Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]3[NH:15][C:14](=[O:16])[O:13][C:11](=[O:12])[C:10]3=[CH:17][CH:18]=2)=[CH:3][CH:2]=1.[CH2:19](N1C2C(=CC=C(C3C=CC=CN=3)C=2)C(=O)C(C(O)=O)=C1)[CH3:20].C(Br)C>>[CH2:19]([N:15]1[C:14](=[O:16])[O:13][C:11](=[O:12])[C:10]2=[CH:17][CH:18]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:8]=[C:9]12)[CH3:20]
Reactant: O=c1[nH]c2cc(-c3ccncc3)ccc2c(=O)o1
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(-c3ccccn3)cc21
Solvent: CCBr
Product: CCn1c(=O)oc(=O)c2ccc(-c3ccncc3)cc21

Procedure:
It was found that the 4-(4-pyridinyl)isatoic anhydride prepared in the preceding examples could be converted to 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acid by (a) alkylating it with ethyl bromide, as in Ranken et al., to produce N-ethyl-4-(4-pyridinyl)isatoic anhydride, (b) reacting the N-ethyl-4-(4-pyridinyl)isatoic anhydride with the potassium salt of ethyl formyl acetate to form ethyl 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylate, and (c) hydrolyzing that ester.
Reaction SMILES: Cl[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=2[F:15])[C:6](=[O:16])[N:5]([CH:17]2[CH2:19][CH2:18]2)[C:4](=[O:20])[CH:3]=1.[CH3:21][NH2:22]>CO>[CH:17]1([N:5]2[C:4](=[O:20])[CH:3]=[C:2]([NH:22][CH3:21])[N:7]([C:8]3[CH:13]=[CH:12][C:11]([I:14])=[CH:10][C:9]=3[F:15])[C:6]2=[O:16])[CH2:19][CH2:18]1
Reactant: CN
Reactant: O=c1cc(Cl)n(-c2ccc(I)cc2F)c(=O)n1C1CC1
Solvent: CO
Product: CNc1cc(=O)n(C2CC2)c(=O)n1-c1ccc(I)cc1F

