Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([F:20])([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=O)=[CH:14][CH:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.Cl.[OH:24][NH2:25].C([O-])(=O)C.[Na+]>O>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([F:20])([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[N:25][OH:24])=[CH:14][CH:13]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=O)cc2)C1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C=NO)cc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 3-fluoro-3-(4-formyl-phenyl)-azetidine-1-carboxylic acid tert-butyl ester (4.5 g, 16.11 mmol, 1 eq) in mixture of methanol (50 mL) and water (40 mL) was added hydroxyl amine hydrochloride (1.66 g, 24.17 mmol, 1.5 eq) followed by addition of sodium acetate (2.37 g, 29.0 mmol, 1.8 eq) at room temperature. Resulting reaction mixture was stirred at room temperature for 24 hours. After complete consumption of starting material, reaction mixture was concentrated in vacuo to afford to yellow colored residue, which was diluted by water (120 mL) and extracted with ethyl acetate (3×80 mL). Combined organic phase was washed with brine solution (70 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get yellow semi solid (2.3 g, Crude). Crude was purified by Combiflash using 40 g Redisep column. Desired compound was eluted in 19% ethyl acetate in hexane to afford title compound as yellow semi solid (1.0 g, 21.1%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.20-4.27 (m, 2H), 4.36-4.44 (m, 2H), 7.47 (d, J=8.28 Hz, 2H), 7.64 (d, J=8.2 Hz, 2H), 8.13 (s, 1H). LC-MS (m/z): 293.1 (M−H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]2)=[O:16])[NH2:14])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[C:32]([C:34]1[CH:35]=[CH:36][C:37]([C:40](O)=[O:41])=[N:38][CH:39]=1)#[N:33]>>[C:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:19][CH2:18]2)=[O:16])[NH:14][C:40]([C:37]2[CH:36]=[CH:35][C:34]([C:32]#[N:33])=[CH:39][N:38]=2)=[O:41])=[CH:8][CH:7]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: N#Cc1ccc(C(=O)O)nc1
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@@H](N)Cc2ccc(OC(C)(C)C)cc2)CC1
Product: CC(C)(C)OC(=O)COC1CCN(C(=O)[C@H](Cc2ccc(OC(C)(C)C)cc2)NC(=O)c2ccc(C#N)cn2)CC1
Yield: 47.8 %

