Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][CH:8]2[CH2:23][N:11]3[CH2:12][CH2:13][N:14]([CH2:16]C4C=CC=CC=4)[CH2:15][CH:10]3[CH2:9]2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+].FC1C=CC(OCC2CN3CCNCC3C2)=CC=1.ClC1[N:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=1.C(=O)([O-])[O-].[Na+].[Na+]>CO.O.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]2[CH2:23][N:11]3[CH2:12][CH2:13][N:14]([C:16]4[N:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=4)[CH2:15][CH:10]3[CH2:9]2)=[CH:24][CH:25]=1
Reactant: Fc1cnc(Cl)nc1
Reactant: Fc1ccc(OCC2CC3CN(Cc4ccccc4)CCN3C2)cc1
Agent: [Pd]
Agent: Fc1ccc(OCC2CC3CNCCN3C2)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CO
Product: Fc1ccc(OCC2CC3CN(c4ncc(F)cn4)CCN3C2)cc1
Temperature: 25 °C
Yield: 49.3 %

Procedure:
A solution of 0.870 g (2.6 mmol) of (7SR,8aSR)-7-(4-fluorophenoxy)methyl-2-phenylmethyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine (Preparation 2) and 1.8 mL (8.9 mmol) of 5M aqueous ammonium formate in 50 mL methanol was treated with an aqueous slurry of 0.100 g of 10% Pd/C. The reaction was refluxed for 24 h. The mixture was filtered and the solvent removed in vacuo to give an oily residue. The crude (7SR,8aSR)-7-(4-fluorophenoxy)methyl-1,2,3,4,6,7,8,8a-octahydro-pyrrolo[1,2-a]pyrazine was combined with 0.373 g (2.8 mmol) of 2-chloro-5-fluoropyrimidine (Dunaiskis, A.; et al. Org. Prep. Proc. Int., 1995, 27, 600-602), 0.650 g (6.1 mmol) of sodium carbonate in 50 mL of water, and the mixture was gently refluxed for 16 hrs. After cooling to room temperature, the mixture was extracted with methylene chloride (3×). The combined organic layers were dried (magnesium sulfate), filtered, and evaporated. Purification by silica gel flash chromatography eluting with 85:15 ethyl acetate:hexane gave 0.444 g (50%) of the title compound. mp (.HCl) 211°-213° C. 13C NMR (base, CDCl3): δ 31.7, 35.2, 43.8, 49.1, 51.4, 56.6, 62.3, 72.5, 115.45, 115.56, 115.89, 144.95, 145.24, 149.9, 153.2, 155.1, 155.6, 158.79, 158.90. Anal calcd for C18H20F2N4O: C, 62.41; H, 5.82; N, 16.18. Found: C, 62.15, H, 5.99; N, 16.38.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20](Cl)(=[O:22])=[O:21])[CH:19]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:24][CH3:25])=[C:18]([S:20]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:21])=[O:22])[CH:19]=1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2cc(Br)ccc2OC)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 5-bromo-2-methoxybenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (14.4 mg) with purity >90%. LCMS (pos) m/z 437.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[S:15][CH:14]3[C:16](=[O:19])[N:17]([CH3:18])[CH:11]([C:12](=[O:21])[N:13]3[CH3:20])[S:10]2)=[CH:5][CH:4]=1.C([Li])CCC.CCCCCC.[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[Na+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[S:15][CH:14]3[C:16](=[O:19])[N:17]([CH3:18])[C:11]([CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:12](=[O:21])[N:13]3[CH3:20])[S:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2SC3C(=O)N(C)C(S2)C(=O)N3C)cc1
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C2SC3C(=O)N(C)C(Cc4ccccc4)(S2)C(=O)N3C)cc1
Temperature: -78 °C
Reaction time: 0.13 h
Yield: 40.2 %

Procedure:
Thioacetal 5 (194 mg, 0.6 mmol, 1 eq.) was dissolved in anhydrous THF (25 mL) and the solution was cooled to −78° C. To the stirred solution 1.54 M n-butyllithium in hexane (545 μL, 0.84 mmol, 1.4 eq.) was added dropwise over a period of 1 min. After 30 second benzyl bromide (356 μL, 513 mg, 3 mmol, 5 eq) was added to the stirred mixture over a period of 30 sec. After the mixture was stirred for 8 min at −78° C. the resulting red, cloudy solution was allowed to warm to room temperature and was stirred. It took about 30 min. The TLC shows one major product and a little (˜5%) of starting material. Saturated NaCl solution was added into the reaction mixture and the solution was extracted with dichloromethane. The organic solution was washed with water twice, dried under MgSO4 and concentrated under vacuum. The oily residue was treated with hexane. One part of the material got solid and the hexane solution was removed. The yellow solid was washed again with hexane and dried under vacuum. The solid crude material was dissolved in dichloromethane (2 mL), methanol (4 mL) and hexane (about 20 mL) was added. The white precipitate was filtered off to give the pure product 100 mg of 26 (40.8%). 1H NMR (CDCl3, TMS, ppm) δ: 7.36 (d, J=8.7 Hz, 2H), 724 (m, 51), 6.88 (d, J=8.7 Hz, 2H), 5.19 (s, 1H), 5.10 (s, 1H), 4.15 (d, J=16.6 Hz, 1H), 3.82 (s, 3H), 3.25 (d, J=16.5 Hz, 1H), 3.15 (s, 3H), 3.11 (5, 1H).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([N:11]([CH3:17])[CH2:12][CH2:13][CH2:14]2)[CH2:9]1)C1C=CC=CC=1.CO>[OH-].[OH-].[Pd+2].CCOC(C)=O>[CH3:17][N:11]1[CH2:12][CH2:13][CH2:14][CH:15]2[CH2:16][NH:8][CH2:9][CH:10]12
