Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.C(N(CC)CC)C.Cl.[CH:18]1([NH:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[NH2:9][C:8]1[N:24]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:25]=[CH:4][C:5]=1[C:6]#[N:7]
Reactant: NNC1CCCCC1
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#Cc1cnn(C2CCCCC2)c1N

Procedure:
First ethoxymethylenemalononitrile (2.43 g, 19.9 mmol) and then 8 ml of triethylamine are added to a solution of cyclohexylhydrazine hydrochloride (3 g, 19.9 mmol) in 36 ml of ethanol at room temperature. The mixture is refluxed for 20 min and then cooled. The solvent is stripped off in a rotary evaporator, and the residue is taken up in DCM, washed with aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product is chromatographed on silica gel (mobile phase: dichloromethane/methanol 0-10%).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([O:12]CC)=[O:11])[N:5]=[CH:4][C:3]=1[NH2:15].[H-].[Na+].[C:18]12([C:28](Cl)=[O:29])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([OH:12])=[O:11])[N:5]=[CH:4][C:3]=1[NH:15][C:28]([C:18]12[CH2:27][CH:22]3[CH2:21][CH:20]([CH2:26][CH:24]([CH2:23]3)[CH2:25]1)[CH2:19]2)=[O:29]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CCOC(=O)Cn1ncc(N)c(Br)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)Cn1ncc(NC(=O)C23CC4CC(CC(C4)C2)C3)c(Br)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Ethyl 2-(5-bromo-4-amino-6-oxopyridazin-1(6H)-yl)acetate (100 mg, 0.362 mmol) in tetrahydrofuran (2 mL) was mixed with sodium hydride (58 mg, 1.46 mmol) and adamantanecarbonyl chloride (144 mg, 0.724 mmol) at room temperature and stirred at room temperature for 30 minutes. After completion of the reaction, the reaction solution was mixed with water and ethyl acetate and extracted with 1 M aqueous sodium hydroxide. The aqueous layer was acidified to pH 1 with 1 M hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed by distillation to give the desired product.
Reaction SMILES: [H][H].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:35])[C@H:14]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:15](CC2C=CC=CC=2)[CH3:16])=[CH:6][CH:5]=1.Cl>C(O)C.[Pd]>[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:35])[C@H:14]([CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[NH:15][CH3:16])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CN(Cc1ccccc1)[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(O)cc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CN[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCCc1ccc(O)cc1

Procedure:
Hydrogen gas was bubbled through a solution of Nα-benzyl-Nδ-Boc-Nα-methylornithine 2-(4-hydroxyphenyl)ethylamide (A) (540 mg) in ethanol (20 ml) in the presence of 1 eq. of conc. hydrochloric acid (1.30 ml) and 5% palladium-on-charcoal (50 mg). After disappearance of starting material, as determined by thin-layer chromatography, the reaction mixture is filtered through a 0.45 μm nylon pad and concentrated in vacuo.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[C:17]([O:23][CH3:24])[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][S:26]([CH2:28][S:29]([CH3:31])=O)=[O:27].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O1CCCC1.CO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[C:28]([S:29][CH3:31])[S:26]([CH3:25])=[O:27])=[C:17]([O:23][CH3:24])[CH:16]=2)([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C2(O)CCN(Cc3ccccc3)CC2)ccc1C=O
Reactant: CS(=O)CS(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(C2(O)CCN(Cc3ccccc3)CC2)ccc1C=C(SC)S(C)=O

Procedure:
3.43 g of 4-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methoxybenzaldehyde was dissolved in 30 ml of tetrahydrofuran. To the resulting solution were added 2.42 ml of methyl methylsulfinylmethyl sulfoxide and 2 ml of a 40% solution of benzyltrimethylammonium hydroxide in methanol and the resulting mixture was heated under reflux for 3 hours. After concentrating the reaction mixture, water was added thereto followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 4.58 g of the title compound as a pale yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][C@H:9]1[C:18](O)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O1CCCC1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[OH:19][CH2:18][C@@H:9]1[CH2:10][CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC[C@H]1C(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1c2ccccc2CC[C@H]1CO
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(S)-1-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroquinoline-2-carboxylic acid (5 g, 18.03 mmol) was dissolved in tetrahydrofuran (40 ml) and the mixture was cooled. Boron hydride-tetrahydrofuran complex (27 ml, 1 mol/l in tetrahydrofuran) was cautiously added dropwise at 0° C. and the mixture was then stirred at room temperature for 15 h. The reaction mixture was cooled again and water (8 ml) was slowly added dropwise at 0° C. Potassium carbonate (4.21 g, 30.65 mmol) was then added and the mixture was stirred for 30 min. After phase separation the aqueous phase was extracted with diethyl ether (2×30 ml) and the combined organic phases were washed with saturated sodium chloride solution (30 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/ethyl acetate 2/1.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@H:13]1[C@@H:16]([CH2:17][CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[NH:15][C:14]1=[O:24].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:5]([O:4][C:2]([NH:12][C@H:13]1[C@@H:16]([CH2:17][CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[NH:15][C:14]1=[O:24])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H]1C(=O)N[C@@H]1CCc1ccco1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1C(=O)N[C@@H]1CCc1ccco1)OCc1ccccc1
Reaction time: 0.5 h
Yield: 59.3 %

