH:42]=1
Reactant: CN1c2ccc(C#CCOC3CCCCO3)cc2C(=O)CS1(=O)=O
Reactant: O=C=NCc1ccc(Cl)cc1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1c2ccc(C#CCOC3CCCCO3)cc2C(O)=C(C(=O)NCc2ccc(Cl)cc2)S1(=O)=O
Reaction time: 4 h
Yield: 28.4 %

Procedure:
To a solution of 1-methyl-6-(3-(tetrahydro-2H-pyran-2-yloxy)-1-propynyl)-1H-2,1-benzothiazin-4(3H)-one 2,2-dioxide (Preparation 52, 1.00 g) and triethylamine (0.60 mL) in DMSO (25 mL) is added a solution of 4-chlorobenzylisocyanate (0.72 g) in DMSO (5 mL) at ambient temperature. After 4 h, 10% HCl (100 mL) is added to the reaction vessel and the aqueous layer is extracted with EtOAc (3×100 mL). The organic layers are combined, dried over MgSO4, filtered, and concentrated in vacuo to afford 0.42 g (28%) of the title compound as a lime green solid. Physical characteristics: m.p. 148-149° C.; 1H NMR (300 MHz, CDCl3) δ15.81, 8.22, 7.93, 7.71, 7.33, 7.16, 4.91, 4.60, 4.52, 3.91, 3.60, 3.48, 1.86, 1.62; IR (diffuse reflectance) 3373, 2940, 1616, 1574, 1543, 1493, 1390, 1327, 1297, 1279, 1253, 1116, 1097, 1077, 1037 cm−1; MS (FAB) m/z 517 (MH+); HRMS (EI) m/z 516.1140 (C25H25ClN2O6S). Anal. Found: C, 57.55; H, 4.95; N, 5.63.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.[CH2:11](Br)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>O1CCCC1>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])=[CH:4][CH:5]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: COc1ccc(Br)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.4 %

Procedure:
An about 3.70 g portion of magnesium was placed in a 100 ml, two-necked round bottom flask. The flask was flamed several times and about 28.5 g of p-bromoanisole and tetrahydrofuran were added. As soon as the reaction stopped it was refluxed for about 2 hours and then added to a boiling solution of about 21.07 g of tetradecyl bromide in tetrahydrofuran. Then about 9 ml of lithium cupric chloride was added and the mixture was refluxed for about 2 hours, then stirred at room temperature for about 16 hours, quenched with dilute hydrochloric acid, washed with ammonium chloride solution, sodium bicarbonate solution, brine and dried, giving about 23 g of the desired title compound, mp 38° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH:12]1([CH2:17]Br)[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:12]1([CH2:17][O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: BrCC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C=O)cc1OCC1CCCC1
Temperature: 60 °C
Yield: 73.5 %

Procedure:
A stirred solution of 3-hydroxy-4-methoxy-benzaldehyde (5.74 g) in dry dimethylformamide (50 mL) is treated with cyclopentylmethyl bromide (7.34 g) and potassium carbonate (15 g), and the solution is heated at 60° C. for 24 hours. After cooling and filtration, the solution is evaporated to low bulk and dissolved in ethyl acetate (100 mL). The organic solution is washed with aqueous sodium hydroxide solution (4×50 mL; 2 N) and water (2×50 mL), dried over magnesium sulfate, and evaporated to give 3-cyclopentylmethoxy-4-methoxybenzaldehyde (6.5 g) in the form of a light brown oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:6]=2[N:5]=[C:4]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=2[N:20]=1)[CH3:2].CN.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.C[CH2:50][N:51](C(C)C)C(C)C>CN(C=O)C>[CH3:50][NH:51][C:12]([C:10]1[CH:9]=[CH:8][C:7]2[N:3]([CH2:1][CH3:2])[C:4]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([O:25][C:26]([F:28])([F:27])[F:29])[CH:22]=[CH:21][C:19]=4[N:20]=3)=[N:5][C:6]=2[CH:11]=1)=[O:14]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC)ccc21

