Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.C(N(CC)CC)C.O>C(#N)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 79.4 %

Procedure:
In 20 ml of acetonitrile were dissolved 2.8 g of 4-nitrofluorobenzene, 3 g of 4-piperidone hydrochloride and 6.9 ml of triethylamine, and the solution was then heated under reflux for 6 hours. After cooling, the reaction mixture was poured into 100 ml of water, and the deposited crystals were collected by filtration. The crystals were washed with water and then with ether, and they were recrystallized from isopropanol/hexane (1/1 in terms of volume ratio), collected by filtration, washed, and dried in order to obtain 3.47 g of 1-(4-nitrophenyl)-4-oxopiperidine (compound 62).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 2 h

Procedure:
To a mixture of 2-chloro-5-nitrobenzoic acid (5.0 g, 25.0 mmol) and dichloromethane (100 ml) was added oxalyl chloride (2.7 ml, 31.0 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 2 hours, the mixture was concentrated under reduced pressure to provide 2-chloro-5-nitro-benzoyl chloride.
Reaction SMILES: [NH2:1][CH:2]([C:39]([OH:48])([C:44]([F:47])([F:46])[F:45])[C:40]([F:43])([F:42])[F:41])[C:3]([NH:5][C@:6]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([O:35][CH:36]([CH3:38])[CH3:37])[CH:29]=1)([C:14]1[CH:19]=[C:18]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:17]=[C:16]([F:27])[CH:15]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=O.B.[H][H].B(F)(F)F.CCOCC.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[NH2:1][CH:2]([CH2:3][NH:5][C@:6]([C:28]1[CH:33]=[CH:32][C:31]([F:34])=[C:30]([O:35][CH:36]([CH3:38])[CH3:37])[CH:29]=1)([C:14]1[CH:19]=[C:18]([O:20][C:21]([F:25])([F:26])[CH:22]([F:24])[F:23])[CH:17]=[C:16]([F:27])[CH:15]=1)[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:39]([C:44]([F:45])([F:46])[F:47])([OH:48])[C:40]([F:43])([F:42])[F:41]
Reactant: [H][H]
Reactant: CC(C)Oc1cc([C@@](Cc2ccccc2)(NC(=O)C(N)C(O)(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: B
Agent: FB(F)F
Agent: [Al+3]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)Oc1cc([C@@](Cc2ccccc2)(NCC(N)C(O)(C(F)(F)F)C(F)(F)F)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Temperature: 100 °C
Yield: 20 %

Procedure:
To a solution of 2-amino-4,4,4-trifluoro-N—((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-hydroxy-3-(trifluoromethyl)butanamide, prepared as described in Example 293, (20 mg, 0.028 mmol) in THF (0.5 mL) was added borane (0.2 mL, 1.0 M solution in THF). After hydrogen evolution ceased, the solution was heated in a sealed microwave vial under microwave irradiation at 100° C. for 5 min. The solvents were removed under a stream of nitrogen then THF (0.5 mL) was added to the residue followed by BF3.Et2O (30 mg, 0.21 mmol) and LAH (0.2 mL, 1.0 M solution in THF). After evolution of hydrogen gas had ceased, the sealed microwave vial was heated at 100° C. for 10 min. The solvents were removed under a stream of nitrogen and the residue dissolved in NH4OH (ca. 10 mL). LiCl (10%, ca. 10 mL) was added and the aqueous extracted with DCM (3×10 mL). The combined organic portions were concentrated under reduced pressure and purified by preparative TLC (25×25 mm, silica gel 1 mm elution with hexane:EtOAc 4:1). 3-Amino-1,1,1-trifluoro-4-((R)-1-(4-fluoro-3-isopropoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethylamino)-2-(trifluoromethyl)butan-2-ol (Example 327, 5 mg, 20% yield) was isolated as a colorless oil at Rf of 0.5. LCMS: RT=3.88 min [M+H] 693.1 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=3.88 min, Purity 91% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm) NMR: 400 MHz 1H (CDCl3) 7.15 ppm, 3H, m; 7.05 ppm, 1H, m; 6.86 ppm, 2H, d, J=8.0 Hz; 6.83 ppm, 3H, m; 6.61 ppm, 2H, d, J=8.0 Hz; 5.87 ppm, 1H, t, t, J=52.0 Hz and J=4.0 Hz; 4.41 ppm, 1H, sept, J=8.0 Hz; 3.57 ppm, 1H, d, J=12.0 Hz; 3.48 ppm, 1H, d, J=12.0 Hz; 2.99 ppm, 2H, m; 2.53 ppm, 1H, brt; 1.27 ppm, 3H, d, J=8.0 Hz; 1.25 ppm, 3H, d, J=8.0 Hz.
Reaction SMILES: [OH-].[K+].C[O:4][C:5](=[O:18])[C:6]1[C:11]([CH3:12])=[C:10]([O:13][CH3:14])[CH:9]=[C:8]([OH:15])[C:7]=1[CH:16]=[O:17].Cl>O>[OH:17][CH:16]1[C:7]2[C:6](=[C:11]([CH3:12])[C:10]([O:13][CH3:14])=[CH:9][C:8]=2[OH:15])[C:5](=[O:18])[O:4]1
Reactant: COC(=O)c1c(C)c(OC)cc(O)c1C=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1cc(O)c2c(c1C)C(=O)OC2O
Temperature: 75 °C
Yield: 98.1 %

