Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:40])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:28]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:35]1[CH:36]=[CH:37][CH:38]=[C:33]([C:29]2[CH:28]=[C:27]([C:26]3[CH2:25][C:24](=[O:40])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:22])([F:20])[F:21])[C:12]([N:14]5[CH2:15][CH2:16][CH2:17][CH2:18]5)=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[CH:34]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2cc(N3CCCC3)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M169) (249 mg, 0.438 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (129 mg, 65%).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20](OCC)=[O:21])[C:10]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30].CCN(C(C)C)C(C)C>O1CCOCC1>[CH2:1]([O:8][N:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]([NH:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:21])[C:10]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CN
Reactant: CCOC(=O)c1c(O)c2ccccc2n(OCc2ccccc2)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1c(O)c2ccccc2n(OCc2ccccc2)c1=O
Temperature: 100 °C
Yield: 37 %

Procedure:
To a stirring suspension of ethyl 1-(benzyloxy)-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (700 mg, 2.063 mmol), ethyl 2-aminoacetate hydrochloride (387 mg, 2.77 mmol) in dioxane (5 mL) was added DIPEA (0.660 ml, 3.78 mmol). Reaction mixture was heated at 100° C. for 12 h. Solvent from reaction mixture was distilled out to get crude product which was then column purified using 15% EtOAC in hexane to get titled product in 37% yield.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([CH:14]=[O:15])[CH:3]=1.[Na].OO.Cl([O-])=[O:20].[Na+]>C(#N)C.O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[C:4]([C:14]([OH:20])=[O:15])[CH:3]=1
Reactant: [O-][Cl+][O-]
Reactant: COc1c(C=O)cc(F)c2ccccc12
Agent: OO
Agent: [Na+]
Agent: [Na]
Solvent: O
Solvent: CC#N
Product: COc1c(C(=O)O)cc(F)c2ccccc12
Reaction time: 2.5 h
Yield: 93.7 %

Procedure:
9.3 g of 4-fluoro-1-methoxynaphthalene-2-carbaldehyde were dissolved in 100 ml of acetonitrile. 2.1 g sodium dihydrogenphsophate monohydrate in 10 ml of water were added, followed by the addition of 9.5 ml hydrogen peroxide (30%). 8.9 g sodium chlorite, dissolved in 20 ml water were added dropwise while maintaining an internal temperature between 5° C. and 15° C. The reaction was then allowed to come to room temp over 2.5 h. The precipitated solid was filtered with suction, and the solid was washed with water, and dried in vacuo at 40° C. to yield 9.4 g of 4-fluoro-1-methoxynaphthalene-2-carboxylic acid. The filtrate was treated with 60 ml of cold 10% aqueous sodium bisulfite solution. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water and brine. The organic layer was washed with 0.2 N NaOH twice. The washes were acidified with 6 N HCl to pH 3, whereupon crystallization occurred. The precipitating product was filtered, washed with water and dried in vacuo at 40° C. to yield a second batch of 1.0 g of 4-fluoro-1-methoxynaphthalene-2-carboxylic acid.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[C:8]1([C@H:18]([N:20]([CH2:28][C@@H:29]2[C@@H:33]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:32][NH:31][CH2:30]2)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.Cl>C1COCC1>[C:23]([O:22][C:21]([N:20]([CH2:28][C@@H:29]1[C@@H:33]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:32][N:31]([C:4](=[O:5])[CH2:3][CH2:2][C:1]([OH:6])=[O:7])[CH2:30]1)[C@@H:18]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][CH:9]=1)[CH3:19])=[O:27])([CH3:24])([CH3:25])[CH3:26]
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)CCC(=O)O)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Succinic anhydride was added to a mixture of 1.0 g of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate, 235 mg of triethylamine and 15 ml of THF at room temperature and stirred overnight. The reaction solution was mixed with 1 M hydrochloric acid to quench the reaction and extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure to obtain 1.72 g of crude 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-4-oxobutanoic acid (compound A) as a colorless amorphous substance. A 1.0 g portion of the thus obtained crude product was purified by a silica gel column chromatography (chloroform-methanol) to obtain 525 mg of 4-[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-4-oxobutanoic acid as a colorless amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:10])=[CH:4][C:3]=1[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)ccc1Cl
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1ccc(Cl)c(C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Chloro-3-methylphenol (28.5 g., 0.2 mole) was dissolved in 400 ml. of acetone. Potassium carbonate (33.1 g., 0.24 mole) and then methyl iodide (34.1 g., 0.24 mole) were added and the mixture stirred for 16 hours at room temperature. The reaction mixture was filtered and the filtrate evaporated to an oil containing solids. This residue was distributed between methylene chloride and water. The organic layer was separated, washed in sequence with two portions of 1 N sodium hydroxide, two portions of water and one portion of brine, dried over anhydrous magnesium sulfate and concentrated to yield 4-chloro-3-methylanisole as an oil [24.6 g., 86%, pnmr/CDCl3 /delta 2.3 (s, 3H), 3.7 (s, 3H) 6.9 (m, 3H)].
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[N:23]=[C:22]5[CH:24]=[CH:25][O:26][C:21]5=[CH:20][CH:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31]C)=[O:30])=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[N:23]=[C:22]5[CH:24]=[CH:25][O:26][C:21]5=[CH:20][CH:19]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:27][C:28]([CH3:34])([CH3:33])[C:29]([OH:31])=[O:30])=[CH:35][CH:36]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4occc4n3)ccc2n1Cc1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(Cc1cc2cc(OCc3ccc4occc4n3)ccc2n1Cc1ccc(Cl)cc1)C(=O)O
Temperature: 50 °C

