Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:5]=[C:6]2[C:29](=[CH:30][CH:31]=1)[C:10]1=[N:11][O:12][C:13]([C:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:16][N:15]=3)=[C:9]1[CH2:8][CH2:7]2.[NH:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([C:38]([O:40]CC)=[O:39])[CH2:33]1.[Cl:43]([O-])(=O)(=O)=O.[Li+].Cl>C(#N)C.CN1CCCC1=O>[OH:1][CH:2]([C:4]1[CH:5]=[C:6]2[C:29](=[CH:30][CH:31]=1)[C:10]1=[N:11][O:12][C:13]([C:14]3[C:18]([C:19]([F:22])([F:20])[F:21])=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:16][N:15]=3)=[C:9]1[CH2:8][CH2:7]2)[CH2:3][N:32]1[CH2:37][CH2:36][CH2:35][C@H:34]([C:38]([OH:40])=[O:39])[CH2:33]1.[ClH:43]
Reactant: FC(F)(F)c1c(-c2onc3c2CCc2cc(C4CO4)ccc2-3)noc1-c1ccccc1
Reactant: [O-][Cl+3]([O-])([O-])[O-]
Reactant: CCOC(=O)[C@H]1CCCNC1
Agent: Cl
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: CC#N
Product: O=C(O)[C@H]1CCCN(CC(O)c2ccc3c(c2)CCc2c-3noc2-c2noc(-c3ccccc3)c2C(F)(F)F)C1
Temperature: 100 °C
Reaction time: 65 h

Procedure:
A 2-dram vial was charged with 7-(oxiran-2-yl)-3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 13A, 0.085 g, 0.200 mmol), N-methyl-2-pyrrolidinone (1 mL), (S)-ethyl piperidine-3-carboxylate (0.062 mL, 0.401 mmol) and lithium per chlorate (4.26 mg, 0.040 mmol). The vial was sealed and the contents were heated at 100° C. for 6.5 h and then left stirring at room temperature for 65 h. The reaction mixture was partitioned between ethyl acetate (20 mL) and brine (2×15 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated to yield a brown oil. To the brown oil was added acetonitrile (2 mL) and 6N hydrochloric acid (2 mL) and the contents were heated at 60° C. for 5 h. The reaction mixture was concentrated under reduced pressure. To the residue was added TFA (5 drops) followed by 2 mL of MeOH and the material was purified by reverse phase preparative HPLC (PHENOMENEX® Luna Axia 30×100 mm; 10 min. gradient; solvent A=10% MeOH, 90% H2O, 0.1% TFA, solvent B=90% MeOH, 10% H2O, 0.1% TFA). Product containing fractions were isolated and concentrated. Acetonitrile (2 mL) and 6N hydrochloric acid (2 mL) were added to the resulting oil and the contents were heated at 60° C. for 2 h. The reaction mixture was concentrated and freeze dried to yield (3S)-1-(2-hydroxy-2-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)ethyl)piperidine-3-carboxylic acid, hydrochloric acid (0.046 g, 0.074 mmol, 37.0% yield) as a pale yellow solid.
Reaction SMILES: C(#N)C1[C:3](=[CH:5]C=[CH:7][CH:8]=1)[NH2:4].[CH2:10]1C2[CH2:15][C:16](=[O:17])C(C2)[CH2:11]1.[OH-:18].[Na+]>[Cl-].[Cl-].[Zn+2].ClCCCl>[NH:4]([CH2:3][CH3:5])[CH2:10][CH3:11].[CH3:15][CH2:16][O:17][C:7]([CH3:8])=[O:18]
Reactant: N#Cc1ccccc1N
Reactant: [OH-]
Reactant: O=C1CC2CCC1C2
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: ClCCCl
Product: CCNCC
Product: CCOC(C)=O
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 5 %

