Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][C:24]2[C:19]([CH:18]=1)=[CH:20][CH:21]=[CH:22][CH:23]=2
Reactant: COC(=O)c1cc2ccccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COC(=O)c1cc2ccccc2cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 2 h
Yield: 4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), methyl 2-hydroxy-3-naphthoate (271 mg), and 4-dimethylaminopyridine (164 mg) were suspended in o-dichlorobenzene (6 ml), and the suspension was stirred at 150° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give the title compound (7 mg, yield 4%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[Ca+2].Cl[CH2:19][CH:20]([OH:23])[CH2:21][OH:22]>O>[CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH:4][CH:21]([OH:22])[CH:20]([OH:23])[CH3:19]
Reactant: OCC(O)CCl
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1N
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: Cc1cc(N)c([N+](=O)[O-])cc1NC(O)C(C)O
Temperature: 0 °C

Procedure:
0.2 mol (33.4 g) of 2-methyl-4-amino-5-nitroaniline and 0.1 mol (10 g) of calcium carbonate, suspended in 100 ml of water, are heated beforehand on a boiling water-bath, whilst stirring. 0.216 mol (24 g) of 1-chloropropane-2,3-diol is added. The reaction mixture is heated for 24 hours on the boiling water-bath, seven portions each containing 0.035 mol (3.5 g) of calcium carbonate and 0.066 mol (7.3 g) of 1-chloropropane-2,3-diol being added, one every three hours. The hot reaction mixture is filtered and the filtrate is diluted with 60 ml of water. After cooling for 24 hours at 0° C., the expected product, which has crystallised, is filtered off. The product is washed with water and recrystallised three times from ethanol. It melts at 150° C.
Reaction SMILES: C(CCC1C(CCCCCCOC2C=C(C3C=CC(F)=C(F)C=3)C=C(C(=O)N(C)C)C=2)=CC=CC=1OCCCC(O)=O)(O)=O.C([O:47][C:48](=[O:94])[CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:58]=[CH:57][CH:56]=[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:67]=[C:68]([C:81]3[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=3)[CH:69]=[C:70]([C:72]([N:74]3[CH2:78][CH2:77][C:76]([F:80])([F:79])[CH2:75]3)=[O:73])[CH:71]=2)[C:54]=1[CH2:87][CH2:88][C:89]([O:91]CC)=[O:90])C.[OH-].[Na+]>CCO>[C:89]([CH2:88][CH2:87][C:54]1[C:55]([CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:67]=[C:68]([C:81]3[CH:82]=[CH:83][CH:84]=[CH:85][CH:86]=3)[CH:69]=[C:70]([C:72]([N:74]3[CH2:78][CH2:77][C:76]([F:80])([F:79])[CH2:75]3)=[O:73])[CH:71]=2)=[CH:56][CH:57]=[CH:58][C:53]=1[O:52][CH2:51][CH2:50][CH2:49][C:48]([OH:94])=[O:47])([OH:91])=[O:90]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCC(F)(F)C3)cc(-c3ccccc3)c2)c1CCC(=O)OCC
Agent: CN(C)C(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCC(F)(F)C3)cc(-c3ccccc3)c2)c1CCC(=O)O
Yield: 99.4 %

Procedure:
The title compound was prepared by the same method as 4-{2-(2-carboxy-ethyl)-3-[6-(5-dimethylcarbamoyl-3′,4′-difluoro-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid starting from 4-[3-{6-[5-(3,3-difluoro-pyrrolidine-1-carbonyl)-biphenyl-3-yloxy]-hexyl}-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (70 mg, 0.101 mmol) and 1.0 N aqueous NaOH (1.01 mL) in EtOH (4 mL) to afford 4-(2-(2-carboxy-ethyl)-3-{6-[5-(3,3-difluoro-pyrrolidine-1-carbonyl)-biphenyl-3-yloxy]-hexyl}-phenoxy)-butyric acid (64 mg, 99%) as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.[N:28]1[C:37]2[CH:36]=[CH:35][NH:34][C:33](=[O:38])[C:32]=2[CH:31]=[CH:30][CH:29]=1.C1CCN2C(=NCCC2)CC1.Cl>CS(C)=O.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[CH:6][C:5]([N:34]2[CH:35]=[CH:36][C:37]3[N:28]=[CH:29][CH:30]=[CH:31][C:32]=3[C:33]2=[O:38])=[CH:4][N:3]=1
Reactant: O=c1[nH]ccc2ncccc12
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3ccc(F)cc3)c2)OC1(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CS(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: O=c1c2cccnc2ccn1-c1cnc(Cl)c(NS(=O)(=O)c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.6 %

Procedure:
A mixture of N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (618 mg, 1.499 mmol), 1,6-naphthyridin-5(6H)-one (PrincetonBio, Monmouth Junction, N.J., 146 mg, 0.999 mmol), copper (II) acetate (363 mg, 1.998 mmol), DBU (0.301 mL, 1.998 mmol) in DMSO (4 mL) in a microwave tube equipped with a magnetic stirring bar was irradiated at 100° C. for 15 min in a CEM microwave (J. Comb. Chem. 2008, 10, 358-360). The mixture was diluted with water (10 mL) and acidified with HCl (5 N) to pH ˜5. After agitating at rt overnight, the slurry was filtered and the solid was washed with water. The solid was washed with DCM (3×), acetone (3×), and MeOH (2×) to remove the less polar fraction. The resulting solid was dissolved in hot DMSO (6 mL) and filtered. The mother liquid was diluted with water (6 mL) and the resulting slurry was filtered and washed with water. The solid was dissolved in DMSO and purified by reverse-phase preparative HPLC (Phenomenex Luna column, 5 micron, C8(2), 100 Å, 150×21.2 mm, 0.1% TFA in CH3CN/H2O, gradient 5% to 90% over 10 min) The product fraction was concentrated, and neutralized with NaHCO3. The slurry was filtered and washed with water to provide N-(2-chloro-5-(5-oxo-1,6-naphthyridin-6(5H)-yl)pyridin-3-yl)-4-fluorobenzenesulfonamide (37 mg, 0.086 mmol, 8.60% yield) as an off-white powder.
Reaction SMILES: [Li]CCCC.[CH:6]([NH:9]C(C)C)(C)[CH3:7].C(#N)C.[O:16]([C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[Cl-].[NH4+].Cl>C1COCC1.O>[NH2:28][C:27]([C:26]1[CH:25]=[CH:24][C:23]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:30][CH:29]=1)=[CH:7][C:6]#[N:9]
Reactant: N#Cc1ccc(Oc2ccccc2)cc1
Reactant: CC(C)NC(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: N#CC=C(N)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
A 2.5 M THF solution of n-BuLi (20.49 mL, 51.2 mmol) was added to a solution of diisopropylamine (7.30 mL, 51.2 mmol) in THF (165 mL) at −78° C. The mixture was stirred at 0° C. for 20 min and cooled to −78° C. Acetonitrile (2.68 mL, 51.2 mmol) was added to give a white cloudy solution. After 30 min at −78° C., a solution of 4-phenoxybenzonitrile (10 g, 51.2 mmol) in THF (35 mL) was added. After 1.5 h at −78° C., saturated ammonium chloride (50 mL), water (25 mL) and 1 N HCl (25 mL) were added. The THF was evaporated in vacuo. The residue was extracted with ethyl acetate (200 mL). The ethyl acetate phase was washed with 0.1 N HCl (50 mL) and brine (10 mL), dried (MgSO4) and concentrated. The resulting mixture was triturated with a mixture of dichloromethane and hexanes. Filtration of the suspension gave 3-amino-3-(4-phenoxyphenyl)acrylonitrile as white solid (7.364 g). The filtrate was concentrated to a small volume and filtered to give additional product (2.501 g). The total amount of the product was 9.865 g (82% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.44-7.50 (2H, m), 7.39 (2H, t, J=7.91 Hz), 7.18 (1H, t, J=7.40 Hz), 6.98-7.08 (4H, m), 4.88 (2H, br. s), 4.22 (1H, s); MS (ES+) m/z: 237 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([Cl:13])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:15](Cl)([O:17]C(=O)OC(Cl)(Cl)Cl)Cl.C(OCC)C>O1CCCC1>[Cl:13][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:2]2[NH:1][C:15](=[O:17])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: COc1cc(Cl)cc(C(=O)O)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(Cl)cc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C

Procedure:
To 2-amino-5-chloro-3-methoxybenzoic acid (0.72 g, 3.57 mmol) in anhydrous tetrahydrofuran (15 mL) was added triphosgene (0.53 g, 1.8 mmol). The mixture was heated to refluxed under a nitrogen atmosphere for 2.5 hours. The resulting solution was cooled to ambient temperature, diethyl ether (10 mL) was added, which caused a solid to precipitate. The solid was collected by filtration and washed with more diethyl ether to yield 6-chloro-8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione. MS (m/z): 226.3, 228.3 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH:8]([CH2:9][OH:10])[C@H:7]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C@@H:4]1[CH2:5][CH2:6]2.CCN(CC)CC.