Procedure:
To a 1:2 mixture (62.9 g) of 6-chloro-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 50 and 6-chloro-1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-1H-pyrimidine-2,4-dione 51 obtained in Step 3 were added methanol (189 ml) and a solution (126 ml) of 40% methylamine in methanol, and the mixture was stirred at room temperature for 2 hrs. The precipitated crystals were filtered off and the filtrate was concentrated under reduced pressure. The residue was extracted with chloroform (200 ml) and water (200 ml), and the organic layer was washed with brine (200 ml) and dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was filtered off and the filtrate was concentrated under reduced pressure to give a 2:1 mixture (34.55 g) of 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyrimidine-2,4-dione 52 and 1-cyclopropyl-3-(2-fluoro-4-iodophenyl)-6-methylamino-1H-pyrimidine-2,4,-dione 53 as yellow crystals, which were used for the next step without purification.
Reaction SMILES: C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:32][C:33]([S:47]([CH2:50][C@@H:51]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:52](O)=[O:53])(=[O:49])=[O:48])([C:35](=[O:46])[N:36]([CH3:45])[CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[CH3:34].Cl.Cl.[CH3:64][O:65][C:66](=[O:75])[CH:67]([CH2:69][C:70]1[N:71]=[CH:72][S:73][CH:74]=1)[NH2:68]>C(#N)C>[CH3:64][O:65][C:66](=[O:75])[CH:67]([CH2:69][C:70]1[N:71]=[CH:72][S:73][CH:74]=1)[NH:68][C:52](=[O:53])[C@@H:51]([CH2:50][S:47]([C:33]([CH3:32])([C:35](=[O:46])[N:36]([CH3:45])[CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)[CH3:34])(=[O:49])=[O:48])[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CN(CCc1ccccn1)C(=O)C(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O
Reactant: COC(=O)C(N)Cc1cscn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1cscn1)NC(=O)[C@H](Cc1ccccc1)CS(=O)(=O)C(C)(C)C(=O)N(C)CCc1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
0.28 ml (2.1 mmol) of triethylamine and 265 mg (0.7 mmol) of HBTU were added to a solution of 328 mg (0.7 mmol) of (S)-α-[[[1-methyl-1-[methyl-[2-(2-pyridyl)ethyl]carbamoyl]ethyl]sulfonyl]methyl]hydrocinnamic acid and 181 mg (0.7 mmol) 3-(thiazol-4-yl)-D,L-alanine methyl ester dihydrochloride in 7 ml of acetonitrile and the mixture was stirred at room temperature overnight. Evaporation of the solution under reduced pressure and chromatography of the residue on silica gel using a 200:10:1 mixture of methylene chloride, methanol and ammonia as the eluent yielded 309 mg of N-[(S)-α-[[[1-methyl-1-[methyl-[2-(2-pyridyl)ethyl]carbamoyl]ethyl]sulfonyl]methyl]hydrocinnamoyl]-3-(thiazol-4-yl)-D,L-alanine methyl ester as a colourless foam, MS: 601 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([OH:19])=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([O:19][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1cc2ccccc2nc1-c1ccc(F)cc1F
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3ccc(F)cc3F)c2cc1OC
Temperature: 145 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
2-(2,4-Difluoro-phenyl)-quinolin-3-ol (220 mg), 4-chloro-6,7-dimethoxyquinoline (237 mg), and 4-dimethylaminopyridine (380 mg) were suspended in o-dichlorobenzene (10 ml), and the suspension was stirred at 145° C. for 8 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (104 mg, yield 27%).
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=3)[C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[NH:32]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]1>C(Cl)Cl.CN(C=O)C>[C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([N:32]4[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33]4)=[O:18])=[CH:15][CH:14]=3)[C:10]3[CH:22]=[CH:23][CH:24]=[CH:25][C:9]=3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc(Cn2c(-c3ccccc3)nc3ccccc32)cc1
Reactant: OC1CCNC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cn2c(-c3ccccc3)nc3ccccc32)cc1)N1CCC(O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-(2-phenyl-benzoimidazol-1-ylmethyl)-benzoic acid (1 g, 3 mmol) in DCM is treated with 2 drops of DMF followed by oxalylchloride (3 mL, 6 mmol, 2M solution in DCM), stirred at room temperature for 2 hours and concentrated in vacuo. The resultant residue is dissolved in DCM, treated with 3-pyrrolidinol (0.3 mL, 3.6 mmol), stirred at room temperature for 8 hours then concentrated to give 1-{4-[(2-phenyl-1H-benzimidazol-1-yl)methyl]benzoyl}pyrrolidin-3-ol identified by HPLC and MS [398.4 m/e (M+H)].
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:19]([O:21]C(=O)C)[CH3:20].O>CN(C=O)C>[O:21]=[C:19]1[NH:10][C:3]2[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=2[O:1][CH2:20]1
Reactant: CCOC(C)=O
Reactant: N#Cc1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)NC(=O)CO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
24 mmol of 4-Hydroxy-3-nitrobenzonitrile were dissolved in DMF. 1.1 eq of Cs2CO3 were added and the reaction stirred at rt for 15 min. 1.5 eq of ethylbromo acetate were added and the reaction mixture heated to 50° C. for 2 h. The intermediate was isolated via extraction from ethylacetate/water. The organic layer was separated and dried over Na2SO4. After evaporation the resulting solid was redissolved in MeOH and sat. NH4Cl (1:1). 8 g of Zn powder were added and the suspension stirred at rt for 2 h. The solid was filtered off and the organic layer evaporated. Ethylacetate was added and the organic layer washed with sat. NaHCO3. The organic layer was separated again, dried over Na2SO4 and reduced resulting in a light brown solid. MS(ISO): 175.2 (MH+)
Reaction SMILES: [CH3:1][CH:2]([CH3:32])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=O)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[CH3:33][N:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)N>>[CH3:1][CH:2]([CH3:32])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[C:41]4[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=4)[N:34]([CH3:33])[C:24]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: CN(N)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCC(=O)c3ccccc3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCc3c(-c4ccccc4)n(C)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(7-oxo-7-phenylheptyl)-4-piperidinyl]phenyl}propanamide and 1-methyl-1-phenylhydrazine: ESMS m/e: 522.3 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:18])[O:3][C:4]1[C:9]2[N:10]=[C:11]([CH2:13][CH3:14])[O:12][C:8]=2[C:7]([C:15]([OH:17])=O)=[CH:6][CH:5]=1.[CH2:19]([N:21]1[C:25]([NH2:26])=[C:24]([CH3:27])[CH:23]=[N:22]1)[CH3:20]>>[CH2:19]([N:21]1[C:25]([NH:26][C:15]([C:7]2[C:8]3[O:12][C:11]([CH2:13][CH3:14])=[N:10][C:9]=3[C:4]([O:3][CH:2]([F:1])[F:18])=[CH:5][CH:6]=2)=[O:17])=[C:24]([CH3:27])[CH:23]=[N:22]1)[CH3:20]
Reactant: CCc1nc2c(OC(F)F)ccc(C(=O)O)c2o1
Reactant: CCn1ncc(C)c1N
Product: CCc1nc2c(OC(F)F)ccc(C(=O)Nc3c(C)cnn3CC)c2o1
Yield: 40 %