Procedure:
A solution of benzyl chloroformate (5.4 mL, 0.0378 mol) in methylene chloride (10 mL) was added dropwise during 0.25 hr to a stirred, cooled (ice/H2O bath) of (3S,4R)-3-amino-4-[2-(2-furyl)ethyl]azetidin-2-one (6.82 g, 0.0378 mol) and diisopropylethylamine (6.6 mL, 0.0378 mol) in methylene chloride (75 mL). Stirring was continued with cooling for 2 hr and then for 0.5 hr at ambient temperatures. The mixture was diluted with additional methylene chloride and was sequentially washed with H2O, dilute hydrochloric acid, H2O, dilute aqueous NaHCO3, H2O and saturated NaCl. The solution was dried over MgSO4 and concentrated. The residue was crystallized from ethyl acetate to afford the title compound (7.05 g, 60% yield) as an off-white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH2:26][C@H:27]([OH:31])[C:28]([OH:30])=[O:29])=[O:24])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([NH:25][CH2:26][C@H:27]([OH:31])[C:28]([OH:30])=[O:29])=[O:24])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(C(=O)NC[C@H](O)C(=O)O)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@H](O)C(=O)O)c1ccc(OCCC2CCNCC2)cc1
Yield: 83.2 %

Procedure:
A solution of 17-3 (45 mg, 0.10 mmol), TFA (1 mL), and CH2Cl2 (1 mL) was stirred at ambient temperature for 1.0 h. Concentration and flash chromatography (silica, 10:1:1 ethanol H2O/NH4OH) gave 17-4 (28 mg) as a white solid. Rf 0.17 (10:1:1 ethanol) H2O/NH4OH).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:51])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[C:31]([O:32][C@H:33]([CH2:35][CH:36]=[CH2:37])[CH3:34])=[CH:30][C:29]([F:38])=[CH:28][C:27]=5[F:39])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:40])[C:12]=2[C@H:41]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([O:44][CH3:45])=[O:43])[CH2:7][CH2:6]1)C=C.C(O[C@@H](C1C(C)=CC2=NC3=CN2C=1N1CCC(C)(OCC=CC[C@H](C)OC2C=C(F)C=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C>>[C:47]([O:46][C@@H:41]([C:12]1[C:13]([CH3:40])=[CH:14][C:15]2=[N:19][C:18]3=[CH:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:51])([O:4][CH2:1][CH:37]=[CH:36][CH2:35][C@H:33]([CH3:34])[O:32][C:31]2[CH:30]=[C:29]([F:38])[CH:28]=[C:27]([F:39])[C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)[C:42]([O:44][CH3:45])=[O:43])([CH3:49])([CH3:50])[CH3:48]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5c(F)cc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)cc(F)c1-c1cccc-3c1
Yield: 65 %

