Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=O)[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[C:25]([O-:28])([O-])=O.[K+].[K+].CN([CH:34]=[O:35])C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:35][CH2:34][CH2:14][N:15]2[C:25](=[O:28])[N:11]3[N:12]=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)=[C:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[C:10]3=[N:16]2)=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: O=c1n(CCOc2ccc(Cl)cc2)nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 70 °C

Procedure:
The solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (30 mg, 0.084 mmol), prepared as described in Example 1,1-(2-bromoethoxy)-4-chlorobenzene (22 mg, 0.094 mmol) and K2CO3 (18 mg, 0.013 mmol) in DMF (1 ml) was heated at 70° C. for 4 hours. After this time, the solution was cool to RT and diluted with ethyl acetate. The resultant solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative HPLC to give the title compound, 2-(2-(4-chlorophenoxy)ethyl)-7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (25.5 mg, 59%) was obtained as a yellow solid. MS M+H=511; 1H NMR (CDCl3) δ 8.19 (1H), 7.34 (4H), 7.28 (2H), 7.18 (2H), 7.28 (2H), 6.80 (2H), 4.44 (2H), 4.36 (2H).
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18](=[O:20])[NH2:19])[CH:13]=[C:12]2[NH:21][C:22]([N:24]1[C@H:29]([C:30](=[O:40])[NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[F:39])[CH2:28][C@@H:27]2[C@H:25]1[CH2:26]2)=[O:23])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:18]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:7][C:6]([OH:41])=[O:5])=[CH:17][CH:16]=2)[C:12]([NH:21][C:22]([N:24]2[C@H:29]([C:30](=[O:40])[NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[F:39])[CH2:28][C@@H:27]3[C@H:25]2[CH2:26]3)=[O:23])=[CH:13]1)(=[O:20])[NH2:19]
Reactant: CC(C)(C)OC(=O)COc1ccc2c(c1)c(NC(=O)N1[C@@H]3C[C@@H]3C[C@H]1C(=O)NCc1ccccc1F)cn2C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)n1cc(NC(=O)N2[C@@H]3C[C@@H]3C[C@H]2C(=O)NCc2ccccc2F)c2cc(OCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (1-carbamoyl-3-{[(1R,3S,5R)-3-(2-fluoro-benzylcarbamoyl)-2-aza-bicyclo[3.1.0]hexane-2-carbonyl]-amino}-1H-indol-5-yloxy)-acetic acid tert-butyl ester Example 390 (18 mg, 0.032 mmol) in CH2Cl2 (0.5 mL) was added TFA (97 μL, 1.27 mmol) and the mixture was stirred at RT overnight. Then concentrated, taken up in CH2Cl2 and filtered-off to give the desired material which was further dried under high vacuum. MS (LC-MS): 510.1 [M+H]+, 532.2 [M+Na]+, 508.1 [M−H]−, 465.1 [M−CONH2]−; tR (HPLC conditions f): 1.52 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH:10][CH:9]2[C:27](O)=[O:28])[CH:5]=[CH:6][CH:7]=1.[F:30][C:31]([F:41])([F:40])[C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH2:35].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>C(Cl)Cl>[F:30][C:31]([F:40])([F:41])[C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][NH:35][C:27]([CH:9]1[CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C:12]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)([C:13]#[N:14])[CH:11]([CH2:22][C:23]([CH3:26])([CH3:24])[CH3:25])[NH:10]1)=[O:28]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)NCc2ccccc2C(F)(F)F)C(c2cccc(Cl)c2)C1(C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.3 %

Procedure:
A mixture of rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (86.2 mg, 0.20 mmol), 2-trifluoromethyl-benzyl amine (52.55 mg, 0.3 mmol), 2-(7-azabenzotriazol-1-yl)-n,n,n′,n′-tetramethyluronium hexafluorophosphate (HATU, 76 mg, 0.2 mmol) and iPr2NEt (0.1 mL, 0.55 mmol) in CH2Cl2 (2 mL) was stirred at rt overnight. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac rac-(2R,3R,4R,5S)-3-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid 2-trifluoromethyl-benzylamide (38 mg, 32.3%) as an off-white powder. HRMS (ES+) m/z Calcd for C31H30Cl2F3N3O+H [(M+H)+]: 588.1791. found: 588.1795.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:12]2[CH:13]=[CH:14][C:15]([F:21])=[C:16]([CH:20]=2)[C:17]([O-:19])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:28]([C:32]1[CH:37]=[CH:36][C:35]([C:38]#[CH:39])=[CH:34][CH:33]=1)[CH2:29][CH2:30][CH3:31].[C:40]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCOCC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[I].[Cu]>[CH2:28]([C:32]1[CH:33]=[CH:34][C:35]([C:38]#[C:39][C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:12]3[CH:13]=[CH:14][C:15]([F:21])=[C:16]([CH:20]=3)[C:17]([O:19][CH3:40])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:36][CH:37]=1)[CH2:29][CH2:30][CH3:31]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C#Cc1ccc(CCCC)cc1
Reactant: CCCCCCN(c1ccc(F)c(C(=O)[O-])c1)S(=O)(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]
Agent: [I]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCN(c1ccc(F)c(C(=O)OC)c1)S(=O)(=O)c1ccc(C#Cc2ccc(CCCC)cc2)cc1
Temperature: 120 °C
Reaction time: 0.42 h
Yield: 221.5 %

