Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].C(=O)([O-])[O-].[K+].[K+].O.Cl[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31]>C(Cl)Cl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 89.4 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Referential Example 7 and potassium carbonate (1.10 g) were suspended in a mixed solvent of methylene chloride (30 ml) and water (20 ml). A solution of benzyl chloroformate (1.35 g) in methylene chloride (10 ml) was added thereto under ice-cooling, and the mixture was stirred for 2 hours at same temperature and then stirred overnight at room temperature. The reaction mixture was separated into organic layer and aqueous layer, the organic layer was successively washed with aqueous 10% oxalic acid solution, water, and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure, to thereby obtain the 2.61 g of titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([OH:18])[S:16][CH:17]=3)[C:10]([CH3:19])=[N:9]2)=[CH:5][CH:4]=1.Cl[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O.[Cu]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([O:18][C:23]4[N:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[S:16][CH:17]=3)[C:10]([CH3:19])=[N:9]2)=[CH:20][CH:21]=1
Reactant: COc1ccc(Cn2cc(-c3csc(O)n3)c(C)n2)cc1
Reactant: Clc1ncccn1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2cc(-c3csc(Oc4ncccn4)n3)c(C)n2)cc1
Temperature: 160 °C
Reaction time: 0.75 h
Yield: 18.2 %

Procedure:
According to Scheme 2, Step 5: A mixture of 4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)thiazol-2-ol (0.99 mmol, 300 mg), 2-chloropyrimidine (0.99 mmol, 114 mg), copper (0.20 mmol, 12.6 mg) and cesium carbonate (2.99 mmol, 973 mg) in DMF (3.3 mL) was stirred at 160° C. under microwave conditions for 45 minutes. Then, the reaction mixture was diluted with EtOAc and was washed with water. The organic phase was dried over MgSO4, was filtered and was evaporated. The crude mixture was purified by flash chromatography over silica gel using cyclohexane/EtOAc (80:20 to 60:40) as eluent to yield 4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazol-4-yl)-2-(pyrimidin-2-yloxy)thiazole (0.18 mmol, 67 mg, 18%) as a yellow oil.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[O:6]=[C:7]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:11]2[S:19][C:20]([C:28](O)=[O:29])=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]=2[CH:9]=[CH:8]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CN1CCOCC1>C(Cl)Cl>[CH3:5][O:4][N:3]([CH3:2])[C:28]([C:20]1[S:19][C:11]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:6])[CH:8]=[CH:9][C:10]=2[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:29]
Reactant: O=C(O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 83.9 %

Procedure:
N,O-Dimethylhydroxylamine hydrochloride (31 mg, 0.32 mmol) was added to a mixture of the compound of Example 59 (101 mg, 0.29 mmol), HOBT (55 mg, 0.41 mmol), EDC (78 mg, 0.41 mmol) and NMM (0.090 mL, 0.81 mmol) in DCM (3 mL). The mixture was stirred for 6 h at room temperature. DCM was added and the mixture washed with 2M HCl(aq). The organic phase was re-extracted with DCM. The combined organics were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by column chromatography on silica (3.5% MeOH in DCM) to give the title compound as a white solid (95 mg, 84%). δH (DMSO-d6) 7.48–7.35 (3H, m), 7.34–7.30 (3H, m), 7.29–7.23 (3H, m), 7.16–7.13 (2H, m), 6.33 (1H, d, J 9.6 Hz), 3.26 (3H, s), 2.79 (3H, s). LCMS (ES+) RT 3.27 minutes, 391.0 (M+H)+.
Reaction SMILES: Cl[C:2]([CH3:10])([CH2:4][CH2:5][C:6](Cl)([CH3:8])[CH3:7])[CH3:3].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[CH3:11][O:12][C:13]1[CH:18]=[C:17]2[C:16](=[CH:15][C:14]=1[O:19][CH3:20])[C:6]([CH3:8])([CH3:7])[CH2:5][CH2:4][C:2]2([CH3:10])[CH3:3]
Reactant: COc1ccccc1OC
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: COc1cc2c(cc1OC)C(C)(C)CCC2(C)C
Temperature: 60 °C
Yield: 44.3 %