Procedure:
1-Ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid methylamide (50.0 mg) was prepared by following General Procedure F starting from 1-ethyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100.0 mg), methylamine (2.0 M solution in THF, 1 mL), DPPA (82.0 mg), and DIEA (0.1 mL) in DMF (1.0 mL). LCMS: m/z 437; and 1H NMR (CD3OD, 400 MHz): δ 7.93 (1H, d), 7.73-7.70 (2H, m), 7.64-7.63 (1H, d), 7.40-7.38 (1H, m), 7.25-7.22 (1H, m), 4.25-4.23 (2H, q), 2.95 (3H, s), 1.41-1.38 (3H, t), 2 —NH proton signals were not observed.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=O)C.O.[NH2:19][NH2:20]>CO>[N:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:11][CH:6]([C:4]([NH:19][NH2:20])=[O:3])[CH2:7][CH2:8]1
Reactant: NN
Reactant: CCOC(=O)C1CCN(c2ccccn2)CC1
Solvent: O
Solvent: CO
Product: NNC(=O)C1CCN(c2ccccn2)CC1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4–Carboxylic acid ethyl ester (1 g, 4.3 mmol)(see reference Farmaco, 1993, 48(10), 1439) was dissolved in methanol (20 ml) containing hydrazine hydrate (620 μl, 20 mmol) and was heated under reflux for 18 hours. The mixture was cooled to room temperature and evaporated under reduced pressure. The solid formed was triturated with propan-2-ol to give the title compound as a white solid (493 mg).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH3:7].[BH4-].[Na+]>CO.O>[C:11]([O:10][C:8]([N:6]([CH2:5][CH2:4][CH2:3][OH:2])[CH3:7])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)CCN(C)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(CCCO)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To a solution of N-t-butoxycarbonyl-N-methyl-β-alanine methyl ester (3.911 g) in methanol (20 ml) and water (20 ml) was added sodium borohydride (6.81 g) portionwise at 4° C. and the mixture was stirred at room temperature for 3 hours. The solution was concentrated in vacuo, and the residue was portioned between ethyl acetate (100 ml) and 0.5 N hydrochloric acid (100 ml). The separated organic layer was washed with 0.5 N hydrochloric acid (100 ml), water (100 ml), aqueous sodium bicarbonate (100 ml), water (100 ml) and brine (100 ml) successively, and dried over magnesium sulfate. Evaporation of the solvent gave 3-(N-t-butoxycarbonyl-N-methylamino)propanol (2.48 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:4][C:5]([CH3:18])=[C:6]([CH3:17])[C:7]=1[NH:8][CH2:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])([CH3:12])[CH3:11].C(N(CC)CC)C.[CH2:33]([O:35][CH2:36][C:37](Cl)=O)[CH3:34]>C(Cl)Cl>[CH2:33]([O:35][CH2:36][C:37]1[N:8]([CH2:9][C:10]([NH:13][C:14](=[O:16])[CH3:15])([CH3:11])[CH3:12])[C:7]2[C:6]([CH3:17])=[C:5]([CH3:18])[N:4]=[C:3]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:2]=2[N:1]=1)[CH3:34]
Reactant: CC(=O)NC(C)(C)CNc1c(C)c(C)nc(Oc2ccccc2)c1N
Reactant: CCOCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CC(C)(C)NC(C)=O
Reaction time: 8 h
Yield: 45.6 %

Procedure:
A solution of N-{2-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]-1,1-dimethylethyl}acetamide (1.80 g, 5.23 mmol) in 50 mL of CH2Cl2 was cooled to 0° C., under N2, and treated with triethylamine (728 μL, 5.23 mmol) and ethoxyacetyl chloride (574 μL, 5.23 mmol). After stirring overnight, the reaction mixture was concentrated under reduced pressure. The resulting syrup was taken up in 50 mL of EtOH and treated with 3 mL of triethylamine. The solution was heated to reflux for 4 d. The reaction mixture was then concentrated and redissolved in 50 mL of xylenes and treated with pyridinium hydrochloride (0.5 g) and the mixture was heated to reflux for 4 d. The reaction mixture was concentrated and taken up in 100 mL of EtOAc and washed with saturated NaHCO3 solution, H2O (2×) and brine. The organic portion was dried over Na2SO4 and concentrated. The resulting syrup was purified by column chromatography (SiO2, 80% EtOAc/hexanes) to give N-{2-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]-1,1-dimethylethyl}acetamide (980 mg) as a mustard colored foam.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11](=[O:30])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)=[CH:14][CH:13]=2)[CH:6]=1.[Li+].[OH-]>>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([C:7]2[CH:6]=[C:5]([CH2:4][C:3]([OH:31])=[O:2])[CH:10]=[CH:9][CH:8]=2)=[O:30])=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1cccc(C(=O)c2ccc(OCc3ccc4ccccc4c3)cc2)c1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)Cc1cccc(C(=O)c2ccc(OCc3ccc4ccccc4c3)cc2)c1
Reaction time: 8 h
Yield: 99.3 %