Procedure:
To a solution of 540 mg(1.1 mmol) of the ester from Step 4 in THF (11 mL) and MeOH (5.5 mL) was added aqueous LiOH 1.0N (3 mL, 3 mmol). The resulting solution was heated at 50° C. for 5 hours. The reaction was diluted with aqueous NH4OAc 25% w/v (50 mL) and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by crystallization in EtOAc/hexane (1:4, 30 mL) to give the title compound as a white solid; m.p. 157° C. The sodium salt was prepared by dissolving the acid in ethanol, adding one equivalent of aqueous NaOH, and freeze drying the resulting solution. The sodium salts of the remaining examples were prepared in the same way.
Reaction SMILES: [N+:1]([C:4]1C(C#N)=[N:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-])=O.[Sn](Cl)Cl.Cl.[C:22]([O:25]CC)(=[O:24])[CH3:23]>CN(C=O)C.C(N(CC)CC)C>[NH2:1][C:4]1[C:23]([C:22]([OH:25])=[O:24])=[N:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:9]=1
Reactant: N#Cc1ncc(-c2ccccc2)cc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1cc(-c2ccccc2)cnc1C(=O)O
Reaction time: 8 h

Procedure:
To a solution of 3-nitro-5-phenylpicolinonitrile (1 eq) in 10 mL of DMF was added tin (II) chloride dehydrate (7.0 eq) at room temperature. The reaction mixture was stirred at that temperature overnight. The mixture was diluted with 150 mL of ethyl acetate and 30 mL of triethyl amine. After filtration, the filtrate was concentrated under reduced pressure to give a solid, which was added 2 mL of concentrated HCl. The mixture was stirred in microwave at 90° C. for 10 minutes. After standing over night, the solid was collected by filtration, which was dissolved in 10 mL of 1N NaOH. The resulting mixture was extracted with 50 mL of ethyl acetate. The aqueous layer was acidified by 1 N HCl to pH 7.0 to yield 3-amino-5-phenylpicolinic acid, which was collected by filtration. LC/MS (m/z): 215.1 (MH+).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:9]2=[O:24])(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][CH2:33][OH:34]>C(#N)C>[OH:34][CH2:33][CH2:32][N:5]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[N:10]([CH2:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:9]2=[O:24])[S:2]([CH3:1])(=[O:3])=[O:4]
Reactant: OCCBr
Reactant: CC(C)(C)OC(=O)CN1C(=O)c2ccc(NS(C)(=O)=O)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1C(=O)c2ccc(N(CCO)S(C)(=O)=O)cc2C1=O
Temperature: 110 °C
Yield: 100 %