Reactant: CN1CCCC2CN(Cc3ccccc3)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN1CCCC2CNCC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-benzyl-1-methyloctahydro-1H-pyrrolo[3,4-b]pyridine (2.00 g) in the mixture solvent of MeOH and EtOAc was added a catalytic amount of 20% Pd(OH)2/C. The reaction mixture was stirred for 2 h at room temperature under H2. The resulted mixture was filtered and the filtrate was concentrated to in vacuo to give the crude product, which was used for the next step without further purification. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 141.2 (M+1).
Reaction SMILES: [O:1]=[S:2]1(=[O:14])[CH2:7][CH2:6][C:5](C(O)=O)([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1>CN(C=O)C>[O:1]=[S:2]1(=[O:14])[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)C1(C(=O)O)CCS(=O)(=O)CC1
Solvent: CN(C)C=O
Product: O=C(O)C1CCS(=O)(=O)CC1
Reaction time: 0.17 h

Procedure:
In a microwave vial is added 1,1-Dioxo-tetrahydro-1λ6-thiopyran-4,4-dicarboxylic acid (112 mg; 0.504 mmol), 2% cross-linked poly-4-vinylpyridine (225 mg) and DMF (2.1 mL). The vial is sealed and placed into microwave oven for 10 minutes at 95° C. After cooling, the mixture is filtered through filter paper and washed the paper with diethyl ether. The filtrate is concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH:1]([N:4]1[CH2:7][CH:6]([O:8][CH2:9][O:10][CH3:11])[CH2:5]1)([CH3:3])[CH3:2].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>CCOCC>[O:18]([CH2:5][CH:6]([O:8][CH2:9][O:10][CH3:11])[CH2:7][NH:4][CH:1]([CH3:2])[CH3:3])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Oc1ccccc1
Reactant: COCOC1CN(C(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COCOC(CNC(C)C)COc1ccccc1
Temperature: 180 °C
Yield: 67 %

Procedure:
To a mixture of 1.6 parts of 1-iso-propyl-3-methoxymethoxyazetidine and 9.4 parts of phenol 0.5 part of sodium hydroxide was addded, and the mixture was heated at 180° C. for 6 hours. The reaction mixture was cooled and 100 parts of ether were added thereto. Excessive phenol was removed by extraction with 2 N-sodium hydroxide aqueous solution, and the remaining ether layer was washed in water and dried over anhydrous sodium sulfate. After distillation of ether, the residue was subjected to distillation to yield 1.6 parts of 1-phenoxy-2-methoxymethoxy-3-(iso-propylamino)-propane boiling at 146°-149° C. under 2 mm Hg. The yield was 67%.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[N:13][C:14]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)C1C=CC=CC=1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]>CO.[Pd]>[C:18]1([C:14]2[N:13]=[CH:12][CH:11]=[C:10]3[C:15]=2[CH2:16][CH2:17][NH:8][CH2:9]3)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1.[C:24]([OH:30])([C:26]([F:29])([F:28])[F:27])=[O:25]
Reactant: c1ccc(CN2CCc3c(ccnc3-c3ccccc3)C2)cc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: c1ccc(-c2nccc3c2CCNC3)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-benzyl-5-phenyl-1,2,3,4-tetrahydro-2,6-naphthyridine, 2 TFA (0.48 g, 0.908 mmol) in MeOH (10 mL) was added Pd/C (0.193 g, 0.182 mmol). The mixture was flushed with N2, then was purged with H2 and stirred at rt under 1 atm. After stirring the reaction for 3 h it was filtered through a pad of CELITE®. The organic solution was concentrated under reduced pressure to give 5-phenyl-1,2,3,4-tetrahydro-2,6-naphthyridine, 2 TFA (0.398 g, 0.908 mmol, 100% yield) as a light-brown oil which crystallized under vacuum. The residue was used in the next step with no additional purification. LC/MS: m/z 211.00 (M+H)+, 0.270 min (method 7). 1H NMR (500 MHz, MeOD) δ ppm 8.66 (d, 1H) 7.74 (d, J=5.49 Hz, 1H) 7.57-7.67 (m, 5H) 4.69 (s, 2H) 3.54 (t, J=6.10 Hz, 2H) 3.11 (t, J=6.10 Hz, 2H).
