Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[CH:16]=[CH:15][S:14][C:13]=2Br)=[O:11])[C:5]([OH:8])=[CH:6][CH:7]=1.[C:18](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:13]3[S:14][C:15]([CH3:18])=[CH:16][C:12]=3[C:10](=[O:11])[NH:9][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1cc(Cl)ccc1O)c1ccsc1Br
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Oc1ccc(Cl)cc1NC2=O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 20.1 %

Procedure:
To a solution of N-(3-chloro-6-hydroxyphenyl)-2-bromo-3-thiophenecarboxamide (4.1 g) in dimethyl sulfoxide (33 ml) was added potassium carbonate (3.3 g), and the mixture was stined at 140-150° C. for 75 minutes. The reaction system was cooled to room temperature and the reaction mixture was poured into ice water. The precipitated crystals were collected by filtration. The filtrate was extracted twice with chloroform, the organic layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure. The residue and the above-mentioned crystals were combined and purified by silica gel column chromatography (chloroform:methanol=20:1, hexane:ethyl acetate=1:1-ethyl acetate:methanol=20:1). The obtained solid was collected by filtration from hexane-ethyl acetate to give 7-chloro-2-methylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (660 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[CH:20]=[C:21]([NH:26][S:27]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=2[F:25])[CH:5]=[CH:4][N:3]=1.[NH4+:38].[OH-]>>[NH2:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[CH:20]=[C:21]([NH:26][S:27]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[CH:32][C:31]=3[F:37])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=2[F:25])[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=S(=O)(Nc1ccc(F)c(-c2nc(N3CCOCC3)sc2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Agent: [OH-]
Product: Nc1nccc(-c2sc(N3CCOCC3)nc2-c2cc(NS(=O)(=O)c3c(F)cccc3F)ccc2F)n1
Temperature: 120 °C

Procedure:
Following a procedure analogous to the procedure described in Example 21 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(4-morpholinyl)-1,3-thiazol-4-yl]-4-fluorophenyl}-2,6-difluorobenzenesulfonamide (150 mg, 0.264 mmol) and NH4OH (3 mL) heated at 120° C. in a microwave reactor for 15 min, the title compound was obtained as a yellow solid (67 mg, 0.122 mmol, 46.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.99 (s, 1H), 7.78 (d, J=5.3 Hz, 1H), 7.59-7.75 (m, 1H), 7.18-7.30 (m, 4H), 7.15 (d, J=5.8 Hz, 1H), 6.57 (s, 2H), 5.59 (d, J=5.2 Hz, 1H), 3.64-3.77 (m, 4H), 3.40-3.47 (m, 4H). m/z (ES+): 549 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([NH:13][C@H:14]([C:42]([OH:44])=O)[CH2:15][C:16](=[O:41])[NH:17][C@@H:18]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][C:21](=[O:23])[CH3:22])(=[O:12])=[O:11])=[C:5]([CH3:45])[C:4]=1[CH3:46].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[ClH:72].[C:73]([C:76]1[CH:92]=[CH:91][C:79]([CH2:80][C@H:81]([C:83]([N:85]2[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]2)=[O:84])[NH2:82])=[CH:78][CH:77]=1)(=[NH:75])[NH2:74]>CN(C=O)C>[ClH:72].[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([NH:13][C@H:14]([C:42]([NH:82][C@@H:81]([C:83]([N:85]2[CH2:90][CH2:89][CH2:88][CH2:87][CH2:86]2)=[O:84])[CH2:80][C:79]2[CH:91]=[CH:92][C:76]([C:73](=[NH:74])[NH2:75])=[CH:77][CH:78]=2)=[O:44])[CH2:15][C:16](=[O:41])[NH:17][C@@H:18]2[O:35][C@H:34]([CH2:36][O:37][C:38](=[O:40])[CH3:39])[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]([O:25][C:26](=[O:28])[CH3:27])[C@H:19]2[O:20][C:21](=[O:23])[CH3:22])(=[O:12])=[O:11])=[C:5]([CH3:45])[C:4]=1[CH3:46]
Reactant: N=C(N)c1ccc(C[C@@H](N)C(=O)N2CCCCC2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)N[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)C(=O)O)c(C)c1C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)N[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)C(=O)N[C@H](Cc2ccc(C(=N)N)cc2)C(=O)N2CCCCC2)c(C)c1C
Reaction time: 24 h

