Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:17]([O:21][C:22]([NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:35])[CH3:34])([C:30](O)=[O:31])[CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:17]([O:21][C:22](=[O:23])[NH:24][C@@H:25]1[CH2:29][CH2:28][C@:27]([CH:33]([CH3:34])[CH3:35])([C:30]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[N:12]=[C:11]([C:13]([F:14])([F:16])[F:15])[CH:10]=[CH:9][N:8]=3)[CH2:2][CH2:3]2)=[O:31])[CH2:26]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CCN(c3nccc(C(F)(F)F)n3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a solution of 2-piperazin-1-yl-4-(trifluoromethyl)pyrimidine (250 mg, 1.08 mmol), (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (300 mg, 1.1 mmol) and triethylamine (0.45 mL, 3.2 mmol) in methylene chloride (10 mL) was added benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (520 mg, 1.2 mmol). After being stirred overnight, the reaction was quenched with saturated NaHCO3. The resulting solution was extracted with EtOAc three times. The combined organic layers were dried (MgSO4) and concentrated. Purification by column chromatography on silica gel (20%-40% EtOAc/hexanes) provided 290 mg of desired product MS calculated for C23H34F3N5O3: (M+H) 486; found 386.1 (M-Boc+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:25]I.[C:27]1([C@@H:33]([CH2:36][CH3:37])[CH2:34]O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[I:25][CH2:34][C@@H:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:36][CH3:37]
Reactant: II
Reactant: CC[C@@H](CO)c1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC[C@@H](CI)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of triphenylphosphine (15.4 g, 59 mmol) and imidazole (3.99 g, 59 mmol) in dichloromethane (150 ml) at room temperature was added portionwise iodine (14.9 g, 50 mmol) at such a rate that the temperature of the reaction mixture did not rise above 30° C. To the mixture was then added a solution of (R)-2-phenyl-butan-1-ol (7.34 g, 41 mmol, CAS 16460-75-6) in dichloromethane (50 ml) and the mixture was then stirred at room temperature overnight. The mixture was then concentrated in vacuo and the residue was resuspended in ether and the resulting crystals collected by filtration. The filtrate was concentrated in vacuo and the residue was triturated in heptane. The resulting crystals were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2, heptane/EtOAc) to yield a colourless oil, (6.38 g, 60%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][C@@:10]2([CH2:12][OH:13])[C@H:8]([CH2:9]2)[N:7]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:5])C.[OH-].[Na+].OS([O-])(=O)=O.[K+].CCOC(C)=O>C1COCC1.O>[C:17]([O:16][C:14]([N:7]1[C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][C@@:10]2([CH2:12][OH:13])[C@@H:8]1[CH2:9]2)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CCOC(=O)[C@@H]1C[C@]2(CO)C[C@@H]2N1C(=O)OC(C)(C)C
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1[C@H]2C[C@@]2(CO)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a diastereoisomeric mixture of (1R,3S,5S) and (1S,3S,5R)-5-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester (ratio 4:6, 100 mg, 0.31 mmol) in THF (1.5 mL) and H2O (0.15 mL) at 0° C. was added NaOH (1 M in water, 0.63 mL, 0.63 mmol). The solution was stirred 1 h at RT and poured into 10% KHSO4 (until pH 1), EtOAc was added and the layers were separated (×3). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude residue was used without further purification in the next step. MS (HPLC/MS): 256.2 [M−H]−, 258.3 [M+H]+, 280.3 [M+Na]+, 200.2 [MH−tBu]+, 515.54 [2M+H]+, 537.4 [2M+Na]+; tR (HPLC conditions f): 1.28 min.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)([O-:3])=[O:2].[I:13]I>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:9]=[C:8]([I:13])[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Reactant: II
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(I)cc([N+](=O)[O-])c1
Temperature: 140 °C
Yield: 172.7 %

Procedure:
A mixture of 1,3-dinitrobenzene (125 g), iodine (97 g) and concentrated sulphuric acid (500 ml) was heated to 140° C. for 3.5 hours. The mixture was cooled, poured onto crushed ice and filtered. The solid was washed with water and dried to give 3,5-dinitroiodobenzene (194 g) in 89% yield, m.p. 101°-102° C.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.[NH2:26][NH:27][C:28]([NH2:30])=[S:29].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH:26][NH:27][C:28]([NH2:30])=[S:29])=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NNC(N)=S
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: NC(=S)NNC(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.1 %