Procedure:
2,5-dichloro-2,5-dimethylhexane (2.2 g, 12 mmol), 1,2-dimethoxybenzene (1.38 g, 10 mmol), anhydrous 1,2-dichloroethane (10 mL) and anhydrous AlCl3 (200 mg) were combined in a 100 mL Schlenk flask under Ar. The mixture was heated at 60° C. for 6 h before quenching with ice water. The layers were then separated, and the aqueous layer extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The remaining residue was purified by flash column chromatography (hexanes/Ethyl acetate=10:1) to afford the title compound (1.1 g, 35% yield). 1H NMR (CDCl3): 1.27 (s, 12H), 1.67 (s, 4H), 3.86 (s, 6H), 6.77 (s, 2H); 13C NMR (CDCl3): 32.07, 34.22, 35.42, 56.01, 109.37, 137.23, 147.05.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O[C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[CH2:40][CH:39]2[CH2:41][C:42]([O:44]CC)=[O:43])=[CH:34][CH:33]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:61]([OH:67])([C:63]([F:66])([F:65])[F:64])=[O:62]>C1COCC1>[F:64][C:63]([F:66])([F:65])[C:61]([OH:67])=[O:62].[CH3:1][NH:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][O:11][C:32]2[CH:37]=[CH:36][C:35]([CH:38]3[CH2:40][CH:39]3[CH2:41][C:42]([OH:44])=[O:43])=[CH:34][CH:33]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: CNc1cccc(CCO)n1
Reactant: CCOC(=O)CC1CC1c1ccc(O)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CNc1cccc(CCOc2ccc(C3CC3CC(=O)O)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15 %

Procedure:
To a solution of 2-[6-(methylamino)pyridin-2-yl]ethanol (1 g, 6.6 mmol) and PPh3 polymer bound (1.4 g, 9.9 mmole) in dry THF (50 mL) was added ethyl [(+)-2-(4-hydroxyphenyl)cyclopropyl]acetate (1.4 g, 6.6 mmol) from example 1 step 1, followed by diisopropyl azodicarboxylate (1.5 ml, 7.7 mmol). The reaction mixture was stirred at room temperature. After 18 hours, PPh3 polymer was filtered through celite and washed with excess THF. Filtrate was concentrated. The concentrated residue was dissolved in 1:1/acetonitrile:water (40 ml) and treated with LiOH (1 g). Reaction was heated two hours at 55° C. then cooled to room temperature. Reaction was acidified by adding TFA and purified on reverse phase HPLC twice to give 0.45 g (15%) of title compound. 1H NMR (400 MHz, CD3OD) δ 7.8 (m, 1 H), 7.0 (d, 2 H, J=8.6 Hz), 6.9-6.6 (m, 4 H), 4.26 (t, 2 H, J=6 Hz), 3.21 (t, 2 H, J=6 Hz), 3.0 (s, 3 H), 2.35-2.33 (m, 2 H), 1.71-1.67 (m, 1 H), 1.21-1.18 (m, 1 H), 0.89-0.76 (m, 2 H). HRMS calcd for C19H22N2O3 (M+H): 327.1703. found 327.1677.
Reaction SMILES: [CH2:1]([C:3]1[CH:21]=[CH:20][C:6]2[C:7]3([OH:19])[C:16](=[O:17])[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:8]3([OH:18])[O:9][C:5]=2[CH:4]=1)[CH3:2].[C:22]([OH:25])(=O)[CH3:23].N1C=CC=CC=1.C1C[O:35][CH2:34][CH2:33]1>>[C:34]([O:9][C:5]1[CH:4]=[C:3]([CH2:1][CH3:2])[CH:21]=[CH:20][C:6]=1[C:7]1([O:19][C:22](=[O:25])[CH3:23])[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:8]1=[O:18])(=[O:35])[CH3:33]
Reactant: CCc1ccc2c(c1)OC1(O)c3ccccc3C(=O)C21O
Reactant: CC(=O)O
Reactant: C1CCOC1
Solvent: c1ccncc1
Product: CCc1ccc(C2(OC(C)=O)C(=O)c3ccccc3C2=O)c(OC(C)=O)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 88 %

