Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C(O)C.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>O>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: C1COCCN1
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(N3CCOCC3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
To a 10 mL reaction vial containing stir bar were added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.060 g, 0.160 mmol), ethanol (1.5 mL), and then morpholine (0.280 mL, 3.21 mmol) via syringe at once. The contents were capped, placed into a heat block, and heated at 120° C. for 18 h and then at 135° C. for 2 hr. After cooling to room temperature, the reaction mixture was diluted with water (40 mL), adjusted to pH 6-7, and stirred for 15 min. The contents were filtered and washed with water. The product was dried in vacuum oven at 50° C. for 5 hr. The product was obtained as 57 mg (79%). LCMS E-S (M+H)=425.0. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44 (d, J=6.57 Hz, 6H), 2.12 (s, 3H), 2.19 (s, 3H), 3.56-3.66 (m, 4H), 3.69-3.78 (m, 4H), 4.35 (d, J=4.80 Hz, 2H), 5.00 (quin, J=6.63 Hz, 1H), 5.89 (s, 1H), 7.13 (s, 1H), 8.03 (s, 1H), 8.65 (t, J=4.93 Hz, 1H), 11.56 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([C:32]5[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=5)=[N:24][N:23]=4)=[CH:17][CH:16]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CC(O)=O.CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([C:32]5[CH:33]=[CH:34][C:35]([CH2:36][N:40]6[CH2:44][CH2:43][CH2:42][CH2:41]6)=[CH:38][CH:39]=5)=[N:24][N:23]=4)=[CH:17][CH:16]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: C1CCNC1
Reactant: Nc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccc(C=O)cc4)c4ccccc34)cc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4ccc(CN5CCCC5)cc4)c4ccccc34)cc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 25 mL RBF under nitrogen was charged with 4-(4-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenylamino)phthalazin-1-yl)benzaldehyde (90 mg, 0.18 mmol), pyrrolidine (125 mg, 1.8 mmol) and MeOH (3.5 mL, 0.05 M). HOAc was added (0.02 mL, 0.36 mmol) and the reaction mixture was stirred at RT for 2 hrs. The reaction mixture was cooled to 0° C. and sodium triacetoxyborohydride (186 mg, 0.90 mmol) was added portionwise. The mixture was stirred at RT overnight, then cooled to 0° C. and basified with aqueous sodium bicarbonate and the product was extracted into DCM. The organic layers were collected, dried over sodium sulfate, filtered and concentrated to give brown residue. The crude residue was purified by Gilson reverse phase liquid chromatography (5%-85% CH3CN/H2O+0.1% TFA). Product-containing fractions were combined and basified with aqueous sodium bicarbonate. This was extracted with EtOAc, dried over sodium sulfate, filtered, concentrated under reduced pressure, and dried under high vacuum to afford N-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-(pyrrolidin-1-ylmethyl)phenyl)phthalazin-1-amine as a light yellow solid. MS m/z=567 [M+H]+. Calc'd for C34H30N8O: 566.7.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:47]([NH:49][CH3:50])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:35][CH2:36][CH:37]([CH2:40][C:41]([N:49]([CH2:47][CH3:48])[CH3:50])=[O:43])[CH2:38][CH2:39]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCNC
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)CC)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with N-ethyl-N-methylamine (Aldrich) to give the title compound. LC-MS (ES+) 706 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:15][CH3:16])[CH3:14])=[CH:9][CH:8]=1)=[O:5].[N:21]1[CH:26]=[C:25]([CH:27]=O)[CH:24]=[N:23][CH:22]=1.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.C(OCC)(=O)C>[CH:13]([C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:1]=[C:27]2[C:25]2[CH:26]=[N:21][CH:22]=[N:23][CH:24]=2)=[CH:8][CH:9]=1)([CH2:15][CH3:16])[CH3:14]
Reactant: O=Cc1cncnc1
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCC(C)c1ccc(-n2c(-c3cncnc3)nc3ccccc3c2=O)cc1
Temperature: 150 °C
Yield: 38.7 %