Procedure:
Reaction of 2.5 g of t-butyl [[1-[3-(p-t-butoxyphenyl)-L-alanyl]-4-piperidinyl]oxy]acetate with 0.85 g of 5-cyano-2-picolinic acid (as in Example 1d) yields 1.55 g of t-butyl [[1-[3-(p-t-butoxyphenyl)-N-[[5-cyano-2-pyridyl]carbonyl]-L-alanyl]-4-piperidinyl]oxy]acetate. M.p. 122°-123° C. (diethyl ether/petroleum ether 4:1). MS (FAB): 565 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl:32][C:33]1[CH:34]=[C:35]([CH:39](O)[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH:36]=[CH:37][CH:38]=1.[C:48]1(=[O:58])[NH:52][C:51](=[O:53])[C:50]2=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]12>O1CCCC1>[Cl:32][C:33]1[CH:34]=[C:35]([CH:39]([N:52]2[C:51](=[O:53])[C:50]3=[CH:54][CH:55]=[CH:56][CH:57]=[C:49]3[C:48]2=[O:58])[CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=2)[CH:36]=[CH:37][CH:38]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC(Cc1ccccn1)c1cccc(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1C(Cc1ccccn1)c1cccc(Cl)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
70 ml of a solution of 16.5 g of triphenylphosphine in tetrahydrofuran was cooled to -50° C., followed by the gradual dropwise addition thereto of 40 ml of a solution of 11.0 g of diethyl azodicarboxylate in tetrahydrofuran. The obtained mixture was stirred at -30° C. for 30 minutes, followed by the dropwise addition thereto of 50 ml of a tetrahydrofuran solution of 13.4 g of the 1-(3-chlorophenyl)-2-(pyridin-2-yl)ethyl alcohol prepared in the Preparative Example 19. The obtained mixture was stirred at that temperature for 30 minutes, followed by the addition thereto of 9.28 g of phthalimide. The obtained mixture was stirred at room temperature for 30 minutes and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to column chromatography and eluted with a toluene/ethyl acetate mixture. Yield: 12.9 g.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=1)[OH:2].[Br:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](Cl)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1.Cl>CS(C)=O>[Br:9][C:10]1[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=1)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:2][C:1]2[CH:8]=[CH:7][C:5]([OH:6])=[CH:4][CH:3]=2)=[C:17]([N+:22]([O-:24])=[O:23])[CH:16]=1
Reactant: O=[N+]([O-])c1cc(OCc2cccc(Br)c2)ccc1Cl
Reactant: Oc1ccc(O)cc1
Agent: Cl
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(OCc2cccc(Br)c2)ccc1Oc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of hydroquinone (276.4 mg, 2.510 mmol) in anhydrous 3.64 mmol) and heated under a nitrogen atmosphere at 120° for 30 minutes. A solution of 4-(3-Bromo-benzyloxy)-1-chloro-2-nitro-benzene (from Example 15A) (774 mg, 2.259 mmol) in dimethylsulfoxide (4 mL) was added dropwise from an addition funnel over a period of 30 minutes at 120°, the mixture was then stirred at this temperature for 1 hour. The reaction was cooled in an ice bath, then poured into ice water (20 mL) and adjusted the pH to 2 with concentrated hydrochloric acid. The mixture was extracted with ethyl ether (3×100 mL), the combined ethereal extracts were washed with water (3×100 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation under vacuum. Purification of the residue by silica gel flash chromatography using 3% ethyl acetate/methylene chloride as eluent afforded the title compound as a dark yellow solid (386 mg, 0.927 mmol, 41%).
Reaction SMILES: N1C=CC=C(CN)C=1.[CH3:9][C:10]1[O:14][N:13]=[C:12]([CH2:15][NH2:16])[CH:11]=1.[F:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][N:23]2[C@@H:27]([CH3:28])[CH2:26][N:25]([C:29]3[S:30][C:31]([C:35](O)=[O:36])=[C:32]([CH3:34])[N:33]=3)[C:24]2=[O:38])=[CH:20][CH:19]=1.FC1C=CC(CN2[C@H](C)CN(C3SC(C(O)=O)=C(C)N=3)C2=O)=CC=1>>[F:17][C:18]1[CH:40]=[CH:39][C:21]([CH2:22][N:23]2[C@H:27]([CH3:28])[CH2:26][N:25]([C:29]3[S:30][C:31]([C:35]([NH:16][CH2:15][C:12]4[CH:11]=[C:10]([CH3:9])[O:14][N:13]=4)=[O:36])=[C:32]([CH3:34])[N:33]=3)[C:24]2=[O:38])=[CH:20][CH:19]=1
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: Cc1cc(CN)no1
Agent: Cc1nc(N2C[C@@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1cc(CNC(=O)c2sc(N3C[C@@H](C)N(Cc4ccc(F)cc4)C3=O)nc2C)no1

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with (5-methylisoxazol-3-yl)methanamine and replace (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with (R)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid the title compound was obtained as a white solid: mp 139-140° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.51 (t, J=5.8 Hz, 1H), 7.40-7.35 (m, 2H), 7.21-7.15 (m, 2H), 6.14 (d, J=0.4 Hz, 1H), 4.60 (d, J=15.6 Hz, 1H), 4.37-4.16 (m, 4H), 3.78-3.71 (m, 1H), 3.55 (dd, J=10.2, 6.8 Hz, 1H), 2.47 (s, 3H), 2.37 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); MS (ES+) m/z 443.9 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:20])[NH:10][O:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])=[CH:3][CH:2]=1.Cl.O1CCOCC1>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9](=[O:20])[NH:10][O:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)CONC(=O)NCc1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(O)CONC(=O)NCc1ccncc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 100.7 %

Procedure:
To a solution of tert-butyl 2-(3-(pyridin-4-ylmethyl)ureidooxy)acetate (Compound V-5) (42.2 mg, 0.15 mmol) in tetrahydrofuran (1 ml) was added 4N HCl/dioxane (2 ml) and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo to obtain the title compound (34 mg, 100%).
Reaction SMILES: Cl.[C@@H:2]1([N:10]2[CH:17]=[CH:16][C:14]([NH2:15])=[N:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]1.[CH2:18](N)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([NH:15][C:14]1[CH:16]=[CH:17][N:10]([C@@H:2]2[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[CH2:3]2)[C:11](=[O:12])[N:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Reactant: NCc1ccccc1
Agent: Cl
Product: O=c1nc(NCc2ccccc2)ccn1[C@H]1C[C@H](O)[C@@H](CO)O1
Temperature: 150 °C