Procedure:
Compound 20 (2.50 g), HOBt (0.65 g) and DCCI (1.15 g) were dissolved in DMF (100 mL) and after 1 h 4-amidino-D-phenylalanine-piperidide hydrochloride (1.50 g) was mixed in. The mixture was stirred for a further 24 h and concentrated by evaporation in vacuo. The residue was dissolved in chloroform and washed with water. The organic phase was concentrated in vacuo. The crude product obtained was purified by column chromatography on silica gel with chloroform and methanol 3:1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](I)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C([Li])CCC.[Si:19]([C:26]1[O:27][C:28]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:29]=2[C:30]=1[CH:31]=[O:32])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCCC1.C1(C)C=CC=CC=1>[Si:19]([C:26]1[O:27][C:28]2[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:29]=2[C:30]=1[C:31](=[O:32])[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[CH:6]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:20])[CH3:21]
Reactant: COc1cc(I)cc(OC)c1OC
Reactant: COc1ccc2c(C=O)c([Si](C)(C)C(C)(C)C)oc2c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COc1ccc2c(C(=O)c3cc(OC)c(OC)c(OC)c3)c([Si](C)(C)C(C)(C)C)oc2c1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of 3,4,5-trimethoxyiodobenzene (377 mg, 1.27 mmol) in dry tetrahydrofuran (1 mL) at −78° C. under nitrogen was added n-butyllithium (795 μL, 1.59 mmol, 2M solution in cyclohexane) and the reaction mixture was stirred at this temperature for 40 minutes. After this time a solution of 2-t-butyldimethylsilyl-3-formyl-6-methoxybenzofuran (310 mg, 1.07 mmol) in dry tetrahydrofuran (1 mL) was added to the reaction dropwise via syringe pipette. The reaction mixture was stirred at −60° C. for 20 minutes and then allowed to warm to 0° C., stirred for 10 minutes, quenched with saturated ammonium chloride solution (2 mL) and diluted with ethyl acetate (20 mL). The organic layer was washed with water (10 mL), dried over magnesium sulfate and the solvent was removed under vacuum to give a residue that was co-distilled with toluene. The crude product (908 mg) was dissolved in dry tetrahydrofuran (10 mL) and treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (900 mg, 1.59 mmol) was added. The reaction mixture was stirred at room temperature for 16 hours (monitored by tlc) and then loaded onto silica (10 g) and purified by flash chromatography (silica gel, eluent=hexane/diethyl ether/triethylamine, 90:9:1) to afford the title compound as a light yellow paste that crystallised on standing (232 mg, 48%); 1H NMR (300 MHz, CDCl3) δ 7.14 (s, 2H, benzoyl Hs), 7.05 (d, 1H, J=2.45 Hz), 6.77 (dd, 1H, J=8.76, 2.17 Hz), 6.56 (d, 1H, J=8.38 Hz), 3.94 (s, 3H, OMe), 3.85 (s, 6H, 2×OMe), 3.78 (s, 3H, OMe), 1.00 (s, 9H), 0.28 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 190.51 (CO), 164.77, 158.23, 158.12, 152.64, 142.35, 133.19, 131.37, 123.19, 121.04, 119.63, 112.26, 107.03, 104.96, 95.00, 60.47, 55.81, 55.60, 55.13, 26.43, 17.29, −6.09.
Reaction SMILES: C([Li])(CC)C.[C:6]([OH:16])(=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.CN(CCN(C)C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29](OCC)=[O:30]>>[F:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=1)[C:29]([C:8]1[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:7]=1[C:6]([OH:16])=[O:15])=[O:30]
Reactant: COc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1cccc(F)c1
Agent: CN(C)CCN(C)C
Agent: [Li]C(C)CC
Product: COc1ccc(C(=O)O)c(C(=O)c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
s-Butyllithium (52 mL, 1.4 M in pentane, 72 mmol) was added at −78° C. over 90 min. to a solution of p-anisic acid (5 g, 33 mmol) and TMEDA (11 ml, 72 mmol) in THE (80 mL). After stirring for 15 min., ethyl 3-fluorobenzoate (5 mL, 40 mmol) was added in one portion. The reaction mixture was stirred for 15 min. then it was quenched with water (20 mL). The reaction mixture was then warmed to room temperature and poured into water (1.5 L) 1N NaOH (30 ml) was added and the reaction mixture was then extracted with EtOAc. The extracts were discarded. The aqueous phase was then acidified with conc. HCl to pH 1 and extracted with EtOAc. Drying (Na2SO4) and concentration gave a residue which was recrystallized from hexanes/EtOAc to give the title compound 59 as a white solid.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[OH:18][C:14]1[C:11]2[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[O:9][C:10]=2[CH:17]=[CH:16][CH:15]=1
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)O)oc2cccc(O)c12

