Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]2[C:12]3[N:13]=[C:14]([NH:18][CH2:19][CH3:20])[N:15]=[C:16]([CH3:17])[C:11]=3[CH:10]=[CH:9][C:8]2=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:22]Br>CC(O)=O.C(Cl)Cl>[Br:22][C:9]1[C:8](=[O:21])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:12]2[N:13]=[C:14]([NH:18][CH2:19][CH3:20])[N:15]=[C:16]([CH3:17])[C:11]=2[CH:10]=1
Reactant: BrBr
Reactant: CCNc1nc(C)c2ccc(=O)n(C3CCCCC3)c2n1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNc1nc(C)c2cc(Br)c(=O)n(C3CCCCC3)c2n1
Yield: 80 %

Procedure:
To 8-cyclohexyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one in AcOH and CH2Cl2 was added Br2 (22 uL, 0.42 mmol) at 80° C. Standard workup and purification by column chromatography gave 65 mg (0.17 mmol, 80% yield) of 6-bromo-8-cyclohexyl-2-(ethylamino)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:15](=[O:30])[NH:14]2)=[O:12])=[CH:6][CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:16]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:15](=[O:30])[NH:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: O=C1NN(C(=O)Nc2ccc([N+](=O)[O-])cc2)C(c2ccccc2)C1c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(NC(=O)N2NC(=O)C(c3ccccc3)C2c2ccccc2)cc1
Yield: 27.1 %

Procedure:
1-[(4-Nitrophenyl)aminocarbonyl]-4,5-diphenyl-3-pyrazolidinone (500 mg, 1.24 mmol) was dissolved in 50 mL EtOH and hydrogenated with 5% Pd/C (500 mg) under 60 p.s.i. H2, overnight at room temperature. The mixture was filtered to remove catalyst, solvent removed in vacuo, and the product isolated by chromatography (0-50% EtOAc:hexane gradient) as 125 mg (27%) solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:9][N:10]=2)[N:7]=1.[F:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[N:36]1[CH2:40][CH2:39][CH2:38][C:37]1=[O:41].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O>>[F:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[N:9][N:10]=3)[N:7]=2)[CH:24]=[CH:23][C:22]=1[N:36]1[CH2:40][CH2:39][CH2:38][C:37]1=[O:41]
Reactant: CC1(C)OB(c2ccc(N3CCCC3=O)c(F)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NCc1nnc2ccc(Cl)nn12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)NCc1nnc2ccc(-c3ccc(N4CCCC4=O)c(F)c3)nn12
Yield: 51.9 %

Procedure:
A 48 mL sealed tube was charged with tert-butyl (6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.150 g, 0.529 mmol), 1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one (0.242 g, 0.793 mmol), PdCl2(dppf)-CH2Cl2Adduct (0.0432 g, 0.0529 mmol), cesium carbonate (0.689 g, 2.11 mmol), 1,4-dioxane (3.62 ml, 42.3 mmol), and water (0.905 ml, 50.2 mmol), flushed with argon, sealed, then placed in a 80° C. oil bath for 5 hours. The contents were transferred to a flask and concentrated. The solid was triturated with water to give a red residue, which was purified by MPLC using a 40 g RediSep column, eluting with 2-6% MeOH/DCM over 40 minutes. tert-butyl (6-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (0.117 g, 51.9% yield) was isolated as a tan solid.
Reaction SMILES: C(OC(=O)[CH2:5][NH:6][S:7](C1C=CC(OCC#CC)=CC=1)(=[O:9])=[O:8])C.C(=O)([O-])[O-].[K+].[K+].Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](CCl)[CH:30]=1>CN(C=O)C.CCOCC.O>[N:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=1[CH2:5][NH:6][SH:7](=[O:9])=[O:8]
Reactant: ClCc1cccnc1
Reactant: CC#CCOc1ccc(S(=O)(=O)NCC(=O)OCC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: O=[SH](=O)NCc1ccccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 201 %

