Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH:12][C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH:20]=[C:19]([C:22](O)=[O:23])[O:18][C:17]=2[CH:25]=1>>[OH:12][C:13]1[CH:14]=[CH:15][C:16]2[O:21][CH:20]=[C:19]([C:22]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:23])[O:18][C:17]=2[CH:25]=1
Reactant: CCCCNc1ccccc1
Reactant: O=C(O)C1=COc2ccc(O)cc2O1
Product: CCCCN(C(=O)C1=COc2ccc(O)cc2O1)c1ccccc1
Yield: 78 %

Procedure:
That compound is obtained in a yield of 78% starting from N-butylaniline and 7-hydroxy-1,4-benzodioxin-2-carboxylic acid.
Reaction SMILES: [C:1]1([CH:7]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([C:28]([CH3:35])([CH3:34])[C:29]([O:31]CC)=[O:30])[N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>C(O)C>[C:36]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([CH:25]=[C:26]([C:28]([CH3:35])([CH3:34])[C:29]([OH:31])=[O:30])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 60.1 %

Procedure:
468 mg of ethyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate was dissolved in 3 ml of ethanol; 2 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 15 hours. After the mixture was concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate; the water layer was adjusted to pH 7 by the addition of 1 N hydrochloric acid, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. Ethyl acetate was added to the residue; the crystal precipitated was collected by filtration, washed with ethyl acetate and dried to yield 267 mg of the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11](OS(C(F)(F)F)(=O)=O)=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:26]3[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=3[F:33])[C:5]2=[O:34])[CH2:3][CH2:2]1.[NH2:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][CH:45]=1)[NH:39][C:40](=[O:42])[CH3:41].CN(C)C(=O)C.N1C(C)=CC=CC=1C>CO.O>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11]([NH:35][C:36]4[CH:37]=[C:38]([NH:39][C:40](=[O:42])[CH3:41])[CH:43]=[CH:44][CH:45]=4)=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:26]3[CH:31]=[CH:30][C:29]([I:32])=[CH:28][C:27]=3[F:33])[C:5]2=[O:34])[CH2:3][CH2:2]1
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: Cc1c(OS(=O)(=O)C(F)(F)F)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(I)cc3F)c2n(C)c1=O
Solvent: CC(=O)N(C)C
Solvent: CO
Solvent: Cc1cccc(C)n1
Product: CC(=O)Nc1cccc(Nc2c(C)c(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2ccc(I)cc2F)c1
Temperature: 130 °C
Reaction time: 5 h
Yield: 99.2 %

Procedure:
To trifluoromethanesulfonic acid 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 43 (25.0 g) obtained in Step 6 and 3′-aminoacetanilide 57 (7.33 g) were added N,N-dimethylacetamide (50.0 ml) and 2,6-lutidine (5.68 ml), and the mixture was stirred at 130° C. for 5 hrs. After allowing to cool to room temperature, methanol-water [1:2 (volume ratio), 150 ml] was added with stirring. The crystals were collected by filtration and dried to give N-{3-[3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-ylamino]phenyl}acetamide 58 (24.8 g, yield 99%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH:9]([F:11])[F:10])=[CH:4][N:3]=1.[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:10][CH:9]([F:11])[C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([C:12]#[N:13])=[N:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C(F)F)cnc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cc(C(F)F)cnc1C#N