Procedure:
4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester (Example 156, Step 2) was dissolved in a 40% TFA/methylene chloride solution at room temperature for 4 hours. 4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid was isolated as a white powder by evaporation of the solvent.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:12])=[C:4]([F:13])[CH:3]=1.C1COCC1.[BH4-].[Na+]>CCO>[Br:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[OH:12])=[C:4]([F:13])[CH:3]=1
Reactant: O=C1CCc2c(F)cc(Br)c(F)c21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OC1CCc2c(F)cc(Br)c(F)c21

Procedure:
To a mixture of 6-bromo-4,7-difluoro-2,3-dihydro-1H-inden-1-one (0.5 g), THF (1 mL) and EtOH (1 mL) was added NaBH4 (100 mg). After 1 hour the reaction mixture was concentrated and the residue distributed between water and EA. The organic phase was washed with water (3 times), dried (Na2SO4), filtered and concentrated. The residue was purified by preparative HPLC to provide the subtitle compound. MS ESI+: m/z=249 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][C:19]([O:21]CC)=[O:20])=[C:13]([F:24])[CH:12]=1.[OH-].[Na+]>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([CH2:18][C:19]([OH:21])=[O:20])=[C:13]([F:24])[CH:12]=1
Reactant: CCOC(=O)Cc1cc(Cl)c(Nc2nc3ccccc3o2)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(Cl)c(Nc2nc3ccccc3o2)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.1 %

Procedure:
Ethyl (4-(2-benzoxazolyl)amino-5-chloro-2-fluorophenyl)acetate (570 mg, 1.63 mmol) was dissolved in THF (5 ml). To the resulting solution was added 1N NaOH (5.0 ml, 5.00 mmol), followed by stirring at room temperature for 20 hours. The reaction mixture was poured in ice-1N HCl to acidify therewith. The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give (4-(2-benzoxazolyl)amino-5-chloro-2-fluorophenyl)acetic acid (497 mg, 95%) as a brown solid.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]3)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:37]1[CH2:39][C@@H:38]1[CH2:40][O:41][C:42]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:43]=1[CH:44]=[CH:45][CH:46]=[N:47]2>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:29]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][N:32]3[CH2:39][C@@H:38]([OH:37])[CH2:40][O:41][C:42]3[CH:51]=[CH:50][CH:49]=[C:48]4[C:43]=3[CH:44]=[CH:45][CH:46]=[N:47]4)=[O:30])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCCCN2)CC1
Solvent: CCO
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(C(=O)C2CCCCN2C[C@@H](O)COc2cccc3ncccc23)CC1
Temperature: 25 °C
Yield: 69.9 %