Procedure:
2-amino-N-(4-sec-butylphenyl)benzamide (0.544 g, 2.03 mmol) and pyrimidine-5-carbaldehyde (0.241 g, 2.23 mmol), NaHSO3 (0.253 g, 2.44 mmol) and p-TsOH (0.039 g, 0.20 mmol) were dissolved in DMA (20 mL) and heated at 150° C. for 18 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (2×200 mL), dried (Na2SO4), filtered, and concentrated. Flash chromatograph on silica gel, eluting with 20% ethyl acetate/heptane to 70% ethyl acetate/heptane, afforded the title compound as a white solid (0.280 g, 39%). 1H-NMR (300 MHz, DMSO-6): δ 9.05 (s, 1H), 8.77 (s, 2H), 8.22-8.25 (m, 1H), 7.92-7.98 (m, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.64-7.69 (m, 1H), 7.31-7.35 (m, 2H), 7.18-7.23 (m, 2H), 2.54-2.61 (m, 1H), 1.37-1.58 (m, 2H), 1.15 (d, J=6.9 Hz, 3H), 0.64 (t, J=7.3 Hz, 3H). MS (APCI) m/z: 357 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([NH:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[C:24]1([CH2:30][C:31](Cl)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[C:24]1([CH2:30][C:31]([N:10]([C:2]([CH3:1])([CH3:9])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)CCNC(C)(C)c1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCN(C(=O)Cc1ccccc1)C(C)(C)c1ccccc1
Reaction time: 24 h
Yield: 89.1 %

Procedure:
47.0 g (0.2 mol) of ethyl 3-(α,α-dimethylbenzylamino)propionate prepared by the method of Reference Example 16, was dissolved in 200 ml of acetone, and 30 g (0.22 mol) of potassium carbonate was added thereto. 31.0 g (0.2 mol) phenyl acetic acid chloride was dropwise added thereto at room temperature. After completion of the dropwise addition, the reaction solution was stirred for one day and night, and the reaction solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate, washed with water and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 63.0 g (yield: 89.1%) of the desired compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.Br.Br.[CH2:23]([N:30]1[CH2:35][C@@H:34]2[CH2:36][C@H:31]1[CH2:32][NH:33]2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:23]([N:30]1[CH2:35][C@@H:34]2[CH2:36][C@H:31]1[CH2:32][N:33]2[C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: c1ccc(CN2C[C@@H]3C[C@H]2CN3)cc1
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)N1C[C@@H]2C[C@H]1CN2Cc1ccccc1

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (1S,4S)-2-benzyl-2,5-diazabicyclo[2.2.1]heptane dihydrobromide (116258-17-4) in the presence of TBTU and DIEA to obtain the title compound as colorless oil; MS (EI): m/e=455.7 [MH+].
Reaction SMILES: Cl.C([O:4][C:5](=[O:17])[CH2:6][NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)C.C([NH:28][C@H:29]([C:31](O)=[O:32])[CH3:30])(OCC1C=CC=CC=1)=O>>[NH2:28][C@H:29]([C:31]([N:7]([CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[CH2:6][C:5]([OH:4])=[O:17])=[O:32])[CH3:30]
Reactant: CCOC(=O)CNC1CCc2ccccc21
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: C[C@H](N)C(=O)N(CC(=O)O)C1CCc2ccccc21
Yield: 60 %

Procedure:
By reacting 13 g of (indan-1-yl)glycine ethyl ester hydrochloride with 11.6 g of N-carbobenzoxy-L-alanine and treating the reaction mixture as in Reference Example 4, there is obtained 8.0 g of L-alanyl-N-(indan-1-yl)glycine as colorless amorphous powder.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([CH2:11][N:12]2[CH2:18][CH2:17][C:16]3[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=3[NH:14][C:13]2=[O:23])[CH2:7][CH2:6]1)=[O:4].[Li+].[OH-].Cl>O1CCOCC1>[O:23]=[C:13]1[NH:14][C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH2:17][CH2:18][N:12]1[CH2:11][C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]1
Reactant: COC(=O)[C@H]1CC[C@H](CN2CCc3ccccc3NC2=O)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C1Nc2ccccc2CCN1C[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of trans-4-(2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-ylmethyl)-cyclohexanecarboxylic acid methyl ester (0.3 g, 0.95 mmol) in dioxane (7 mL) at 0° C. was added a 2N solution of LiOH. The reaction mixture was stirred at 0° C. for 20 min, allowed to reach ambient temperature and stirred additionally for 2 h. Then a 1N solution of HCl was added until acid pH, and the mixture was extracted with EtOAc, The organic layer was dried over Na2SO4 and solvent removed under reduced pressure to afford the titled compound (0.3 g, 96%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=2[CH3:20])[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C(O)(C(F)(F)F)=O.[NH2:28][C:29]1[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=1>C(OCC)(=O)C>[C:13]1([CH3:20])[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[C:12]=1[O:11][C:4]1[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=[C:2]([NH:28][C:29]2[CH:36]=[CH:35][C:32]([C:33]#[N:34])=[CH:31][CH:30]=2)[N:3]=1
Reactant: N#Cc1ccc(N)cc1
Reactant: Cc1cc(C)c(Oc2nc(Cl)nc3ccsc23)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(Oc2nc(Nc3ccc(C#N)cc3)nc3ccsc23)c(C)c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 62.8 %