Reaction SMILES: [Br-].C1(C(C2C=CC=CC=2)[N+:9]23[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]2)[C:11](=[O:17])[CH2:10]3)C=CC=CC=1>C1CC=CCCC=C1.C1CC=CCCC=C1.[Cl-].[Cl-].[Rh].[Rh].CO>[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([OH:17])[CH2:10]2
Reactant: O=C1C[N+]2(C(c3ccccc3)c3ccccc3)CCC1CC2
Agent: [Rh]
Agent: C1=C\CC/C=C\CC/1
Agent: [Br-]
Solvent: C1=CCCC=CCC1
Solvent: CO
Product: O[C@H]1CN2CCC1CC2
Reaction time: 19 h
Yield: 96.8 %

Procedure:
100 g (268 mmol) of 1-(diphenylmethyl)-3-oxoquinuclidinium bromide, 66 mg (0.133 mmol) of bis(1,5-cyclooctadiene)dirhodium(I) dichloride, 145 mg (0.267 mmol) of (S)-1-[(R)-2-(diphenylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine (IIIa, mirror image; corresponding to an educt/catalyst molar ratio of 1000) and 500 ml of degassed methanol were introduced into an autoclave (1liter) under argon. The reaction mixture was hydrogenated for 19 hours at 75° C. and 10-14 bar of H2. The mixture was then cooled, filtered and evaporated. The residue was taken up with 200 ml of water and100 ml of ethyl acetate and the aqueous phase was washed again twice with 50 ml of ethyl acetate. The aqueous phase was adjusted to pH 14 with sodium hydroxide solution (30 percent) and evaporated to dryness. The residue was extracted four times with 100 ml of dichloromethane and the combined organic extracts were dried over MgSO4 and evaporated to give 33.0 g (96.6 percent) of (R)-3-quinuclidinol in the form of a white crystalline solid. Recrystallization from ethyl acetate gave 28.3 g (83 percent) of (R)-3-quinuclidinol with 58 percent ee. Other data concerning the product was:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].C[CH:20](C)[CH:21]([C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1C)O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:21]([C:23]2[S:27][C:26]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:32][CH:33]=3)=[N:25][CH:24]=2)[CH3:20])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(C)C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OC(C)c2cnc(-c3ccc(C(F)(F)F)cc3)s2)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [rac]-1-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethanol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield 2-ethoxy-3-(2-methyl-4-{1-[2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-phenyl)-propionic acid ethyl ester as a mixture of two diastereomeric racemates as colorless liquid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25](COC([Si](C)(C)C)C)[N:24]=[C:23]4[CH3:37])[N:15]=2)[CH2:10][C@@H:9]1[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[CH2:38]([C@@H:9]1[NH:8][CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][N:24]=[C:23]4[CH3:37])[N:15]=2)[CH2:10]1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: Cc1nn(COC(C)[Si](C)(C)C)c2ccc(-c3cncc(N4CCN(C(=O)OC(C)(C)C)[C@@H](Cc5ccccc5)C4)n3)cc12
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2ccc(-c3cncc(N4CCN[C@@H](Cc5ccccc5)C4)n3)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
2-[(S)-4-Boc-3-benzylpiperazinyl]-6-[3-methyl-1-(trimethylsilyl)ethoxymethyl-1H-indazol-5-yl]pyrazine 118 (0.115 g, 0.187 mmol) was dissolved in a 90% aqueous trifloroacetic acid solution (10 mL). The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 2-[(S)-3-benzylpiperazinyl]-6-[3-methyl-1H-indazol-5-yl]pyrazine 119 (0.072 g, 0.187 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=O)[C:6]([NH2:12])=[CH:5][CH:4]=1.C(O)(=O)C.[O-:17][C:18]#[N:19].[K+].[OH-].[Na+]>O>[OH:17][C:18]1[N:19]=[C:8]([OH:10])[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=2)[N:12]=1
