Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:12]1[N:13]=[N+:14]([O-:26])[C:15]2[CH:25]=[C:24]3[C:19]([CH2:20][CH2:21][CH2:22][O:23]3)=[CH:18][C:16]=2[N:17]=1>COCCOC>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:12]2[N:13]=[N+:14]([O-:26])[C:15]3[CH:25]=[C:24]4[C:19]([CH2:20][CH2:21][CH2:22][O:23]4)=[CH:18][C:16]=3[N:17]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)OCCC3
Reactant: NCCCN1CCOCC1
Solvent: COCCOC
Product: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)OCCC3
Yield: 93 %

Procedure:
3-(4-Morpholinyl)propylamine (0.71 mL, 4.8 mmol) was added to a stirred solution of chloride 240 (380 mg, 1.6 mmol) in DME (40 mL) and the solution stirred at reflux temperature for 4 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 243 (514 mg, 93%) as a yellow solid: mp (MeOH/EtOAc) 151-152° C.; 1H NMR δ 7.60 (s, 1H, H-10), 7.30 (s, 1H, H-5), 6.00 (br s, 1H, NH), 4.26 (br dd, J=5.3, 5.2 Hz, 2H, H-8), 3.75 (br t, J=4.7 Hz, 4H, 2×CH2O), 3.55 (dt, J=6.3, 5.9 Hz, 2H, CH2N), 2.97 (br t, J=6.3 Hz, 2H, H-6), 2.45-2.52 (m, 6H, 3×CH2N), 2.02-2.08 (m, 2H, H-7), 1.79-1.86 (m, 2H, CH2); 13C NMR δ 158.1, 152.9, 143.6, 135.1, 130.0, 126.1, 104.4, 67.0 (2), 66.9, 57.3 (2), 53.8, 40.7, 25.9, 25.3, 21.7. Anal. calcd for C17H23N5O3: C, 59.1; H, 6.7; N, 20.3. Found: C, 59.4; H, 6.6; N, 20.3%.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])=[O:4].C1(C)C(C)=CC=CC=1.[NH2:29][CH2:30][CH:31](O)[CH3:32].C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C.CCCCCC>[Cl:20][C:17]1[CH:18]=[CH:19][C:6]2[NH:5][C:3](=[O:4])[CH2:2][N:29]3[CH2:30][CH:31]([CH3:32])[O:9][C:8]3([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:7]=2[CH:16]=1
Reactant: CC(O)CN
Reactant: O=C(CBr)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1CN2CC(=O)Nc3ccc(Cl)cc3C2(c2ccccc2)O1

Procedure:
A solution of 67 g. (0.19 mole) of 2-(2-bromoacetamido)-5-chloro-benzophenone, 500 ml. of xylene, 15.7 g. (0.21 mole) of 1-amino-2-propanol and 25 ml. of triethylamine was stirred at reflux for 20 hours. The reaction mixture was concentrated in vacuo to a residue which was partitioned between methylene chloride and water. The organic layer was washed with water, dried and concentrated to an oil which was crystallized from ethyl acetate to give 18.3 g. of a colorless solid, m.p. 181°-184°. Thin layer chromatography on Eastman alumina plates with an eluant of 3 parts of hexane and 2 parts of ethyl acetate revealed the presence of two compounds. The product was dissolved in chloroform and chromatographed over Woelm neutral alumina I. A mixture concentrated in the above-titled product (the faster of the two compounds) was collected in 30% ethyl acetate-70% hexane. Recrystallizations from methylene chloride gave colorless prisms, m.p. 188°-189°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]2[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=2[CH3:25])=[O:16])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=2[N:7]=1.[CH3:28][N:29]([CH3:48])[S:30]([C:33]1[CH:38]=[CH:37][C:36](B2OC(C)(C)C(C)(C)O2)=[CH:35][CH:34]=1)(=[O:32])=[O:31].C(=O)(O)[O-].[Na+].O>COCCOC.O>[CH3:28][N:29]([CH3:48])[S:30]([C:33]1[CH:34]=[CH:35][C:36]([C:2]2[CH:3]=[C:4]([C:15]([NH:17][CH2:18][C:19]3[C:20](=[O:27])[NH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[O:16])[C:5]3[C:10]([CH3:11])=[N:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:6]=3[N:7]=2)=[CH:37][CH:38]=1)(=[O:31])=[O:32]
Reactant: CN(C)S(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(S(=O)(=O)N(C)C)cc3)nc3c2c(C)nn3C(C)C)c(=O)[nH]1
Yield: 81.4 %