Procedure:
A solution of 2-chloro-5-difluoromethyl-3-methyl-pyridine (337 mg, 1.898 mmol), Zn(CN)2 (159 mg, 1.328 mmol) and Pd(PPh3)4 (132 mg, 0.114 mmol) in DMF (10 ml) was stirred for 10 min at 120° C. in a microwave, filtered over hyflo and washed with water and brine. The combined aqueous layers were extracted with TBME, the combined organic layers were dried over sodium sulfate, filtered and concentrated. 5-Difluoromethyl-3-methyl-pyridine-2-carbonitrile was obtained as a yellow oil after flash chromatography on silica gel (cyclohexane/EtOAc gradient 0-3 min 100:0, 3-35 min 100:0 to 80:20). ESI MS: 169 [M+H]; 1H NMR (400 MHz, CDCl3): δ=8.68 (s, 1H), 7.84 (s, 1H), 6.75 (t, 1H), 2.65 (s, 3H).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[N:23]=[C:22]([CH:31]=[C:32](Br)Br)[CH:21]=2)=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]([CH:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]3)[N:23]=[C:22]([C:31]#[CH:32])[CH:21]=2)=[CH:16][CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: BrC(Br)=Cc1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1cc(-c2ccc(OCc3ccccc3)cc2)n(C2CCCCC2)n1
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
n-Butyllithium (1.6 M BuLi in hexanes, 1.65 ml, 2.64 mmol) was added dropwise to a solution of 7.1 (620 mg, 1.20 mmol) in THF (6 ml) at −50°. The mixture was stirred at −50° C. for 30 min, quenched with H2O, diluted with EtOAc, washed with 1N HCl, H2O, brine, and dried (Na2SO4). The crude product was purified by SiO2 chromatography to afford 261 mg (61%) of 7.2. MS (ESI) 357.3 (MH+).
Reaction SMILES: Cl.[NH:2]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:3]1[C:4]([O:6][CH3:7])=[O:5].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[CH3:7][O:6][C:4]([CH:3]1[CH2:8][CH2:9][CH2:10][CH2:11][N:2]1[CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)=[O:5]
Reactant: O=Cc1ccccn1
Reactant: COC(=O)C1CCCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCCCN1Cc1ccccn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
Methyl pipecolinate hydrochloride (9.0 g, 50 mmol) was mixed with pyridine-2-carbaldehyde (5.4 g, 50 mmol) and triethylamine (5.05 g, 50 mmol) in dichloroethane (180 mL) at room temperature. Sodium triacetoxyborohydride (14.8 g, 70 mmol) was added in one portion. After the reaction mixture was stirred at room temperature for 1.5 h, saturated sodium carbonate was added. Then the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried with sodium sulfate, filtered and concentrated to give 10.9 g (93.6%) of the title compound as a pale brown oil. 1H NMR (CDCl3), δ(ppm): 8.53 (d, 1H), 7.65 (td, 1H), 7.49 (d, 1H), 7.14 (t, 1H), 3.89 (d, 1H), 3.73 (s, 3H), 3.68 (d, 1H), 3.25 (dd, 1H), 2.97 (m, 1H), 2.25 (m, 1H), 1.85 (m, 2H), 1.30-1.76(m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-])=O)[C:12]=1[CH3:20].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[Cl-].[NH4+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:17][C:13]1[C:12]([CH3:20])=[C:11]([CH2:3][CH2:2][C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(Br)cccc1[N+](=O)[O-]
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(N)cccc1CCC(=O)OC(C)(C)C
Temperature: 125 °C
Reaction time: 36 h

Procedure:
Under argon, 201 ml (1.39 mol) of tert-butyl prop-2-enoate were added dropwise to a solution of 100 g (463 mmol) of 1-bromo-2-methyl-3-nitrobenzene, 322 ml (2.31 mol) of triethylamine, 28.18 g (92.58 mmol) of tri-2-tolylphosphine and 10.39 g (46.29 mmol) of palladium(II) acetate in 2 liters of DMF, and the mixture was then stirred at 125° C. for 36 h. After cooling to room temperature, the reaction mixture was stirred with saturated aqueous ammonium chloride solution, and the organic phase was separated off. The aqueous phase was extracted three times with tert-butyl methyl ether, and the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulphate. After filtration, the solvent was removed to dryness under reduced pressure. The residue obtained was purified by flash chromatography on silica gel (mobile phase petroleum ether/ethyl acetate 9:1). This gave 89 g (338 mmol, 73% of theory) of the intermediate tert-butyl (2E)-3-(2-methyl-3-nitrophenyl)prop-2-enoate as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C@H:12]2[CH2:18][C:19]([NH:21][C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([CH2:32][CH:33]=O)=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C@H:12]2[CH2:18][C:19]([NH:21][C@H:22]2[C:31]3[C:26](=[CH:27][C:28]([CH2:32][CH2:33][N:35]4[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]4)=[CH:29][CH:30]=3)[CH2:25][CH2:24][CH2:23]2)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=CCc1ccc2c(c1)CCC[C@H]2NC(=O)C[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: O=C(C[C@@H]1C(=O)NCCN1S(=O)(=O)c1ccc(Cl)cc1)N[C@@H]1CCCc2cc(CCN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from step E (63 mg, 0.116 mmol) and piperidine (20 mg, 0.23 mmol) in 1 mL of dichloroethane was added sodium triacetoxyborohydride (49 mg, 0.23 mmol). After stirring overnight at room temperature, the reaction solution was diluted with EtOAc and washed with sat. NaHCO3 and brine. The organic phase was dried over Na2SO4 and evaporated to dryness in vaco. Flash chromatography (SiO2, EtOAc to EtOAc/MeOH=100:10 to 100:12) afforded the title compound as a white solid. MS: 573.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](OC(OCC)OCC)(=O)C>C(OCC)(=O)C>[N:8]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH:1][CH:9]=1
Reactant: CCOC(OCC)OC(C)=O
Reactant: Nc1ccncc1N
Solvent: CCOC(C)=O
Product: c1cc2nc[nH]c2cn1