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:29][S:30]([O:10][CH2:9][CH:8]1[CH:3]([CH2:2][O:1][S:30]([CH3:29])(=[O:32])=[O:31])[C@H:4]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[C@@H:7]1[CH2:6][CH2:5]2)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1[C@@H]2CC[C@H]1C(CO)C2CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1C(COS(C)(=O)=O)[C@@H]2CC[C@H]1N2C(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of (1R,4S)-benzyl 2,3-bis(hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (LI) (1.85 g, 6.35 mmol) and Et3N (2.65 mL, 19.05 mmol) in DCM (70 mL) at −30° C. was added a solution of MsCl (1.47 mL, 19.05 mmol) in DCM (15 mL) dropwise. The reaction mixture was stirred for 15 min at −10° C. then for 1.5 h at 0° C. The reaction mixture was dilluted with DCM, washed with 1 M HCl, 1 M K2CO3, brine and then dried over MgSO4. The solvent was removed under vacuum to give (1R,4S)-benzyl 2,3-bis((methylsulfonyloxy)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (LII) as a very thick, light yellow oil (2.70 g, 6.03 mmol, 95% yield). 1H NMR (CDCl3) δ ppm 1.74 (brs, 4H), 1.88 (brs, 1H), 2.16 (brs, 1H), 2.97 (brs, 2H), 3.03 (brs, 3H), 3.97-4.09 (m, 1H), 4.10-4.18 (m, 1H), 4.22 (brs, 1H), 4.26-4.34 (m, 1H), 4.40 (brs, 1H), 5.11 (brs, 2H), 7.35 (brs, 5H); ESIMS found for C18H25NO8S2 m/z 448 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][C@H:9]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=2[N:23]2[CH:27]=[CH:26][C:25]([CH3:28])=[N:24]2)[C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([N:29]2[CH2:58][CH2:57][C:32]3([CH2:36][C@@H:35]([C:37]([O:39][CH2:40][C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:38])[N:34]([C:47]([O:49][CH2:50][C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)=[O:48])[CH2:33]3)[CH2:31][CH2:30]2)[N:3]=1.[CH3:59][C:60](O)([C:65]([F:68])([F:67])[F:66])[C:61]([F:64])([F:63])[F:62].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[NH2:1][C:2]1[N:3]=[C:4]([N:29]2[CH2:58][CH2:57][C:32]3([CH2:36][C@@H:35]([C:37]([O:39][CH2:40][C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)=[O:38])[N:34]([C:47]([O:49][CH2:50][C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)=[O:48])[CH2:33]3)[CH2:31][CH2:30]2)[CH:5]=[C:6]([O:8][C@H:9]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([O:20][C:60]([CH3:59])([C:65]([F:68])([F:67])[F:66])[C:61]([F:64])([F:63])[F:62])=[O:19])=[CH:16][C:15]=2[N:23]2[CH:27]=[CH:26][C:25]([CH3:28])=[N:24]2)[C:10]([F:12])([F:11])[F:13])[N:7]=1
Reactant: Cc1ccn(-c2cc(C(=O)O)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCc3ccccc3)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Reactant: CC(O)(C(F)(F)F)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccn(-c2cc(C(=O)OC(C)(C(F)(F)F)C(F)(F)F)ccc2[C@@H](Oc2cc(N3CCC4(CC3)C[C@@H](C(=O)OCc3ccccc3)N(C(=O)OCc3ccccc3)C4)nc(N)n2)C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-[(1R)-1-[2-amino-6-[(2S)-2,3-bis(benzyloxycarbonyl)-3,8-diazaspiro[4.5]decan-8-yl]pyrimidin-4-yl]oxy-2,2,2-trifluoro-ethyl]-3-(3-methylpyrazol-1-yl)benzoic acid (80 mg, 0.1 mmol) in CH2Cl2 (4 mL) was added DMAP (73 mg, 0.6 mmol), (CF3)2MeCOH (108 mg, 0.6 mmol), followed by EDCI (114 mg, 0.6 mmol). The reaction mixture was stirred at RT for 12 h, diluted with CH2Cl2 and washed with water. The aqueous solution was extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification by normal phase silica gel column (EtOAc/heptane) provided dibenzyl (2S)-8-[2-amino-6-[(1R)-2,2,2-trifluoro-1-[2-(3-methylpyrazol-1-yl)-4-[2,2,2-trifluoro-1-methyl-1-(trifluoromethyl)ethoxy]carbonyl-phenyl]ethoxy]pyrimidin-4-yl]-3,8-diazaspiro[4.5]decane-2,3-dicarboxylate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]1[C:7]([CH:12]=O)=[N:8][CH:9]=[CH:10][N:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:14]([C:17]1[CH:30]=[CH:29][CH:28]=[CH:27][C:18]=1[O:19][CH2:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)(=[O:16])[NH2:15].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[C:1]([O:5][C:6]1[C:7]([CH2:12][N:24]2[CH2:23][CH2:22][CH:21]([CH2:20][O:19][C:18]3[CH:27]=[CH:28][CH:29]=[CH:30][C:17]=3[C:14]([NH2:15])=[O:16])[CH2:26][CH2:25]2)=[N:8][CH:9]=[CH:10][N:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)c1ccccc1OCC1CCNCC1
Reactant: CC(C)(C)Oc1nccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)Oc1nccnc1CN1CCC(COc2ccccc2C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
After dissolving 106 mg of 3-tert-butoxypyrazine-2-carboxaldehyde and 105 mg of 4-(2-carbamoylphenoxymethyl)piperidine in 5 ml of dichloromethane, 153 mg of sodium triacetoxyborohydride was added and the mixture was stirred overnight at room temperature. Aqueous sodium bicarbonate solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (171 mg, 95% yield).