Procedure:
To a solution of 0.300 g (0.965 mmol) of the product of Example 20 in 5.0 mL of DMF was added 0.419 g (3.038 mmol) of potassium carbonate followed by 0. 166 g (1.013 mmol) of 3-picolyl chloride hydrochloride. The resulting mixture was stirred at room temperature for 15 h and then diluted with ether and water. The organics were washed with water, dried over Na2SO4, filtered and concentrated in vacuo to give a pale yellow solid. The solid was washed with ether/hexanes (1:1) and dried in vacuo to provide 0.334 g (86%) of the N-picolyl sulfonamide as a tan solid. Electrospray Mass Spec 402.9 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:21])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][F:20])[CH2:14]3)[CH:11]=2)[C:6](=[O:22])[C:5]([C:23]([OH:25])=[O:24])=[CH:4]1)[CH3:2].[CH:26]([O-])=O.[Na+].[OH-].[Na+]>C(O)(=O)C.C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:21])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:26])[CH:15]([CH2:19][F:20])[CH2:14]3)[CH:11]=2)[C:6](=[O:22])[C:5]([C:23]([OH:25])=[O:24])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(CF)C3)cc21
Reactant: O=C[O-]
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(CF)C3)cc21

Procedure:
A 100 mg portion of 1-ethyl-6-fluoro-7-[3-(fluoromethyl)-1-piperazinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 300 mg of sodium formate were dissolved in a mixture of 3 ml of glacial acetic acid and 3 ml of 37% formaldehyde and refluxed overnight. The mixture was cooled, basified with sodium hydroxide, acidified with glacial acetic acid and evaporated. The residue was triturated with hot chloroform and the solid crystallized from methanol, giving 91 mg of the desired product, mp 230°-235° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][C:8]([CH3:15])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>>[CH2:13]([O:12][C:9]1[CH:10]=[C:11]2[C:6](=[N:7][C:8]=1[CH3:15])[N:5]=[CH:4][C:3]([C:16]#[N:17])=[C:2]2[NH:24][C:23]1[CH:25]=[CH:26][C:20]([O:19][CH3:18])=[CH:21][CH:22]=1)[CH3:14]
Reactant: CCOc1cc2c(Cl)c(C#N)cnc2nc1C
Reactant: COc1ccc(N)cc1
Product: CCOc1cc2c(Nc3ccc(OC)cc3)c(C#N)cnc2nc1C

Procedure:
A mixture of 4-chloro-6-ethoxy-7-methyl-1,8-naphthyridine-3-carbonitrile (2.66 g), 4-methoxyaniline (1.35 g) and IMS (50 ml) was boiled under reflux for 2.5 hours. The mixture was cooled in ice and the precipitate was collected by filtration. This solid was boiled in IMS (50 ml), with 5M sodium hydroxide solution (1.2 ml) under reflux for 30 minutes. The mixture was cooled and evaporated. The residue was purified by flash chromatography on silica using dichloromethane/IMS, 19:1 as the mobile phase to give a solid which was ground up in IMS (15 ml) and filtered to give 6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridine-3-carbonitrile, m.p. 190°-192° C. Active (1/1) at 30 mg/kg.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[C:23](Br)[CH:24]=[N:25][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[Pd].C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[C:1]1([S:7]([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:20]#[N:21])=[C:18]([OH:19])[C:13]=3[C:12]3[CH:22]=[CH:23][CH:24]=[N:25][C:11]2=3)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ncc2c(c1O)c1cc(Br)cnc1n2S(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ncc2c(c1O)c1cccnc1n2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 97.6 %