Procedure:
3H-Imidazolo[4,5-c]pyridine was prepared by the method of Stanovik and Tisler, Synthesis, 2, 120 (1974). A mixture of 2.2 g (0.02 mole) of 3,4-diaminopyridine and 5 ml of diethoxymethyl acetate was heated at reflux for two hours. The reaction mixture was cooled and diluted by addition of ethyl acetate. The solid precipitate was collected by filtration and sublimed at 170° C. and 50 torr to give 0.84 g of 3H-imidazolo[4,5-c]pyridine; mp 165°-168° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C1COCC1>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc(CCl)cc1
Solvent: C1CCOC1
Product: Cc1ccc(CN2CCNCC2)cc1

Procedure:
Synthesized according to General Procedure A: 4-methylbenzyl chloride (4{13}, 6.1 mL, 46.2 mmol, 1 equiv.), piperazine (23.9 g, 277.4 mmol, 6 equiv.), THF (100.9 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5{13} (6.56 g, 96%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 7.18 (d, 2H, J=8.0 Hz), 7.09 (d, 2H, J=7.5 Hz), 3.42 (s, 2H), 2.84 (t, 4H, J=5.0 Hz), 2.37 (br s, 4H), 2.31 (s, 3H), 1.54 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 136.3, 134.7, 129.0, 128.6, 63.2, 54.3, 45.9, 20.9.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[NH2:9][NH2:10]>N1C=CC=CC=1>[NH:9]([C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1)[NH2:10]
Reactant: NN
Reactant: Clc1ccc(I)cn1
Solvent: c1ccncc1
Product: NNc1ccc(I)cn1
Temperature: 25 °C
Yield: 27.5 %

Procedure:
The solution of 2-chloro-5-iodopyridine (2.0 g, 20.9 mmol), anhydrous hydrazine (3.3 mL, 105 mmol) in pyridine (40 mL) was heated at reflux overnight. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added 1 N sodium hydroxide solution and it was extracted with EtOAc. The organic layer was separated, dried (sodium sulfate) and concentrated under reduced pressure. To the residue was added hexanes, and the precipitate was collected and dried in vacuo to afford the title compound (1.35 g, 69% yield) as off-white crystals. MS (ES+, m/z): 236.2 (M++1).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>O>[CH2:8]([O:15][C:16]1[CH:17]=[CH:18][C:19]([C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])=[CH:20][CH:21]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCOc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: CCCCCCCOc1ccc(C(=O)CCC(=O)O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 75.3 %

Procedure:
Succinic anhydride (62.4 g) mashed by a mortar and pestle was placed in a 1 l three-necked flask, followed by adding heptyloxybenzene (100 g) and nitrobenzene (300 ml), portion-wise adding anhydrous aluminum chloride (150 g) under ice cooling, heating the mixture up to 50° C., agitating for 2 hours, allowing to stand overnight, after which the resulting reaction solution was poured in water, and subjected to steam distillation to distil off excess nitrobenzene, followed by ice-cooling, filtering off the resulting solids, heating under reflux together with toluene to remove water by means of Dien-Stark type drain tube, filtering off the solution while hot, recrystallizing from the filtrate, and further filtering off the resulting crystals, to obtain 3-(4-heptyloxybenzoyl)propionic acid (114.5 g). m.p.: 103.5°-105.7° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][C:10]([OH:12])=O)(=[O:3])[CH3:2].[NH2:16][CH2:17][CH:18]([OH:30])[CH2:19][N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[O:8][CH2:9][C:10]([NH:16][CH2:17][CH:18]([OH:30])[CH2:19][N:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:12])(=[O:3])[CH3:2]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CC(=O)Nc1cccc(OCC(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.8 %