Procedure:
To a solution of 5-[({4-bromophenyl)sulfonyl](hexyl)amino]-2-fluorobenzoate (400 mg; 0.85 mmol) in DMF (15 mL) under nitrogen were added (p-butylphenyl)acetylene (0.16 mL; 0.93 mmol), bis(triphenylphosphine)palladium chloride (29.7 mg; 0.04 mmol), triphenylphosphine (44.4 mg; 0.17 mmol), copper iodine (8.1 mg; 0.04 mmol) and TEA (0.35 mL; 2.54 mmol). The reaction mixture was stirred under MW at 120° C. for 1500 s. The mixture was diluted with Et2O (75 mL) and the precipitate obtained filtrated off. Filtrate was washed with HCl 1N and with brine. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification by flash chromatography on silicagel (c-Hex/EtOAc, 95:5 then 90:10) gave 207 mg (44.5%) of the title compound as a yellow cream. HPLC, Rt: 6.17 min (purity=98.5%). LC/MS: M+(ESI): 500.3, 1H NMR (CDCl3) δ: 7.55 (m, 6H), 7.32 (m, 1H), 7.10 (m, 4H), 3.91 (s, 3H), 3.52 (t, J=6.9 Hz, 2H), 2.63 (t, J=7.9 Hz, 2H), 1.30 (m, 12H), 0.95 (m, 3H), 0.85 (t, 3H.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]=[C:10]([C:15](=O)[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]([O:13][CH3:14])=[O:12].[NH2:25][C:26]([CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][C:28]([O:30][CH3:31])=[O:29]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:15]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:25][C:26]([CH2:27][C:28]([O:30][CH3:31])=[O:29])=[C:32]1[C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)C=C(N)CC(=O)OC
Reactant: COC(=O)C(=Cc1c(Cl)cccc1Cl)C(=O)CCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2)N1
Temperature: 120 °C

Procedure:
A mixture of methyl 2-(2,6-dichlorophenylmethylidene)-3-oxo-5-phenylpentanoate(the crude product from the preceding experiment) and dimethyl 2-amino-1-propene-1,3-dicarboxylate (8.4 g, 48.5 mmol) was heated without solvent at 120° C. for 18 h. TLC showed a strong fluorescent spot at Rf=0.3 (dichloromethane/ethyl acetate: 24/1). This reaction mixture was chromatographed on 1.5 kg silica gel to yield 3.93 g of product. An additional 2 g of slightly impure product was also obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4](I)[CH:3]=1.[CH2:10]([S:12]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[C:17]([O:30][CH3:31])[CH:16]=1)(=[O:14])=[O:13])[CH3:11].C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([C:18]2[CH:19]=[CH:20][C:15]([S:12]([CH2:10][CH3:11])(=[O:14])=[O:13])=[CH:16][C:17]=2[O:30][CH3:31])[CH:3]=1
Reactant: CCS(=O)(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(OC)c1
Reactant: Fc1ccc(Br)cc1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1ccc(-c2cc(Br)ccc2F)c(OC)c1
Temperature: 110 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
A suspension of 4-bromo-1-fluoro-2-iodobenzene (420 mg, 1.39 mmol), 2-(4-(ethylsulfonyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Preparation 21, 500 mg, 1.53 mmol), 2M aqueous sodium carbonate solution (2.5 mL) and dioxane (10 mL) was degassed with nitrogen for 30 minutes. Tetrakis(triphenylphosphine)palladium(0) (80 mg, 0.07 mmol) was added and the reaction warmed to 110° C. and stirred for 1 hour. The reaction was cooled to room temperature, diluted with water (10 mL), extracted with EtOAc (2×10 mL), dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified using silica gel column chromatography eluting with heptanes/EtOAc 7/3 to afford the title compound as a pale yellow solid in 73% yield, 418 mg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[C:22]([NH2:23])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:16][C:17]1[C:22]([NH:23][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1cccc(Oc2ncccc2N)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCNc1cccnc1Oc1cccc(CCNC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 54.3 %