Procedure:
1-(Piperidine-2-carbonyl)-piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (6) (243.4 mg; 0.497 mmol) is dissolved in ethanol (12 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (100.0 mg; 0.497 mmol) is added, then the mixture is refluxed for 17 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (50%→100% acetone in hexanes, then 5%→20% ethanol in acetone) affording the desired product (240 mg) as a white solid. ESMS: MH+ 691.4
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:9][CH:8]=1)C.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([OH:30])=[CH:29][C:24]=2[O:23][CH2:22]1.[OH-].[Na+]>>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([O:30][CH2:16][CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCCBr)cc1)OC
Reactant: Oc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc3c(c2)OCO3)cc1)C(=O)O

Procedure:
(2S)-3-[4-(3-Bromo-propoxy)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 173, Step A was treated with Benzo[1,3]dioxol-5-ol under the Standard Procedure J. The compound thus obtained was allowed to react under Standard hydrolysis procedure C (NaOH) to give the title compound. MS(ES) for C20H22O7 [M+Na]+: 397, [M+H]+: 375.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:14]3([CH2:18][C:19]#[N:20])[CH2:17][NH:16][CH2:15]3)[CH:13]=2)[N:6]2[CH:21]=[CH:22][N:23]=[C:5]2[CH:4]=1.CCN(C(C)C)C(C)C.FC(F)(F)S(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>CN(C=O)C>[Cl:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:14]3([CH2:18][C:19]#[N:20])[CH2:17][N:16]([CH2:39][C:40]([F:43])([F:42])[F:41])[CH2:15]3)[CH:13]=2)[N:6]2[CH:21]=[CH:22][N:23]=[C:5]2[CH:4]=1
Reactant: N#CCC1(n2cc(-c3nc(Cl)cc4nccn34)cn2)CNC1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#CCC1(n2cc(-c3nc(Cl)cc4nccn34)cn2)CN(CC(F)(F)F)C1
Yield: 61.4 %

Procedure:
In 1.5 mL of DMF were combined 2-(3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (0.059 g, 0.14 mmol), DIEA (0.15 mL, 0.84 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.049 g, 0.21 mmol) and allowed to proceed at ambient temperature with stirring. After 2 hours the DMF was removed under reduced pressure with heating and the crude was purified by means of silica gel chromatography eluting with 1:1 EtOAc/hexanes containing 0.25% NH4OH to afford 2-(3-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)-1-(2,2,2-trifluoro ethyl)azetidin-3-yl)acetonitrile (0.034 g, 0.086 mmol, 62% yield). MS (apci) m/z=396.1 (M+H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]1=[O:21])[CH3:2].[F:22][C:23]1[CH:24]=[C:25]([N+:30]([O-:32])=[O:31])[CH:26]=[CH:27][C:28]=1F.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:28]2[CH:27]=[CH:26][C:25]([N+:30]([O-:32])=[O:31])=[CH:24][C:23]=2[F:22])=[CH:5][C:4]=1[CH:10]1[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[O:13][C:12]([CH3:20])([CH3:19])[C:11]1=[O:21])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CCc1ccc(O)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccc(Oc2ccc([N+](=O)[O-])cc2F)cc1C1C(=O)C(C)(C)OC(C)(C)C1=O
Temperature: 80 °C