Procedure:
Starting from 4-difluoromethoxy-2-ethylbenzooxazole-7-carboxylic acid (150 mg) and 2-ethyl-4-methyl-2H-pyrazol-3-ylamine (90 mg). Purification by column chromatography on silica eluting 2:1 ethyl acetate-heptane followed by ethyl acetate afforded the title compound as a white solid (85 mg).
Reaction SMILES: [OH:1][C:2]1[CH:17]=[C:16]([OH:18])[C:5]([C:6](=[O:15])[CH:7]=[CH:8][CH:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH2:10]2)=[C:4]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>CN(C)C=O>[CH2:31]([O:1][C:2]1[CH:17]=[C:16]([OH:18])[C:5]([C:6](=[O:15])[CH:7]=[CH:8][CH:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH2:14]2)=[C:4]([O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH:3]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)COc1cc(O)cc(O)c1C(=O)C=CC1C=CC=CC1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(OCc2ccccc2)cc(O)c1C(=O)C=CC1C=CC=CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4′,6′-dihydroxy-2′-(methoxycarbonylmethoxy)dihydrochalcone (0.6 g) in N,N-dimethylformamide (10 mL) were added potassium carbonate (0.26 g) and benzyl bromide (0.22 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the precipitated crystals were collected by filtration and dried under reduced pressure to give the title compound (0.53 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1.[F:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[C:29]([F:31])[CH:30]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][C:12]([O:32][C:27]3[CH:26]=[C:25]([F:24])[CH:30]=[C:29]([F:31])[CH:28]=3)=[CH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(Cl)nnc2-c2ccc(OC)cc2)cc1
Reactant: Oc1cc(F)cc(F)c1
Product: COc1ccc(-c2cc(Oc3cc(F)cc(F)c3)nnc2-c2ccc(OC)cc2)cc1

Procedure:
In a similar manner as in Example 2, 3,4-bis(4-methoxyphenyl)-6-chloropyridazine (250 mg, 0.766 mmol) and 3,5-difluorophenol were reacted as starting materials at 150° C. for 6 hours and post-treatment was then conducted, whereby the title compound was obtained as colorless needles (315.0 mg, 98.0%). Melting point: 135.1-137.5° C. (ethyl acetate-diethyl ether-hexane).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][O:18][C:19]2[CH:28]=[C:27]3[C:22]([CH2:23][CH2:24][N:25]([C:29](=[N:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]3)=[CH:21][CH:20]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>O1CCCC1.C(O)C.[C].[Pd]>[C:42]([O:41][C:39]([NH:38][C:29]([N:25]1[CH2:24][CH2:23][C:22]2[C:27](=[CH:28][C:19]([O:18][CH2:17][CH:14]3[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)=[CH:20][CH:21]=2)[CH2:26]1)=[N:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:40])([CH3:43])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCN(C(=O)OCc4ccccc4)CC3)cc2C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCc2ccc(OCC3CCNCC3)cc2C1
Yield: 207.7 %

Procedure:
4-[2-(N,N′-Di-tert-butoxycarbonylamidino)-1,2,3,4-tetrahydroisoquinolin-7-yloxymethyl]piperidine-1-carboxylic acid benzyl ester (500 mg) was hydrogenated using 7.5% palladium carbon (150 mg) in a mixture of tetrahydrofuran (5 ml) and ethanol (100 ml) at 3 atm over 3 hours. After completion of the reaction, the reaction mixture was filtered through celite, and the solvent was evaporated. The residue was dried under reduced pressure to give the title compound (815 mg).
Reaction SMILES: C(OC(=O)C)(=O)C.I([O-])(=O)(=O)=O.[Na+].[I:14]I.S(=O)(=O)(O)O.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1>C(O)(=O)C>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][C:24]=1[I:14]
Reactant: Cc1ccc(Br)cc1
Reactant: II
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(Br)cc1I
Yield: 197.9 %