Procedure:
To 2'-deoxycytidine hydrochloride (5.28g, 20 mmol, U.S. Biochemical Corp., Cleveland, Ohio) was added benzylamine (20 ml), and the mixture was heated at 150° C. for 3 hours under an argon atmosphere. The solution was concentrated under vacuum to yield a viscous yellow oil, which was partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous phase was washed with ethyl acetate (100 ml) and separated. The aqueous phase was concentrated under vacuum to yield a yellow syrup (13 g), which was purified by silica gel column chromatography with 15:1 methylene chloride:methanol as eluant, to yield the desired product (5.8 g, 91.5%), as a colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[N:15]1([N:21]=[CH:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:10][C@@:11]([CH3:14])([OH:12])[CH2:13][N:18]2[CH2:17][CH2:16][N:15]([N:21]=[CH:22][C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:27][CH:28]=3)[CH2:20][CH2:19]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: C[C@@]1(Cn2cc([N+](=O)[O-])nc2Cl)CO1
Reactant: FC(F)(F)c1ccc(C=NN2CCNCC2)cc1
Solvent: CN(C)C=O
Product: C[C@](O)(CN1CCN(N=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 75 °C
Reaction time: 7 h
Yield: 84.7 %

Procedure:
A mixture of (R)-2-chloro-1-(2-methyloxiran-2-ylmethyl)-4-nitroimidazole prepared in Example 12 (218 mg, 1 mmol), N-(piperazin-1-yl)-N-(4-trifluoromethylbenzylidene)amine (283 mg, 1.1 mmol) and DMF (2 ml) was stirred at 70-80° C. for 7 hours. The reaction mixture was allowed to return to room temperature and then added water, and the resulting solution was extracted with ethyl acetate twice. The organic phases were combined, washed with water 3 times and a saturated saline solution, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/acetone=1/1) to afford (S)-1-(2-chloro-4-nitroimidazol-1-yl)-2-methyl-3-{4-[(4-trifluoromethylbenzylidene)amino]piperazin-1-yl}propan-2-ol (402 mg, yield 85%) as a light yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH:28]=[O:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[BH4-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:26][CH2:27][CH2:28][OH:29])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCC=O)c[nH]c34)no2)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCCO)c[nH]c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
To a solution of 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]propanal (D92) (300 mg) was added NaBH4 (138 mg). The reaction mixture was stirred at 20° C. overnight. The reaction mixture was evaporated and the residue was partitioned between DCM (50 mL) and water (25 mL). The organic phase was washed with water and brine, dried over sodium sulphate and evaporated in vacuo to afford the product 3-[7-(5-{3-chloro-4-[(1-methyl ethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]-1-propanol as a white solid (D99) (280 mg). MS (ES): C22H22ClN3O3 requires 411; found 412.2 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].[Br:14]Br>C(Cl)(Cl)Cl>[Br:14][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH:8]=1)[C:5]([OH:7])=[O:6]
Reactant: BrBr
Reactant: COc1ccc(C(=O)O)c(OC)c1
Solvent: ClC(Cl)Cl
Product: COc1cc(OC)c(C(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 2,4-dimethoxybenzoic acid (4.0 g, 0.022 mol) in chloroform (60 ml) was added bromine (1.13 ml, 0.022 mol) in chloroform (20 ml) dropwise. After stirring overnight at room temperature the precipitate was filtered off and dried to afford the title compound as a white solid (2.87 g).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>CO>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Solvent: CO
Product: COC(=O)c1cc([N+](=O)[O-])ccc1N1CCN(C)CC1

Procedure:
A solution of methyl 2-fluoro-5-nitro-benzoate (3.487 g, 17.511 mmol) and N-methylpiperazine (3.855 mL, 3.508 g, 35.022 mmol) in 30 mL of anhydrous methanol was heated to reflux for 5 hours.
Reaction SMILES: [CH3:1][C:2]([CH3:15])=[CH:3][CH2:4][NH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[NH:8][CH:9]=[N:10]2.Br[CH2:17][CH2:18][Cl:19].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:1][C:2]([CH3:15])=[CH:3][CH2:4][NH:5][C:6]1[N:14]=[CH:13][N:12]=[C:11]2[C:7]=1[N:8]=[CH:9][N:10]2[CH2:17][CH2:18][Cl:19]
Reactant: ClCCBr
Reactant: CC(C)=CCNc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)=CCNc1ncnc2c1ncn2CCCl
Yield: 60 %