Procedure:
Anthranilonitrile (2.40 g) was mixed together with norcamphor (4.40 g) and then 4.0 g of freshly fused ZnCl2 was added and the reaction mixture was heated at 120° C. After 1.5 hours it became so thick that it could not be stirred, so 10 ml of 1,2-dichloroethane was added and the reaction mixture was refluxed for 1 hour. At the end of this time, 40 ml of 10% NaOH was added and the mixture was stirred overnight. It was then extracted several times with 2-butanone which gave a crude product that was purified by flash chromatography (EtOAc, then 5% Et2NH/EtOAc) to give 3.04 g of foam. Recrystallization from CH2Cl2 /pentane gave 2.30 g of analytically pure product, m.p. 186°-188°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:12][C:13]([O:15]CC)=[O:14])=[O:4].O[Li].O>C1COCC1.CCO.O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:8][C:9]=1[NH:10][CH:11]([CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:12][C:13]([OH:15])=[O:14])=[O:4]
Reactant: CCOC(=O)CC(Nc1cc(-c2ccccc2)sc1C(=O)OC)C1CCCCC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: COC(=O)c1sc(-c2ccccc2)cc1NC(CC(=O)O)C1CCCCC1
Temperature: 55 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(1-cyclohexyl-2-ethoxycarbonyl-ethylamino)-5-phenyl-thiophene-2-carboxylic acid methyl ester (300 mg, 0.72 mmol, 1.0 equiv) in THF (2.0 mL), EtOH (1.0 mL) and water (2.0 mL) was added LiOH.H2O (152 mg, 3.6 mmol, 5.0 equiv). The mixture was stirred at 55° C. for 20 minutes. The organic solvent was then evaporated. To the resulting solution was added 3.0 N HCl aq. solution until pH=5˜6. The solid was then collected by filtration and washed with water. The filtrate was extracted with EtOAc and the organic layer was washed with sat. NaHCO3 aq. solution, brine, dried over Na2SO4, and concentrated in vacuo. The crude material was continued to the next step with no further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:12]=[S:13]1(=[O:30])[CH2:18][CH2:17][N:16]2[CH2:19][CH2:20][CH2:21][C@@H:22]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:15]2=[N:14]1.N1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC#N.C(O[Cu]OC(=O)C)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:29][C:26]1[CH:25]=[CH:24][C:23]([C@H:22]2[C:15]3=[N:14][S:13](=[O:30])(=[O:12])[CH2:18][CH2:17][N:16]3[CH2:19][CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(O)cc3)C2=N1
Reactant: Cc1cc(F)cc(B(O)O)c1
Agent: CC(=O)O[Cu]OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: c1ccncc1
Solvent: CC#N
Product: Cc1cc(F)cc(Oc2ccc([C@@H]3CCCN4CCS(=O)(=O)N=C34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.5 %