Procedure:
A suspension of 9-benzenesulfonyl-3-bromo-5-hydroxy-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (5.0 g, 11.7 mmol) and 10% palladium on carbon (500 mg) in industrial methylated spirits (120 mL), ethyl acetate (25 mL), dimethylformamide (25 mL) and triethylamine (25 mL) was stirred at ambient temperature under an atmosphere of hydrogen for 20 h. The reaction vessel was purged with nitrogen then the reaction mixture was filtered through celite. The filtrate was evaporated in vacuo. The resultant brown residue was suspended in aqueous hydrochloric acid (1M, 40 mL) and sonicated for 20 minutes then filtered to afford the title compound as a beige solid (4.0 g, 98%). 1H NMR (DMSO-D6, 300 MHz): 9.27 (d, J=0.8 Hz, 1H), 8.73-8.65 (m, 2H), 8.19 (d, J=7.9 Hz, 2H), 7.78-7.69 (m, 1H), 7.65-7.54 (m, 3H).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[Br:9][C:10]1[C:11]([N:13]([CH3:26])[C:14](=[O:25])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:12].[Cl-].[Na+]>CN(C=O)C>[Br:9][C:10]1[C:11]([N:13]([CH3:26])[C:14](=[O:25])[C:15]=1[C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]([CH3:1])[CH:17]=1)=[O:12]
Reactant: O=C([O-])[O-]
Reactant: CN1C(=O)C(Br)=C(c2c[nH]c3ccccc23)C1=O
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)C(Br)=C(c2cn(C)c3ccccc23)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Potassium carbonate (140 mg, 0.98 mmol) and methyl iodide (0.06 mL, 0.98 mmol) were added under ice cooling to 2-bromo-3-(1H-indol-3-yl)-N-methylmaleimide (100 mg, 0.33 mmol) synthesized according to a known method (Tetrahedron, Vol. 44, p. 2887, 1988) and dissolved in DMF (5 mL), and the whole was stirred for 2 hours. The reaction mixture was warmed to room temperature, added with saturated aqueous sodium chloride solution, and extracted with ethyl acetate. The extract was dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=1:1) to obtain 2-bromo-3-(1-methyl-1H-indol-3-yl)-N-methylmaleimide (99 mg, 95.1%) as red solids.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])[CH:13]=[C:12]3[Br:20])=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:28])[C:14](=[O:19])[CH:13]=[C:12]3[Br:20])=[CH:6][CH:7]=1
Reactant: O=c1cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(=O)cc(Br)c2cc(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 6-[bis(4-chlorophenyl)methyl]-4-bromo-1,2-dihydroquinolin-2-one (700 mg, 1.52 mmol, 1.00 equip) in N,N-dimethylformamide (15 mL), potassium carbonate (630 mg, 4.56 mmol, 3.00 equip), and CH3I (0.33 g, 1.50 equip). The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of water (30 mL). The resulting solution was extracted with ethyl acetate (3×50 mL) and the organic layers combined. The resulting mixture was washed with water (2×50 mL) and saturated brine (1×50 mL). The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield 6-[bis(4-chlorophenyl)methyl]-4-bromo-1-methyl-1,2-dihydroquinolin-2-one as a yellow solid. (ES, m/z): [M+H]+ 474
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[F:19][C:20]([F:30])([F:29])[O:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1>>[CH3:18][O:17][C@@H:13]([CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][O:1][C:25]2[CH:24]=[CH:23][C:22]([O:21][C:20]([F:19])([F:29])[F:30])=[CH:27][CH:26]=2)=[CH:7][CH:8]=1)[C:14]([OH:16])=[O:15]
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Reactant: Oc1ccc(OC(F)(F)F)cc1
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(OC(F)(F)F)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 4-trifluoromethoxyphenol and cleavage from the resin (Standard Procedure G) gave an oily solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14]([OH:16])=O)=[N:4][C:5]([O:12][CH3:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:18][CH2:19][C@:20]([CH3:26])([OH:25])[C:21]([F:24])([F:23])[F:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.CCOC(C)=O>[F:22][C:21]([F:24])([F:23])[C@:20]([OH:25])([CH3:26])[CH2:19][NH:18][C:14]([C:3]1[C:2]([NH2:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[C:5]([O:12][CH3:13])[N:4]=1)=[O:16]
Reactant: C[C@](O)(CN)C(F)(F)F
Reactant: COc1nc(C(=O)O)c(N)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COc1nc(C(=O)NC[C@](C)(O)C(F)(F)F)c(N)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid (Intermediate D) (10 g, 42.3 mmol) and (S)-3-amino-1,1,1-trifluoro-2-methylpropan-2-ol hydrochloride (Intermediate RA)(7.60 g, 42.3 mmol) in NMP (400 ml) was added HATU (19.3 g, 50.8 mmol) followed by dropwise addition of DIPEA (22.19 ml, 127 mmol) over ˜1 hr. After stirring at room temperature for 30 min, the mixture was added to EtOAc (2 L), washed with 1M NaOH (2×1 L), water (1 L), brine (1 L), dried (MgSO4) and evaporated under reduced pressure to give the crude product as a dark brown oil. Purification by chromatography on silica eluting with a gradient of 1 to-25% of EtOAc in iso-hexane afforded a yellow oil. Recrystallisation of the oil from iso-hexane/DCM afforded 3-amino-6-methoxy-5-trifluoromethyl-pyridine-2-carboxylic acid ((S)-3,3,3-trifluoro-2-hydroxy-2-methyl-propyl)-amide as a crystalline solid;
Reaction SMILES: [OH:1][C@H:2]1[C@@:6]2([O:9][CH2:8][CH2:7]2)[C@H:5]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[NH:12][C:11]2=[O:17])[O:4][C@@H:3]1[CH2:18][OH:19].CN1C=CN=C1.Cl[C:27]1[CH:43]=[CH:42][CH:41]=[CH:40][C:28]=1[O:29][P:30](=[N:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36][CH3:37])=[O:35])=[O:31]>C1COCC1>[O:17]=[C:11]1[NH:12][C:13](=[O:16])[CH:14]=[CH:15][N:10]1[C@@H:5]1[O:4][C@H:3]([CH2:18][O:19][C:40]2[CH:41]=[CH:42][CH:43]=[CH:27][C:28]=2[O:29][P:30](=[N:32][C:33]([CH3:39])([CH3:38])[C:34]([O:36][CH3:37])=[O:35])=[O:31])[C@@H:2]([OH:1])[C@:6]21[O:9][CH2:8][CH2:7]2
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@]23CCO3)c(=O)[nH]1
Reactant: COC(=O)C(C)(C)N=[P+]([O-])Oc1ccccc1Cl
Agent: Cn1ccnc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)N=[P+]([O-])Oc1ccccc1OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@@]2(CCO2)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.4 %