Procedure:
To a solution of 2-chloro-4-(mesityloxy)thieno[3,2-d]pyrimidine (32.4 mg, 0.11 mmol), TFA (0.13 mL, 1.71 mmol) in TFE (0.7 mL) was added 4-aminobenzonitrile (100 mg, 0.88 mmol) in a sealed tube. The reaction was stirred at 90° C. for 15 h. Reaction mixture was diluted with ethyl acetate (5 mL) and washed with saturated NaHCO3 (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep HPLC afforded the product as a white solid (26.7 mg, 63%):
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]3[CH:18]=[CH:19][CH:20]=[CH:21][C:12]3=[C:11]([CH2:22][OH:23])[C:10]=2[CH2:9]1)=O)(C)(C)C.O.[C:25]1([S:31]([OH:34])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CO>[C:25]1([S:31]([OH:34])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[C:25]1([S:31]([OH:34])(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[OH:23][CH2:22][C:11]1[C:10]2[CH2:9][NH:8][CH2:17][CH2:16][C:15]=2[N:14]=[C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=12
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccccc3c(CO)c2C1
Agent: O=S(=O)(O)c1ccccc1
Solvent: CO
Solvent: O
Product: OCc1c2c(nc3ccccc13)CCNC2
Temperature: 70 °C
Yield: 105.9 %

Procedure:
2-t-Butoxycarbonyl-10-hydroxymethyl-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine (202 mg, 0.643 mmol) was dissolved in methanol (1.3 ml), followed by adding thereto benzenesulfonic acid monohydrate (226.3 mg, 1.285 mmol), and the resulting mixture was heated under reflux at 70° C. for 3 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure to obtain the desired compound (361.2 mg, quant.) as a brown substance.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.Br[CH2:34][C:35]([N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)=[O:36]>>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:34][C:35]([N:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[O:36])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: O=C(CBr)N1CCOCC1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(ccn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C(CN1C(=O)S/C(=C\c2ccc3c(ccn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O)N1CCOCC1