Procedure:
A solution of 28 g of potassium hydroxide in 0.2 l of water was added to 44.8 g of 2-formyl-3-hydroxy-5-methoxy-6-methylbenzoic acid methyl ester. The mixture was warmed to 75° C. within 30 rain and subsequently cooled to 5° C. Upon addition of 50 ml of 10N hydrochloric acid, a precipitate was formed immediately. The mixture was stirred at 0° C. for 30 rain and then filtered. The solid material was washed with water and dried in vacuo. The crude product was triturated with 160 ml of hot ethyl acetate. The mixture was cooled and 0.9 l of hexane were added. The solid was isolated by filtration to yield 41.2 g of (RS)-3,4-dihydroxy-6-methoxy-7-methyl-1,3-dihydro-iso-benzofuran-1-one, m.p. >255° C. (dec.).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14](OC)[CH:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[CH:34][C:35]3[S:39][CH:38]=[N:37][C:36]=3[CH:40]=2)O1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.CO.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[S:39]1[C:35]2[CH:34]=[CH:33][C:32]([C:2]3[N:3]=[C:4]([NH:11][C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=4)[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[CH:7]=3)=[CH:40][C:36]=2[N:37]=[CH:38]1
Reactant: CC1(C)OB(c2ccc3scnc3c2)OC1(C)C
Reactant: COc1cc(Nc2nc(Br)cn3ccnc23)cc(OC)c1OC
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2nc(-c3ccc4scnc4c3)cn3ccnc23)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.7 %

Procedure:
A mixture of 6-bromo-N-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyrazin-8-amine (2) (209 mg, 0.601 mmol), and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (3) (180 mg, 0.689 mmol) in 1 M aqueous sodium carbonate (0.76 mL) and 1,4-dioxane (2.4 mL) was sparged with nitrogen while stirring for 5 min. Tetrakis(triphenyl-phosphine) palladium(0) (69 mg, 0.06 mmol) was then added and the resulting mixture reacted under microwave irradiation at 135° C. for 30 min. After this time, the reaction was cooled to ambient temperature, diluted with 1:9 methanol/ethyl acetate (75 mL), and washed with water (50 mL) then brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by chromatography (silica, gradient 0% to 10% methanol in methylene chloride) to afford 6-(benzo[d]thiazol-5-yl)-N-(3,4-dimethoxyphenyl)imidazo[1,2-a]pyrazin-8-amine (4) (169 mg, 70%) as an off-white solid: mp 179-181° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.56 (s, 1H), 9.45 (s, 1H), 8.78 (s, 1H), 8.76 (d, 1H, J=1.2 Hz), 8.26 (d, 1H, J=8.7 Hz), 8.14 (m, 2H), 8.00 (s, 1H), 7.66 (s, 1H), 7.58 (dd, 1H, J=8.7, 2.4 Hz), 6.99 (d, 1H, J=8.7 Hz), 3.87 (s, 3H), 3.76 (s, 3H); MS m/z 404.6 [M+H]+; HPLC, 6.475 min, 98.6% (AUC).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[S:13]([OH:16])(=[O:15])=[O:14]>>[CH3:1][C:2]1[C:10]2[O:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[S:13]([OH:16])(=[O:15])=[O:14]
Reactant: Cc1cccc2[nH]c(=O)oc12
Reactant: O=S(=O)(O)Cl
Product: Cc1c(S(=O)(=O)O)ccc2[nH]c(=O)oc12
Yield: 60 %