Procedure:
A mixture of (3-fluoro-5-methylphenyl)boronic acid (824 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenol (500 mg), pyridine (3.60 mL), cesium carbonate (581 mg), diacetoxycopper (648 mg), and powdered 4A MS (5.0 g) in MeCN (18 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with EtOAc in hexane then MeOH in EtOAc) then recrystallized from EtOAc to give the title compound (267 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[N:6][CH:7]=1.C([Li])CCC.CN(C)[CH:22]=[O:23]>C(OCC)C>[F:1][C:2]1[CH:3]=[C:4]([CH:22]=[O:23])[C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(F)cn1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1ncc(F)cc1C=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-(5-fluoro-pyridin-2-yl)-2,2-dimethylpropionamide (39.2 g) in dry diethyl ether (1200 ml) under an atmosphere of nitrogen at −78° C. was added dropwise t.-butyl lithium in hexanes (1.7M, 300 ml). The mixture was stirred at −78° C. for 2 hours then dry N,N-dimethylformamide (160 ml) was added and the slurry stirred at −78° C. for 1 hour then allowed to slowly warm to ambient temperature and stirred for an additional 1 hour. The mixture was quenched with aqueous 2M hydrochloric acid until a clear biphasic solution was formed and the organic phase separated. The aqueous phase was further extracted with diethyl ether. The extracts were combined, washed with brine (300 ml), dried over magnesium sulfate, filtered and evaporated under reduced pressure to give the required product as a pale yellow solid, 40 g. 1H NMR (CDCl3) δ: 11.20 (1H, s), 9.94 (1H, s), 8.59 (1H, d), 7.84 (1H, dd), 1.42 (9H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=O)=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1>C(O)C.N1CCCCC1>[N:19]1([CH2:24][CH2:25][NH:26][C:27]([C:29]2[CH:33]=[C:32]([CH3:34])[NH:31][C:30]=2[CH:35]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:12]2=[O:18])=[O:28])[CH:23]=[CH:22][N:21]=[N:20]1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)cc2C(=O)NCCn2ccnn2)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.1 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 2-Formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(4-Methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (61 mg, 52%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[C:30]([O:34][C:35](=[O:41])[C@@H:36]1[CH2:40][CH2:39][CH2:38][NH:37]1)([CH3:33])([CH3:32])[CH3:31]>O1CCCC1.C(Cl)(Cl)Cl>[C:30]([O:34][C:35](=[O:41])[C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[C:14](=[O:16])[C@H:12]([CH3:13])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
In 210 ml of tetrahydrofuran is dissolved 26.1 g of N-benzyloxycarbonyl-L-alanine, and a solution of 16.4 ml of triethylamine in 20 ml of tetrahydrofuran is added dropwise to the solution at the temperature below -10° C. with stirring. Then, a solution of 11.2 ml of ethyl chlorocarbonate in 20 ml of tetrahydrofuran is added dropwise to the solution. After stirring for 20 minutes, a solution of 15.4 g of L-proline tert-butyl ester in 102 ml of chloroform is added dropwise to the mixture at the temperature below -10° C. over a period of 48 minutes. After the addition is completed, stirring is continued for 1 hour under cooling and for 1.5 hours at room temperature. The reaction solution is poured into 600 ml of ice-water, and the chloroform layer is separated and concentrated under reduced pressure. The residue is dissolved in 304 ml of ethyl acetate, and the solution is washed with 1N aqueous sodium hydroxide, saturated aqueous sodium chloride, 20% aqueous phosphoric acid and saturated aqueous sodium chloride, successively. The ethyl acetate layer is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 33.8 g of N-(N-benzyloxycarbonyl-L-alanyl)-L-proline tert-butyl ester as an oil. This product is dissolved in 304 ml of methanol containing 8.12 g of oxalic acid, and 10% palladium-carbon (50% wet, 3.6 g) are added to the solution to conduct catalytic reduction at ambient temperature and under atmospheric pressure. The catalyst is filtered off, and the filtrate is concentrated under reduced pressure. 400 ml of ethyl ether is added to the residue, and the crystals which separate out are collected by filtration to give 20.2 g of N-(L-alanyl)-L-proline tert-butyl ester.oxalate as a colorless powder.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.C1CCN2C(=NCCC2)CC1.Cl.[N:33]1([CH:38]2[CH2:42][CH2:41][NH:40][CH2:39]2)[CH:37]=[CH:36][N:35]=[N:34]1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:40]4[CH2:41][CH2:42][CH:38]([N:33]5[CH:37]=[CH:36][N:35]=[N:34]5)[CH2:39]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: c1cn(C2CCNC2)nn1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCC(n4ccnn4)C3)c(F)cc2c1=O
Temperature: 7580 °C

Procedure:
A mixture of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (138.5 mg, 0.486 mmol), DBU (190 mg, 1.25 mmol), and 3-(1,2,3-triazol-1-yl)pyrrolidine hydrochloride (216 mg, 1.25 mmol) in pyridine (8 ml) was heated for 20 h at 7580° C. and then pyridine was removed under vacuum. The residue was diluted with acetonitrile. The precipitated solid was washed with acetonitrile, ether and dried at 40° C. Yield: 65 mg (33%), m.p. 244°-246° C. (dec). 1H NMR (TFA) δ: 1.5 (m, 4H), 2.8 (m, 2H), 4.5 (m, 4H), 4.75 (bs, 1H), 5.8 (bs, 1H), 8.15 (d, 1H), 8.6 (s, 1H), 8.7 (s, 1H), 9.25 (s, 1H).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH2:10].[CH3:18][S:19](Cl)(=[O:21])=[O:20]>O>[F:7][C:8]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:9]=1[NH:10][S:19]([CH3:18])(=[O:21])=[O:20]
Reactant: Nc1cc([N+](=O)[O-])ccc1F
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc([N+](=O)[O-])ccc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 72.8 %

