Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C@@H]1C[C@H]1C1C=CC(N)=CC=1)=O)C.FC(F)(F)C1C=C(OC2C=C(C=CC=2)C=O)C=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:49][C:50]([F:81])([F:80])[C:51]1[CH:52]=[C:53]([O:57][C:58]2[CH:59]=[C:60]([CH2:64][NH:65][C:66]3[CH:71]=[CH:70][C:69]([CH:72]4[CH2:74][CH:73]4[C:75]([O:77]CC)=[O:76])=[CH:68][CH:67]=3)[CH:61]=[CH:62][CH:63]=2)[CH:54]=[CH:55][CH:56]=1.[OH-].[Na+].Cl>ClC(Cl)C.C1COCC1.CCO.O>[F:49][C:50]([F:80])([F:81])[C:51]1[CH:52]=[C:53]([O:57][C:58]2[CH:59]=[C:60]([CH2:64][NH:65][C:66]3[CH:71]=[CH:70][C:69]([C@@H:72]4[CH2:74][C@H:73]4[C:75]([OH:77])=[O:76])=[CH:68][CH:67]=3)[CH:61]=[CH:62][CH:63]=2)[CH:54]=[CH:55][CH:56]=1
Reactant: CCOC(=O)C1CC1c1ccc(NCc2cccc(Oc3cccc(C(F)(F)F)c3)c2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCOC(=O)[C@@H]1C[C@H]1c1ccc(N)cc1
Agent: Cl
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3cccc(C(F)(F)F)c3)c2)cc1
Reaction time: 18 h
Yield: 100 %