Procedure:
In a 25 mL sealable tube under nitrogen were combined 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-3-methyl-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (75 mg, 0.19 mmol) and N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (90 mg, 0.29 mmol) in DME/water (3 ml:1 ml). PdCl2 (dppf)-CH2Cl2 adduct (7.9 mg, 0.009 mmol) was added and the resulting mixture was degassed with nitrogen for 10 min. Sodium bicarbonate (48.7 mg, 0.58 mmol) was added, the vessel was sealed, and the reaction mixture was irradiated (microwave) at 150° C. for 30 min. After cooling, 2 mL of water was added and solids that precipitated were filtered. DCM/MeOH (1:1) was added, the mixture was pre-absorbed on silica gel and purified by silica gel chromatography (eluent: gradient 0 to 90:10:1 DCM/MeOH/NH4OH). The isolated product was treated with EtOH/EtOAc (1:1), the solids filtered and washed with EtOAc and DCM, and then dried to afford the title compound (83 mg, 78%) as a white solid. LCMS E-S (M+H)=537.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1 H) 8.79 (t, J=4.93 Hz, 1 H) 8.47 (m, J=8.59 Hz, 2 H) 7.90 (m, J=8.59 Hz, 2 H) 7.80 (s, 1 H) 5.89 (s, 1 H) 5.28 (quin, J=6.69 Hz, 1 H) 4.40 (d, J=5.05 Hz, 2 H) 2.66 (s, 6 H) 2.47 (s, 3 H) 2.25 (s, 3 H) 2.12 (s, 3 H) 1.53 (s, 3 H) 1.51 (s, 3 H).
Reaction SMILES: [NH+]1[CH:5]=[CH:4]NC=1.[N:6]1([C:11]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=3[S:13](=[O:25])(=[O:24])[N:12]=2)[CH:10]=[CH:9]N=C1.C1(CN)CC1>>[CH:9]1([CH2:10][NH:6][C:11]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=3[S:13](=[O:24])(=[O:25])[N:12]=2)[CH2:5][CH2:4]1
Reactant: c1c[nH+]c[nH]1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Agent: NCC1CC1
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=C(NCC1CC1)N2

Procedure:
3-(Imidazol-1-yl)-7-nitro-4H-1,2,4-benzothiadiazine 1,1-dioxide imidazolium salt was treated with cyclopropylmethylamine according to the general procedure Method D to give the title compound; m.p.: 276-278° C.; IR (KBr): 3290, 3193, 3104, 2994, 1635, 1603,1564, 1539, 1499, 1486, 1347, 1276, 1251,1153, 1111 cm−1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(Cl)(=O)C(Cl)=O.O[C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl.CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([O:15][C:25]2[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=2)=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
Prepared using General Procedure 2: To a stirring solution of 4-(heptyloxy)benzoic acid (1.0 g, 4.23 mmol) in DCM (10 mL) were added DMF (1 drop) and oxalyl chloride (0.47 mL, 5.5 mmol). The reaction mixture was stirred at room temperature for 1 h. Solvent was evaporated under high vacuum. DCM (10 mL) was added and the reaction mixture evaporated again to dryness. The residue was dissolved in DCM (10 mL) then added to a stirring mixture of 4-hydroxy benzaldehyde (0.56 g, 4.6 mmol) and TEA (0.706 mL, 5.07 mmol) in DCM (5 mL) at 0° C. The reaction mixture was allowed to stir at room temperature for 2 h. The reaction mixture was quenched with NaHCO3 (10 mL). The aqueous phase was extracted with DCM and the combined organic phases were dried over MgSO4 and concentrated to give 977 mg (62%) of 4-formylphenyl 4-(heptyloxy)benzoate INT-12 which was used in the next step without purification. LCMS-ESI (m/z) calculated for C21H24O4: 340; found 341 [M+H]+, tR=11.91 min (Method 2). 1H NMR (400 MHz, DMSO) δ 10.03 (s, 1H), 8.19-7.91 (m, 4H), 7.63-7.41 (m, 2H), 7.24-7.01 (m, 2H), 4.09 (t, J=6.5 Hz, 2H), 1.86-1.62 (m, 2H), 1.50-1.07 (m, 8H), 0.87 (t, J=6.9 Hz, 3H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17].[CH2:18]([O:20][C:21](=[O:35])[C:22]1[CH:27]=[C:26]([CH2:28][CH2:29][CH3:30])[C:25]([OH:31])=[C:24]([CH2:32][CH2:33][CH3:34])[CH:23]=1)[CH3:19].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CC(C)=O>[CH2:18]([O:20][C:21](=[O:35])[C:22]1[CH:27]=[C:26]([CH2:28][CH2:29][CH3:30])[C:25]([O:31][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=2[O:16][CH3:17])=[C:24]([CH2:32][CH2:33][CH3:34])[CH:23]=1)[CH3:19]
Reactant: CCCc1cc(C(=O)OCC)cc(CCC)c1O
Reactant: COc1cccc(CCCCCCBr)c1OC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(C(=O)OCC)cc(CCC)c1OCCCCCCc1cccc(OC)c1OC