Procedure:
7-Methyl-3H-benzooxazol-2-one [5.0 g, 33 mmol, prepared according to the procedure described in J. Org. Chem. (1982), 47(14), 2804–6) was treated with chlorosulphonic acid as described in Example 15 (i) to give the title compound as an off-white solid (4.5 g, 60%).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[CH2:13][NH:14][CH:15]1[CH2:17][CH2:16]1)([CH3:3])[CH3:2].[C:19](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH:1]([O:4][C:5](=[O:18])[C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][C:7]=1[CH2:13][N:14]([CH:15]1[CH2:16][CH2:17]1)[CH3:19])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)c1ccc(Br)cc1CNC1CC1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CC(C)OC(=O)c1ccc(Br)cc1CN(C)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
A solution of 4-bromo-2-cyclopropylaminomethyl-benzoic acid isopropyl ester (Intermediate 119, 1.33 g, 4.26 mmol) in acetone (8 mL) was treated with potassium carbonate (2.36 g, 17.05 mmol) and methyl iodide (0.53 mL, 8.52 mmol) and the resulting reaction mixture was stirred at ambient temperature for 3 h. The volatiles were evaporated in vacuo, the residue was diluted with water and extracted with diethyl ether (×2). The combined organic phase was dried over anhydrous magnesium sulfate, filtered over a short bed of silica gel (230-400 mesh) and evaporated in vacuo to afford the title product (1.23 g, 70%).
Reaction SMILES: [CH3:1][O:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([CH2:13][N:14]4[C:18]([CH3:19])=[CH:17][CH:16]=[N:15]4)([CH2:6]3)[CH2:4]1)[CH2:10]2.[I:20]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[I:20][C:17]1[CH:16]=[N:15][N:14]([CH2:13][C:5]23[CH2:6][CH:7]4[CH2:8][CH:9]([CH2:10][C:3]([O:2][CH3:1])([CH2:12]4)[CH2:4]2)[CH2:11]3)[C:18]=1[CH3:19]
Reactant: COC12CC3CC(CC(Cn4nccc4C)(C3)C1)C2
Reactant: O=C1CCC(=O)N1I
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC12CC3CC(CC(Cn4ncc(I)c4C)(C3)C1)C2

Procedure:
A mixture of EXAMPLE 16D (0.116 g) and N-iodosuccinimide (0.11 g) in 1 mL DMF was stirred overnight. The mixture was taken up in ethyl acetate, and the resulting solution was washed three times with water, and brine, then dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with 0-50% ethyl acetate/hexanes to provide the title compound.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([NH:18][C:19](=[O:34])[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:22][CH:21]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[NH:16])[NH:14][OH:15])=[C:9]([F:17])[CH:8]=1)C.C(OC(=O)C(N[C:52](=O)[C:53]1[CH:58]=[CH:57][C:56]([NH:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[CH:55][CH:54]=1)CC1C=CC(C#N)=C(F)C=1)C.NO.Cl.C([O-])(O)=O.[Na+]>CCO>[C:30]([O:29][C:27]([NH:26][C:23]1[CH:22]=[CH:21][C:20]([C:19]([NH:18][CH:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:16]=[C:52]([C:53]4[CH:54]=[CH:55][C:56]([NH:59][C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])=[CH:57][CH:58]=4)[O:15][N:14]=3)=[C:9]([F:17])[CH:8]=2)[C:4]([OH:3])=[O:35])=[O:34])=[CH:25][CH:24]=1)=[O:28])([CH3:33])([CH3:31])[CH3:32]
Reactant: CCOC(=O)C(Cc1ccc(C(=N)NO)c(F)c1)NC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Reactant: CCOC(=O)C(Cc1ccc(C#N)c(F)c1)NC(=O)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: NO
Agent: O=C([O-])O
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(C(=O)NC(Cc2ccc(-c3noc(-c4ccc(NC(=O)OC(C)(C)C)cc4)n3)c(F)c2)C(=O)O)cc1
Temperature: 120 °C

Procedure:
2-(4-tert-Butoxycarbonylamino-benzoylamino)-3-[3-fluoro-4-(N-hydroxycarbamimidoyl)-phenyl]-propionic acid ethyl ester. A mixture of 2-(4-tert-butoxycarbonylamino-benzoylamino)-3-(4-cyano-3-fluoro-phenyl)-propionic acid ethyl ester (214 mg, 0.47 mmol), NH2OH.HCl (49 mg 0.71 mmol), and NaHCO3 (79 mg, 0.94 mmol) in EtOH (10 mL) was heated under microwave at 120° C. for 20 min and then allowed to cool to room temperature. The mixture was filtered, concentrated in vacuo, and purified by silica gel chromatography to give the title compound (170 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:33]=[CH:32][C:23]([C:24]([NH:26][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30])=[O:25])=[CH:22][CH:21]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=O)=[C:4]([CH3:34])[CH:3]=1.Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:20]2[CH:33]=[CH:32][C:23]([C:24]([NH:26][CH2:27][C@@H:28]([OH:31])[CH2:29][OH:30])=[O:25])=[CH:22][CH:21]=2)[CH2:9]/[C:10](=[N:36]\[OH:37])/[C:12]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([CH3:19])[CH:13]=2)=[C:4]([CH3:34])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC[C@@H](O)CO)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC[C@@H](O)CO)cc1