Reactant: COc1ccc(N)c(C(=O)O)c1
Reactant: N#C[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2nc(O)nc(O)c2c1
Yield: 82 %

Procedure:
A mixture of 5-methoxy anthranilic acid (40 g, 0.24M), acetic acid (18.0 g, 0.3M) and 1 liter warm water (35° ) was stirred and allowed to cool. A solution of potassium cyanate (24.3 g, 0.3M) in water (100 ml) was added over 15 minutes and then stirred for a further 30 minutes. Sodium hydroxide (320 g, 8.0M) solid was added portionwise and the reaction was then heated at 90° for 30 minutes and allowed to cool overnight. The solid was filtered off and dissolved in hot water (500 ml) and then acidified with dilute sulphuric acid to precipitate the product. The solid was filtered off and washed free of acid with water and then dried at 100°/vacuum to yield the title compound (37.7 g) m.p. >290°.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].CN(C1C=CC=CN=1)C.[C:24](O)([CH3:27])([CH3:26])[CH3:25].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:14])[C:11]([O:13][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)(C)O
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CC(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A mixture of 2-(4-nitrophenyl)propanoic acid (15.0 g, 76.9 mmol), dimethylaminopyridine (4.70 g, 38.4 mmol) and tert-butanol (8.10 mL, 84.6 mmol) in methylene chloride (300 mL) was stirred at 0° C. for 2 h. After this time, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (17.0 g, 84.6 mmol) was added and the reaction stirred for a further 2 h. The ice bath was then removed and the reaction left to stir at room temperature overnight. After this time, the solvents were concentrated under reduced pressure and the solids redissolved in ethyl acetate (200 mL). The organic layer was then washed with saturated sodium bicarbonate (200 mL), 1 M citric acid (200 mL) and brine (200 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash chromatography (silica, 1:20 ethyl acetate/hexanes) afforded tert-butyl 2-(4-nitrophenyl)propanoate (14.4 g, 75%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J=9.2 Hz, 2H), 7.46 (d, J=9.2 Hz, 2H), 3.73 (q, J=7.1 Hz, 1i), 1.49 (d, J=7.1 Hz, 3H), 1.40 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>O1CCCC1>[CH3:38][S:39]([NH:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1)(=[O:41])=[O:40]
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 60.7 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), triethylamine (76 μL, 0.544 mmol), methanesulfonyl chloride (34 μL, 0.435 mmol) and tetrahydrofuran (5 mL) as starting materials and in the same manner as in Example 388, the title compound (108 mg, 61%) was obtained as a pale-green-powder.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([NH:32][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(CNCCOc2cccc(-c3noc4ccsc34)c2)cc1
Yield: 81 %

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, and benzylamine in two separate reactions using acetonitrile and 90% aqueous acetonitrile, respectively, essentially as described above in example 18 except that the reaction mixtures are filtered through 2 g of silica (ethyl acetate then dichloromethane). Combine and concentrate the appropriate fractions. Purify by column chromatography on silica gel. Elute the column with a step gradient of 50% ethyl acetate in heptane to 100% ethyl acetate to give the title compound (0.350 g, 81%). mp=60–63° C. Microanalysis (C, H, N) is consistent with the final compound.