Procedure:
To a solution of 10 (1.0 eq., 0.28 mmol, 75 mg) in dry THF (3 mL) was added 1-methylimidazole (NMI; 12.0 eq., 3.33 mmol, 0.27 mL) at room temperature. A solution of intermediate 11 (1.4 eq., 0.39 mmol, 0.43 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. The reaction mixture was washed three times with 0.5 M HCl. The organic layer was dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (0-10% methanol in CH2Cl2) to give compound 12e (24 mg, yield=15%, purity=95%) as a mixture of diastereomers. HPLC Condition A; Rt: 1.49 min, m/z=526 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33 (s, 3H), 1.37 (s, 3H), 2.42-2.43 (m, 2H), 3.56 (s, 3H), 3.70-3.79 (m, 1H), 3.80-3.88 (m, 0.4; H), 3.88-3.96 (m, 0.6; H), 4.09-4.20 (m, 1H), 4.26-4.48 (m, 3H), 5.50-5.56 (m, 1H), 5.61-5.69 (m, 1H), 5.88-5.97 (m, 1H), 5.97-6.04 (m, 1H), 7.12-7.24 (m, 3H), 7.31-7.41 (m, 2H), 7.44 (d, J=8.22 Hz, 0.4; H), 7.52 (d, J=8.02 Hz, 0.6; H), 11.49 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:51]([O:55][C:56]([N:58]1[CH2:63][CH2:62][CH:61]([CH2:64][C:65](O)=[O:66])[CH2:60][CH2:59]1)=[O:57])([CH3:54])([CH3:53])[CH3:52]>C(OCC)(=O)C.O.CN(C)C=O>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:65](=[O:66])[CH2:64][CH:61]3[CH2:62][CH2:63][N:58]([C:56]([O:55][C:51]([CH3:53])([CH3:52])[CH3:54])=[O:57])[CH2:59][CH2:60]3)[CH:7]=2)=[CH:10][C:11]=1[Cl:16]
Reactant: Nc1cc(Oc2ccc(N)c(Cl)c2)ccn1
Reactant: CC(C)(C)OC(=O)N1CCC(CC(=O)O)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: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CC(=O)Nc2cc(Oc3ccc(N)c(Cl)c3)ccn2)CC1
Reaction time: 18 h
Yield: 30.1 %