Procedure:
To a stirred solution of tert-butyl 2-(5-(methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (1 g, 2.82 mmol) (prepared in an analogous manner as previously described in Example 34, Scheme 34, Steps 1, 2, 3) in acetonitrile (15 ml), K2CO3 (0.585 g, 4.23 mmol) and 2-bromoethanol (0.500 ml, 7.05 mmol) were added, and the reaction was heated under MW irradiation at 110° C. for 3 hours. The insoluble inorganic salts were filtered off, and the filtrate was evaporated to dryness. The resulting crude tert-butyl 2-(5-(N-(2-hydroxyethyl)methylsulfonamido)-1,3-dioxoisoindolin-2-yl)acetate (1.12 g, 2.81 mmol, 100% yield MS/ESI+ not detectable [MH]+) was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13]Br)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:22]([CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13][N:22]([CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: c1ccc(CNCc2ccccn2)nc1
Reactant: COC(=O)c1cc(CBr)cc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cc(CN(Cc2ccccn2)Cc2ccccn2)cc(CN(Cc2ccccn2)Cc2ccccn2)c1

Procedure:
Methyl 3,5-bis(bromomethyl)-benzoate (500 mg, 1.6 mmol) and di-(2-picolyl)-amine (800 mg, 725 μL, 4 mmol) were dissolved in ACN followed by the addition of dry K2CO3 (1.1 g, 7.9 mmol). The reaction mixture was refluxed overnight under reflux condenser equipped with a CaCl2 tube. The reaction mixture was filtered and filtrate was evaporated under reduced pressure. Yellow residue was purified by flash chromatography (Al2O3 neutral, firstly AcOEt was used to elute impurities and then MeOH/AcOEt=1:9 (v/v)) affording a pure product as a yellow oil. Yield: 850 mg (95%). 1H NMR (500 MHz, CDCl33) δ 8.51 (m, 4H), 7.94 (d, J=1.5 Hz, 2H), 7.70 (s, 1H), 7.61 (m, 8H), 7.12 (m, 4H), 3.92 (s, 3H), 3.81 (s, 8H), 3.73 (s, 4H). 13C NMR (101 MHz, CDCl3) δ 197.9, 167.1, 159.5, 148.9, 139.7, 136.2, 133.8, 130.2, 128.7, 122.8, 121.9, 60.1, 58.2, 52.0. MS (ESI, m/z): calculated: 558.7 observed: 559.5 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].[CH3:28][S:29]([NH:32][CH2:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[N:38]([CH2:44][C:45](O)=[O:46])[C:37]2=[O:48])(=[O:31])=[O:30].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:45](=[O:46])[CH2:44][N:38]1[C:37](=[O:48])[C:36]2[C:40](=[CH:41][CH:42]=[C:34]([CH2:33][NH:32][S:29]([CH3:28])(=[O:31])=[O:30])[CH:35]=2)[C:39]1=[O:43]
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: CS(=O)(=O)NCc1ccc2c(c1)C(=O)N(CC(=O)O)C2=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc2c(c1)C(=O)N(CC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.9 %

Procedure:
(S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.229 g, 0.544 mmol), 2-(5-(methylsulfonamidomethyl)-1,3-dioxoisoindolin-2-yl)acetic acid (0.170 g, 0.544 mmol), EDC (0.313 g, 1.633 mmol) and DMAP (0.133 g, 1.089 mmol) were dissolved in DCM (20 ml), and the solution was stirred at room temperature for 20 hours. The mixture was diluted with DCM and washed with 0.5N HCl, aqueous 5% NaHCO3 and brine. The organic phase was dried over sodium sulfate, and the solvent removed under vacuum. The crude was purified by preparative HPLC (Method 1) to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(methylsulfonamido methyl)-1,3-dioxoisoindolin-2-yl)acetoxy)ethyl)pyridine 1-oxide (0.120 g, 0.168 mmol, 30.9% yield, MS/ESI+ 714.06 [MH]+, [aD]=−27.89, c=0.9, DCM; 1H NMR (300 MHz, DMSO-d6) δ ppm 8.44 (s, 2H), 7.88-7.94 (m, 2H), 7.85 (dd, 1H), 7.77 (t, 1H), 7.19 (d, 1H), 7.08 (s, 1H), 6.96 (dd, 1H), 7.08 (t, 1H), 6.01 (dd, 1H), 4.42 (s, 2H), 4.23-4.56 (m, 2H), 3.83-4.00 (m, 2H), 3.39 (dd, 1H), 3.22 (dd, 1H), 2.95 (s, 3H), 1.10-1.34 (m, 1H), 0.49-0.67 (m, 2H), 0.30-0.46 (m, 2H)
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]1[CH2:8][C@@H:7]([O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11])[CH2:6][N:5]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24].[BH4-].[Li+]>O1CCCC1>[Si:10]([O:9][C@H:7]1[CH2:6][N:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])[C@H:4]([CH2:3][OH:2])[CH2:8]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: COC(=O)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1c1ccccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](CO)N(c2ccccc2[N+](=O)[O-])C1
Temperature: 0 °C
Yield: 95.9 %