Procedure:
A mixture of 4-(2-ethyl-5-hydroxyphenyl)-2,2,6,6-tetramethylpyran-3,5-dione (135 mg, 0.47 mmol), 3,4-difluoro-1-nitrobenzene (90 mg, 0.56 mmol), and potassium carbonate (130 mg, 0.94 mmol) in N,N-dimethylformamide (3 ml) is heated to 80° C. for 3 hours. The mixture is cooled to room temperature, poured into 2M aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel to give 4-[2-ethyl-5-(2-fluoro-4-nitrophenoxy)phenyl]-2,2,6,6-tetramethylpyran-3,5-dione.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22](/[C:25](/[Sn](CCCC)(CCCC)CCCC)=[CH:26]\[CH2:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:21][CH:20]=3)[O:17][CH:18]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[I:50]I>C1COCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]([C:19]3[CH:24]=[CH:23][C:22](/[C:25](/[I:50])=[CH:26]\[CH2:27][CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:21][CH:20]=3)[O:17][CH:18]=2)=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCC[Sn](CCCC)(CCCC)/C(=C/CCCC(=O)OC(C)(C)C)c1ccc(-c2nc(C(=O)NCCCCC3CCCCC3)co2)cc1
Reactant: II
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCC/C=C(/I)c1ccc(-c2nc(C(=O)NCCCCC3CCCCC3)co2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 2-necked 50 mL round bottom flask was charged under nitrogen atmosphere with a stir bar, the above alkyne (148.6 mg, 0.302 mmol), and tetrakis(triphenylphosphine)palladium(O) (17.4 mg, 0.0015 mmol). Anhydrous toluene (5 mL) was added via syringe, and the mixture was stirred until the two solids dissolved. A 2 mL solution of tributyltin hydride (0.392 mmol) in anhydrous toluene was added, and the reaction stirred at room temperature for 30 minutes. The solution was then transferred to a dry 50 mL round bottom flask and the toluene was removed in vacuo to afford tert-butyl (E)-6-[4-[4-[[(4-cyclohexylbutyl)amino]carbonyl]-2-oxazolyl]phenyl]-6-(tributylstannyl)hex-5-enoate as a residue which was used directly. The stannane was dissolved in 10 mL anhydrous THF and the flask was cooled to 0° C. in an ice bath. A 10 mL solution of iodine (84.2 mg, 0.3318 mmol) in anhydrous THF was added dropwise via pressure equalizing addition funnel over 30 minutes. The ice bath was removed and the reaction stirred at room temperature for 2 hours. Saturated sodium bisulfite solution (50 mL) was added, and the organics were extracted three times with ethyl acetate. The combined extracts were dried over MgSO4. Filtration and solvent removal gave a yellow oil which was purified by radial chromatography (2 mm plate, 10% ethyl acetate in hexanes) to give 193.6 mg of a pale yellow oil: 1H NMR (CDCl3) δ8.24 (s, 1H), 8.00 (d, 2H), 7.41 (d, 2H), 7.05 (broad t, 1H), 6.52 (t, 1H), 3.45 (q, 2H), 2.15 (q, 2H), 2.04 (q, 2H), 1.70 (m, 7H), 1.40 (m, 9H), 1.23 (m, 6H), 0.93 (m, 4H); IR (cm-1) 2926, 2853, 1721, 1664, 1599. High Resolution MS Accurate mass calculated for C30H42IN2O4 : 621.2189. Found: 621.2183.
Reaction SMILES: [CH3:1][C:2]([N:5]1[CH:9]=[C:8]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[C:12]([NH:20][CH2:21][C@:22]3([F:35])[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[N:11]=2)[CH:7]=[N:6]1)([CH3:4])[CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:4][C:2]([N:5]1[CH:9]=[C:8]([C:10]2[N:11]=[C:12]([NH:20][CH2:21][C@:22]3([F:35])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[C:13]3[CH:14]=[CH:15][CH:16]=[N:17][C:18]=3[CH:19]=2)[CH:7]=[N:6]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CNc2nc(-c3cnn(C(C)(C)C)c3)cc3ncccc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)n1cc(-c2cc3ncccc3c(NC[C@]3(F)CCCNC3)n2)cn1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 93.1 %