Procedure:
To 334 ml of a pyridine solution containing 52.1 g of 2-fluoro-5-nitroaniline was added 42.1 g of methanesulfonyl chloride under ice-cooling, followed by stirring at room temperature for 7 hours. Water was added to the reaction solution, the precipitate was collected by filtration, and the crude crystals were recrystallized from ethanol to give 56.9 g of N-(2-fluoro-5-nitrophenyl)methanesulfonamide as pale yellow needles.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH:16][NH2:17])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.C(O[C:22](=[NH:24])[CH3:23])C.CCN(CC)CC>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:24][C:22]([CH3:23])=[N:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(C)=N
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nnc(C2CCN(C(=O)OC(C)(C)C)CC2)[nH]1
Temperature: 100 °C
Yield: 10.5 %

Procedure:
4-Hydrazinocarbonyl-piperidine-1-carboxylic acid tert-butyl ester (1.19 g, 5 mmol) was mixed with ethylacetimidate hydrochloride (0.91 g, 7 mmol) in DMF (5 ml) and Et3N (2 ml, 15 mmol) was added. The reaction was stirred for 1 h after which time the DMF was evaporated, the residue redissolved in AcOH and 0.5 g of ammonium acetate added and the reaction heated to 100° C. for a further 3 h. The reaction was then concentrated, redissolved in CH2Cl2, washed with NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (CH2Cl2:MeOH 1:0-9:1) to afford the title product (0.14 g, 10%) as a colourless gum. MS: 267.4 (MH+)
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[F:23])[C:17](O)=[O:18].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:22]([F:23])=[C:14]([Cl:13])[CH:15]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1ccc(F)c(Cl)c1
Reaction time: 0.17 h
Yield: 71.4 %

Procedure:
A solution of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 3-chloro-4-fluorobenzoic acid (319 mg, 1.83 mmol), BOP-Cl (465 mg, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) in DCM (5 mL) at room temperature was stirred for 2 hours. 3M aqueous LiOH (3 mL) was then added, and the mixture was stirred for 10 minutes. Next, water (10 mL) and DCM (10 mL) were added, and the resulting precipitate was filtered. The solid isolated was triturated with 10:1 CH2Cl2:MeOH and filtered to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide (240 mg, 71% yield) as a solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[F:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN1CCCC1=O>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:44]([F:45])=[C:23]([NH:22][C:8]([C:7]5[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=5)=[O:10])[CH:24]=4)=[N:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: CCn1nccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: CCn1nccc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 53 %

Procedure:
Using 1-ethyl-1H-pyrazole-5-carboxylic acid (140 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (10 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (119 mg, yield 53%) was obtained. melting point 209° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([OH:17])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22].[CH:38](Br)([CH3:40])[CH3:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:18][CH3:19])=[C:14]([O:17][CH:38]([CH3:40])[CH3:39])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1)=[O:22]
Reactant: COc1cc2c(cc1O)C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NC1CCc3ccccc31)CC2
Reactant: CC(C)Br
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NC2CCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-7-hydroxy-6-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(indan-1-yl)-acetamide with isopropyl bromide
Reaction SMILES: [C:1]([OH:11])(=O)[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:25][NH:26][O:27][CH3:28].C(N(CC)CC)C>C(Cl)Cl>[CH3:28][O:27][N:26]([CH3:25])[C:1](=[O:11])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNOC
Reactant: O=C(O)CCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)CCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
A suspension of 10.2 grams (68.1 mmol) of hydrocinnamic acid, 14.4 grams (74.9 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 7.31 grams (74.9 mmol) of N,O-dimethylhydroxylamine hydrochloride in 250 mL of methylene chloride was cooled to 0° C. and treated with 19.1 mL (13.9 grams, 136 mmol) of triethylamine. The mixture was stirred for 16 hours with slow warming to rt and was then concentrated. The residue was taken up in 250 mL of ethyl acetate, washed with aqueous 1N hydrochloric acid solution (2×150 mL), saturated aqueous sodium hydrogencarbonate solution (2×100 mL), brine (1×100 mL), dried (Na2SO4), and evaporated to give 13.11 grams (99%) of the title compound as an oil. Anal. Calcd for C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.65; H, 8.11; N, 7.18.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[CH3:28]O>>[CH3:28][O:11][C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCO)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccc(OCCO)cc1
Yield: 80 %