Procedure:
A mixture of 1.20 (4.0 mmol) of 1-(6-bromohexyl)-2,3-dimethoxybenzene, 1.00 g (4.0 mmol) of 3,5-dipropyl-4-hydroxybenzoic acid ethyl ester, 1.10 g (8 mmol) of potassium carbonate and 0.6 g (4 mmol) of sodium iodide in 35 mL of acetone was stirred at reflux for 47 hours. Workup and purification as in Example 16 gave 4-[6-(2,3-dimethoxyphenyl)hexyloxy]-3,5-dipropylbenzoic acid ethyl ester as an oil.
Reaction SMILES: [CH:1]1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.I[C:31]1[C:39]2[C:38](=[O:40])[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:36]=[CH:35][C:34]=2[N:33]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH:32]=1.CB(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][C:31]1[C:39]2[C:38](=[O:40])[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[N:36]=[CH:35][C:34]=2[N:33]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH:32]=1
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(I)cn2COCC[Si](C)(C)C)c1=O
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CB(O)O
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 917.4 %

Procedure:
1 ml of tetrahydrofuran was added to 34 mg (0.15 mmol) of palladium acetate and 126 mg (0.306 mmol) of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, the mixture was degassed under reduced pressure and replaced with argon. Then, the mixture was stirred at room temperature for 30 minutes. Thereafter, 1.59 g (3.04 mmol) of 3-iodo-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 18-(b), 551 mg (9.20 mmol) of methylboronic acid, 2.62 g (12.3 mmol) of potassium phosphate and 9 ml of toluene were added to the mixture, and after the resulting mixture was again degassed under reduced pressure and replaced with argon, the mixture was stirred at 100° C. for 4 hours. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=19:1→3:2 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 1.15 g of the title compound as a yellowish solid. (Yield: 92%)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:16])([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](O)=[O:50])=[CH:47][N:46]=1>C1COCC1.C(N(C(C)C)C(C)C)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:16][C:49]([C:48]2[CH:47]=[N:46][C:45]([Cl:44])=[CH:53][CH:52]=2)=[O:50])([C:14]#[N:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.8 %

Procedure:
To a solution of 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (0.527 g, 2.34 mmol, 1.0 equiv; prepared as described in WO 03/104 236 A1 (Bristol-Myers Squibb Company); [CAS RN 331281-25-5]) in anhydrous THF (12 mL) and N-ethyl diisopropylamine (0.48 mL) was added in the presence of (benzotriazol-1-yloxy)-tris-(dimethylamino)phosphonium hexafluorophosphate (1.138 g, 2.58 mmol, 1.1 equiv; BOP reagent) 6-chloro-nicotinic acid (0.369 g, 2.34 mmol, 1.0 equiv) and the reaction mixture stirred at rt for 12 h. The reaction mixture was poured on crashed ice/NH4Cl, extracted with ethyl acetate (2×200 mL) and the combined organic phases washed with a sat. solution of NaCl (2×100 mL) and water (2×100 mL). The organic phase was dried over Na2SO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography eluting with a mixture of ethyl acetate/triethylamine (97:3) providing 0.63 g (74%) of the title compound as off-white solid. MS (ISP): 365.1 [M+H]+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][C@H:11]3[C:15]([CH3:17])([CH3:16])[CH2:14][N:13]([C:18]([C:20]4([C:23]#[N:24])[CH2:22][CH2:21]4)=[O:19])[CH2:12]3)=[C:8]([C:25]([NH2:27])=[O:26])[CH:7]=[N:6][N:5]2[CH:28]=1.[CH3:29][O:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:23]([C:20]1([C:18]([N:13]2[CH2:14][C:15]([CH3:17])([CH3:16])[CH:11]([NH:10][C:9]3[C:4]4[N:5]([CH:28]=[C:2]([C:35]5[CH:34]=[CH:33][N:32]=[C:31]([O:30][CH3:29])[CH:36]=5)[CH:3]=4)[N:6]=[CH:7][C:8]=3[C:25]([NH2:27])=[O:26])[CH2:12]2)=[O:19])[CH2:21][CH2:22]1)#[N:24]
Reactant: COc1cc(B(O)O)ccn1
Reactant: CC1(C)CN(C(=O)C2(C#N)CC2)C[C@H]1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: COc1cc(-c2cc3c(NC4CN(C(=O)C5(C#N)CC5)CC4(C)C)c(C(N)=O)cnn3c2)ccn1
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 21.1 %