Procedure:
1,1-Dimethylethyl (3R)-3-[({7-[1-(1,1-dimethylethyl)-1H-pyrazol-4-yl]-1,6-naphthyridin-5-yl}amino)methyl]-3-fluoro-1-piperidinecarboxylate (1.586 g, 3.29 mmol) was dissolved in DCM (5 ml) and trifluoroacetic acid (5.06 ml, 65.7 mmol) was added. The reaction was stirred for 20 min at 20° C. LCMS showed main peak of product. The reaction mixture was loaded onto a 20 g SCX cartridge and washed with methanol. The compound was eluted with 2M methanolic ammonia. The solvent from the ammonia fractions was evaporated and was kept under high vacuum for 2 h to give a yellow crystalline solid (1.171 g). The free base (1.12 g) was purified by High pH preparative MDAP (Method B). The appropriate fractions were combined, concentrated in vacuo and kept on high vacuum overnight to give the title compound as a yellow crystalline solid (688.1 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:14])[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[N:6]=2.O[C:16]1[CH:48]=[CH:47][C:19]([CH2:20][CH:21]2[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]2=[O:46])=[CH:18][CH:17]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1>[CH3:13][O:12][C:7]1[N:6]=[C:5]2[N:4]([CH3:14])[C:3]([CH2:2][O:1][C:16]3[CH:48]=[CH:47][C:19]([CH2:20][CH:21]4[S:25][C:24](=[O:26])[N:23]([C:27]([C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)([C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[C:22]4=[O:46])=[CH:18][CH:17]=3)=[N:11][C:10]2=[CH:9][CH:8]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2nc(CO)n(C)c2n1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: COc1ccc2nc(COc3ccc(CC4SC(=O)N(C(c5ccccc5)(c5ccccc5)c5ccccc5)C4=O)cc3)n(C)c2n1

Procedure:
A procedure similar to that described in Preparation 4 was repeated, except that 0.25 g of 2-hydroxymethyl-5-methoxy-3-methylimidazo[5,4-b]pyridine (prepared as described in Preparation 69), 0.66 g of 5-(4-hydroxy-benzyl)-3-triphenylmethylthiazolidine-2,4-dione, 0.35 ml of tributylphosphine, 0.36 g of 1,1'-(azodicarbonyl) di-piperidine and 15 ml of toluene were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 1:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 0.70 g of the title compound, melting at 80-85° C. (softening).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=3[N:10]=[C:4]2[CH:3]=1.[F:22][C:23]([F:38])([F:37])[C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][NH:33][C:32](=[O:36])[CH:31]=2)=[CH:26][CH:25]=1>>[O:36]=[C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:37])([F:22])[F:38])=[CH:25][CH:26]=2)[CH:35]=[CH:34][N:33]1[C:2]1[CH:7]=[CH:6][N:5]2[C:8]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:11][C:9]=3[N:10]=[C:4]2[CH:3]=1
Reactant: O=c1cc(-c2ccc(C(F)(F)F)cc2)cc[nH]1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3cc(Br)ccn3c2C1
Product: CC(C)(C)OC(=O)N1CCc2nc3cc(-n4ccc(-c5ccc(C(F)(F)F)cc5)cc4=O)ccn3c2C1
Yield: 63.5 %

Procedure:
tert-Butyl 7-bromo-3,4-dihydropyrido[4′,3′:4,5]imidazo[1,2-a]pyridine-2(1H)-carboxylate (150 mg, 0.426 mmol) and 4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (103 mg, 0.426 mmol) were reacted according to Example 18 (step g) to provide the title compound (138 mg, 64%) as a yellow solid: ESI MS m/z 511 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[C:24](C(F)(F)F)[C:22]=5[N:23]=4)[C:15]([NH2:18])=[N:16][CH:17]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.Cl[C:33]1SC2C=CC(C#N)=CC=2[N:37]=1>>[NH2:18][C:15]1[C:14]([C:19]2[S:20][C:21]3[CH:27]=[CH:26][C:25]([C:33]#[N:37])=[CH:24][C:22]=3[N:23]=2)=[CH:13][C:12]([C:10]2[CH:9]=[N:8][N:7]([CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[CH:11]=2)=[CH:17][N:16]=1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)cccc2s1
Reactant: N#Cc1ccc2sc(Cl)nc2c1
Product: N#Cc1ccc2sc(-c3cc(-c4cnn(C5CCNCC5)c4)cnc3N)nc2c1

Procedure:
Following the procedure for 5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-3-(4-trifluoromethylbenzothiazol-2-yl)-pyridin-2-ylamine, but using 2-chloro-1,3-benzothiazole-5-carbonitrile, the title compound was obtained as yellow solid. MS (ES+): m/z=402.13 [MH+].