Procedure:
To a solution of 4-phenylbenzoic acid (10.0 g), 1-hydroxybenzotriazole (7.5 g) and thiosemicarbazide (5.1 g) in dimethylformamide (50 ml) was added 1-ethyl-3-(3′-dimethylaminopropyl) carbodiimide hydrochloride (14.45 g) and stirred for 12 hours at ambient temperature. The reaction mixture was pulverized with water. The precipitate was collected by filtration and dried under reduced pressure to give 1-(4-phenylbenzoyl)-3-thiosemicarbazide (10.274 g).
Reaction SMILES: CN(C)CCO.[Li]CCCC.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.[CH2:24]([Sn:28](Cl)([CH2:33][CH2:34][CH2:35][CH3:36])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH3:27]>CCCCCC.O>[CH2:33]([Sn:28]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:29][CH2:30][CH2:31][CH3:32])[C:17]1[N:12]=[C:13]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[CH:14]=[CH:15][CH:16]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: c1ccc(N2CCOCC2)nc1
Agent: CN(C)CCO
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Product: CCCC[Sn](CCCC)(CCCC)c1cccc(N2CCOCC2)n1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 7.3 %

Procedure:
To a solution of 2-dimethylaminoethanol (0.46 mL, 4.56 mmol) in hexane (7.0 mL, HPLC grade) cooled at −5° C. was added drop wise n-BuLi (1.60 M, 5.70 mL, 9.12 mmol) under nitrogen atmosphere. After 30 min at 0° C., 4-pyridin-2-yl-morpholine (0.25 g, 1.52 mmol) in hexane (2.0 mL) was added drop wise. After stirring the reaction mixture for 1 h at 0-5° C., the reaction medium was cooled to −78° C. followed by drop wise addition of tributyl tin chloride (1.03 mL, 3.70 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then allowed to stir at 0-5° C. for 2 h. The reaction mixture was then allowed to come to room temperature. After the completion of reaction (TLC monitoring), the reaction mass was cooled to 0° C. and water was added slowly. The aqueous phase was extracted with diethyl ether (3×20 mL). The combined organic layers were dried over anhydrous Na2SO4, and evaporated to dryness. The crude residue was purified over silica gel (230-400 M) using EtOAc-Hexane (2:98) to provide the compound as yellow oil (0.050 g, 7.20%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12]Br)[CH:8]=[CH:7]2.[CH3:14][NH2:15]>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12][NH:15][CH3:14])[CH:8]=[CH:7]2
Reactant: CN
Reactant: BrCc1ccc2cccc(Br)c2n1
Solvent: C1CCOC1
Product: CNCc1ccc2cccc(Br)c2n1
Reaction time: 0.5 h

Procedure:
To a solution of 3 (1 g, 3.32 mmol) in THF (5 mL) was added methylamine (10.5 mL of 40% water solution). The solution was stirred for 30 min and then extracted with EtOAc (30 mL). The organic phase was washed with DI water (2×20 mL), dried and concentrated to give a red oil. Purification by chromatography (MeOH/DCM 1:99) yielded yellow solid.(0.8 g, 96%) 1H NMR (400 MHz CDCl3) δ8.09 (1H, d, J=8.4 Hz), 8.02 (1H, d, J=7.2 Hz), 7.77 (1H, d, J=8 Hz), 7.49 (1H, d, J=8.4 Hz), 7.36 (1H, t, J=8.0 Hz), 4.12 (2H, s), 2.58 (3H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.NN>C(O)C.[Pd]>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]([C:8]([N:10]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[CH2:14][N:13]3[CH:20]=[CH:21][CH:22]=[C:12]3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1Cc2cccn2Cc2ccsc21
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccsc32)cc1