Procedure:
Prepared in 65% yield from (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′,4′-difluoro-6′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the same procedure as methyl(2S)-2-(tert-butoxy)-2-[(22S)-18-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18,24-undecaen-3-yl]acetate. 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J=8.0 Hz, 1H), 8.01 (s, 1H), 7.79 (s, 1H), 7.72 (dd, J=5.6, 3.4 Hz, 1H), 7.58-7.49 (m, 1H), 7.33 (s, 1H), 6.63-6.49 (m, 2H), 6.18-6.00 (m, 2H), 5.77 (d, J=15.1 Hz, 1H), 4.49 (br. s., 1H), 4.18-4.08 (m, 1H), 4.05-3.92 (m, 2H), 3.80-3.71 (m, 1H), 3.69 (s, 3H), 3.07 (d, J=10.5 Hz, 1H), 2.69 (d, J=12.0 Hz, 1H), 2.51-2.45 (m, 4H), 2.41 (br. s., 1H), 1.97 (t, J=11.7 Hz, 1H), 1.86-1.64 (m, 2H), 1.51-1.39 (m, 1H), 1.33 (s, 3H), 1.26 (s, 9H), 1.15 (d, J=6.3 Hz, 3H); LCMS (ESI, M+1): 674.3.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C@@H:15]([NH:18]C(OC(C)(C)C)=O)[CH2:16][F:17])[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O>ClCCl>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:26])[C@@H:15]([NH2:18])[CH2:16][F:17])[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CF)NC(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCOC(=O)N1CCN(C(=O)[C@@H](N)CF)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 230 mg 4-((R)-2-tert-Butoxycarbonylamino-3-fluoro-propionyl)-piperazine-1-carboxylic acid butyl ester in 5 ml dichloromethane was added 1.0 ml TFA. After 12 h stirring at RT the solvents were removed and the residue was codistilled twice with toluene. Yield: 307 mg.
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][CH:11]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-])=O)[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CCOC(C)=O.CO.[Pd]>[CH2:1]([N:8]1[CH:9]2[CH2:15][CH2:14][CH:13]1[CH2:12][CH:11]([NH:16][C:17]1[C:18]([NH2:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:10]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1NC1CC2CCC(C1)N2Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccccc1NC1CC2CCC(C1)N2Cc1ccccc1
Reaction time: 3.5 h
Yield: 79.2 %

Procedure:
2.92 g (9.04 mmol) 8-benzyl-N-(2-nitrophenyl)-8-azabicyclo[3.2.1]octan-3-amine was dissolved in 150 ml EtOAc and 25 ml Methanol. 1 g Pd/C was then added and the mixture was stirred at 1 atm H2 for 3.5 hrs. Yellow color disappeared and the reaction mixture was filtered through celite. The solvent was removed to afford 2.2 g of desired solid.
Reaction SMILES: NC1C2C=CC=C(C([NH:14][C:15]3[C:24]([CH3:25])=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][N:19]=[C:20]4[NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29](C(F)(F)F)[CH:28]=3)=O)C=2C=CN=1.[Cl:37]C1C=CC(N)=CC=1>>[Cl:37][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:20]2[C:21]3[CH:22]=[CH:23][C:24]([CH3:25])=[C:15]([NH2:14])[C:16]=3[CH:17]=[CH:18][N:19]=2)=[CH:28][CH:29]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1NC(=O)c1cccc2c(N)nccc12
Product: Cc1ccc2c(Nc3ccc(Cl)cc3)nccc2c1N
Yield: 50 %

Procedure:
The procedures of Steps (1) and (2) of Example 18 were repeated step by step, except for using 4-chloroaniline instead of aniline in Step (1) of Example 18 to obtain the title compound (0.83 g, 50%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([CH2:12][O:13][C:14]2[N:15]=[CH:16][C:17]([C:20]([OH:22])=O)=[N:18][CH:19]=2)=[CH:10][O:9][N:8]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>>[CH:23]([NH:26][C:20]([C:17]1[CH:16]=[N:15][C:14]([O:13][CH2:12][C:11]2[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][O:9][CH:10]=2)=[CH:19][N:18]=1)=[O:22])([CH3:25])[CH3:24]
Reactant: CC(C)N
Reactant: O=C(O)c1cnc(OCc2conc2-c2ccccn2)cn1
Product: CC(C)NC(=O)c1cnc(OCc2conc2-c2ccccn2)cn1
Yield: 68 %

Procedure:
As described for example 19f, 5-(3-pyridin-2-yl-isoxazol-4-ylmethoxy)-pyrazine-2-carboxylic acid (83.6 mg, 2.8 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (SiO2, heptane:ethyl acetate 4:1 to 3:7, 65 mg, 68%) which was obtained as a white solid. MS: m/e=340.2 [M+H]+.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[NH:6][C:5]1=[O:24])[CH:2]=[CH2:3].[CH3:26][N:27]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[N:28]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1.C(O[Cu]OC(=O)C)(=O)C>[CH2:1]([C@@:4]1([CH3:25])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C:30]2[CH:29]=[N:28][N:27]([CH3:26])[CH:31]=2)[C:5]1=[O:24])[CH:2]=[CH2:3]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Agent: CC(=O)O[Cu]OC(C)=O
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(c2cnn(C)c2)C1=O
Temperature: 115 °C
Reaction time: 13 h