Procedure:
To a stirred mixture of 2-(3-acetamidophenoxy)acetic acid (85 mg, 0.41 mmol) in DCM (5 mL) was added TEA (0.5 mL), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (83.8 mg, 0.41 mmol) and HATU (171 mg, 0.451 mmol). The mixture was stirred at 25° C. for 3 hours. The reaction mixture was quenched by addition of water (20 mL) and extracted with DCM (3×20 mL) and the combined extracts washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the title product (55 mg, Yield 35%). 1H NMR (400 MHz, MeOD) δ=7.36 (s, 1H), 7.27-7.17 (m, 1H), 7.19-7.01 (m, 6H), 6.68-6.66 (m, 1H), 4.53 (s, 2H), 4.03-4.00 (m, 1H), 3.71-3.62 (m, 2H), 3.50-3.35 (m, 2H), 2.95-2.85 (m, 2H), 2.83-2.74 (m, 2H), 2.56 (d, J=6.3 Hz, 2H), 2.12 (s, 3H). LCMS (m/z): 398.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([N:8]([C@@H:10]2[CH2:15][CH2:14][N:13]([N:16]=O)[CH2:12][C@H:11]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.O.Cl.C(OCC)(=O)C>C(O)(=O)C.[Zn]>[ClH:1].[NH2:16][N:13]1[CH2:14][CH2:15][C@@H:10]([N:8]([CH3:9])[C:6](=[O:7])[C:5]2[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@H:11]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)[CH2:12]1
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(N=O)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(N)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 153.9 %

Procedure:
To a solution of the compound obtained in Example 548 (300 mg) in acetic acid (3 mL) was added Zn powder (229 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The obtained residue was treated with 1 equivalent of 4N hydrogen chloride/ethyl acetate to give the title compound (243 mg, 76%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.Cl.NC1NC=C(CCCCCC2[N:34]=[N:35][N:36]([CH2:38][CH2:39][NH:40][C:41]([C:43]3[CH:48]=[CH:47][C:46]([C:49]4C=[CH:53][CH:52]=[CH:51][CH:50]=4)=[CH:45][CH:44]=3)=[O:42])C=2)N=1>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:34]=[N:35][N:36]([CH2:38][CH2:39][NH:40][C:41](=[O:42])[C:43]3[CH:48]=[CH:47][C:46]([CH2:49][CH2:50][CH2:51][CH2:52][CH3:53])=[CH:45][CH:44]=3)[CH:13]=2)[N:6]=1
Reactant: Nc1nc(CCCCCc2cn(CCNC(=O)c3ccc(-c4ccccc4)cc3)nn2)c[nH]1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Agent: Cl
Product: CCCCCc1ccc(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.113 g, 0.408 mmol) was reacted with N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)biphenyl-4-carboxamide hydrochloride (0.106 g, 0.408 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-pentylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.75 (s, 1H), δ 7.57 (d, 2H), δ 7.27 (s, 1H), δ 7.12 (d, 2H), δ 4.48 (s, 2H), δ 3.84 (s, 2H), δ 2.55 (m, 4H), δ 2.22 (s, 2H0, δ 1.50 (s, 13H), δ 1.23 (s, 8H), δ 0.80 (t, 3H); 13C NMR (75 MHz, CDCl3) δ ppm 168.3, 150.5, 149.5, 148.2, 147.2, 138.6, 131.5, 128.7, 127.4, 106.4, 84.8, 49.4, 40.2, 35.9, 31.6, 31.0, 29.3, 28.9, 28.1, 27.9, 25.6, 22.6, 14.2; HRMS (ESI) calcd for C29H43N7O3 (M+) 537.3427, found 537.3420, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-pentylbenzamide hydrochloride (0.178 g, 92% yield). 1H NMR (300 MHz, CD3OD) δ 8.41 (s, 1H), δ 7.69 (d, 2H), δ 7.21 (d, 2H), δ 6.46 (s, 1H), δ 4.84 (s, 2H), δ 3.90 (s, 2H), δ 2.79 (s, 2H), δ 2.58 (t, 2H), δ 2.39 (t, 2H), δ 1.68 (s, 2H), δ 1.55 (s, 4H), δ 1.26 (s, 6H), δ 0.84 (t, 3H) ppm; 13C NMR (75 MHz, CD3OD) δ 169.2, 159.5, 158.9, 147.5, 147.3, 131.1, 128.5, 127.6, 127.4, 108.5, 54.2, 51.9, 39.5, 35.6, 31.4, 30.9, 30.6, 28.4, 27.9, 27.6, 26.9, 24.1, 23.5, 22.9, 22.4, 13.3 ppm; HRMS (ESI) calcd for C24H35N7O (M+) 437.2903, found 437.2892.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.[C:11]1(C)[CH:16]=[CH:15][C:14](S(O)(=O)=O)=[CH:13][CH:12]=1.O>C1(C)C=CC=CC=1>[CH3:14][C:13]1[N:1]([C:2]2[N:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=2)[C:16]([CH3:15])=[CH:11][CH:12]=1
Reactant: Cc1nc(N)nc(C)c1Br
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(-n2c(C)ccc2C)nc(C)c1Br