Procedure:
(5Z)-5-[(1-{[2,4-Bis(trifluoromethyl)phenyl]methyl}-1H-indol-5-yl)methylidene]-3-(2-morpholin-4-yl-2-oxoethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[2,4-bis-(trifluoromethyl)benzyl]-1H-indol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 238) and 4-bromoacetyl morpholine following General Procedure H.
Reaction SMILES: N(OCCCC)=O.[Br:8][C:9]1[CH:15]=[C:14]([CH3:16])[C:13]([F:17])=[CH:12][C:10]=1N.[ClH:18]>C(#N)C>[Br:8][C:9]1[C:10]([Cl:18])=[CH:12][C:13]([F:17])=[C:14]([CH3:16])[CH:15]=1
Reactant: Cc1cc(Br)c(N)cc1F
Reactant: Cl
Agent: CCCCON=O
Solvent: CC#N
Product: Cc1cc(Br)c(Cl)cc1F
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
Cupric chloride (6 g) and butyl nitrite (4.8 g) were added to acetonitrile (16 ml), and the mixture was stirred at 60° C. for 10 minutes. A solution of 2-bromo-5-fluoro-4-methylaniline (7.6 g) in acetonitrile (30 ml) was added dropwise to the mixture at the same temperature, and the resultant mixture was then stirred at the same temperature for 30 minutes. After the reaction mixture was allowed to cool, 2N hydrochloric acid was added to acidify the reaction mixture, and it was extracted with diethyl ether. After an organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was subjected to column chromatography on silica gel to conduct elution with n-hexane, thereby obtaining the title compound (5.6 g) as a pale yellow oil.
Reaction SMILES: [O:1]([CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH:18]2[O:20][CH2:19]2)=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH2:34][CH2:35][C:36](=[O:39])[NH:37][N:38]=2)=[CH:29][C:28]=1[CH3:40]>>[O:1]([CH2:8][CH2:9][O:10][CH2:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][NH:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH2:34][CH2:35][C:36](=[O:39])[NH:37][N:38]=3)=[CH:29][C:28]=2[CH3:40])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(OCCOCc2ccc(OCC3CO3)cc2)cc1
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCN
Product: Cc1cc(C2=NNC(=O)CC2)ccc1OCCNCC(O)COc1ccc(COCCOc2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-phenoxyethoxymethyl)phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-methyl-phenyl]-4,5-dihydro-3-(2H)-pyridazinone.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[CH:11]=[C:10]([C:20]([O:22]C)=[O:21])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][C:15]3[S:16][CH:17]=[CH:18][N:19]=3)[CH:11]=[C:10]([C:20]([OH:22])=[O:21])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(Oc2nccs2)cc(-c2ccc(C)cc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(-c2cc(Oc3nccs3)cc(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 4′-methyl-5-(thiazol-2-yloxy)biphenyl-3-carboxylate (560 mg, 1.6 mmol) in tetrahydrofuran (20 mL) was added 2.5 M aqueous lithium hydroxide solution (6.7 mL, 17 mmol). After being stirred at room temperature overnight, the mixture was acidified to pH=5 by addition of 2N aq. HCl and extracted with EtOAc. The organic layer was dried over sodium sulfate, and concentrated to afford the title product. 1H NMR (CD3OD, 400 MHz): 8.18 (t, 1H, J=1.6 Hz), 7.82 (dd, 1H, J=2.4, 1.2 Hz), 7.74 (t, 1H, J=2.0 Hz), 7.57 (d, 2H, J=8.0 Hz), 7.30 (d, 2H, J=8.4 Hz), 7.28 (d, 1H, J=4.0 Hz), 7.13 (d, 1H, J=4.0 Hz), 2.39 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH3:19])[CH:10]=1.[I-].[K+].[OH:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:32][CH2:33][C@H:34]([N:39]2[CH2:44][CH2:43][N:42]([S:45]([CH3:48])(=[O:47])=[O:46])[CH2:41][CH2:40]2)[C:35]([O:37][CH3:38])=[O:36])(=[O:31])=[O:30])=[CH:25][CH:24]=1>CC(C)=O>[CH3:48][S:45]([N:42]1[CH2:41][CH2:40][N:39]([C@@H:34]([CH2:33][NH:32][S:29]([C:26]2[CH:25]=[CH:24][C:23]([O:22][CH2:8][C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=[C:11]([CH3:19])[CH:10]=3)=[CH:28][CH:27]=2)(=[O:31])=[O:30])[C:35]([O:37][CH3:38])=[O:36])[CH2:44][CH2:43]1)(=[O:46])=[O:47]
Reactant: Cc1cc(CCl)c2ccccc2n1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(O)cc1)N1CCN(S(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CC(C)=O
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1)N1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.8 %