Procedure:
(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one (Example 71, Step D) (90 mg, 0.24 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (125 mg, 0.60 mmol), diacetoxycopper (44 mg, 0.24 mmol) and N,N-dimethylpyridin-4-amine (88 mg, 0.72 mmol) were dissolved in 1.2 mL of toluene. Sodium bis(trimethylsilyl)amide (480 μL, 0.48 mmol) was added and the reaction apparatus was outfitted with a reflux condenser and was allowed to stir at 115° C. for 13 hours. The reaction mixture was cooled to room temperature, quenched with water and extracted (2×EtOAc). The combined organic layers were washed with sat. aq. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography (0 to 60% EtOAc/hexanes) provided the title compound as a colorless solid.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH:3]=[C:2]1[C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[CH3:20]O>>[CH3:20][O:13][C:12]([C:2]1[O:1][C:10]2[C:5]([C:4](=[O:11])[CH:3]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:14]
Reactant: CO
Reactant: O=C(O)c1cc(=O)c2ccccc2o1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(=O)c2ccccc2o1
Temperature: 0 °C

Procedure:
Combine chromone-2-carboxylic acid (2.0 g, 10.5 mmol) and methanol (25 mL). Add sulfuric acid (2.5 mL) and heat to reflux. After 2 hours pour the reaction mixture into ice water and filter. Rinse the filter cake with water and a cold dilute aqueous solution of sodium bicarbonate. Chromatograph on silica gel eluting with tetrahydrofuran to give a residue. Recrystallize the residue from methanol to give the title compound as a solid: mp; 120°-122° C.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:10]=1[O:11][C:12]1[C:13]([C:23]2[C:24]3[CH:33]=[N:32][N:31](COCC[Si](C)(C)C)[C:25]=3[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)=[CH:14][CH:15]=[C:16]2[C:21]=1[NH:20][C:19](=[O:22])[CH2:18][NH:17]2>C(Cl)Cl>[F:8][C:9]1[CH:45]=[C:44]([F:46])[CH:43]=[CH:42][C:10]=1[O:11][C:12]1[C:13]([C:23]2[C:24]3[CH:33]=[N:32][NH:31][C:25]=3[C:26](=[O:30])[N:27]([CH3:29])[CH:28]=2)=[CH:14][CH:15]=[C:16]2[C:21]=1[NH:20][C:19](=[O:22])[CH:18]=[N:17]2
Reactant: Cn1cc(-c2ccc3c(c2Oc2ccc(F)cc2F)NC(=O)CN3)c2cnn(COCC[Si](C)(C)C)c2c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(-c2ccc3ncc(=O)[nH]c3c2Oc2ccc(F)cc2F)c2cn[nH]c2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
Trifluoroacetic acid (0.40 mL, 5.19 mmol) was added dropwise at RT to a solution of 8-(2,4-difluorophenoxy)-7-(6-methyl-7-oxo-1-{[2-(trimethylsilyl)ethoxy]methyl}-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-4-yl)-3,4-dihydroquinoxalin-2(1H)-one (10.5 mg, 0.0190 mmol, mixture of oxidized (quinoxalin) and reduced (dihydroquinoxalin) forms from previous step) in methylene chloride (0.40 mL), and the reaction mixture was stirred at RT for 1 h. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (4 mg, 50%). 1H NMR (500 MHz, DMSO-d6) δ 14.05 (br s, 1H), 12.50 (br s, 1H), 8.19 (s, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.42 (d, J=8.3 Hz, 1H), 7.35 (s, 1H), 7.16-6.99 (m, 1H), 6.70-6.56 (m, 1H), 6.55-6.34 (m, 1H), 3.48 (s, 3H); LCMS calculated for C21H14F2N5O3 (M+H)+: m/z=422.1. found: 422.0.
Reaction SMILES: O.ON1C2C=CC=CC=2N=N1.Cl.CN(CCCN=C=NCC)C.C(N(CC)CC)C.[CH:31]1([CH2:34][N:35]2[C:43]([N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[N:42][C:41]3[C:36]2=[N:37][C:38]([C:56]2[CH:57]=[N:58][C:59]([NH2:62])=[N:60][CH:61]=2)=[N:39][C:40]=3[N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH2:33][CH2:32]1.C(O[C:68]([N:70](C)[CH2:71][C:72](O)=[O:73])=O)(C)(C)C>ClCCl.CO.CN(C)C=O>[CH:31]1([CH2:34][N:35]2[C:43]([N:44]3[CH2:49][CH2:48][N:47]([C:72](=[O:73])[CH2:71][NH:70][CH3:68])[CH2:46][CH2:45]3)=[N:42][C:41]3[C:36]2=[N:37][C:38]([C:56]2[CH:61]=[N:60][C:59]([NH2:62])=[N:58][CH:57]=2)=[N:39][C:40]=3[N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)[CH2:32][CH2:33]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC4CC4)c3n2)cn1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CNCC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CC1
Reaction time: 72 h
Yield: 57.5 %

