Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:32][CH2:33]C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)[C:29]([OH:31])=[O:30])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1.[F:47][C:48]([F:76])([C:66]([F:75])([F:74])[C:67]([F:73])([F:72])[C:68]([F:71])([F:70])[F:69])[CH2:49][CH2:50]CCC(CCCCCC=C)C(OCC)=O>>[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH:28]([CH2:32][CH2:33][CH2:50][CH2:49][C:48]([F:47])([F:76])[C:66]([F:74])([F:75])[C:67]([F:72])([F:73])[C:68]([F:71])([F:70])[F:69])[C:29]([OH:31])=[O:30])[C:7]([C:13]3[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=3)([CH3:12])[CH2:8][S:9]2)=[CH:4][CH:3]=1
Reactant: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O
Reactant: C=CCCCCCC(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)OCC
Product: CC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 8 and the ethyl 2-(5,5,6,6,7,7,8,8,8-nonafluorooctyl)-8-nonenoate prepared in Example 5, a procedure analogous to that as shown in Example 8 was repeated to give 10-[(3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methylthiochroman-4-yl]-2-(5,5,6,6,7,7,8,8,8-nonafluorooctyl)decanoic acid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:11]([O:13][CH2:14][C@H:15]([OH:26])[C:16]([NH:18][C:19]1[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=1)=[O:17])[CH3:12].Cl[C:28]1[N:33]=[CH:32][N:31]=[C:30]2[N:34]([C:37]3[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=3)[N:35]=[CH:36][C:29]=12>C1COCC1.CCOC(C)=O>[Cl:43][C:42]1[C:37]([N:34]2[C:30]3[N:31]=[CH:32][N:33]=[C:28]([O:26][C@@H:15]([CH2:14][O:13][CH2:11][CH3:12])[C:16]([NH:18][C:19]4[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][N:20]=4)=[O:17])[C:29]=3[CH:36]=[N:35]2)=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCOC[C@H](O)C(=O)Nc1cnc(C)cn1
Reactant: Clc1cccnc1-n1ncc2c(Cl)ncnc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC[C@H](Oc1ncnc2c1cnn2-c1ncccc1Cl)C(=O)Nc1cnc(C)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 51.8 %

Procedure:
A solution of lithium bis(trimethylsilyl)amide (1.40 mL, 1.40 mmol) was added dropwise to a stirred solution of (S)-3-ethoxy-2-hydroxy-N-(5-methylpyrazin-2-yl)propanamide (Intermediate H1) (315 mg, 1.40 mmol) in THF (15 mL) over a period of 3 minutes under nitrogen. The resulting suspension was stirred at ambient temperature for 10 minutes and then a solution of 4-chloro-1-(3-chloropyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidine (Intermediate B15) (372 mg, 1.40 mmol) in anhydrous THF (3 mL) added dropwise over 1 minute and the reaction heated to 50° C. for 3 hours. The reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (2×25 mL) and saturated brine (25 mL). The organic layer was dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography eluting with EtOAc to afford (2S)-2-[1-(3-chloropyridin-2-yl)pyrazolo[4,5-e]pyrimidin-4-yl]oxy-3-ethoxy-N-(5-methylpyrazin-2-yl)propanamide (330 mg, 52%). 1H NMR (400 MHz, CDCl3) δ 1.24 (3H, t), 2.54 (3H, s), 3.60-3.68 (2H, m), 4.07-4.16 (2H, m), 6.09 (1H, t), 7.47 (1H, dd), 8.01 (1H, dd), 8.12 (1H, d), 8.47 (1H, s), 8.62 (1H, dd), 8.64 (1H, s), 8.66 (1H, s), 9.44 (1H, d); m/z (ESI+) (M+H)+=455; HPLC tR=1.77 min.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(Cl)nc1-c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
1 mmol 2,6-dichloro-3-nitropyridine, 1.05 mmol of 2,4-dichlorobenzeneboronic acid, and 3 mmol of Na2CO3, were dissolved in 1.5 ml THF and 0.5 ml water and purged with nitrogen. 0.05 mmol of [1,1′-Bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) was added to reaction and stirred at room temperature under nitrogen for fourteen hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluting with 10% ethylacetate 90% hexanes to obtain 2-(2,4-dichlorophenyl)-6-chloro-3-nitropyridine.
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][C:19]([OH:23])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.Br[CH2:35][CH2:36][OH:37]>>[CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:11]([CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:23][CH2:35][CH2:36][OH:37])=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3cc(O)ccc32)cc1
Reactant: OCCBr
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3cc(OCCO)ccc32)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(4-dimethylaminophenyl)methyl]-6-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) and 2-bromoethanol (0.16 mL) as starting materials, N-[(4-dimethylaminophenyl)methyl]-6-(2-hydroxyethoxy)-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.28 g) was obtained. melting point: 141.4° C.