Procedure:
In analogy to example 151, step 3, 4-(1-(4-chloro-2-methylphenyl)-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxopropyl)-N—((R)-2,3-dihydroxypropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound containing less than 10% of the corresponding Z isomer as an off-white solid, MS (ESI+): m/z=498.2 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O>[CH3:14][CH:9]1[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[C:11](=[O:13])[CH2:10]1
Reactant: CC(CCc1ccccc1)CC(=O)O
Solvent: O
Product: CC1CCc2ccccc2C(=O)C1
Temperature: 70 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
5-Phenyl-3-methylpentanoic acid (0.10 g, 0.52 mmol) was added to polyphosphoric acid (7 g), and the resulting mixture was stirred at 70° C. for 1 hour. Water was added to the reaction mixture, followed by extraction with ethyl acetate, and the extract solution was washed with water, a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 0.07 g of 7-methyl-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one.
Reaction SMILES: [C:1]1(/[CH:11]=[C:12]2/[CH:13]([OH:22])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:38](O)(=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>CN(C1C=CN=CC=1)C>[C:1]1(/[CH:11]=[C:12]2/[CH:13]([O:22][C:38](=[O:46])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:14]#[C:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[C:21]/2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Reactant: CCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Product: CCCCCCCC(=O)OC1C#CCCCCC#C/C1=C\c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
To a solution of Compound 20b (10.0 mg, 3.50×10−2 mmol), DCC (7.2 mg, 3.50×10−2 mmol), and DMAP (8.5 mg, 6.99×10−2 mmol) in dry Ch2Cl2 (4 mL) cooled in an ice-water bath was added n-octanoic acid (7.5 mg, 5.24×10−2 mmol) followed by stirring at room temperature for 4 hours. The reaction mixture was filtered through a short plug of Celite with rinsing by EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography (silica gel, 20 percent EtOAc in hexane) to give 11.2 mg (78 percent) of Compound 37: pale yellow oil; Rf=0.65 (20 percent EtOAc in hexane); IR (neat) 2932, 1724, 1177, 1037 cm−1; 1H NMR (300 MHz, CDCl3) δ8.31 (d, J=7.26 Hz, 1H), 8.01 (d, J=7.41 Hz, 1H), 7.86-7.78 (m, 2H), 7.56-7.46 (m, 3H), 7.44 (s, 1H), 6.24 (s, 1H), 2.54-2.22 (m, 4H), 2.42 (t, J=7.53 Hz, 2H), 1.97-1.60 (m, 6H), 1.40-1.16 (m, 8H), 0.84 (t, J=7.02 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ173.9, 134.2, 133.0, 132.7, 132.2, 129.6, 129.3, 127.0, 127.0, 126.5, 126.0, 124.2, 123.8, 103.2, 93.6, 80.9, 79.5, 69.2, 35.2, 32.3, 29.7, 29.6, 28.3, 28.2, 25.7, 23.3, 22.6, 21.4, 14.7; MS (+CI) m/z (relative intensity) 413 (M+, 6), 269 (100).
Reaction SMILES: C([O:8][C:9](=O)[C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=[CH:12][C:11]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)C1C=CC=CC=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:25]([O:24][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]=1[CH2:9][OH:8])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(OCc1ccccc1)c1c(OCc2ccccc2)cccc1OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1c(OCc2ccccc2)cccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,6-bis-benzyloxybenzoic acid benzyl ester (3.0 g, 6.6 mmol) in THF (15 mL) at 0° C. is added dropwise 7.92 mL of LiAlH4 (1.0M in THF) then the mixture is stirred at RT for 18 h. Saturated sodium sulfate solution (1 ml) is added carefully and the resulting precipitate is filtered. The filtrate is evaporated to give the title compound. This is used directly in the next reaction.
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][OH:19])[CH2:3][CH2:4][N:5]1[C:10](=[O:11])[CH:9]=[N:8][C:7]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[N:15][C:6]1=2.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:36]1([CH3:46])[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>ClCCl.O>[CH3:46][C:36]1[CH:41]=[CH:40][C:39]([S:42]([O:19][CH2:18][C@H:2]([OH:1])[CH2:3][CH2:4][N:5]2[C:10](=[O:11])[CH:9]=[N:8][C:7]3[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[N:15][C:6]2=3)(=[O:44])=[O:43])=[CH:38][CH:37]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2ncc(=O)n(CC[C@@H](O)CO)c2n1
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CC[C@@H](O)COS(=O)(=O)c3ccc(C)cc3)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.1 %