Reaction SMILES: Br[C:2]1[C:3]([CH3:42])=[C:4]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([NH:20][CH2:21][C:22]3[C:23]([NH:35][CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)=[C:24]4[CH:32]=[N:31][N:30]([CH2:33][CH3:34])[C:25]4=[N:26][C:27]=3[CH2:28][CH3:29])=[O:19])[CH:13]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH3:43][C@H:44]1[CH2:49][N:48]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[C:53](B3OC(C)(C)C(C)(C)O3)[CH:52]=2)[CH2:47][CH2:46][N:45]1C(OC(C)(C)C)=O.C([O-])([O-])=O.[Na+].[Na+].C(O)(C(F)(F)F)=O>O1CCOCC1.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:33]([N:30]1[C:25]2=[N:26][C:27]([CH2:28][CH3:29])=[C:22]([CH2:21][NH:20][C:18]([C:14]3[CH:15]=[CH:16][CH:17]=[C:12]([C:10]([NH:9][CH2:8][C:4]4[C:3]([CH3:42])=[C:2]([C:53]5[CH:54]=[CH:55][CH:56]=[C:51]([CH2:50][N:48]6[CH2:47][CH2:46][NH:45][C@@H:44]([CH3:43])[CH2:49]6)[CH:52]=5)[CH:7]=[CH:6][CH:5]=4)=[O:11])[CH:13]=3)=[O:19])[C:23]([NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[C:24]2[CH:32]=[N:31]1)[CH3:34]
Reactant: C[C@H]1CN(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CCN1C(=O)OC(C)(C)C
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(Br)c2C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4CCN[C@@H](C)C4)c3)c2C)c1
Reaction time: 1.5 h
Yield: 59.1 %

Procedure:
A mixture of N-[(3-bromo-2-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (93 mg, 0.00015 mol) in dioxane (4 mL) with 1,1-dimethylethyl (2S)-2-methyl-4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperazinecarboxylate (81.2 mg, 0.000195 mol) was treated with Na2CO3 (48 mg, 0.00045 mol) and 0.75 mL H2O. The mixture was degassed for 15 min with N2, then treated with (PPh3)4Pd (17.3 mg, 0.000015 mol). The mixture was microwaved at 150° C. for 30 min. The reaction was quenched with H2O, then diluted and extracted with EtOAc (2×) combined organic extracts were washed with H2O, sat. aq. NaCl and dried (Na2SO4) and concentrated to give crude t-Boc product. The crude product was taken up in DCM (10 mL) containing 33% TFA and allowed to stand at room temperature for 1.5 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on a Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as an ivory colored glassy solid [65.9 mg (58%)]. LC-MS m/z 743.7 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([C:13](=[O:15])[CH3:14])[N:8]=2)=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([CH:13]([OH:15])[CH3:14])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)c1nccc(Oc2ccc(F)cc2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(O)c1nccc(Oc2ccc(F)cc2)n1
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
1-(4-(4-fluorophenoxy)pyrimidin-2-yl)ethanone (0.150 g 0.646 mmol) was taken up in 2.5 mL 4:1 MeOH:DCM, and cooled to 0° C. NaBH4 (49 mg 1.30 mmol) was added. Fizzing was observed. After 10 min, cold bath was removed, and the reaction was stirred 1 h. Solvent was removed in vacuo. White residue was taken up in 10 mL water, and extracted with (2×10 mL) EtOAc. Washed organics with 10 mL brine. Dried over Na2SO4. Filtered and concentrated to give 143 mg (95%) 1-(4-(4-fluorophenoxy)pyrimidin-2-yl)ethanol as a colorless oil. Anal. RP-HPLC tR=1.38 min. (Column=Inertsil C8 Column, 3.0 μm, 3.0×30 mm. Column Temperature=50° C. Eluents=A: Water (5 mM Ammonium formate, 2% ACN); B: ACN. Flow Rate=2 mL/min. Gradient=0 min 5% B; 5% to 95% B in 1.70 min; 0.3 min 95% B; 2.1 min 1% B.) MS m/z 235.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](O)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].P(Br)(Br)([Br:22])=O.O>C(#N)C>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([Br:22])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: O=P(Br)(Br)Br