Procedure:
To a stirred solution containing 2.00 g (9.89 mmol) of 2-amino-5-bromo-4,6-dimethylpyrimidine (3) in 16 mL of anhydrous toluene were added 1.36 mL (11.5 mmol) of 2,5-hexadienone followed by 96 mg (0.50 mmol) of p-toluene sulfonic acid. The reaction mixture was stirred at reflux overnight under argon atmosphere. The reaction mixture was poured into 150 mL of water and then extracted with a portion of 200 mL of ethyl acetate. The organic solution was washed with a portion of 150 mL of brine, dried (MgSO4) and then concentrated under diminished pressure. The residue was purified by chromatography on a silica gel column. Elution with hexanes-ethyl acetate 5:1 gave the expected product as light yellow crystals: yield 2.23 g (81%). 1H-NMR (CDCl3) δ 5.90 (s, 2H), 2.67 (s, 6H), 2.34 (s, 6H); 13C-NMR (CDCl3) δ 166.92, 155.32, 129.56, 118.62, 108.74, 24.90, 14.50.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:7][C:8]=1[CH3:9])#[N:2].[Se](=O)=[O:22]>CCOCC>[C:1]([C:3]1[CH:4]=[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:7][C:8]=1[CH:9]=[O:22])#[N:2]
Reactant: O=[Se]=O
Reactant: CCOC(=O)c1cc(C#N)c(C)nc1N1CCCCC1
Solvent: CCOCC
Product: CCOC(=O)c1cc(C#N)c(C=O)nc1N1CCCCC1
Reaction time: 1.5 h

Procedure:
27 g of 5-cyano-6-methyl-2-piperidinyl-3-pyridine-carboxylic acid, ethyl ester (0.1 mol) and 12.2 g selenium dioxide (0.11 mol) are refluxed together in diethyleneglycoldimethyl ether with stirring for 1.5 hours. The solvent is distilled off in vacuo and the oily residue crystallized with diethyl ether. Yield 19 g (66%); m.p. 62°-64° C. (ether).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][O:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1.[H-].[Na+].I[CH2:23][C:24]1[N:25]=[C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[O:27][C:28]=1[CH2:29][CH3:30].C(OCC)(=O)C>CC(OC)(C)C>[CH2:29]([C:28]1[O:27][C:26]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)=[N:25][C:24]=1[CH2:23][O:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([CH2:8][O:9][C:10]([CH3:19])([CH3:18])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3]1)[CH3:30]
Reactant: CC(C)(C)OC(=O)C(C)(C)OC[C@@H]1CCC[C@H](O)C1
Reactant: CCc1oc(-c2cccc(OC)c2)nc1CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COC(C)(C)C
Product: CCc1oc(-c2cccc(OC)c2)nc1CO[C@H]1CCC[C@@H](COC(C)(C)C(=O)OC(C)(C)C)C1

Procedure:
200 mg of tert-butyl 2-((1R,3S)-3-hydroxycyclohexylmethoxy)-2-methylpropionate are added dropwise as solution in MTBE to a suspension of 65 mg of sodium hydride (60% by weight in mineral oil) in 10 ml of MTBE. After gas evolution ceases, 503 mg of 4-iodomethyl-5-ethyl-2-(3-methoxyphenyl)oxazole are added as solution in MTBE, and the suspension is heated under reflux overnight. Ethyl acetate (MTBE can also be used) is added to the reaction mixture, and the mixture is washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated. The residue is chromatographed on silica gel (heptane/ethyl acetate gradient), resulting in 323 mg of tert-butyl 2-{(1R,3S)-3-[5-ethyl-2-(3-methoxyphenyl)oxazol-4-ylmethoxy]cyclohexylmethoxy}-2-methylpropionate as yellow oil.