Procedure:
To a solution of 5 mmol of 9,10-dihydro-10-(4-nitrobenzoyl)-4H-pyrrolo-[1,2-a]thieno[2,3-e][1,4]diazepine in 25 ml of ethyl alcohol is added 0.13 g of 10% Pd/C and 15 mmol of hydrazine followed by stirring and heating under reflux for 3 hours. The cooled reaction mixture is filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated in vacuo to give the desired product which is purified by flash chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:40]1([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)[CH:45]=[CH:44][C:43]([CH2:46][C@@H:47]([NH:64][CH3:65])[C:48]([N:50]([CH3:63])[C@@H:51]([C:59](=[O:62])[NH:60][CH3:61])[CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[O:49])=[CH:42][CH:41]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:64]([C@@H:47]([C:48](=[O:49])[N:50]([CH3:63])[C@@H:51]([C:59](=[O:62])[NH:60][CH3:61])[CH2:52][C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[CH2:46][C:43]1[CH:42]=[CH:41][C:40]([C:66]2[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=2)=[CH:45][CH:44]=1)[CH3:65])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)NC
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.24 g; 0.98 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.13 g; 0.98 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.2 g; 1.02 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-3-(1,1′-Biphenyl-4-yl)-N-methyl-2-methylamino-N-((1R)-1-methylcarbamoyl-2-phenylethyl)propionamide (0.38 g; 0.89 mmol) and diisopropylethylamine (0.17 mL; 0.98 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. Methylene chloride (50 mL) was added and the reaction mixture was washed with water (50 mL), an aqueous solution of sodium hydrogen sulfate (10%; 50 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 50 mL) and water (50 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (4×20 cm) using ethyl acetate/heptane (2:1) as eluent to afford 0.46 g of ((3E)-4-(((1R)-2-(1,1′-biphenyl-4-yl)-1-(methyl-((1R)-1-methylcarbamoyl-2-phenylethyl)-carbamoyl)ethyl)methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butylester.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[C:15]([Cl:17])[CH:16]=2)[C:12]#[N:13])=[C:6]([F:18])[C:5]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][N:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][OH:30])[N:21]=2)=[CH:4][CH:3]=1.C(Cl)Cl.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:19][C:20]2[C:28]3[C:23](=[N:24][N:25]=[CH:26][CH:27]=3)[N:22]([CH2:29][O:30][C:34](=[O:36])[CH3:35])[N:21]=2)=[C:6]([F:18])[C:7]=1[O:8][C:9]1[CH:10]=[C:11]([C:12]#[N:13])[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Br)ccc(Cc3nn(CO)c4nnccc34)c2F)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCn1nc(Cc2ccc(Br)c(Oc3cc(Cl)cc(C#N)c3)c2F)c2ccnnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 12 (0.1 g, 0.2 mmol) and DCM (3 mL) was added pyridine (0.08 mL, 1.0 mmol) and acetic anhydride (612 mg, 6 mmol). The resulting solution was stirred overnight at RT under an inert atmosphere. Starting material was still evident and additional aliquots of pyridine (0.08 mL) and Ac2O (0.612 g) were added and the resulting mixture stirred at 55° C. for ca. 5 h. The volatile contents were evaporated and the residue purified in two batches on a preparative SiO2 TLC plate developed with 60% EtOAc/hexane containing 1% TEA. The product was eluted from the plate and crystallized from DCM/hexane to afford 0.076 g of I-8: Anal. Calcd. for C22H14BrClFN5O3: C, 49.79; H, 2.66; N, 13.20. Found: C, 49.87; H, 2.63; N, 12.92.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:5]=2[C:25]([OH:27])=O)[CH2:3][CH2:2]1.[N:28]1([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=3)[N:7]=[C:6]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:5]=2[C:25]([N:36]2[CH2:37][CH2:38][CH:33]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[CH2:34][CH2:35]2)=[O:27])[CH2:3][CH2:2]1
Reactant: O=C(O)c1c(-c2cccnc2)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1
Reactant: C1CCN(C2CCNCC2)C1
Product: O=C(c1c(-c2cccnc2)nn(-c2cccc(C(F)(F)F)c2)c1C1CC1)N1CCC(N2CCCC2)CC1
Yield: 70 %

Procedure:
In analogy to the procedure described in Example 160E], 5-cyclopropyl-3-pyridin-3-yl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-(1-pyrrolidinyl)piperidine gave the title compound as a light yellow solid (70%). MS: 510.4 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[CH:9][CH:10]=2)[O:5][C:4](=[O:16])[CH:3]=1.[CH3:17][O:18]C1C2C(=CC=CC=2)C(O)=CC=1>>[OH:1][C:2]1[C:11]2[C:6](=[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]3=[C:9]([O:18][CH3:17])[CH:10]=2)[O:5][C:4](=[O:16])[CH:3]=1
Reactant: O=c1cc(O)c2ccc3ccccc3c2o1
Reactant: COc1ccc(O)c2ccccc12
Product: COc1cc2c(O)cc(=O)oc2c2ccccc12
Yield: 18 %