Reactant: CCCCOC(=O)c1nc(O)c2ccccc2c1O
Solvent: O
Solvent: CC#N
Product: CCCCOC(=O)c1nc(Br)c2ccccc2c1O
Temperature: 80 °C
Reaction time: 64 h
Yield: 3.9 %

Procedure:
2 g (7.7 mmol) of 1,4-Dihydroxy-isoquinoline-3-carboxylic acid butyl ester (from Example D-20b) dissolved in 100 ml of acetonitrile. 15.4 g (53.6 mmol) of phosphorous oxybromide added to solution and mixture stirred at 80° C. for 64 h. 100 ml of water was added to mixture, and mixture was removed from heat. Mixture was partitioned between ethyl acetate and water. Two phases were separated and the aqueous layer was extracted with ethyl acetate. Organic layers were combined, washed with brine, dried over magnesium sulfate, filtered, and evaporated. Residue was purified by silica gel flash chromatography to give 0.1 g (0.3 mmol) of product. 1H NMR (200 MHz, CDCl3) δ 11.89 (s, 1H), 8.41 (m, 1H), 8.25 (m, 1H), 7.84 (m, 2 H), 4.49 (t, J=7.0 Hz, 2H), 1.87 (m, 2H), 1.47 (m, 2H), 1.00 (t, J=7.2 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:15][C:16]1[NH:17][N:18]=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC>[CH3:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:15][C:16]3[NH:17][N:18]=[C:19]([CH3:21])[CH:20]=3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: Cc1cc(N)[nH]n1
Reactant: CC1CCN(c2ccnc(Cl)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: Cc1cc(Nc2nccc(N3CCC(C)CC3)n2)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of 2-chloro-4-(4-methylpiperidin-1-yl)-pyrimidine (prepared using a procedure similar to the one reported in Eur. J. Med. Chem., 26(7) 729(1991)) (222 mg, 1.05 mmol) in BuOH (5 mL) was added 3-amino-5-methyl-2H-pyrazole (305 mg, 3.15 mmol) and the reaction mixture was then heated under reflux overnight. The solvent was evaporated and the residue dissolved in a mixture ethanol/water (1/3, 4 mL). Potassium carbonate (57 mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water twice and rinsed with ether twice to give the title compound as a white solid (143 mg, 50%): mp 193–195° C.; 1H NMR (DMSO) δ 0.91 (3H, d), 1.04 (2H, m), 1.67 (3H, m), 2.16 (3H, s), 2.83 (2H, t), 4.31 (2H, m), 6.19 (2H, m), 7.87 (1H, d), 8.80 (1H, br s), 11.71 (1H, s); IR (solid) 1627, 1579, 1541, 1498, 1417, 1388, 1322, 1246; MS 273.3 (M+H)+.
Reaction SMILES: O=[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[N:4][NH:3]1.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[N:3]=[N:4][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)=[CH:6][CH:7]=1
Reactant: O=c1ccc(-c2c(-c3ccccc3)nn3ccccc23)n[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ccc(-c2c(-c3ccccc3)nn3ccccc23)nn1

Procedure:
A mixture of 3-(3-oxo-2,3-dihydropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.91 g) and phosphorus oxychloride (10 ml) was heated under reflux for 1 hour. Phosphorus oxychloride was evaporated in vacuo. The residue was neutralized by saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform (30 ml×3). The combined extract was washed with a saturated aqueous solution of sodium chloride (20 ml) and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was triturated with ethanol, collected by filtration, washed with ethanol and dried to give crystals of 3-(3-chloropyridazin-6-yl)-2-phenylpyrazolo[1,5-a]pyridine (2.42 g).