Procedure:
To a solution of (R)-tert-butoxycarbonylamino-[4-(2-hydroxy-ethoxy)-phenyl]-acetic acid (1.0 g, 3.21 mmol) in methanol (10 mL) was added a catalytic amount of concentrated sulfuric acid. The reaction mixture was stirred at reflux for 3 hours. The solvent was evaporated and the crude (R)-tert-butoxycarbonylamino-[4-(2-hydroxy-ethoxy)-phenyl]-acetic acid methyl ester (0.836 g, 80% yield) was carried on to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:19][CH3:20])[C@:4]1([CH3:18])[C@H:9]2[O:10][C@H:8]2[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)=[CH:24][CH:23]=1>>[CH3:1][O:2][CH:3]([O:19][CH3:20])[C@@:4]1([CH3:18])[C@@H:9]([OH:10])[C@H:8]([N:28]([C:25]2[CH:26]=[CH:27][C:22]([Cl:21])=[CH:23][CH:24]=2)[CH2:29][C:30]2[NH:31][CH:32]=[CH:33][N:34]=2)[C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: Clc1ccc(NCc2ncc[nH]2)cc1
Reactant: COC(OC)[C@@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H]2O[C@@H]21
Product: COC(OC)[C@]1(C)Oc2ccc([N+](=O)[O-])cc2[C@@H](N(Cc2ncc[nH]2)c2ccc(Cl)cc2)[C@@H]1O
Yield: 119.6 %

Procedure:
The title compound (269 mg, 63%) was prepared using (2S,3S,4S)-3,4-dihydro-2-dimethoxymethyl-3,4-epoxy-2-methyl-6-nitro-2H-1-benzopyran (129 mg, 0.46 mmol) and 4-chlorophenyl-1H-imidazol-2-ylmethylamine (183 mg, 0.88 mmol), according to the same procedure used for the preparation of example 1 above.
Reaction SMILES: [Cl:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[CH2:26]Br)=[O:22])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[CH2:26][N:12]2[C:5]3[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=3[C:3]([Cl:13])=[C:2]2[Cl:1])=[O:22])=[CH:31][CH:32]=1
Reactant: Cn1ncc2[nH]c(Cl)c(Cl)c2c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ncc2c(c(Cl)c(Cl)n2Cc2cccc(C(=O)c3ccc(Cl)cc3)c2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 16.8 %

Procedure:
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo [2,3-d]pyridazin-4(5H)-one (303 mg) in DMF (50 ml) was dripped into a suspension of 60% sodium hydride-oil (72 mg) in DMF (10 ml) on an ice-water bath. The mixture was stirred at room temperature for 2.5 hours, after which a solution of 3-(4-chlorobenzoyl) benzyl bromide (511 mg) in DMF (10 ml) was added and the mixture was further stirred at room temperature for 17 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:1) to provide the title compound as white powder (104 mg, yield 16%).
Reaction SMILES: [CH3:1][CH2:2]N=C=NCCCN(C)C.C(O)C.[Br:15][C:16]1[CH:20]=[CH:19][O:18][C:17]=1[C:21]([OH:23])=[O:22]>CN(C)C1C=CN=CC=1.ClCCl>[Br:15][C:16]1[CH:20]=[CH:19][O:18][C:17]=1[C:21]([O:23][CH2:1][CH3:2])=[O:22]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1occc1Br
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1occc1Br
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.7 %

Procedure:
WSC (17.3 g), 4-dimethylaminopyridine (1.1 g) and ethanol (5.2 ml) were added to a dichloromethane solution (100 ml) of 17.2 g 3-bromo-2-furancarboxylic acid and stirred for 5 hours at 25° C. The reaction solution was washed with saturated brine and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/30), thereby giving 17.5 g of the desired compound.