Procedure:
7-Ethyl-4b,9b-dihydroxy-4bH-benzo[d]indeno[1,2-b]-furan-10(9bH)-one (2.00 g, 7.0 mmol) was completely dissolved in anhydrous THF (20 ml). This solution was added with anhydrous acetic acid (1.44 ml, 14.1 mmol), pyridine (0.56 ml, 7.0 mmol), and 4-dimethyl aminopyridine (0.2 g), and stirred at room temperature for 12 hrs. After the reaction mixture was extracted with dichloromethane, the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (2.28 g, 88%).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.C(N(C(C)C)CC)(C)C.[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=1[O:32][CH3:33].O.ON1C2C=CC=CC=2N=N1.[NH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]1>ClCCl>[Cl:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:45][CH2:46][CH:47]2[CH2:52][CH2:51][N:50]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:49][CH2:48]2)=[O:29])=[CH:25][C:24]=1[O:32][CH3:33]
Reactant: COc1cc(C(=O)O)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)NCC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Reaction time: 0.08 h
Yield: 86.7 %

Procedure:
1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (2.26 g) and diisopropylethylamine (2.05 mL) were added to a room temperature solution of 4-chloro-3-methoxybenzoic acid (2.00 g) and 1-hydroxybenzotriazole hydrate (1.81 g) in dichloromethane (53 mL). After the reaction was stirred for five minutes, tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (2.53 g) was added and the mixture was stirred overnight. The reaction was then partitioned between 1 N hydrochloric acid and dichloromethane. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated and purified by column chromatography on silica gel (dichloromethane:methanol=19:1). The resulting residue was triturated in diethyl ether and the solids were collected by filtration to obtain the title compound (3.56 g) having the following physical data. 1H NMR (DMSO-d6): δ 8.60 (t, J=5.7 Hz, 1H), 7.61-7.39 (m, 3H), 3.91 (m, 5H), 3.15 (t, J=6.0 Hz, 2H), 2.81-2.62 (m, 2H), 1.72-1.51 (m, 3H), 1.39 (s, 9H), 1.12-0.92 (m, 2H)+;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[N+:20]([O-])=O)[NH:13][C:12]2([CH3:27])CC(O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C(C#N)=C2C(=CC=1)N([CH2:38][C:39]([O:41][CH3:42])=[O:40])C(C)=C2S(C1C=CC(Cl)=CC=1)(=O)=O.[C:56](O)(=O)C>[Pt]>[NH2:20][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[C:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:10])=[O:9])=[C:12]([CH3:27])[N:13]2[CH2:38][C:39]([O:41][CH2:42][CH3:56])=[O:40]
Reactant: CC(=O)O
Reactant: CC1(CC(=O)O)Nc2cccc([N+](=O)[O-])c2C1S(=O)(=O)c1ccc(Cl)cc1
Reactant: COC(=O)Cn1c(C)c(S(=O)(=O)c2ccc(Cl)cc2)c2c(C#N)c(Cl)ccc21
Agent: [Pt]
Product: CCOC(=O)Cn1c(C)c(S(=O)(=O)c2ccc(Cl)cc2)c2c(N)cccc21

Procedure:
A suspension of the product from example 20 part (c) (1 g) in glacial acetic acid (50 ml) was stirred in the presence of 5% Pt/C (0.5 g) under 3 bar pressure of H2 for 24 hours. The catalyst was removed by filtration and the filtrates concentrated in vacuo. Purification by flash column chromatography (20% EtOAc/hexane as eluent) gave the subtitle compound (0.45 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:3]=[CH:4][C:5]=1[O:15][CH3:16])=[O:14]
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Br)cc1NC(=O)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C#C[Si](C)(C)C)cc1NC(=O)C(F)(F)F
Temperature: 60 °C
Yield: 43.1 %