Reaction SMILES: [N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:2]=1[CH3:3].[CH3:12][OH:13].S(=O)(=O)(O)O.NOS(O)(=O)=O>O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2].[Fe].O>[OH:13][CH2:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[N:1]=[C:2]([CH3:3])[CH:4]=1
Reactant: CO
Reactant: Cc1ccc2ccccc2n1
Agent: [Fe+2]
Agent: [Fe]
Agent: NOS(=O)(=O)O
Solvent: O
Product: Cc1cc(CO)c2ccccc2n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To a 25 mL round-bottomed flask equipped with a magnetic stirrer and under a N2 (g) purge was placed sequentially: quinaldine (0.57 g, 4.0 mmol), methanol (8 mL), and water (4 mL). The solution was cooled to 0° C. prior to the sequential addition of: concentrated sulfuric acid (0.2 mL, 4 mmol), iron (II) sulfate heptahydrate (0.33 g, 1.2 mmol), and iron powder (0.067 g, 1.2 mmol). After stirring the heterogeneous mixture for 10 min, hydroxylamine-O-sulfonic acid (HOSA) (1.36 g, 12 mmol) was added and the resulting mixture was stirred for 6 h prior to quenching the reaction with 50% NaOH until the pH was ca. 10. The brown solution was filtered through a pad of celite and then extracted with methylene chloride (4×15 mL). The combined organic phases were washed with water (20 mL), brine (15 mL), dried (NaSO4), and concentrated in-vacuo to afford a brown solid that was purified by Combiflash (0 to 60% ethyl acetate in hexanes over 30 min) to afford 360 mg (52%) of pure 4-hydroxymethyl-2-methyl quinoline. LCMS (ESI): 174 (M+H′).
Reaction SMILES: Br[C:2]1[C:3]([C@@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1>CO.[OH-].[Pd+2].[OH-].[Pd]>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[C@@H:8]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1Br
Agent: [Pd+2]
Agent: [Pd]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-tert-butyl ((3-bromopyridin-2-yl)(4-(trifluoromethyl)-phenyl)methyl)carbamate (2.24 g, 5.19 mmol) in MeOH (20 mL) was added palladium hydroxide, (20 wt % Pd (dry basis) on carbon, wet, degussa type) (0.365 g, 2.60 mmol). The resulting mixture was then stirred at rt under H2 overnight. The mixture was filtered through Celite® brand filter agent and the solids were washed with a solution of MeOH/EtOAc (1:1, 3×20 mL). The combined filtrates were concentrated and dried to give the desired product as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8](O)=[O:9])[N:3]=1.[Cl:14]C(OC(Cl)(Cl)Cl)=O.CN(C)C=O>O1CCCC1>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([Cl:14])=[O:9])[N:3]=1
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 30.0 ml of tetrahydrofuran (THF), 10.0 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 5.43 g of trichloromethyl chloroformate at 5° C. to a mixture of 80 ml of THF and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, the reaction mixture was poured into 200 ml of ice water to precipitate crystals. The crystals were collected by filtration, washed with 100 ml of ice water, collected by filtration, and then stirred for 30 minutes in 100 ml of n-hexane. After filtration, the resulting crystals were dried under reduced pressure, whereby the title compound was obtained. Yield: 9.2 g (84.3%). Purity: 96.5%.
Reaction SMILES: [CH:1]([CH:4]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[N:9]=[C:8](Br)[C:7]3[N:16]=[CH:17][CH:18]=[CH:19][C:6]=3[C:5]1=2)([CH3:3])[CH3:2].[C:20]([Cu])#[N:21].N>>[CH:1]([CH:4]1[CH2:13][C:12](=[O:14])[NH:11][C:10]2[N:9]=[C:8]([C:20]#[N:21])[C:7]3[N:16]=[CH:17][CH:18]=[CH:19][C:6]=3[C:5]1=2)([CH3:3])[CH3:2]
Reactant: N#C[Cu]
Reactant: CC(C)C1CC(=O)Nc2nc(Br)c3ncccc3c21
Agent: N
Product: CC(C)C1CC(=O)Nc2nc(C#N)c3ncccc3c21
Reaction time: 1 h
Yield: 21 %

Procedure:
1.6 g (0.005 mol) of 1-isopropyl-6-bromo-1,2-dihydropyrido[2,3-c][1,8]naphthyridin-3(4H)-one are melted at 220° C. in a heavy-oil bath with 0.45 g (0.05 mol) of CuCN. After 1 hour, the melt is cooled, and the residue is ground in a mortar and stirred with concentrated ammonia solution. The precipitate is filtered off under suction, washed with water, dried and purified on a silica gel column with chloroform. 0.28 g (21% of theory) of 1-isopropyl-6-cyano-1,2-dihydropyrido[2,3-c][1,8]naphthyridin-3(4H)-one is obtained.