Procedure:
To a mixture of (+)-(trans)-ethyl-2-(4-aminophenyl)cyclopropanecarboxylate (III-1b) (0.093 g, 0.453 mmol) in dichloroethane (3.5 mL) was added 3-{[3-(trifluoromethyl)phenyl]oxy}benzaldehyde (70 uL, 0.404 mmol). The mixture was stirred for 18 h followed by addition of sodium triacetoxyborohydride (0.135 g, 0.637 mmol). The mixture was stirred for 12 h at RT. Water was added (10 mL), and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×10 mL). The combined organics were dried with MgSO4 and concentrated. The crude material was purified by chromatography (EtOAc/hexanes) to give ethyl 2-(4-{[(3-{[3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]amino}phenyl)cyclopropanecarboxylate as a colorless oil (0.159 g, mixture of ethyl and methyl ester). The material was dissolved in THF/EtOH (1 mL each) and a 1M sodium hydroxide solution was added (1 mL). The mixture was heated at 85 C for 3.5 h. Upon cooling, the mixture was acidified (pH=2-3) with a 5M hydrochloric acid solution. Water was added (5 mL), and the mixture was extracted with CH2Cl2 (3×10 mL). The organics were washed with water and brine (1×10 mL each) and dried with MgSO4 to give the title compound as an orange oil (0.153 g, >100%, residual THF present). 1H NMR (400 MHz, DMSO-d6): δ 7.41 (t, J=8.1 Hz, 1H), 7.30-7.35 (m, 2H), 7.20 (m, 1H), 7.10-7.17 (m, 2H), 7.02 (m, 1H), 6.92 (d, J=8.4 Hz, 2H), 6.90 (m, 1H), 6.56 (d, J=8.4 Hz, 2H), 4.31 (s, 2H), 2.50 (m, 1H), 1.77 (m, 1H), 1.57 (m, 1H), 1.32 (m, 1H). ES-MS m/z 428.16 (MH+).
Reaction SMILES: [Mg].II.Br[CH:5]([CH2:7][CH2:8][CH3:9])[CH3:6].[CH2:10]([N:17]1[CH2:21][CH:20]([CH2:22]I)[CH2:19][C:18]1=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[CH2:10]([N:17]1[CH2:21][CH:20]([CH2:22][CH:5]([CH3:6])[CH2:7][CH2:8][CH3:9])[CH2:19][C:18]1=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCCC(C)Br
Reactant: O=C1CC(CI)CN1Cc1ccccc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCC(C)CC1CC(=O)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
To a suspension of magnesium turnings (0.50 g, 0.021 mol) in 15 mL of dry THF under nitrogen, was added an iodine crystal and 2-bromopentane (2.88 g, 0.019 mol). After an exothermic reaction which was periodically cooled in an ice bath, the reaction was stirred at room temperature for 2 hours. Eight milliliters of Li2CuCl4 (made from 84 mg LiCl and 134 mg CuCl2 in 10 mL of dry THF) was added at 0° C. followed by dropwise addition of 1-Benzyl-4-iodomethyl-pyrolidine-2-one 75 in 15 mL dry THF, and the resulting suspension was let stir at 0° C. for 3 hours. Stirring was continued at room temperature for 1 hour before quenching with a saturated solution of ammonium chloride. Water was added to dissolve the precipitate formed, and the solution was then extracted with ether and dried over magnesium sulfate. The solvent was evaporated under vacuum and the residue chromatographed on silica eluting with 1:1 acetone/hexane to give 1.13 g, 69% of the 1-benzyl-4-(2-methyl-pentyl)-pyrrolidin-2-one 76. 1H NMR (CDCl3) 67 7.30 (m, 5H), 4.44 (m, 2H), 3.32 (m, 1H), 2.86 (m, 1H), 2.56 (m, 1H), 2.40 (m, 1H), 2.10 (m, 1H), 1.30 (m, 6H), 1.10 (m, 1H), 0.90 (m, 6H). MS, m/z (relative intensity): 261 [M+2H, 100%], 301 [M−H+CH3CN, 82%], 260 [M+H, 72%].
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[OH:13][C:14]([CH3:19])([CH3:18])[C:15](O)=[O:16].[C:20]([C:24]1[O:28][C:27]([C:29]2[C:30]([NH2:47])=[N:31][CH:32]=[C:33]([C:35]3[N:39]([CH3:40])[N:38]=[C:37]([CH:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)[N:36]=3)[N:34]=2)=[N:26][N:25]=1)([CH3:23])([CH3:22])[CH3:21].OC1C=CC=C[N+]=1[O-].N1C=CC=CC=1>CN1C(=O)CCC1>[NH2:47][C:30]1[N:31]=[CH:32][C:33]([C:35]2[N:39]([CH3:40])[N:38]=[C:37]([CH:41]3[CH2:46][CH2:45][N:44]([C:15](=[O:16])[C:14]([OH:13])([CH3:19])[CH3:18])[CH2:43][CH2:42]3)[N:36]=2)=[N:34][C:29]=1[C:27]1[O:28][C:24]([C:20]([CH3:23])([CH3:21])[CH3:22])=[N:25][N:26]=1
Reactant: CC(C)(O)C(=O)O
Reactant: Cn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [O-][n+]1ccccc1O
Solvent: c1ccncc1
Solvent: CN1CCCC1=O
Product: Cn1nc(C2CCN(C(=O)C(C)(C)O)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.2 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) was added in one portion to 2-hydroxy-2-methylpropanoic acid (38.0 mg, 0.37 mmol), 3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-5-(1-methyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine (100 mg, 0.26 mmol) and 2-hydroxy-pyridine N-oxide (57.9 mg, 0.52 mmol) dissolved in NMP (1.2 mL) under argon. The resulting solution was stirred at 25° C. for 3 hours. Pyridine (100 μL, 1.24 mmol) was added and the mixture was stirred for 18 hours. Additional 2-hydroxypyridine 1-oxide (57.9 mg, 0.52 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) was added. The mixture was then heated up to 70° C. for 48 hours, more 2-hydroxy-2-methylpropanoic acid (15 mg, 0.14 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (50.0 mg, 0.26 mmol) and 2-hydroxypyridine 1-oxide (25.0 mg, 0.23 mmol) were added and the mixture was then kept to 70° C. for 8 hours. The solution was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent to afford the title compound (71 mg, 58%) as a pale yellow solid. 1H NMR Spectrum: (CDCl3) 1.55 (15H, s br), 1.90 (2H, m), 2.15 (2H, m), 3.05-3.3 (4H, m), 4.32 (3H, s), 4.6 (1H, m), 9.03 (1H, s); Mass Spectrum [M+H]+=470.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1)=O.Cl.[NH2:32][OH:33].N1C=CC=CC=1>C(O)C.C(OCC)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1)=[N:32][OH:33]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1oc(-c2ccccc2)nc1CCC(=NO)c1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83 %