Procedure:
To a solution of (2S, 4R)-4-(tert-butyldimethylsilyloxy)-1-(2-nitrophenyl) proline methyl ester (9.62 g) obtained in Reference Example 40 ml anhydrous tetrahydrofuran (300 ml), there was added, in small portions, 0.96 g of lithium borohydride under ice-cooling. After stirring the reaction liquid at room temperature over 15 hours, it was poured into ice water and then extracted with ethyl acetate. The organic phase thus obtained was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The residue thus obtained was subjected to silica gel column chromatography and then eluted with ethyl acetate/hexane (1/9) to give 8.55 g (yield 96.1%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]2[CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[C:12](=[O:13])[C:3]=12.[CH3:26][N:27]1[C:31](B(O)O)=[CH:30][CH:29]=[N:28]1>>[CH3:9][N:6]1[C:7](=[O:8])[C:2]([C:31]2[N:27]([CH3:26])[N:28]=[CH:29][CH:30]=2)=[C:3]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)[CH2:10][C:4]2=[CH:5]1
Reactant: Cn1nccc1B(O)O
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2
Product: Cn1nccc1-c1c2c(cn(C)c1=O)CN(CCc1ccc3ccccc3n1)C2=O

Procedure:
The title compound was prepared in analogy to the process of Example 13 starting from 7-chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-3,5-dihydro-2H-pyrrolo[3,4-c]pyridine-1,6-dione (see Example c4)) and 2-methyl-2H-pyrazol-3-ylboronic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:12]([OH:14])=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:15]1([C:21]2[N:22]=[C:23]([NH2:26])[S:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.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(#N)C>[C:15]1([C:21]2[N:22]=[C:23]([NH:26][C:12]([C:9]3([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)[CH2:10][CH2:11]3)=[O:14])[S:24][CH:25]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: COc1ccc(C2(C(=O)O)CC2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C2(C(=O)Nc3nc(-c4ccccc4)cs3)CC2)cc1
Reaction time: 64 h
Yield: 47.6 %

Procedure:
1-(4-Methoxy-phenyl)-cyclopropanecarboxylic acid (2.18 g, 11.4 mmol) and 4-phenyl-thiazol-2-ylamine (2.00 g, 11.4 mmol) were dissolved in acetonitrile (50 mL) containing triethylamine (3.17 mL, 22.8 mmol). Benzotriazol-1-yloxy tris(dimethylamino)-phosphonium hexafluorophosphate (BOP, 4.95 g, 11.4 mmol) was added and the solution was allowed to stir for 64 hours. The reaction mixture was evaporated to dryness and purified by column chromatography on silica gel using a gradient of 5-20% ethyl acetate in hexanes. The pure fractions were combined and evaporated to dryness to yield a white solid (1.9 g, 5.43 mmol, 47.5%). ESI-MS m/z calc. 350.1. found 351.1 (M+1)+. Retention time of 3.68 minutes. 1H NMR (400 MHz, CD3CN) δ 1.27 (q, J=3.6 Hz, 2H), 1.66 (q, J=3.6 Hz, 2H), 3.87 (s, 3H), 7.04 (m, 2H), 7.40 (m, 6H), 7.82 (m, 2H), 8.79 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]>CC#N>[N+:19]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:13]=1[N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=[N+]([O-])c1cnccc1-n1cccn1
Reaction time: 0.33 h