Procedure:
2-Amino-4-(4-amino-3-chlorophenoxy)pyridine (1.0 g), Bop reagent (1.9 g), triethylamine (1.2 ml), 2-[1-(tert-butoxycarbonyl)-4-piperidyl]acetic acid (1.0 g) and dimethylformamide (10 ml) were stirred at 60° C. for 2 hours and then at room temperature for 18 hours. Water was added to the reaction solution, and extraction was performed with ethyl acetate. Silica gel was added to the extract solution and the solvent was distilled off under reduced pressure. The silica gel was charged into a dry column packed with silica gel, and purification was performed by column chromatography (hexane:ethyl acetate=1:1) to obtain 570 mg of a light brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:20][CH3:21]>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:6][CH:7]=1)[CH3:21]
Reactant: CCBr
Reactant: Oc1ccc(-c2nccs2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1ccc(-c2nccs2)cc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a mixture of 2-(4-hydroxyphenyl)thiazole (21.27 g, 0.12 mol) and K2CO3 (82.93 g, 0.60 mol) in acetone (1000 mL) was added bromoethane (39.24 g, 0.36 mol) with stirring at rt. The reaction mixture was heated at 60° C. for 11 h, then cooled to rt, filtered and concentrated in vacuo to give the title compound as a white solid (24.54 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].C(O[CH:17](OCC)[N:18]([CH3:20])[CH3:19])C>>[CH2:1]([O:3][C:4](=[O:13])[C:5]([C:6]1[C:7]([CH3:12])=[N:8][CH:9]=[CH:10][CH:11]=1)=[CH:17][N:18]([CH3:20])[CH3:19])[CH3:2]
Reactant: CCOC(=O)Cc1cccnc1C
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)c1cccnc1C

Procedure:
600 mg (3.35 mmol) of the compound from Example 39A are heated in 1.7 ml (10.0 mmol) dimethylformamide diethyl acetal overnight at 100° C. After cooling, the mixture is concentrated and the residue is purified by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][C:15]([NH2:17])=O)[CH:9]=[CH:10][C:11]=1[CH3:12].[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>O1CCCC1.O>[CH3:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][CH2:15][NH2:17])[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccc(CCC(N)=O)cc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: O=S(Cl)Cl
Product: Cc1ccc(CCCN)cc1C
Yield: 79 %