Procedure:
Title product of Example 9 (0.10 g, 0.238 mmol), hydroxylamine hydrochloride (0.041 g, 0.595 mmol) and 2 mL of pyridine were combined in 3 mL of ethanol and the mixture stirred 18 hours at room temperature, then stripped of solvent and the residue taken up in 7.5 mL ethyl acetate, washed with 5 mL of cold 18% HCl and then 5 mL brine, dried (MgSO4) and stripped to yield 0.086 g of present title product as a white solid; mp 202°-205° C.; tlc Rf 0.53 (1:1 hexane:ethyl acetate).
Reaction SMILES: [SH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31].[C:32]1([C:38](Cl)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1COCC1>[C:38]([S:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: OCCOCCOCCOCCOCCOCCOCCCCCCCCCCCS
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: OCCOCCOCCOCCOCCOCCOCCCCCCCCCCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.2 %

Procedure:
To a solution of 2-{2-[2-(2-{2-[2-(11-mercapto-undecyloxy)-ethoxy]ethoxy}-ethoxy)-ethoxy]-ethoxy}-ethanol (3) (1.22 g, 2.6 mmol) prepared according to the method of Pale-Grosdemange et al.†, dissolved in 10 mL of THF was added triphenylmethyl chloride (1.46 g, 5.2 mmol). After stirring at room temperature for 48 hours, the reaction mixture was concentrated. The crude residue was purified by flash chromatography (gradient elution, EtOAc to 20:1 EtOAc/MeOH) to afford 910 mg (49%) of 4. 1H NMR (CDCl3, 400 MHz) d 7.36 (d, J=X Hz, 6H), 7.22 (t, J=X Hz, 6H), 7.15 (t, J=X Hz, 3H), 3.72–3.48(br m, 24H), 3.40 (t, J=X Hz, 2H), 2.08 (t, J=X Hz, 2H), 1.52 (m, 2H), 1.4–0.9(br, 16H). ES-MS: m/z 733.4 (M+Na+). † Pale-Grosdemange, C.; Simon, E. S.; Prime, K. L.; Whitesides, G. M. J. Am. Chem. Soc, 1991, 113, 12–20.
Reaction SMILES: N1C=CN=C2NC=CC=12.C[Sn](C)(C)[Sn](C)(C)C.[Sn].[CH3:19][Si:20]([CH3:39])([CH3:38])[CH2:21][CH2:22][O:23][CH2:24][N:25]1[C:29]2=[N:30][CH:31]=[C:32]([Sn](C)(C)C)[N:33]=[C:28]2[CH:27]=[CH:26]1.Br[C:41]1[C:42]([NH:49][C@H:50]2[CH2:55][CH2:54][CH2:53][N:52]([S:56]([CH3:59])(=[O:58])=[O:57])[CH2:51]2)=[N:43][C:44]([S:47][CH3:48])=[N:45][CH:46]=1>C1(C)C=CC=CC=1>[CH3:59][S:56]([N:52]1[CH2:53][CH2:54][CH2:55][C@H:50]([NH:49][C:42]2[C:41]([C:32]3[N:33]=[C:28]4[CH:27]=[CH:26][N:25]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:39])([CH3:38])[CH3:19])[C:29]4=[N:30][CH:31]=3)=[CH:46][N:45]=[C:44]([S:47][CH3:48])[N:43]=2)[CH2:51]1)(=[O:58])=[O:57]
Reactant: CSc1ncc(Br)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1
Reactant: C[Si](C)(C)CCOCn1ccc2nc([Sn](C)(C)C)cnc21
Agent: C[Sn](C)(C)[Sn](C)(C)C
Agent: [Sn]
Agent: c1cnc2[nH]ccc2n1
Solvent: Cc1ccccc1
Product: CSc1ncc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(N[C@H]2CCCN(S(C)(=O)=O)C2)n1
Temperature: 97.5 °C