Procedure:
1-Hydroxybenzotriazole monohydrate (35.1 mg, 0.23 mmol), 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (65.9 mg, 0.34 mmol), and triethylamine (86.2 μl, 0.62 mmol) were added to an N,N-dimethylformamide suspension (2.0 ml) of 5-[9-(cyclopropylmethyl)-6-morpholin-4-yl-8-piperazin-1-yl-9H-purin-2-yl]pyrimidin-2-amine (100.0 mg, 0.23 mmol) and N-tert-butoxycarbonyl-N-methylglycine (52.0 mg, 0.27 mmol) at room temperature. The resulting mixture was stirred for 3 days and the reaction mixture was poured into dichloromethane-methanol (10:1), washed with saturated aqueous sodium bicarbonate solution and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was dissolved in dichloromethane (4.0 ml) followed by the addition of trifluoroacetic acid (2.0 ml) with ice cooling. The resulting mixture was stirred at room temperature for 2 hours and concentrated, dichloromethane was added to the residue, and the resulting mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The resulting mixture was extracted with dichloromethane-methanol (10:1), dried over anhydrous sodium sulfate, and filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=5:1) to give the title compound (67.1 mg, 58%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]([CH3:13])([CH3:12])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1.[Cl:14][C:15]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:16]=1[O:17][CH2:18][CH:19]1[O:21][CH2:20]1>CO>[Cl:14][C:15]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:16]=1[O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:1][C:2]([CH3:13])([CH3:12])[CH2:3][O:4][C:5]1[N:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: CC(C)(N)COc1ccc(Cl)nn1
Reactant: Cc1cccc(OCC2CO2)c1Cl
Solvent: CO
Product: Cc1cccc(OCC(O)CNC(C)(C)COc2ccc(Cl)nn2)c1Cl
Yield: 66.6 %

Procedure:
A solution of 6.04 g of 3-(2-amino-2-methylpropoxy)-6-chloropyridazine obtained in Example 1, (a) and 5.95 g of 1-(2-chloro-3-methylphenoxy)-2,3-epoxypropane in 120 ml of methanol was refluxed for 3 hours. The solvent was evaporated under reduced pressure. A solution of the residue in benzene was extracted with 175 ml of 0.2N hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and extracted with chloroform. The chloroform layer was dried over sodium sulfate. The solvent was evaporated and the residue (10 g) was purified by column chromatography (50 g of Florisil; eluted with chloroform) to give 7.98 g of 1-(2-chloro-3-methylphenoxy)-3-[1,1-dimethyl-2-(3-chloro-6-pyridazinyloxy)ethylamino]-2-propanol as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH2:10][CH:11]=C)[CH:5]=[CH:6][C:7]=1[Cl:8].I([O-])(=O)(=O)=[O:20].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.Cl.C1(C)C=CC=CC=1.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]([CH2:13][N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH2:10][CH:11]=[O:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CC[C@H](Cn1ccnc1)c1ccc(Cl)c(Cl)c1
Agent: O=[Os](=O)(=O)=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: O
Product: O=CC[C@H](Cn1ccnc1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.33 h
Yield: 89.9 %

Procedure:
4(S)-(3,4-Dichlorophenyl)-5-(imidazol-1-yl)pent-1-ene (4.75 g) (see Preparation 95) was dissolved in a mixture of acetonitrile (75 ml), water (13 ml) and 1N aqueous hydrochloric acid solution (17 ml). Osmium tetroxide (3.4 ml of a 0.05M solution in toluene) was added and the mixture stirred for 20 minutes. Sodium periodate (5.3 g) was then added together with a further quantity of acetonitrile (30 ml) and stirring continued overnight. Water (ca. 100 ml) was added and the acetonitrile removed under reduced pressure to give an aqueous suspension which was basified to pH>7 by the addition of solid sodium carbonate. The mixture was then extracted (three times) with ethyl acetate and the combined organic extracts washed sequentially with water and brine before being dried over anhydrous sodium sulphate. Removal of the solvent under reduced pressure gave 3(S)-(3,4-dichlorophenyl)-4-(imidazol-1-yl)butan-1-al (4.3 g) as an oil.