Procedure:
The procedure was identical to that used for the preparation of 10a: 18% yield (starting with 4-methoxy-1-naphthol 9e); 1H NMR (DMSO) δ 4.02 (3H, s, OCH3-6), 5.69 (1H, s, H-3), 7.12 (1H, s, H-5), 7.74 (2H, m, H-8, 9), 8.23 (1H, m, H-7), 8.33 (1H, m, H-10).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]([CH3:13])([CH3:12])[C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]([CH3:12])([CH3:13])[C:8]([NH:10][CH3:11])=[O:9])=[CH:14][CH:15]=1
Reactant: CNC(=O)C(C)(C)Oc1ccc(O)cc1
Reactant: Clc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)C(C)(C)Oc1ccc(OCc2cccc(Cl)c2)cc1

Procedure:
In analogy to the procedure described in Example 3 b), the alkylation of 2-(4-hydroxy-phenoxy)-2,N-dimethyl-propionamide with 3-chloro-benzylbromide in 2-butanone using potassium carbonate as the base yielded the 2-[4-(3-chloro-benzyloxy)-phenoxy]-2,N-dimethyl-propionamide as an brown oil; MS: m/e=334 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1)#[N:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][CH:56]=1>CN(C=O)C.CCOC(C)=O>[Cl:54][C:55]1[CH:61]=[CH:60][C:58]([NH:59][C:18](=[O:20])[CH2:17][CH2:16][C:13]2[CH:12]=[CH:11][C:10]([O:9][C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:1]#[N:2])[CH:8]=3)=[CH:15][CH:14]=2)=[CH:57][CH:56]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: N#Cc1cc(Oc2ccc(CCC(=O)O)cc2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cc(Oc2ccc(CCC(=O)Nc3ccc(Cl)cc3)cc2)ccn1

Procedure:
A solution of 3-{4-[(2-cyanopyridin-4-yl)oxy]phenyl}propanoic acid (400 mg, 1.49 mmol), HATU (681 mg, 1.79 mmol), DIPEA (0.5 mL, 2.98 mmol), and 4-chloroaniline (209 mg, 1.63 mmol) in DMF (5 mL) was stirred overnight at rt. The reaction mixture was diluted with EtOAc and washed with 1N HCl, 1N NaOH and brine, dried over Na2SO4 and concentrated. The resulting solid was triturated with DCM and filtered to give A-21 (187 mg, 33%). 1H NMR (300 MHz, d6-DMSO): δ 10.02 (s, 1H), 8.56 (dd, J1=0.50 Hz, J2=5.8 Hz, 1H), 7.57-7.63 (m, 3H), 7.31-7.40 (m, 4H), 7.10-7.17 (m, 3H), 2.95 (t, J=7.5 Hz, 2H), and 2.65 (t, J=7.8 Hz, 2H).
Reaction SMILES: C([O:8][C:9](=[O:47])[CH2:10][N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14](=[O:28])[CH:13]([CH2:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[N:32]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:31]=2)[C:12]1=[O:46])C1C=CC=CC=1>C(OCC)(=O)C.[Pd]>[C:42]([O:41][C:39]([N:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30]([CH2:29][CH:13]2[C:12](=[O:46])[N:11]([CH2:10][C:9]([OH:47])=[O:8])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[N:15]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:14]2=[O:28])=[N:31]1)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)n1nc(CC2C(=O)N(CC(=O)OCc3ccccc3)c3ccccc3N(c3ccccc3)C2=O)c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1nc(CC2C(=O)N(CC(=O)O)c3ccccc3N(c3ccccc3)C2=O)c2ccccc21
Yield: 85.6 %

Procedure:
(0.3 g, 0.95 mM) of tert-butyl 3-({1-[2-(benzyloxy)-2-oxoethyl]-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-3-yl}methyl)-1H-indazole-1-carboxylate were dissolved in 10 ml of ethyl acetate and 50 mg of 10% Pd/C were added. Reaction mixture was hydrogenated at atm. Pressure overnight. Catalyst was removed by filtration and was solvent evaporated under reduced pressure. 0.22 g of product was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([N:14]2[CH2:23][CH2:22][C:17]3([O:21][CH2:20][CH2:19][O:18]3)[CH2:16][CH2:15]2)=[C:11]([F:13])[CH:12]=1)=[O:5])[CH3:2].C[C:25](C)([O-:27])C.[Li+].C(OC(=O)CCC)[C@@H]1OC1>O1CCCC1>[O:21]1[C:17]2([CH2:16][CH2:15][N:14]([C:10]3[CH:9]=[CH:8][C:7]([N:6]4[CH2:2][C@H:1]([CH2:25][OH:27])[O:3][C:4]4=[O:5])=[CH:12][C:11]=3[F:13])[CH2:23][CH2:22]2)[O:18][CH2:19][CH2:20]1
Reactant: CCOC(=O)Nc1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Reactant: CC(C)(C)[O-]
Agent: CCCC(=O)OC[C@H]1CO1
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)CN1c1ccc(N2CCC3(CC2)OCCO3)c(F)c1
Reaction time: 0.08 h