Procedure:
A mixture of 18.5 g of the compound obtained in step 1 and 50 ml of thionyl chloride was refluxed for 2 hours, concentrated under a reduced pressure and the residue was dissolved in 100 ml of ethyl ether. The resulting solution was added to a mixture of 200 ml of ethyl ether, 150 ml of water and 50 ml of 30% aqueous ammonia solution with stirring. The organic layer was discarded and the remaining aqueous layer was extracted twice with 150 ml of dichloromethane. The organic solvent was distilled off to obtain a residue which was essentially 3-(3,4-dimethylphenyl)propionamide. This residue dissolved in 150 ml of tetrahydrofuran was added to a mixture of 8.0 g of LiAlH4 and 200 ml of tetrahydrofuran. The resultant mixture was refluxed for 5 hours; then 30 ml of 30% aqueous NaOH solution and 20 ml of water were added thereto. After separating the tetrahydrofuran layer, the solid residue was dissolved in 300 ml of water and extracted twice with 200 ml of ethyl ether. The tetrahydrofuran layer and the ethyl ether extract were combined, and the resulting solution was concentrated under a reduced pressure. The residue so obtained was distilled under a reduced pressure(140° to 150° C., 0.5 mmHg) to obtain 13.4 g of the title compound(yield: 79%).
Reaction SMILES: [CH2:1]1[O:26][C:25]2[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]3[CH:22]=[CH:21][C:11]([C:12]([NH:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=O)=[CH:10][CH:9]=3)=[CH:4][C:3]=2[O:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]1[O:26][C:25]2[CH:24]=[CH:23][C:5]([CH2:6][O:7][C:8]3[CH:22]=[CH:21][C:11]([CH2:12][NH:14][C:15]4[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=4)=[CH:10][CH:9]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=C(Nc1ccncc1)c1ccc(OCc2ccc3c(c2)OCO3)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: c1cc(NCc2ccc(OCc3ccc4c(c3)OCO4)cc2)ccn1

Procedure:
18-6 (0.32 g, 0.9 mmol) was reduced with lithium aluminum hydride (0.30 g, 8 mmol) as in Example 10. The product 18-7 was obtained as an oil. The hydrochloride salt melted at 190°-193° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[CH:12]1[N:20]2[C:15]([CH2:16][S:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=32)=[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:13]=1>CN(C=O)C.C(Cl)Cl.[Pd]>[C:2]1([C:12]2[N:20]3[C:15]([CH2:16][S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=43)=[C:14]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[N:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1CSc1ccccc1-2
Reactant: Ic1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(-c2ccccc2)n2c1CSc1ccccc1-2
Temperature: 140 °C
Yield: 31 %

Procedure:
Iodo benzene (0.15 mL, 1.15 mmol, 2 eq), palladium (Il) acetate (6.4 mg, 0.03 mmol, 0.05 eq), and Cul (0.22 g, 1.15 mmol, 2 eq) are taken in pressure tube to which is added ethyl 4H-imidazo[5,1-c][1,4]benzothiazine-3-carboxylate (0.15 g, 0.576 mmol, 1 eq) taken in degassed DMF (6 mL) and the contents are heated at 140° C. for 12 h. The reaction mixture is diluted with DCM and filtered through celite. The filtrate is concentrated, passed through a plug of silica gel and concentrated to get the crude product 60 mg which is taken as such to next step. MS (ESI+): 337.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:4]=1[CH:5]=O.[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)(=[O:21])[CH3:20]>>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:4]=1/[CH:5]=[CH:20]/[C:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1)=[O:21]
Reactant: COc1cc(OC)c(-c2cnccn2)cc1C=O
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Product: COc1cc(OC)c(-c2cnccn2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1
Yield: 4 %

Procedure:
The title compound was prepared by condensing 2,4-dimethoxy-5-pyrazin-2-yl-benzaldehyde (Ex-46D) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp 238° C. (dec.), 4% yield. 1H-NMR (DMSO-D6) δ 9.04 (d, J=2 Hz, 1H), 8.75–8.76 (m, 1H), 8.56 (d, J=2 Hz, 1H), 8.32 (s, 1H), 8.19 (d, J=9 Hz, 2H), 8.05–8.11 (m, 3H), 7.83 (d, J=16 Hz, 1H), 6.90 (s, 1H), 4.05 (s, 3H), 4.00 (s, 3H). HRMS m/z=calc. 391.1294. found 391.1313.