Procedure:
To an oven-dried flask under N2 was added N-[5-bromo-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (1.53 g, 0.005 mol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)palladium(II) (0.45 g, 0.6 mmol), copper(I) iodide (73 mg, 0.38 mmol), and trimethylsilylacetylene (1.26 g, 13 mmol). Next, triethylamine (5.19 g, 50 mmol) was added dropwise and the resulting mixture was heated at 60° C. overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.68 g, 42%) as an off white solid. ESIMS (M−H)−=314.
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]23[C:15](=[O:16])[N:14]([C:17]4[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=4)[C:13](=[O:25])[N:12]2[CH2:11][CH2:10][NH:9][CH2:8]3)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[CH3:47][N:48]([CH3:53])[CH2:49][C:50](O)=[O:51]>C1COCC1.C(Cl)CCl>[CH3:47][N:48]([CH2:49][C:50]([N:9]1[CH2:8][C:7]2([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Br:1])=[CH:3][CH:4]=3)[N:12]([C:13](=[O:25])[N:14]([C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[CH:18]=3)[C:15]2=[O:16])[CH2:11][CH2:10]1)=[O:51])[CH3:53]
Reactant: CN(C)CC(=O)O
Reactant: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)C2(Cc3ccc(Br)cc3)CNCCN12
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)CC(=O)N1CCN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)C2(Cc2ccc(Br)cc2)C1
Reaction time: 8 h

Procedure:
To a solution of 6-(4-bromobenzyl)-8-(3,5-dichlorophenyl)-1,4,8-triazabicyclo[4.3.0]nonane-7,9-dione (0.085 g) in THF (5 mL) was added DIEA (0.1 mL), HOBt (0.57 g), EDC (0.054 g) and N,N-dimethylglycine (0.037 g). After stirring overnight, the reaction was concentrated and the residue was diluted with EtOAc and washed with water, NaHCO3, and brine, dried (Na2SO4), filtered, and concentrated. Purification by chromatography (Silica gel: 2% MeOH/CH2Cl2, Chromatotron) afforded the titled compound. (0.093 g). MS (m/z) 553 (MH+). mp 73.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH2:24]>C(O)C>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][NH:24][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: COc1cccc(CN)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Solvent: CCO
Product: COc1cccc(CNc2cc(C(F)(F)F)nc(-c3cccnc3)n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20.1 %

Procedure:
A mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3-methoxybenzylamine (37 μl, 0.290 mmol) in 10 ml of ethanol was stirred at room temperature for 48 h. The mixture was rotary evaporated to dryness and purified by preparative TLC with hexane:ethyl acetate (3:1) to give a yellow solid (14 mg, 20%). 1H NMR (CDCl3): 9.60–9.59 (m, 1H), 8.70–8.66 (m, 2H), 7.40–7.32 (m, 1H), 7.30 (d, J=7.8 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.91 (s, 1H), 6.85 (dd, J=2.7, 8.4 Hz, 1H), 6.62 (s, 1H), 5.75 (bs, 1H), 4.73 (s, 2H), 3.79 (s, 3H).
Reaction SMILES: B.C1COCC1.[I:7][C:8]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:9]=1[C:10](O)=[O:11]>C1COCC1>[I:7][C:8]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][C:9]=1[CH2:10][OH:11]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1I
Agent: B
Solvent: C1CCOC1
Product: OCc1cc(C(F)(F)F)ccc1I