Procedure:
A degassed toluene solution of 2-bromo-5-(2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine (200 mg, 0.61 mmol) and 1,1,1,2,2,2-hexamethyldistannane (220 mg, 0.67 mmol) was treated with tetrakistriphenylphosphine palladium (0) (35 mg, 0.03 mmol) and heated to 95-100° C. for 2 hours. When LCMS indicated conversion to the tin product, 5-(2-trimethylsilanyl-ethoxymethyl)-2-trimethylstannanyl-5H-pyrrolo[2,3-b]pyrazine, (MS (ES+): 412), the reaction was treated with (5-bromo-2-methylsulfanyl-pyrimidin-4-yl)-((S)-1-methanesulfonyl-piperidin-3-yl)-amine (80 mg, 0.21 mmol) and additional tetrakistriphenylphosphine palladium (0) (35 mg, 0.03 mmol) and heated to 100° C. for 16 hours. The reaction was cooled, filtered through celite, evaporated and purified by flash chromatography (60% ethyl acetate/hexane+2% triethylamine) to give 60 mg of ((S)-1-methanesulfonyl-piperidin-3-yl)-{2-methylsulfanyl-5-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyrimidin-4-yl}-amine. MS (ES+): 550.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15](F)[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26].[NH2:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31].C(N(CC)CC)C>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:20])=[C:15]([NH:27][CH2:28][CH:29]([OH:32])[CH2:30][OH:31])[C:16]=3[Cl:18])[C:11](=[O:21])[C:10]([C:22]([OH:24])=[O:23])=[CH:9]2)[C:5]([F:25])=[CH:4][C:3]=1[F:26]
Reactant: NCC(O)CO
Reactant: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(NCC(O)CO)c(Cl)c32)c(F)cc1F
Temperature: 50 °C
Reaction time: 18 h

Procedure:
1-(6-Amino-3,5-difluoropyridin-2-yl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (150 mg), 3-amino-1,2-propanediol (45 ml) and triethylamine (150 mg) were added to pyridine (500 mg), and the mixture was stirred at 50° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. A process of adding ethanol (2 ml) to the residue and then concentrating the mixture under reduced pressure was conducted twice repeatedly. Concentrated hydrochloric acid (60 mg) was added to the residue, and the mixture was concentrated under reduced pressure. Ethanol (1.5 ml) was added to the resultant residue, and deposits were collected by filtration and washed with ethanol and diisopropyl ether in that order to obtain the title compound (107 mg) as a colorless powder.
Reaction SMILES: CN(C=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:15]1[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][N:16]=1.[CH2:25](B1C2CCCC1CCC2)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.CC(=O)OCC>[CH2:25]([C:15]1[CH:20]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:18]=[CH:17][N:16]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Reactant: COC(=O)c1ccnc(Cl)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccnc(Cc2ccccc2)c1
Temperature: 60 °C
Yield: 84.1 %