Procedure:
5-Ethoxycarbonylamino-2-(1,4-dioxa-8-azaspiro[4,5]dec-8-yl)fluorobenzene (22.9 g, 0.071 M) was dissolved in dry tetrahydrofuran (250 ml) under nitrogen, cooled to −70°, and treated dropwise over 30 minutes with a solution of lithium t-butoxide (1M in tetrahydrofuran, 77.6 ml), keeping the temperature below −70°. After stirring for 5 minutes, (R)-glycidylbutyrate (11.19 g, 0.077 M) was added, and stirring continued at −65° for 1 hour, before allowing the temperature to rise to ambient over 16 hours. The precipitate was collected and washed with tetrahydrofuran to give the desired product (17.8 g).
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([CH2:9][CH2:10][C:11](O)=[O:12])=O)=[CH:5][CH:4]=1.Br.O.[NH2:18][NH2:19]>O.C(O)C>[OH:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]2[CH2:9][CH2:10][C:11](=[O:12])[NH:18][N:19]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Reactant: NN
Agent: Br
Solvent: CCO
Solvent: O
Product: O=C1CCC(c2ccc(O)cc2)=NN1
Temperature: 110 °C
Yield: 41053.6 %

Procedure:
A mixture of 25.0g (0.120 mmol) of 3-(4-methoxybenzoyl)propionic acid and 175 ml of 48% HBr is heated under N2 at 110° C. for 5 hrs. After cooling, the mixture is diluted with an equal volume of water and exhaustively extracted with EtOAc (5×100 ml). The organic phase is washed with saturated NaCl, dried (MgSO4), filtered and the solvent removed to leave a white solid. After recrystallization from EtOAc, 16.8 g of 3-(4-hydroxybenzoyl)propionic acid, m.p. 157°-159° C., is obtained. Yield, 72. A mixture of 10.0 g (51.5 mmol) of the acid prepared above and 6.2 ml (128 mmol) of 98% hydrazine monohydrate in 172 ml of ethanol is heated at reflux overnight under N2. The resulting white solid is collected by suction filtration to give 9.37 g of 6-(4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone as a white powder, m.p. >300 ° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH:13]2[CH2:17][CH2:16][N:15]([CH3:18])[C:14]2=[O:19])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl.CN(C)CC(O)=O.I[C:29]1[CH:34]=[CH:33][C:32]([C:35]2[O:36][C:37]([CH3:40])=[N:38][N:39]=2)=[CH:31][CH:30]=1>O1CCOCC1.[Cu](I)I>[CH3:40][C:37]1[O:36][C:35]([C:32]2[CH:31]=[CH:30][C:29]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH:13]4[CH2:17][CH2:16][N:15]([CH3:18])[C:14]4=[O:19])[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:34][CH:33]=2)=[N:39][N:38]=1
Reactant: Cc1nnc(-c2ccc(I)cc2)o1
Reactant: COC(=O)c1cc(O)cc(OC2CCN(C)C2=O)c1
Agent: I[Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(OC2CCN(C)C2=O)c1
Yield: 30.7 %

Procedure:
To a stirred mixture of Methyl 3-hydroxy-5-(1-methyl-2-oxopyrrolidin-3-yloxy)benzoate (15 g) (Intermediate 3), N,N-dimethylglycine hydrochloride (2.3 g), copper (II) iodide (1 g) in dry 1,4-dioxane was added 2-(4-iodophenyl)-5-methyl-1,3,4-oxadiazole (15.4 g) (Intermediate 4) under nitrogen. The reaction mixture was refluxed for 24 h. The reaction mixture was cooled, quenched with water and extracted with DCM. Combined organic washings were washed with water, brine, dried over Na2SO4, filtered and concentrated in vacuo to get the crude product. The crude product was purified by column chromatography using silica gel as stationary phase and ethyl acetate: petroleum ether (9:1) as mobile phase to give the product (7 g) as thick liquid.