Procedure:
A suspension of pyrazole (150 mg, 2.2 mmol) and Cs2CO3(526 mg, 1.6 mmol) in anhydrous MeCN (3.5 mL) was stirred for 20 min under an inert atmosphere. 4-chloro-3-nitro-pyridine (233 mg, 1.47 mmol) was then added and stirred overnight at 75° C. The insoluble was filtered off and the filtrate was concentrated under reduced pressure yielding 3-nitro-4-(1H-pyrazol-1-yl)pyridine that was used without further purification. (410 mg, 98%). MS (ES+) 191.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=2)[C:28](O)=[O:29])[N:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=[N:25][CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: NCCc1csc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cncc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCCc1csc(-c2ccc(F)cc2)n1)c1cncc(-c2noc(C(F)(F)F)n2)c1
Yield: 17 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)thiazol-4-yl)ethanamine and 5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)nicotinic acid as described in example 8 step 6 (30 mg, yield 17%). 1H NMR (400 MHz, DMSO-d6) δ 9.45 (br s, 1H), 9.26 (br s, 1H), 8.82 (t, J=2.0 Hz, 1H), 7.96-7.92 (m, 3H), 7.14-7.08 (m, 3H), 3.94-3.89 (m, 2H), 3.19-3.16 (m, 2H). MS (ESI) m/z: Calculated for C20H13F4N5O2S: 463.07. found: 464.0 (M+H)+.
Reaction SMILES: [CH:1]1[C:18]2=[C:19]3[C:8]([C:9]4[C:20]5[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=5)[CH:12]=[CH:11][CH:10]=4)=[CH:7][CH:6]=[C:5]2[C:21](=[O:25])[NH:22][C:23](=[O:24])[C:3](=[C:4]23)[CH:2]=1.[CH3:26][O-].[Na+]>C(O)C>[CH3:26][N:22]1[C:21](=[O:25])[C:5]2[C:4]3[C:19]4[C:8](=[CH:7][CH:6]=2)[C:9]2[C:20]5[C:13]([CH:12]=[CH:11][CH:10]=2)=[CH:14][CH:15]=[CH:16][C:17]=5[C:18]=4[CH:1]=[CH:2][C:3]=3[C:23]1=[O:24]
Reactant: O=C1NC(=O)c2ccc3c4cccc5cccc(c6ccc1c2c63)c54
Reactant: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CN1C(=O)c2ccc3c4cccc5cccc(c6ccc(c2c36)C1=O)c54
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.2 %

Procedure:
1.29 g (4 mmol) of perylene-3,4-dicarboximide and 0.56 g (14.7 mmol) of sodium methylate are suspended in 50 ml of ethanol and the mixture is stirred for 5 h at room temperature. After removing the solvent by evaporation under reduced pressure, 50 ml of N-methyl-pyrrolidone and 1.01 ml of methyl iodide are added and the mixture is stirred for 2 h at room temperature. The solvent is removed by distillation under reduced pressure and the residue is washed with 100 ml of sulfuric acid (20%) and is then collected by suction and dried at 130° C. under reduced pressure, giving 1.17 g (87%) of red N-methylperylene-3,4-dicarboximide. IR (KBr): ν=1692 cm-1 (s), 1657 (s), 1570 (s), 1361 (s), 1238 (m), 810 (s), 748 (m). C23H13O2N (335,36) cacld.: C 82.37 H 3.91 N 4.18 found: C 81.71 H 4.01 N 3.98
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[OH:17][C:18]1[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=1)[C:21]([O:23][CH3:24])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:14]1([C:12]([NH:11][C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([O:17][C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][CH:27]=4)[C:21]([O:23][CH3:24])=[O:22])=[N:7][N:6]3[CH:8]=2)=[O:13])[CH2:16][CH2:15]1
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 110 °C
Reaction time: 48 h
Yield: 40.4 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (518 mg, 1.58 mmol), methyl 3-hydroxybenzoate (360 mg, 2.37 mmol), potassium carbonate (654 mg, 4.73 mmol) and N,N-dimethylformamide (4.0 mL) was stirred at 110° C. for 2 days. The solvent was evaporated under reduced pressure, ethyl acetate, tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80→85/15) to give methyl 3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoate (225 mg, 41%) as a white powder.