Procedure:
To 35 ml of anhydrous DMF under argon in a sealed tube were added tripotassium phosphate (9.28 g, 43.71 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl (SPhos, 0.239 g, 0.58 mmol), palladium(II) acetate (0.065 g, 0.29 mmol) and then methyl 2-chloro-pyridine-4-carboxylate (2.50 g, 14.57 mmol) and B-benzyl-9-borabicyclo[3.3.1]nonane (6.80 g, 32.05 mmol). The mixture was heated overnight at 60° C. After cooling to room temperature, the mixture was diluted into 200 ml of EA, the solution washed three times with 100 ml of a 1 N sodium hydroxide solution and twice with 100 ml of brine. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was then purified by chromatography on silica gel (cyclohexane/EA, 100:0, then 80:20) to give 2.784 g of the title compound as an orange oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Cl)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Li+].C[Si]([N-:55][Si](C)(C)C)(C)C>C1COCC1.Cl.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]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:55])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Clc1cc(OCc2ccccc2)ccn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: C1CCOC1
Product: Nc1cc(OCc2ccccc2)ccn1
Temperature: 50 °C
Reaction time: 2 h
Yield: 70.2 %

Procedure:
4-(benzyloxy)-2-chloropyridine (18.6 g, 84.7 mmol), XPHOS (4.04 g, 8.47 mmol), and Pd2dba3 (3.88 g, 4.23 mmol) were mixed in THF (250 mL). LHMDS (93.1 ml, 93.1 mmol) was added and the reaction was heated at 50° C. for 1.5 hours. The solution was cooled and diluted with 1N HCl (50 mL) and stirred at ambient temperature for 2 hours. The reaction was concentrated and the residue was extracted with EtOAc. The aqueous layer was basified with saturated K2CO3 and the aqueous layer was extracted with EtOAc. The combined organic layers were dried and concentrated to give the desired product (11.9 g, 70.2% yield) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1.BrC1C=C[C:16]([OH:19])=[C:15](CC)C=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:16](=[O:19])[CH3:15])=[C:4]([CH:9]([CH3:11])[CH3:10])[CH:3]=1
Reactant: CC(C)c1cc(Br)ccc1O
Reactant: CCc1cc(Br)ccc1O
Product: CC(=O)Oc1ccc(Br)cc1C(C)C

Procedure:
The title compound was prepared as described in Step 2 of Example A(22) where 4-Bromo-2-isopropyl-phenol from step 1, was substituted in place of 4-Bromo-2-ethyl-phenol.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([CH:25]([CH3:27])[CH3:26])[N:23]=[CH:24][C:10]=13)[CH2:2]2.C(N(CC)CC)C.Cl[C:36](Cl)([O:38][C:39](=O)[O:40]C(Cl)(Cl)Cl)Cl.N(C1C=CC(C2N=C3N(C(C)C)N=CC3=C(N3CC4OC(CC4)C3)N=2)=CC=1)=C=O>ClCCl.CO>[CH3:36][O:38][C:39](=[O:40])[NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:13]2[N:12]=[C:11]3[N:22]([CH:25]([CH3:27])[CH3:26])[N:23]=[CH:24][C:10]3=[C:9]([N:3]3[CH2:2][CH:1]4[O:8][CH:5]([CH2:6][CH2:7]4)[CH2:4]3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: CC(C)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CC(C)n1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N=C=O)cc3)nc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C(C)C)c3n2)cc1
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (0.027 g, 0.07 mmol) in dichloromethane (2 mL) was treated with triethylamine (0.028 mL), followed by a solution of triphosgene (0.011 g, 0.04 mmol) in dichloromethane (1 mL). After the passage of 10 minutes, the appropriate nucleophile—in the case, methanol (excess)—was added to the 3-(6-(4-isocyanatophenyl)-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (“isocyanate”) mixture. After 10 minutes, the reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 5% acetonitrile/95% of 0.1% aqueous trifluoroacetic acid to 100% acetonitrile over 35 minutes to provide methyl{4-[1-isopropyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}carbamate (15 mg, 48%). MS (ES+): 423.2 (M+H)+
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][O:4]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CS(C)=O.[OH-].[K+]>[Cl-].[Na+].O.O1CCCC1>[CH2:28]([O:1][CH2:2][C:3]1([CH2:8][OH:9])[CH2:7][CH2:6][CH2:5][O:4]1)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCCCCCCCBr
Reactant: OCC1(CO)CCCO1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCC1(CO)CCCO1