Procedure:
2-Methyl-5-bromo-iodobenzene was synthesized according to the method described by Lulinski, P., Skulski, L., Bull. Chem. Soc. Jpn. 2000 73:951-956. To a mixture of acetic acid (100 ml) and acetic anhydride (50 ml), cooled in an ice bath, was added sodium periodate (15.4 g, 72 mmol) and iodine (12.2 g, 48 mmol). While stirring vigorously, concentrated sulfuric acid (21 ml) was added slowly followed by 4-bromotoluene (23.1 g, 135 mmol). After stirring for 2 hours, the ice bath was removed and the mixture was protected from light. After stirring for 16 hours, the mixture was poured into a mixture of 10% aqueous sodium sulfite solution (250 ml) and ice (250 g), and extracted with dichloromethane (3×100 ml). The combined extracts were washed with water (100 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residual oil was purified by distillation (87-92° C., 1 mm) to provide 2-methyl-5-bromo-iodobenzene (28.2 g, 70% yield) as colorless oil. 1H NMR (DMSO-d6) δ 7.99 (s, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 2.33 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.Cl.[NH2:16][C@H:17]([CH3:23])[CH:18]([CH:20]1[CH2:22][CH2:21]1)[OH:19].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:16][C@H:17]([CH3:23])[CH:18]([CH:20]3[CH2:22][CH2:21]3)[OH:19])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: C[C@@H](N)C(O)C1CC1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C(O)C1CC1
Temperature: 25 °C
Yield: 30.2 %

Procedure:
6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (272 mg, 0.989 mmol), (2R)-2-amino-1-cyclopropylpropan-1-ol hydrochloride (300 mg, 1.978 mmol) and DIPEA (0.691 ml, 3.96 mmol) were heated to 110° C. in NMP (3.297 ml) for 4 hrs. The reaction was then cooled to rt and ice-water added. After the ice had melted, the mixture was extracted with ethyl acetate (3×). The combined organics were then dried (MgSO4) and evaporated in vacuo before purifying by column chromatography using hexane ethyl acetate as eluent to give 6-bromo-4-(((2R)-1-cyclopropyl-1-hydroxypropan-2-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide (111 mg, 0.299 mmol, 30.2% yield) as a mixture of diastereoisomers. 1H NMR (500 MHz, CCl3D) δ 7.93-7.78 (m, 1H), 7.68-7.52 (m, 1H), 6.93 (d, J=1.7 Hz, 1H), 5.44 (br. s., 1H), 4.53-4.27 (m, 1H), 4.13 (q, J=7.2 Hz, 1H), 2.99 (dd, J=9.2, 3.1 Hz, 1H), 1.48 (d, J=6.7 Hz, 3H), 1.27 (t, J=7.1 Hz, 2H), 1.14-0.99 (m, 1H), 0.65-0.53 (m, 2H), 0.43-0.27 (m, 2H).
Reaction SMILES: C([N:8]([C@H](C1C=CC=CC=1)C)[C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][OH:12])C1C=CC=CC=1>CCO.[Pd]>[NH2:8][C@@H:9]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:10][CH2:11][OH:12]
Reactant: CCCC[C@@H](CCO)N(Cc1ccccc1)[C@@H](C)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCC[C@H](N)CCO
Reaction time: 24 h
Yield: 89.3 %

Procedure:
A solution of the product from step (iv) (5 g) and 5% Pd/C (0.5 g) in EtOH (25 mL) was hydrogenated under 5 bar at rt for 5 days. A further portion of 5% Pd/C (1.5 g) was added, and the reaction mixture hydrogenated under 5 bar at rt for a further 1 day. The reaction mixture was filtered and the solvent evaporated to give the subtitle compound 1.8 g.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:7][O:8][C:9]=1[CH3:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])O.[Na+]>C(O)C>[CH3:10][C:9]1[O:8][N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:5]=1[C:3]1[N:17]=[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]2[CH:2]=1
Reactant: Nc1ccccn1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
A mixture of 4-(bromoacetyl)-5-methyl-3-phenylisoxazole (commercially available) (140 mg, 0.5 mmol) and 2-aminopyridine (47 mg, 0.5 mmol) in ethanol (3.1 mL) was heated under reflux under argon for 3.5 h. Then another portion of 2-aminopyridine (24 mg, 0.25 mmol) was added and heating under reflux continued for another 1 h. The resulting mixture was then cooled to room temperature and then sodium hydrogen carbonate (63 mg, 0.75 mmol) added and the resulting mixture heated under reflux for 2 h. After cooling to room temperature, the mixture was poured onto water and extracted with ethyl acetate. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated to leave a yellow oil. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 50:50) afforded the title compound (76 mg, 55%) which was obtained as a light yellow gum. MS: m/e=276.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([O:16][Si](C(C)(C)C)(C)C)[CH2:13][CH:12]1[C:24]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][CH:12]1[C:24]([C:26]1[C:34]2[C:29](=[CH:30][C:31]([F:35])=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CC(C(=O)c2c[nH]c3cc(F)ccc23)N(C(=O)OCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C(c1c[nH]c2cc(F)ccc12)C1CC(O)CN1C(=O)OCc1ccccc1
Reaction time: 9 h
Yield: 24.6 %