Procedure:
A solution of the ester (1.29 g, 3.15 mmole) of Step A, is treated dropwise with 1N-LiOH and the mixture is stirred under nitrogen overnight. The solvent is evaporated and the residue is dissolved in water, acidified in the cold with 10% acetic acid (to pH 3) and extracted with ethyl acetate (3x). The extracts are dried (MgSO4) and evaporated to dryness. The residue (1.24 g, quantitative yield) is recrystallized by dissolving it in a relatively large volume of warm ethyl acetate-dichloromethane followed by concentrating to half volume. The precipitate is collected and dried at 45° C. in vacuo (0.610 g, 48.8%), m.p. 150°-152° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25]CC)=[O:24])=[CH:21][CH:20]=1.[OH-].[K+].C(O)C.Cl>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1ccc(NCCCCCCOc2ccc3ccccc3c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCCCCCOc2ccc3ccccc3c2)cc1

Procedure:
A solution of 4.8 g. of ethyl p-{[6-(2-naphthyloxy)hexyl]amino}benzoate and 4.8 g. of potassium hydroxide in 100 ml. of 95% ethanol is refluxed for 3 hours. The solution is cooled, diluted with water and acidified with concentrated hydrochloric acid. The mixture is filtered and the solid washed with ethanol and water and recrystallized from ether-methylene chloride and acetone to give crystals, m.p. 157°-159° C.
Reaction SMILES: [H-].[Na+].CC[O:5][C:6]([CH:8](P(OCC)(OCC)=O)[CH3:9])=[O:7].[CH2:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([O:34]COC)=[C:23]([O:32][CH3:33])[CH:24]=[C:25]2[CH:30]=O)[CH3:19].O>CN(C)C=O>[CH2:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[C:22]([OH:34])=[C:23]([O:32][CH3:33])[CH:24]=[C:25]2/[CH:30]=[C:8](\[CH3:9])/[C:6]([OH:5])=[O:7])[CH3:19]
Reactant: CCc1cccc2c(C=O)cc(OC)c(OCOC)c12
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cccc2c(/C=C(\C)C(=O)O)cc(OC)c(O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 122 %

Procedure:
36 g of 60% sodium hydride was suspended in 500 ml of N,N-dimethylformamide and 268 g of triethyl 2-phosphonopropionate was added at ice bath temperature. After stirring at room temperature for 1 hour, a solution of 206 g of 5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthalenecarbaldehyde was added. After stirring at room temperature for 15 minutes, ice cooled water was gradually added at ice bath temperature. The mixture was extracted with ethyl acetate and the combined organic layer was washed with brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated and the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane) to obtain 262.4 g of the titled compound as a yellow oil (containing a small amount of Z isomer).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]1[NH:8][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[CH:10][N:11]=1.[CH3:30][N:31]=[C:32]=[O:33].C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[CH3:30][NH:31][C:32]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@H:6]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[C:7]1[NH:8][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)=[CH:10][N:11]=1)=[O:33]
Reactant: CN=C=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCN)c1ncc(-c2ccc3ccccc3c2)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNC(=O)NCCCC[C@H](NC(=O)OC(C)(C)C)c1ncc(-c2ccc3ccccc3c2)[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a stirred solution (0.18 M) of the product from step 1 in DCM/DMF (2:1) at 0° C., methyl isocyanate (1 eq.) was added. The reaction mixture was stirred at 0° C. for 1 h. Then, NaHCO3 (saturated solution) was added and extracted with EtOAc. The combined organic layers were dried. Evaporation of the solvent gave a crude that was purified by flash chromatography on silica gel (95:5 DCM/MeOH) to yield (63%) the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[C:18][CH2:19][CH2:20]O.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:20][CH2:19][C:18]#[C:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=1)=[O:5]
Reactant: O=C(O)c1ccccc1Cl
Reactant: OCCC#Cc1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(OCCC#Cc1ccccn1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To solution of 2-chlorobenzoic acid (330 mg, 2.10 mmol), 4-(pyridin-2-yl)but-3-yn-1-ol (310 mg, 2.1 mmol), in DCM (7 mL), was successively added EDCI.HCl (600 mg, 3.2 mmol) and DMAP (13 mg, 0.105 mmol). The resulting mixture was then stirred overnight at ambient temperature. The reaction mixture was concentrated.