Procedure:
A mixture of tert-butyl[2-[3-(3-amino-2-pyridyloxy)phenyl]ethyl]carbamate (3.3 g, 10 mmols), ethyl 4-bromobutyrate (2.8 ml, 20 mmols), potassium carbonate (1.4 g, 10 mmols) and N,N-dimethylformamide (30 ml) was stirred at 60° C. for 72 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate. This was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography to give an oil of ethyl 4-[2-[3-[2-(tert-butoxycarbonylamino)ethyl]phenoxy]-3-pyridyl]aminobutyrate (2.41 g, 54.4%).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:25][CH3:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[CH2:13][C@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:34][C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@@H:10]2[O:25][CH3:26])=[O:8])[CH2:5][CH2:4]1)#[N:2]
Reactant: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(F)cc2Cl)C[C@@H]1C(=O)NC1(C#N)CC1
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CO[C@H]1C[C@@H](S(=O)(=O)c2ccc(Oc3ccc(F)cc3)cc2Cl)C[C@@H]1C(=O)NC1(C#N)CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 68.7 %

Procedure:
(1R,2R,4R) and (1S,2S,4S)-4-(2-Chloro-4-fluoro-benzenesulfonyl)-2-methoxy-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (25 mg, 0.062 mmol, example 56) was dissolved in DMF (1.5 ml) and 4-fluorophenol (14 mg, 0.125 mmol) and Cs2CO3 (61 mg, 0.187 mmol) were added. The reaction mixture was stirred for 4 h at 50° C. Then water was added and the mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and concentrated. The remaining residue was purified by silica gel chromatography (DCM/EtOAc 9:1) to obtain the title compound (21 mg, 63%) as white solid. MS (EI): 491.1 (M−H)−.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[O:6].[H-].[Na+].C(OCC)(=O)C>CN(C=O)C.C1COCC1>[N:10]1[CH:11]=[CH:12][CH:13]=[C:8]([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[CH:9]=1
Reactant: O=C(NCCCl)Nc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1NCCN1c1cccnc1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
1-(2-Chloro-ethyl)-3-pyridin-3-yl-urea (I-1a: 1000 mg, 5.0 mmol) in dry DMF (10 mL) was added to a stirred solution of sodium hydride (216 mg, 9.0 mmol) in THF (10 mL) at 0° C. The reaction temperature was maintained at room temperature for 30 minutes. The reaction was monitored by TLC (100% ethyl acetate). The reaction mixture was quenched with MeOH (5 mL) at 0° C. The reaction mixture was concentrated under reduced pressure and partitioned between ice water and chloroform. The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 800 mg (97% yield) of 1-pyridin-3-yl-imidazolidin-2-one.
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O)C>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCO
Reactant: CCOC(=O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: CCO
Product: C=C(C)C(=O)OCCOC(=O)C(=O)OCC
Reaction time: 4 h
Yield: 76.5 %

Procedure:
A 500 ml flask equipped with a decanter, a thermometer, a stirrer and an inlet for nitrogen gas was charged with 65.1 g (0.5 mol) of 2-hydroxyethyl methacrylate and 365.4 g (2.5 mol) of diethyl oxalate, to which 2 g (10 mmol) of p-toluenesulfonic acid (catalyst) and 4 g of hydroquinone (polymerization inhibitor) were added. The mixture was heated to keep 120° C. for 4 hours in nitrogen atmosphere with distilling 14 ml (0.25 mol) of ethanol away. The reaction mixture was evaporated to remove excess diethyl oxalate and then distilled under vacuum to obtain 88.1 g (yield 76.5%) of 2-ethoxalyloxyethyl methacrylate (colorless transparent liquid) (bp 98° C./0.3 mmHg).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Br)[CH3:2].[CH2:10]([NH:12][CH2:13][CH3:14])[CH3:11]>>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][N:12]([CH2:13][CH3:14])[CH2:10][CH3:11])[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: CCNCC
Product: CCOC(CN(CC)CC)OCC
Temperature: 40 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
Bromoacetaldehyde diethylacetal, 52.4 g (0.26 mol), was mixed carefully with approximately 70.7 g (0.967 mol) diethylamine and stirred at 40° C. overnight. The reaction mixture was concentrated under reduced pressure and the residue dissolved in water and basified with cold 5 N sodium hydroxide. The reaction mixture was extracted twice with diethyl ether, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a tan oil. Distillation gave 35.8 g (72.8%) diethylaminoacetaldehyde diethylacetal as a clear liquid. B.p. 65°-75° C. @1.0 mmHg.
Reaction SMILES: Cl.Cl.C[O:4][C:5]1[CH:10]=[CH:9][C:8](N2CCNCC2)=[CH:7][CH:6]=1.[C:17](Cl)(=O)[CH2:18][CH:19](C)[CH3:20].[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>C(Cl)(=O)CCCCCCCCC>[C:5]([N:37]1[CH2:38][CH2:39][N:34]([C:26]2[CH:27]=[C:28]([F:33])[C:29]([O:31][CH3:32])=[CH:30][C:25]=2[F:24])[CH2:35][CH2:36]1)(=[O:4])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CC(C)CC(=O)Cl
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Agent: CCCCCCCCCC(=O)Cl
Agent: Cl
Product: CCCCCCCCCC(=O)N1CCN(c2cc(F)c(OC)cc2F)CC1