Procedure:
6-[(3-methylbut-2-en-1-yl)amino]purine (2 g, 9.8 mmol), 1-bromo-2-chloroethane (1.4 g, 9.8 mmol) and K2CO3 (3 g, 29 mmol) were stirred in 50 ml DMSO for 12 h. The reaction mixture was poured onto ice (200 ml) and extracted in ethylacetate (50 ml). The solid residue was recrystallized from hexane to obtain white crystals. Yield: 60%. 1H NMR (DMSO-d6): 1.66 (3H, s), 1.70 (3H, s), 4.06 (2H, t, J=5.76), 4.10 (2H, s (br), H12), 4.50 (2H, t, J=5.76), 5.31 (1H, t, J=6.57), 7.767 (1H, s (br)), 8.15 (1H, s), 8.20 (1H, s).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[C:8]([N+:10]([O-])=O)[N:7]=[C:6]2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3][CH2:2]1.[H][H]>C1COCC1.[Ni]>[NH2:10][C:8]1[N:7]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:5]([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH:9]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1nc([N+](=O)[O-])cn1CC1CC1
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N)cn1CC1CC1

Procedure:
3.89 g (16.26 mmol) of ethyl 1-(cyclopropylmethyl)-4-nitro-1H-imidazole-2-carboxylate are dissolved in 50 ml of THF, and a spatula tip of Raney nickel is added. The reaction mixture is hydrogenated with hydrogen in the hydrogenation apparatus at room temperature. The catalyst is filtered off and the filtrate is evaporated in vacuo. The residue from evaporation is further used directly for the next reaction.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]([C@@H:24]2[N:33]([C:34]([C@@H:36]3[CH2:39][C@H:38]([CH2:40][C:41]([OH:43])=[O:42])[CH2:37]3)=[O:35])[CH2:32][CH2:31][C:30]3[N:29]=[C:28]([O:44][CH3:45])[CH:27]=[CH:26][C:25]2=3)=[O:23])[CH:13]=[C:14]2[C:18]=1[C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C.C(OCC)(=O)C.CCCCCC>[F:9][C:10]1[CH:11]=[C:12]([NH:21][C:22]([C@@H:24]2[N:33]([C:34]([C@@H:36]3[CH2:39][C@H:38]([CH2:40][C:41]([O:43][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:42])[CH2:37]3)=[O:35])[CH2:32][CH2:31][C:30]3[N:29]=[C:28]([O:44][CH3:45])[CH:27]=[CH:26][C:25]2=3)=[O:23])[CH:13]=[C:14]2[C:18]=1[C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15]2
Reactant: BrCc1ccccc1
Reactant: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: O
Product: COc1ccc2c(n1)CCN(C(=O)[C@H]1C[C@@H](CC(=O)OCc3ccccc3)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Benzyl bromide (84 μL, 0.71 mmol) was added to a mixture of (cis-3-(((5R)-5-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5H)-yl)carbonyl)cyclobutyl)acetic acid (300 mg, 0.59 mmol) and potassium carbonate (98 mg, 0.71 mmol) in DMF (5 mL) at room temperature, and the mixture was stirred at room temperature for 2.5 hr. To the reaction mixture was added water (60 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent so gradient; 20→41% ethyl acetate/hexane) to give the title compound (282.3 mg, 0.471 mmol, 80%) as a colorless amorphous solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH3:18])[NH:6][CH2:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:17])[CH3:2]>C(O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH3:18])[NH:6][CH2:7][C:8]1[C:9]([Cl:17])=[CH:10][CH:11]=[CH:12][C:13]=1[NH2:14])[CH3:2]
Reactant: CCOC(=O)[C@H](C)NCc1c(Cl)cccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: CCOC(=O)[C@H](C)NCc1c(N)cccc1Cl
Yield: 98.4 %

Procedure:
A solution of 14.3 g of N-(2-chloro-6-nitrobenzyl)-L-alanine ethyl ester in 50 ml of absolute ethanol was hydrogenated in the presence of 1 g of Raney nickel. After completion of the hydrogenation, the catalyst was filtered off and the filtrate was evaporated to dryness. There were obtained 12.6 g (99% of theory) of N-(2-amino-6-chlorobenzyl)-L-alanine ethyl ester; nD22 =1.5430.
Reaction SMILES: C([NH:9][C:10]([NH:27][CH2:28][CH2:29][CH2:30][C:31]1[N:32]=[CH:33][NH:34][CH:35]=1)=[N:11][CH2:12][CH2:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C1C=CC=CC=1>Cl>[NH:34]1[CH:35]=[C:31]([CH2:30][CH2:29][CH2:28][NH:27][C:10]([NH:11][CH2:12][CH2:13][CH:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[NH:9])[N:32]=[CH:33]1
Reactant: O=C(NC(=NCCC(c1ccccc1)c1ccccc1)NCCCc1c[nH]cn1)c1ccccc1
Agent: Cl
Product: N=C(NCCCc1c[nH]cn1)NCCC(c1ccccc1)c1ccccc1