Procedure:
Borane-THF (1.0M solution in THF; 94 mL; 94 mmol) was added to a stirred solution of 2-iodo-5-(trifluoromethyl)benzoic acid (2.97 g; 9.4 mmol) in THF (300 mL) at 0° C. under N2. The reaction was heated at reflux for 90 min and then carefully quenched with 6N HCl until no further gas evolution. The reaction was diluted with H2O (250 mL) and extracted with EtOAc (3×250 mL). The combined extracts were washed with brine (300 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (0-25% EtOAc/hexanes gradient) to afford [2-iodo-5-(trifluoromethyl)phenyl]methanol as a white solid. LCMS=285.0 (M−17)+. 1H NMR (CDCl3, 500 MHz): δ 7.97 (d, J=8.3 Hz, 1H), 7.79 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 4.75 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:24]([O:25][CH2:26][CH3:27])=[CH:23][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][N:15]=3)[CH2:9][CH2:8]2)=[CH:4][C:3]=1[O:28][CH2:29][CH3:30].[NH2:31][CH2:32][CH2:33][OH:34].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[C:24]([O:25][CH2:26][CH3:27])=[CH:23][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH:10]([NH:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH:31][CH2:32][CH2:33][OH:34])=[O:20])=[CH:16][N:15]=3)[CH2:11][CH2:12]2)=[CH:4][C:3]=1[O:28][CH2:29][CH3:30]
Reactant: NCCO
Reactant: CCOc1cc(CN2CCC(Nc3ccc(C(=O)O)cn3)CC2)cc(OCC)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc(CN2CCC(Nc3ccc(C(=O)NCCO)cn3)CC2)cc(OCC)c1Cl
Temperature: 60 °C
Yield: 42 %

Procedure:
To a mixture of 6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-nicotinic acid (65.09 mg, 0.15 mmol, 1.0 equiv; example 70) and 2-amino-ethanol (46.4 mg, 0.25 mmol, 1.67 equiv; commercially available) in dry DMF (2.0 mL) and N-ethyl diisopropylamine (0.3 mL) was added HATU (68.44 mg, 0.18 mmol, 1.2 equiv; commercially available) and the reaction stirred at 60° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 30.1 mg (42%) of the title compound. MS (ISP): 477.3 [M+H]+.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([NH:7][CH3:8])=[CH2:6].Cl[C:11](=[CH2:14])[C:12]#N.C([N:17](CC)CC)C>C(#N)C>[CH2:11]([C:14]1[CH:3]=[CH:4][C:5]([C:6]#[N:17])=[N:7][CH:8]=1)[CH3:12]
Reactant: C=C(C=CN(C)C)NC
Reactant: CCN(CC)CC
Reactant: C=C(Cl)C#N
Solvent: CC#N
Product: CCc1ccc(C#N)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
39.3 g of 1-dimethylamino-1-aza-3-ethyl-1,3-butadiene, 35 g of 2-chloroacrylonitrile and 112 ml of triethylamine are stirred in 400 ml of acetonitrile for 7 hours at 70° C. The brown reaction mixture is cooled and then filtered and concentrated by evaporation. The residue is dissolved in dioxane and gaseous HCl is introduced. The batch is stirred for 1 hour at room temperature, then concentrated by evaporation, and the residue is partitioned between chloroform and 2N sodium carbonate solution. The organic phase is separated, dried and concentrated by evaporation. The oily residue is distilled under a high vacuum, affording 30.6 g of a yellowish oil with a boiling point of 75°-79° C./3·10-1 mbar.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH:9]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([CH2:19]O)[NH:11][C:10]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C1(C)C=C[C:32]([S:35]([O-])(=O)=O)=[CH:31]C=1.FC1C=CC=C[N+]=1C.S1C=CC=C1CC(O)=[O:55]>CC(C)=O.C1C=CC=CC=1>[C:32]([S:35][CH2:19][CH:12]1[NH:11][C:10](=[O:21])[CH:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)(=[O:55])[CH3:31]
Reactant: CC(C)(C)OC(=O)CC1CCCCCCC(CO)NC1=O
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: O=C(O)Cc1cccs1
Agent: C[n+]1ccccc1F
Solvent: c1ccccc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)SCC1CCCCCCC(CC(=O)OC(C)(C)C)C(=O)N1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3-t-Butoxycarbonylmethyl-10-hydroxymethyl-2-oxo-1-azacyclodecane (0.50 g, 1.67 mmol) is dissolved in acetone (5.0 mL) and benzene (5.0 mL). Triethylamine (0.26 mL, 1.9 mmol) is added, followed by 2-fluoro-1-methylpyridinium toluene-4-sulfonate (0.54 g, 1.9 mmol), and the reaction is stirred at room temperature for 90 minutes. Thiolacetic acid (0.14 mL, 1.9 mmol) and more triethylamine (0.26 mL, 1.9 mmol) are added, and the reaction is heated to reflux for 2 hours. The solvent is then removed, the crude product is partitioned between methylene chloride and water, and the aqueous phase is extracted several times with methylene chloride. The combined organic layers are dried (MgSO4) and the solvent is evaporated. The crude product is purified by silica gel chromatography (15% ethyl acetate/hexane) to give 10-(acetylthiomethyl)-3-t-butoxycarbonylmethyl-2-oxo-1-azacyclodecane, MS: M+1=358.
Reaction SMILES: [CH3:1][OH:2].Cl.Cl.Cl.[CH2:6]([NH:13][C:14]([NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[NH:18])=[NH:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].[CH2:32]([OH:34])[CH3:33]>O.CC(C)=O>[C:32]([OH:2])(=[O:34])[CH3:33].[CH3:1][C:32]1([CH3:33])[N:15]=[C:14]([NH:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:16][C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:18]1
Reactant: CO
Reactant: CCCCCCCCCCNC(=N)NC(=N)NCc1ccccc1
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)O
Product: CCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccccc2)N1