Procedure:
In dichloromethane (80 ml) was dissolved 4-[(3R)-3,4-dihydroxybutyl]-6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (4.38 g, 16.51 mmol) and triethylamine (2.76 ml, 19.81 mmol), dimethylamino pyridine (403 mg, 3.30 mmol) and p-toluene sulfonyl chloride (3.46 g, 18.16 mmol) were added thereto under cooling on ice and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, water was added to the reaction solution, which was extracted with dichloromethane. After drying the extract over anhydrous sodium sulfate, the solvent was removed under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform/methanol) to yield 4.30 g (62%) of the title compound in the form of an orange oily product.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:9]([C:16]#[N:17])=[C:10]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]2=[N:4][CH:3]=1.[F:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:8]1[C:9]([C:16]#[N:17])=[C:10]([O:11][CH2:12][CH:13]([CH3:15])[CH3:14])[C:5]2[N:6]([C:2]([C:31]3[CH:30]=[CH:29][N:28]=[C:27]([F:26])[CH:32]=3)=[CH:3][N:4]=2)[CH:7]=1
Reactant: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(Br)cnc12
Reactant: OB(O)c1ccnc(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)COc1c(C#N)c(-c2ccc(Cl)cc2Cl)cn2c(-c3ccnc(F)c3)cnc12
Temperature: 150 °C
Yield: 40 %

Procedure:
In a sealed tube, a mixture of 3-bromo-6-(2,4-dichloro-phenyl)-8-isobutoxy-imidazo[1,2-a]pyridine-7-carbonitrile (115 mg, 0.25 mmol, prepared according to Example 35, Step 20.2), 2-fluoro-4-pyridine-boronic acid (45.3 mg, 0.32 mmol), PdCl2(PPh3)2 (9.6 mg, 0.014 mmol) and Na2CO3 (2.0 M solution in water, 0.43 mL) in DME (1 mL) was heated at 150° C. for 25 min in a microwave oven. The reaction mixture was cooled to RT, diluted in AcOEt (20 mL) and washed with water (2×10 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to dryness. The remaining residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, hexane/TBME 95:5→6:4) to yield the title compound (46.6 mg, 0.10 mmol, 41%) as a white solid. MS: 455 [M+1]+; HPLC: AtRet=3.18; TLC: RF 0.25 (hexane/TBME 1:1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[CH:29]1(B(O)O)[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH:29]1([C:2]2[CH:3]=[C:4]3[N:10]=[CH:9][N:8]([CH2:11][C:12]4[CH:28]=[CH:27][C:15]5[N:16]=[C:17]([NH:19][C@@H:20]6[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]6[OH:26])[S:18][C:14]=5[CH:13]=4)[C:5]3=[N:6][CH:7]=2)[CH2:31][CH2:30]1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Reactant: OB(O)C1CC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(C5CC5)cnc43)cc2s1
Temperature: 100 °C
Yield: 3.6 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol from Example 29 (30 mg, 0.0656 mmol), cyclopropylboronic acid (11 mg, 0.131 mmol), K2CO3 (36 mg, 0.262 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (16 mg, 0.0328 mmol) and anhydrous toluene (1 mL) was degassed under argon for 15 min. Tris(dibenzylideneacetone)dipalladium (0) (6 mg, 0.0066 mmol) was added. The reaction vessel was sealed and the mixture was heated at 100° C. for 15 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Phenomenex Luna C-18 column as the stationary phase to afford (1R,2R)-2-((6-((6-cyclopropyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (1 mg, 4%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.24 (d, J=1.5 Hz, 1H), 8.03 (d, J=7.3 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H), 7.63 (s, 1H), 7.28 (m, 1H), 7.19 (m, 1H), 5.44 (s, 2H), 4.82 (br s, 1H), 1.97-2.13 (m, 2H), 1.85 (m, 1H), 1.54-1.74 (m, 3H), 1.09-1.34 (m, 4H), 0.92-1.02 (m, 2H), 0.70-0.80 (m, 2H). LCMS (ESI) m/z 420 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:11][O:12][C:13](=[O:16])[CH2:14]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:11][O:12][C:13]([CH2:14][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:16]
Reactant: COC(=O)CBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)COc1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 4-nitrophenol, methylbromoacetate and caesium carbonate analogously to Example XIXa.