Procedure:
A solution of (S)-6-bromo-4-(1-(1-cyanocyclopropanecarbonyl)-4,4-dimethylpyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (10 mg, 0.022 mmol) in 1,4-Dioxane (0.5 mL), was added (2-methoxypyridin-4-yl)boronic acid (4.12 mg, 0.027 mmol), palladium (II) acetate (0.25 mg, 1.123 mmol), X-Phos (1.07 mg, 2.25 mmol) and potassium phosphate (2M, 0.04 mL, 0.08 mmol). The reaction vial was purged with nitrogen, sealed and heated at 100° C. overnight. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 25-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (2.2 mg, 17% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.43 (dd, J=5.4, 2.5 Hz, 1H), 8.23-8.09 (m, 1H), 7.99-7.93 (m, 1H), 7.90 (dd, J=10.4, 1.5 Hz, 1H), 7.61 (s, 2H), 7.17-7.08 (m, 1H), 6.86 (d, J=8.4 Hz, 1H), 4.12 (dd, J=12.9, 6.4 Hz, 1H), 3.96 (s, 3H), 3.95-3.87 (m, 1H), 3.64-3.55 (m, 1H), 3.50-3.44 (m, 1H), 3.01 (s, 1H), 2.88 (s, 1H), 1.75-1.53 (m, 4H), 1.35-1.24 (m, 6H). MS (ES+) m/z: 474.2 (M+H); LC retention time: 1.41 min (analytical HPLC Method I).
Reaction SMILES: NC1C(OC)=CC=CC=1[C:4](OC)=[O:5].[CH:14]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][CH:23]([N:27]([C:43](=[O:45])[CH3:44])[CH2:28][C:29]2[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=2)[C:22]2[CH:46]=[CH:47][CH:48]=[CH:49][C:21]1=2)=[O:19])([CH3:16])[CH3:15]>>[C:43]([N:27]([CH2:28][C:29]1[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[C:31]([C:39]([F:40])([F:41])[F:42])[CH:30]=1)[CH:23]1[CH2:24][CH2:25][CH2:26][N:20]([C:18]([O:17][CH:14]([CH3:16])[CH3:15])=[O:19])[C:21]2[C:49]([O:5][CH3:4])=[CH:48][CH:47]=[CH:46][C:22]1=2)(=[O:45])[CH3:44]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccccc21
Reactant: COC(=O)c1cccc(OC)c1N
Product: COc1cccc2c1N(C(=O)OC(C)C)CCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)=O