Procedure:
280 mg (0.85 mmol) of cesium carbonate followed by 160 mg (0.85 mmol) of 4-chloromethyl-2-methylquinoline and by 15 mg of potassium iodide are added to a solution of 300 mg (0.71 mmol) of methyl (S)-3-(4-hydroxybenzenesulfonylamino)-2-(4-methanesulfonylpiperazin-1-yl)propanoate in 10 ml of acetone. The reaction medium is stirred at ambient temperature for 18 h, filtered and concentrated under vacuum. The crude product is purified by chromatography on silica gel, elution being carried out with a 40/60 heptane/ethyl acetate mixture. 130 mg (32%) of methyl (S)-2-(4-methanesulfonylpiperazin-1-yl)-3-[4-(2-methylquinolin-4-ylmethoxy)benzenesulfonylamino]propanoate are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[CH2:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3]1.[N:14](OCCC(C)C)=[O:15].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[OH:15][N:14]=[C:7]1[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[CH2:4][CH2:3][N:2]([CH3:1])[C:8]1=[O:9]
Reactant: CN1CCc2ccccc2CC1=O
Reactant: CC(C)CCON=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCc2ccccc2C(=NO)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
In a 22 L flask, under nitrogen, was 3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one (606 g, 3.46 mol) and isoamyl nitrite (543 g, 4.5 mol) in THF (7.88 L). The mixture was cooled to about 0° C. before LiHMDS (1 N THF solution, 4.5 L, 04.5 mol) was added at a rate such that the temperature remained below about 7° C. After addition, the reaction was allowed to stir at room temperature for about 2 h while monitoring for the reaction progress by HPLC. Upon completion of the reaction, the mixture was cooled to about 0° C., and the pH adjusted from 12 to about 2-1 using aqueous HCl (2N). The resulting precipitate was stirred for about 6 h before isolation by filtration and drying to provide 1-hydroxyimino-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-2-one 604.7 g (85.6%).
Reaction SMILES: [Na+].[I-:2].CNCCNC.Br[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([N:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)[CH:14]=[C:13]2[CH3:27].CCOC(C)=O>O1CCOCC1.[Cu]I>[I:2][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[C:15]([N:20]1[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]1)[CH:14]=[C:13]2[CH3:27]
Reactant: Cc1cc(N2CCC(C)CC2)nc2ccc(Br)cc12
Reactant: [I-]
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cc(N2CCC(C)CC2)nc2ccc(I)cc12
Temperature: 110 °C
Reaction time: 14 h

Procedure:
Under an argon atmosphere, 39 mg (0.2 mmol) of CuI, 0.6 g (4.0 mmol) of NaI, and 43 μL N,N′-dimethylethylenediamine are added to a solution of 0.69 g (2.0 mmol) of 6-bromo-4-methyl-2-(4-methylpiperidin-1-yl)quinoline in 2 mL of 1,4-dioxane and the reaction mixture is shaken for 14 hours at 110° C. After cooling, it is combined with 60 mL of EtOAc, and the organic phase is washed twice with 20 mL of 5% NH3 solution and dried over magnesium sulfate. After the desiccant and solvent have been eliminated, the residue is reacted further without purification. Yield: 0.65 g (88% of theoretical); C16H19IN2 (M=366.240); calc.: molpeak (M+H)+: 367; found: molpeak (M+H)+: 367; HPLC-MS: 7.0 min (method A).
Reaction SMILES: C(CCC1C(CCCCCCOC2C=C(C3C=CC(F)=C(F)C=3)C=C(C(=O)N(C)C)C=2)=CC=CC=1OCCCC(O)=O)(O)=O.C([O:47][C:48](=[O:97])[CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:71]=[C:70]([C:72]([N:74]3[CH2:78][CH2:77][C:76]([F:80])([F:79])[CH2:75]3)=[O:73])[CH:69]=[C:68]([C:81]3[CH:89]=[CH:88][C:84]4[O:85][CH2:86][O:87][C:83]=4[CH:82]=3)[CH:67]=2)[C:54]=1[CH2:90][CH2:91][C:92]([O:94]CC)=[O:93])C.[OH-].[Na+]>CCO>[O:85]1[C:84]2[CH:88]=[CH:89][C:81]([C:68]3[CH:67]=[C:66]([CH:71]=[C:70]([C:72]([N:74]4[CH2:78][CH2:77][C:76]([F:79])([F:80])[CH2:75]4)=[O:73])[CH:69]=3)[O:65][CH2:64][CH2:63][CH2:62][CH2:61][CH2:60][CH2:59][C:55]3[C:54]([CH2:90][CH2:91][C:92]([OH:94])=[O:93])=[C:53]([CH:58]=[CH:57][CH:56]=3)[O:52][CH2:51][CH2:50][CH2:49][C:48]([OH:97])=[O:47])=[CH:82][C:83]=2[O:87][CH2:86]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCC(F)(F)C3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Agent: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCC(F)(F)C3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)O
Yield: 65.7 %

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid starting from 4-[3-{6-[3-benzo[1,3]dioxol-5-yl-5-(3,3-difluoro-pyrrolidine-1-carbonyl)-phenoxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (120 mg, 0.163 mmol) and 1.0 N aqueous NaOH (1.63 mL) in EtOH (5.7 mL) to afford 4-[3-{6-[3-benzo[1,3]dioxol-5-yl-5-(3,3-difluoro-pyrrolidine-1-carbonyl)-phenoxy]-hexyl}-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (73 mg, 66%) as a white amorphous solid.