Procedure:
To a solution containing 3 (227 g) in THF (600 mL) was added 1 M TBAF in THF (160 mL) at ambient temperature. After 9 h, another 20 mL of the 1 M TBAF/THF solution was added. After ca. 48 h, the reaction mixture was concentrated in vacuo and then redissolved in EtOAc (600 mL). The organic solution was washed with water (310 mL) and the product precipitated to form a thick suspension which was filtered (slow). The solids were washed with EtOAc (165 mL in portions) and dried to provide 43 g of 4. The combined filtrate was concentrated in vacuo to precipitate an additional 4.8 g of 4 after drying. 1H NMR (300 MHz, d6-DMSO), mixture of rotomers: δ12.08 (br s, 1H), 8.43 (d, J=10.5 Hz, 1H), 8.16 (ddd, J=5.4, 8.7, 14.1 Hz, 1H), 7.36-7.31 (m, 2H), 7.27 (app. d, J=10.2 Hz, 1H), 7.09-6.93 (m, 4H), 5.24 (dt, J=8.1, 15.6 Hz, 1H), 5.14 (br s, 1H), 5.04 (app. d, J=6.4 Hz, 1H), 4.90 (app. dd, J=13.4, 28.4 Hz, 1H), 4.30 (br s, 1H), 3.58-3.43 (m, 2H), 2.27 (m, 1H), 1.93 (m, 1H) ppm; 13C NMR (75 MHz, d6-DMSO), mixture of rotomers: δ194.0, 193.6, 159.9 (d, JCF=235.2 Hz), 154.6 (d, JCF=9.6 Hz), 138.1. 137.5 (d, JCF=26.9 Hz), 136.0, 129.0, 128.5, 128.1 (d, JCF=40.0 Hz), 123.4, 123.3, 123.0, 122.9, 114.4 (d, JCF=11.7 Hz), 110.6 (d, JCF=23.7 Hz), 99.3 (d, JCF=25.2 Hz), 69.5, 68.8, 66.4, 66.3, 61.4, 61.1, 56.2, 55.7 ppm. Mass spectrum (ESI), m/z 382.6 [(M)+; calcd for C21H19FN2O4: 382.3].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: Nc1ccc(CCO)cc1
Product: O=[N+]([O-])c1cc(F)ccc1Nc1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,5-difluoronitrobenzene and 4-aminophenylethyl alcohol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C@@H:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:9]([OH:12])[CH:10]=[CH2:11])([CH3:4])([CH3:3])[CH3:2].CO[C:22](OC)([CH3:24])[CH3:23].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[C@@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:9]([CH:10]=[CH2:11])[O:12][C:22]1([CH3:24])[CH3:23])=[O:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(C)(C)OC
Reactant: C=C[C@H](O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C=C[C@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@H]1c1ccccc1
Temperature: 82.5 °C
Reaction time: 2.5 h

Procedure:
(1S,2S)-(2-hydroxy-1-phenyl-but-3-enyl)-carbamic acid tert-butyl ester (160 grams, 0.608 mole) was dissolved in toluene (1600 mL). Dimethoxypropane (745 mL, 6.08 mole) was added at temperature in the range of 20-40° C. followed by addition of pyridinium p-toluene sulphonate (2.3 grams, 0.00912 mole). The mixture was heated to 80-85° C., and stirred at the same temperature for about 2-3 hours. The reaction mixture was cooled to 45° C., neutralized with pyridine (3 mL), and concentrated under reduced pressure to get the semi-solid compound (4S,5R)-2,2-dimethyl-4-phenyl-5-vinyl-oxazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:18]([Mg]Cl)#[CH:19]>C1COCC1>[OH:15][CH:14]([C:13]1[CH:16]=[CH:17][C:10]([O:9][CH2:8][CH2:7][N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[CH:11][CH:12]=1)[C:18]#[CH:19]
Reactant: O=Cc1ccc(OCCN2CCOCC2)cc1
Reactant: C#C[Mg]Cl
Solvent: C1CCOC1
Product: C#CC(O)c1ccc(OCCN2CCOCC2)cc1

Procedure:
3-Hydroxy-3-[4-[2-(4-morpholinyl)-ethoxy]-phenyl]-1-propyne was prepared according to Method A above from 4-[2-(4-morpholinyl)-ethoxy]-benzaldehyde (0.630 g, 2.68 mmol) (see below) in THF (20 mL) and ethynylmagnesium chloride (3.0 mmol, 6 mL, 0.5M solution in tetrahydrofuran) (Aldrich). (Yield 492 mg, 70%).