Procedure:
Production Example 3 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and isovaleryl chloride were replaced with 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (228 mg) and decanoyl chloride (205 μL), respectively, to provide crude 1-decanoyl-4-(2,5-difluoro-4-methoxyphenyl)piperazine (371 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[CH:9]=2)[C:4](=[O:27])[O:3]1.[ClH:28]>O1CCOCC1>[ClH:28].[CH3:1][C@@H:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH:9]=2)[C:4](=[O:27])[O:3]1
Reactant: C[C@@H]1Cc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)O1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1Cc2cc(CCN3CCNCC3)ccc2C(=O)O1

Procedure:
A solution of tert-butyl 4-{2-[(3R)-3-methyl-1-oxo-3,4-dihydro-1H-isochromen-6-yl]ethyl}piperazine-1-carboxylate (850 mg, 2.27 mmol) was stirred in 4N HCl in Dioxane for 4 hours. The excess solvent was then removed to give the free amine as the HCl salt.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[CH3:18])=[N:5]1.[F:20][C:21]([F:31])([F:30])[C:22]1[S:23][CH:24]=[C:25]([C:27](O)=[O:28])[N:26]=1>>[Cl:17][C:11]1[C:10]([CH3:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:27]([C:25]3[N:26]=[C:22]([C:21]([F:31])([F:20])[F:30])[S:23][CH:24]=3)=[O:28])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: O=C(O)c1csc(C(F)(F)F)n1
Reactant: Cc1c(-c2ccn(C[C@H](C)N)n2)ccc(C#N)c1Cl
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(C(F)(F)F)n3)n2)ccc(C#N)c1Cl
Yield: 13.35 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(trifluoromethyl)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-methylbenzonitrile (376 mg, 1.370 mmol) and 2-(trifluoromethyl)thiazole-4-carboxylic acid (324 mg, 1.644 mmol). The product was triturated using DCM and heptane. Yield 13.35%. 1H-NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 2.57 (s, 3H), 4.31 (dd, 1H), 4.46 (dd, 1H), 4.65 (m, 1H), 4.45 (d, 1H), 7.51 (d, 1H), 7.53 (d, 1H), 7.57 (d, 1H), 8.03 (d, 1H), 8.33 (s, 1H).
Reaction SMILES: [OH-].[Na+].ClC1C=CC(S([N:13]2[C:17]3[CH2:18][CH:19]4[N:24]([S:25]([C:28]5[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=5)(=[O:27])=[O:26])[CH:23]([C:16]=3[CH:15]=[N:14]2)[CH2:22][CH:21]([C:35]#[N:36])[CH2:20]4)(=O)=O)=CC=1.ClC1C=CC(S(N2C=C3C4N(S(C5C=CC(Cl)=CC=5)(=O)=O)C(CC3=N2)CC(C#N)C4)(=O)=O)=CC=1>C1COCC1.CCOC(C)=O>[Cl:34][C:31]1[CH:32]=[CH:33][C:28]([S:25]([N:24]2[CH:19]3[CH2:18][C:17]4[NH:13][N:14]=[CH:15][C:16]=4[CH:23]2[CH2:22][CH:21]([C:35]#[N:36])[CH2:20]3)(=[O:27])=[O:26])=[CH:29][CH:30]=1
Reactant: N#CC1CC2Cc3c(cnn3S(=O)(=O)c3ccc(Cl)cc3)C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: N#CC1CC2Cc3nn(S(=O)(=O)c4ccc(Cl)cc4)cc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CC1CC2Cc3[nH]ncc3C(C1)N2S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Sodium hydroxide (130 μL of a 3N aqueous solution) was added to a solution of 1,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazole-6-carbonitrile and 2,10-bis[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-2H-4,8-epiminocycloocta[c]pyrazole-6-carbonitrile (61) (69 mg, 0.13 mmol) in THF (0.5 mL) and the resulting solution was stirred at room temperature for 5 h. The reaction mixture was diluted with EtOAc and washed with brine. The organic phase was dried (Na2SO4), filtered, concentrated and purified by preparative HPLC to give 10-[(4-chlorophenyl)sulfonyl]-4,5,6,7,8,9-hexahydro-1H-4,8-epiminocycloocta[c]pyrazole-6-carbonitrile (62). MS (ESI) 363.1 (M+H). 