Procedure:
To a mixture of 2.64 g (0.002 mol) of 2,2-bis(hydroxymethyl)-tetrahydrofuran and 2.2 g (0.0066 mol) of bromooctadecane in 8 ml of 1:1 mixture of dimethylsulfoxide and tetrahydrofuran was added 1.84 g (0.0264 mol) of finely powdered potassium hydroxide. The resultant mixture was then stirred at room temperature for 2 hours, after which time it was poured onto 100 ml of water, diluted with 20 ml of an aqueous saturated sodium chloride solution and extracted with ether. The ether extract was then washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate and the ether was removed under reduced pressure. The crude product was then purified by column chromatography on silica gel employing a mixture of methyl-t-butyl ether and hexane (3:1 ratio) as the eluent to yield the desired compound as a wax.
Reaction SMILES: [SiH](CC)(CC)CC.B(F)(F)F.CCOCC.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31](O)[C:32]([CH3:43])([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33]([OH:35])=[O:34])=[CH:27][C:26]=1[O:45][CH3:46])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([CH3:43])([O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:33]([OH:35])=[O:34])=[CH:27][C:26]=1[O:45][CH3:46])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc(C(O)C(C)(Oc2ccccc2)C(=O)O)ccc1OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(CC(C)(Oc2ccccc2)C(=O)O)ccc1OCc1ccccc1
Temperature: -10 °C
Reaction time: 1.5 h

Procedure:
A stirred solution of Et3SiH (8.67 mL, 54.3 mmol) in CH2Cl2 (45 mL) was treated with BF3.Et2O (6.8 mL, 54.3 mmol). 3-(4-Benzyloxy-3-methoxyphenyl)-3-hydroxy-2-methyl-2-phenoxypropionic acid (7.39 g, 18.1 mmol) in CH2Cl2 (90.5 mL) was then added dropwise via addition funnel, maintaining temperature below −7° C. After the addition was complete, the reaction was stirred for 1.5 h at −10° C., then quenched with 1 M NaOH (18.1 mL) and diluted with H2O (12 mL). 1N HCl was used to adjust pH to 4, followed by separation of layers. The aqueous layer was extracted with CH2Cl2 (2×15 mL), and combined organic layers were washed first with 1N HCl (15 mL), then H2O (15 mL), followed by drying over Na2SO4 and concentration to a gummy orange solid (6.86 g, 97%): MS (EI) 410.2 (M +NH4)+, 391.3 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1.[NH2:17][NH2:18].O>C(O)C>[NH:17]([C:2]1[N:7]=[N:6][C:5]2[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=3[CH2:10][CH2:11][CH2:12][C:4]=2[CH:3]=1)[NH2:18]
Reactant: NN
Reactant: Clc1cc2c(nn1)-c1ccccc1CCC2
Solvent: O
Solvent: CCO
Product: NNc1cc2c(nn1)-c1ccccc1CCC2
Temperature: 25 °C
Yield: 98.4 %

Procedure:
A mixture of the compound of formula (Df), 3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine, (4.3 g, 18.6 mmol) and anhydrous hydrazine (11.7 mL, 370 mmol) in 45 mL of ethanol was refluxed for 16 h. After cooling to ambient temperature, 5 mL of water was added and the volatiles were then evaporated. To the solid residue was added cold water (about 80 mL). After sonication for 10 min, the resulting solid was collected by filtration and washed with cold water three times. After freeze-drying, the compound of formula (D-1), 3-hydrazino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine, (4.14 g, 98%) was obtained as a slight yellow solid, 1H NMR (300 MHz, CD3OD) δ: 7.59 (m, 1H), 7.39-7.26 (m, 3H), 7.04 (s, 1H), 2.54 (t, J=6.9 Hz, 2H), 2.47 (t, J=6.9 Hz, 2H), 2.18 (quant, J=6.9 Hz, 2H); LC-MS: purity: 100%; MS (m/e) : 227 (MH+).