Procedure:
0.84 g (1.8 mmol) of N-benzoyl-N'-[3-(imidazol-4-yl) propyl]-N"-(3,3-diphenylpropyl)-guanidine are heated under reflux in 45 ml of 20% hydrochloric acid for 7 hours. The method of working up is analogous to that of Example 58.
Reaction SMILES: [C:1]([O:12][CH3:13])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=O)=[CH:4][CH:3]=1.[C:14]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN(C(C)C)C(C)C>O=S(Cl)Cl>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([NH:22][C:6]([C:5]2[CH:4]=[CH:3][C:2]([C:1]([O:12][CH3:13])=[O:11])=[CH:10][CH:9]=2)=[O:8])=[CH:23][CH:24]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
mono-Methyl terephthalate (1.02 g, 5.67 mmol) was refluxed in SOCl2 (10 mL) for 1 hour, allowed to cool to room temperature, and concentrated under reduced pressure. The residue was taken up in tetrahydrofuran (30 mL) and treated with 4tert-butylaniline (0.9 mL, 5.65 mmol) and DIEA (5 mL, 28.8 mmol) at room temperature. After stirring overnight, the mixture was concentrated under reduced pressure and the residue was taken up in ethyl acetate. The ethyl acetate was washed with H2O and brine, dried over Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was triturated with 3:2 hexanes:ethyl acetate and the solid air-dried to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.08 (m, 4H), 7.69 (m, 2H), 7.39 (m, 2H), 3.90 (s, 3H), 1.29 (s, 9H); MS (ESI—) m/z 312 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[CH2:9]([N:13]1[N:17]=[C:16]2[CH:18]=[C:19]([F:23])[CH:20]=[C:21]([F:22])[C:15]2=[N:14]1)[CH2:10][C:11]#[CH:12]>>[F:22][C:21]1[C:15]2[C:16](=[N:17][N:13]([CH2:9][CH2:10][C:11]#[C:12][C:2]3[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=3)[N:14]=2)[CH:18]=[C:19]([F:23])[CH:20]=1
Reactant: C#CCCn1nc2cc(F)cc(F)c2n1
Reactant: Nc1cccc(Br)n1
Product: Nc1cccc(C#CCCn2nc3cc(F)cc(F)c3n2)n1
Yield: 62.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 6-bromo-pyridin-2-ylamine (60 mg, 0.35 mmol) and 2-but-3-ynyl-4,6-difluoro-2H-benzo[d][1,2,3]triazole (72 mg, 0.35 mmol, Example 135(B)). Reaction time: 3 hours. The crude residue was purified by flash chromatography (DCM/AcOEt 1:1) to yield 65 mg (0.22 mmol, 63%) of 6-(4-(4,6-difluoro-2H-benzo[d][1,2,3]triazol-2-yl)but-1-ynyl)pyridin-2-amine as a brown solid.
Reaction SMILES: C([N:8]([CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([C:39](=[O:41])[NH2:40])[CH:33]=1)[CH2:9][CH:10]([OH:28])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=2)=[CH:15][CH:14]=1)C1C=CC=CC=1>[Pd].CO>[C:39]([C:34]1[CH:33]=[C:32]([CH:37]=[CH:36][C:35]=1[OH:38])[O:31][CH2:30][CH2:29][NH:8][CH2:9][CH:10]([OH:28])[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[S:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:23]=2)=[CH:17][CH:18]=1)(=[O:41])[NH2:40]
Reactant: NC(=O)c1cc(OCCN(Cc2ccccc2)CC(O)COc2ccc(-c3nc(C(F)(F)F)cs3)cc2)ccc1O
Agent: [Pd]
Solvent: CO
Product: NC(=O)c1cc(OCCNCC(O)COc2ccc(-c3nc(C(F)(F)F)cs3)cc2)ccc1O

Procedure:
After the addition of a total of 5 g of palladium-on-carbon catalyst (5%), a solution of 2.95 g of crude 1-[N-benzyl-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-[4-(trifluoromethyl)-thiazol-2-yl]-phenoxy]-2-propanol in 80 ml of methanol is hydrogenated at 60° and a pressure of 4 bar until the absorption of hydrogen has ceased, the reaction product partly precipitating out of the solution. The suspension is diluted with 50 ml of dioxan/methanol, heated and filtered through a filter aid. The filtrate is freed of solvent in a rotary evaporator and the residue is recrystallised twice from methanol, yielding 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-[4-(trifluoromethyl)-thiazol-2-yl]-phenoxy]-2-propanol having a melting point of 202°-203°.