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J=8.8 Hz, 2H), 7.43 (s, 1H), 7.35 (d, J=8.8 Hz, 2H), 5.38 (bs, 1H), 4.61-4.52 (m, 1H), 2.93 (dd, J=17.0, 6.6 Hz, 1H), 2.71-2.52 (m, 2H), 2.32-1.98 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10](N)SC=2C(C2N=C(C3C=NC(C)=CC=3)SC=2)=CC=1.C(N(CC)CC)C.[C:32](Cl)(Cl)=[O:33].N1CC[O:39]CC1>O1CCOCC1.O>[N:9]1([C:32]([OH:33])=[O:39])[CH2:10][CH2:1][O:2][CH2:3][CH2:8]1
Reactant: C1COCCN1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(-c2csc(-c3ccc(C)nc3)n2)c2sc(N)nc12
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C(O)N1CCOCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.1 g of 4-methoxy-7-[2-(6-methyl-pyridin-3-yl)-thiazol-4-yl]-benzothiazol-2-ylamine (0.00028 Mol) were dissolved in dioxane (2 ml) and treated with 0.047 ml triethylamine (0.00034 Mol) and 0.164 ml of phosgene (20% in toluene) (0.00031 Mol). After stirring for 2 hrs. at room temperature 0.122 ml of morpholine (0.0014 Mol) were added and the whole mixture was stirred for 16 hrs. at ambient temperature. Upon addition of water (5 ml) a precipitation formed, which was filtered, washed with water and dried. This crude material was triturated with hot MeOH and after cooling to room temperature filtered. The filtrate was evaporated and the residue subjected to column chromatography (silicagel, CH2Cl2/MeOH+1% NH4OH). The title compound was obtained as a light yellow solid (7%); MS (ISP): m/e=468 (M+H+).
Reaction SMILES: [CH3:1][N:2]1CC[O:5][CH2:4][CH2:3]1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=[C:21]([Br:31])[C:22]2[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CNCCO>CN(C=O)C.CCOC(C)=O>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=[C:21]([Br:31])[C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:29])[N:2]([CH2:3][CH2:4][OH:5])[CH3:1])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccc(C(=O)O)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNCCO
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(CCO)C(=O)c1ccc(C(Br)=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 0.17 h
Yield: 772 %

Procedure:
N-Methylmorpholine (6.7 mL, 60 6 mmol) and 4-[bromo-(4-carboxy-phenyl)-methylene]-piperidine-1-carboxylic acid tert-butyl ester (prepared as for compound 5 in WO2001074806) (20.0 g, 50.5 mmol) in DMF (240 mL) were treated with TBTU (17.8 g, 55.6 mmol) under nitrogen. After stirring for 10 min., 2-(methylamino)ethanol (5.3 mL, 65.7 mmol) was added and the solution stirred for 2 h. The reaction was diluted with EtOAc (350 mL), washed with 2% citric acid, 3% NaHCO3, and brine. The aq. washes were extracted with EtOAc (50 mL). The combined organic phases were dried over Na2SO4 then concentrated in vacuo to a solid. After stirring in hexanes for 5 h, the white solid was collected by filtration and dried under high vacuum to afford 21.0 g (92%) of 1A. 1H NMR (500.333 MHz, CDCl3) δ 7.44 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 3.91 (br s, 2H), 3.74 (br s, 2H), 3.54 (t, J=5.8 Hz, 3H), 3.34 (t, J=5.7 Hz, 2H), 3.09 (s, 3H), 3.01 (br s, 1H), 2.64 (t, J=5.9 Hz, 2H), 2.23 (t, J=5.8 Hz, 2H), 1.47 (s, 9H). MS ES+ 453.1.