Procedure:
This compound was prepared utilizing the same methodology described in Example 1 wherein replacement of 2-amino-benzoic acid methyl ester with methyl 2-amino-3-methoxybenzoate following the procedure of Example 1, Steps 1-8 for the synthesis of 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester. CI MS 547 (M+H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[C:25]4[N:26]([CH:40]=[CH:41][N:42]=4)[C:27]([C:30]4[CH:31]=[C:32]5[C:36](=[CH:37][CH:38]=4)[C:35](=[O:39])[NH:34][CH2:33]5)=[CH:28][CH:29]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:9]1)=O)(C)(C)C.ClC1N2C=CN=C2C(NC2C=CC(N3CCN(C(C)C)CC3)=CC=2)=CC=1.Cl>O1CCOCC1>[O:39]=[C:35]1[C:36]2[C:32](=[CH:31][C:30]([C:27]3[N:26]4[CH:40]=[CH:41][N:42]=[C:25]4[C:24]([NH:23][C:20]4[CH:19]=[CH:18][C:17]([S:14]([NH:13][CH:10]5[CH2:11][CH2:12][NH:8][CH2:9]5)(=[O:15])=[O:16])=[CH:22][CH:21]=4)=[CH:29][CH:28]=3)=[CH:38][CH:37]=2)[CH2:33][NH:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(Nc3ccc(-c4ccc5c(c4)CNC5=O)n4ccnc34)cc2)C1
Agent: CC(C)N1CCN(c2ccc(Nc3ccc(Cl)n4ccnc34)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1NCc2cc(-c3ccc(Nc4ccc(S(=O)(=O)NC5CCNC5)cc4)c4nccn34)ccc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-{4-[5-(1-oxo-2,3-dihydro-1H-isoindol-5-yl)-imidazo[1,2-a]pyridin-8-ylamino]-benzenesulfonylamino}-pyrrolidine-1-carboxylic acid tert-butyl ester (16 mg, 0.027 mmol), prepared using methods as described for compound 12, is suspended in a 4M solution of HCl in dioxane (0.5 mL) and the mixture is stirred under nitrogen at room temperature for 16 hours. The mixture is concentrated under reduced pressure. The crude product is purified by reverse phase HPLC to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:15]O)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14].[ClH:17]>O1CCOCC1>[Cl:17][CH2:15][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]#[C:12][CH2:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: CCC#CCOc1ccc(CO)cc1OC
Reactant: Cl
Solvent: C1COCCO1
Product: CCC#CCOc1ccc(CCl)cc1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of (3-methoxy-4-pent-2-ynyloxy-phenyl)-methanol (27 g, 0.12 mol) in 450 ml of dioxan is added dropwise to 240 ml of concentrated hydrochloric acid. The reaction mixture is stirred for 1.5 hours at room temperature. Subsequently it is poured on water and extracted with ethyl acetate. The combined organic layer is washed with brine, dried over magnesium sulfate and evaporated in vacuo to obtain 4-chloromethyl-2-methoxy-1-pent-2-ynyloxy-benzene as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17]Cl)=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[I-:25].[Na+]>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[CH:22]=[CH:21][C:11]([O:12][C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][I:25])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)OCCl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)OCI
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Chloromethyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate 1 (3.0 g, 8.2 mmol) was dissolved in acetone (50 mL) at room temperature. Sodium iodide (2.4 g, 16.3 mmol, 2 eq) was added and the clear solution was stirred 10 min at room temperature, then heated to 50° C. for 6 hr. The mixture was cooled to room temperature, diluted with ethyl acetate (200 mL) and filtered. The filtrate was washed with water (3×10 mL) and brine then dried over sodium sulfate. The drying agent was filtered off and the solution was concentrated by rotary evaporation to leave iodomethyl 2-(4-(4-chlorobenzoyl)phenoxy)-2-methylpropanoate 2 as a thick, yellow oil (3.7 g, 99% yield) that was used directly in the next reaction without further purification. 1H-NMR (CDCl3) δ 7.74 (d, 2 H), 7.71 (d, 2 H), 7.45 (d, 2 H), 6.85 (d, 2 H), 5.97, (s, 2 H), 1.67 (s, 6 H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][NH:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:44]1([CH3:54])[CH:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=1>ClCCl.CN(C)C1C=CN=CC=1.O.Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][C@H:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C@@H:9]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]3[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=3[CH:36]=2)[CH2:8][N:7]1[S:50]([C:47]1[CH:48]=[CH:49][C:44]([CH3:54])=[CH:45][CH:46]=1)(=[O:52])=[O:51])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@H](c2ccc(OC)cc2)[C@@H](OCc2ccc3c(c2)N(CCCOC)CCO3)CN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
To a solution of 1.51 g of (2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-2-carboxylic acid ethyl ester (from example 1a) in 25 ml of dichlormethane are added 1.97 ml of triethylamine, 3.5 mg of 4-dimethylaminopyridine and 0.57 g of 4-toluenesulfonylchloride at 0° C. The reaction mixture is allowed to warm to room temperature overnight, diluted with water and 1N hydrochloric acid and the organic phase is separated and dried over sodium sulfate. The organic phase is concentrated under reduced pressure and the residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless oil. Rf=0.50 (EtOAc-heptane 1:1); Rt=5.44.
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:13]=1C=O>CCN(CC)CC.C(O)=O>[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:13]=1[CH2:4][CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=Cc1c(Cl)cc(Cl)cc1Cl
Reactant: CC1(C)OC(=O)CC(=O)O1
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O=C(O)CCc1c(Cl)cc(Cl)cc1Cl
Temperature: 120 °C
Yield: 85.4 %

Procedure:
Meldrum's acid (2.06 g, 14.32 mmoles) was added to TEAF (7.05 ml) at ambient temperature under stirring and the reaction mixture was kept under nitrogen atmosphere. After 10 min 2,4,6-trichloro benzaldehyde (3 g, 14.32 mmoles) was added to the reaction mixture. It was then refluxed at 120° C. for 3 hrs. On completion of the reaction, the mixture was cooled at ambient and was poured into ice water (50 ml). Then aq. layer was extracted with ethyl acetate (3×80 ml), the combined organic layer was washed with brine (40 ml) and dried over sodium sulphate. Organic layer was concentrated under vacuum. 3.10 g (86.0% of theory) of 3-(2,4,6-trichloro-phenyl)-propionic acid was obtained in form of a white solid.