Procedure:
140 ml of methanol, 100 ml of acetone and 0.6 ml of concentrated hydrochloric acid were added to 8.5 g (21.0 mmol) of N1-benzyl-N5-decyl-biguanide dihydrochloride, and the mixture was refluxed for 24 hours. The solvent was distilled off under reduced pressure to give a residue, which was dissolved in 150 ml of ethanol. To the solution were added 100 ml of water and 10 ml of 5N aqueous sodium hydroxide, and the mixture was refluxed for 1.5 hours. The solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. The extract was washed with water, concentrated under reduced pressure to remove the solvent, and dried well under reduced pressure to obtain 8 g of a colorless solid (1). Then, 3.6 g (9.6 mmol) of the solid was dissolved in 30 ml of 70% aqueous acetonitrile, and to the solution was added 16 g (15.4 mmol) of malonic acid. The mixture was dissolved under heating, and then cooled. The resulting crystals were recrystallized from 70% aqueous acetonitrile to obtain 3.9 g of colorless crystals (2) having a melting point of 78 to 81° C.
Reaction SMILES: O[C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[C:23]([O-:26])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:13]([O:11][C:6]1[CH:7]=[C:8]([O:10][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:9]=[C:2]([O:26][CH2:23][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:3]=1[CH:4]=[O:5])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=Cc1c(O)cc(O)cc1O
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCBr
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCOc1cc(OCCCCCCCCCC)c(C=O)c(OCCCCCCCCCC)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
A mixture of 2,4,6-trihydroxybenzaldehyde (3.00 g, 19.5 mmol), 1-bromodecane (25.87 g, 117.0 mmol), K2CO3 (8.07 g, 58.4 mmol), and KI (549 mg, 3.3 mmol) in DMF (150 mL) was stirred for 24 h at 110° C. and then one more portion of 1-bromodecane (5.0 g, 22.6 mmol) was added and continued stirring for another 24 h. The reaction mixture was cooled to 20° C. and extracted with CH2Cl2. The organic phase was washed with brine, dried (Na2SO4), and evaporated. Column chromatography (silica gel, hexane/CH2Cl2, 1:1, v/v) afforded the product (9.86 g, 88%) as yellow oil.