Reaction SMILES: [NH:1]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:2][C:3]([OH:5])=O.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.[NH2:29][C:30]1[N:59]=[C:33]2[N:34]([C:49]3[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:58])([F:57])[F:56])[CH:50]=3)[C:35]([CH3:48])=[C:36]([C:46]#[N:47])[C@@H:37]([C:38]3[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=3)[N:32]2[N:31]=1>C1COCC1>[C:46]([C:36]1[C@@H:37]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)[N:32]2[N:31]=[C:30]([NH:29][C:3](=[O:5])[CH2:2][NH:1][C:6](=[O:7])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[N:59]=[C:33]2[N:34]([C:49]2[CH:54]=[CH:53][CH:52]=[C:51]([C:55]([F:57])([F:56])[F:58])[CH:50]=2)[C:35]=1[CH3:48])#[N:47]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)CNC(=O)OC(C)(C)C)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of argon protective gas, N-Boc-Gly-OH (5 mg, 28 μmol) and NMM (5.3 mg, 52 μmol, 2.4 eq.) were dissolved in abs. THF (1 ml), and isobutyl chloroformate (4.2 mg, 31 μmol, 1.4 eq.) was added at −15° C. (solution A). At −78° C., (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (10 mg, 22 μmol) and NMM (2.2 mg, 22 μmol, 1 eq.) were added, and the mixture was stirred overnight, during which time it slowly warmed to RT. Since the conversion was still incomplete, more solution A consisting of in each case 285 μmol of N-Boc-Gly-OH, isobutyl chloroformate and NMM in abs. THF was added at −15° C., and the mixture was stirred for 3 d, warming to RT. The reaction mixture was then directly purified by preparative HPLC (Gromsil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (6.3 mg, 50% of theory).
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](=[S:14])[NH2:13])=[CH:8]2.[C:24]([O:29][CH2:30][CH3:31])(=[O:28])[C:25]#[C:26][CH3:27].C(P(CCCC)CCCC)CCC.ClCCl>O1CCCC1>[CH3:1][N:2]([S:15]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:14][CH:26]([CH2:25][C:24]([O:29][CH2:30][CH3:31])=[O:28])[CH2:27][N:13]=1)=[CH:8]2
Reactant: CN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccnc1
Reactant: CC#CC(=O)OCC
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccnc4)c3[nH]2)S1
Temperature: 25 °C
Reaction time: 15 h
Yield: 30.2 %

Procedure:
A mixture of 7-[methyl(pyridin-3-ylsulfonyl)amino]-1H-indole-2-carbothioamide (150 mg), ethyl but-2-ynoate (120 mg), tributylphosphine (90 mg), dichloromethane (20 mL) and tetrahydrofuran (40 mL) was stirred at room temperature for 15 hr, and the mixture was stirred at 50° C. for 3 hr. The reaction mixture was concentrated, and the residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:4, volume ratio). The obtained crystals were further subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:4, volume ratio) to give pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (60 mg, yield 30%) as pale-yellow prism crystals. melting point 146-147° C.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[Br:14][C:15]1[C:16]2[O:34][CH2:33][CH2:32][C:31](=O)[C:17]=2[CH:18]=[C:19]2[C:23]=1[N:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[N:21]=[CH:20]2>COCCOC>[Br:14][C:15]1[C:16]2[O:34][CH2:33][CH2:32][C:31](=[CH:3][C:1]#[N:2])[C:17]=2[CH:18]=[C:19]2[C:23]=1[N:22]([C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[N:21]=[CH:20]2
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=C1CCOc2c1cc1cnn(-c3ccc(F)cc3)c1c2Br
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: N#CC=C1CCOc2c1cc1cnn(-c3ccc(F)cc3)c1c2Br
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
Diethyl (cyanomethyl)phosphonate (11.2 mL, 69.2 mmol) was added dropwise to a slurry of sodium hydride (60 wt % in oil, 2.76 g, 68.9 mmol) in DME (120 mL) under a nitrogen atmosphere at about 0° C. over about 15 min. After completion of addition, the ice bath was removed. After about 30 min, the solution was added to a slurry of 9-bromo-1-(4-fluorophenyl)-6,7-dihydropyrano[3,2-f]indazol-5 (1H)-one (99, R1=4-Fluorophenyl) (12.5 g, 34.5 mmol) and DME (60 mL) rinsing with DME (60 mL). After about 43 h, the volatiles were removed under under reduced pressure and the residue was dissolved with EtOAc (300 mL) and sat. aq. NH4Cl solution (300 mL). The layers were separated. The organic layer was washed with sat. aq. NaCl (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was slurried in DCM (20 mL). The solid was collected by filtration rinsing with DCM (10 mL) then dried under reduced pressure to afford 2-(9-Bromo-1-(4-fluorophenyl)-6,7-dihydropyrano[3,2-f]indazol-5(1H)-ylidene)acetonitrile (100, R1=4-Fluorophenyl) (2.41 g, 18% yield) as an ivory solid. The mother liquor was purified on silica gel (220 g) using a gradient of 0-2% EtOAc in DCM. The fractions containing the product were combined and concentrated under reduced pressure to afford 2-(9-Bromo-1-(4-fluorophenyl)-6,7-dihydropyrano[3,2-f]indazol-5(1H)-ylidene)acetonitrile (100, R1=4-Fluorophenyl) (4.92 g, 37% yield) as an ivory solid. LC/MS, method 3, Rt=2.42 min, MS m/z 384 and 386 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.69 (s, 0.33H), 8.50 (s, 0.33H), 8.46 (s, 0.67H), 8.39 (s, 0.67H), 7.60-7.51 (m, 2H), 7.42-7.30 (m, 2H), 6.50-6.46 (m, 0.67H), 5.84-5.81 (m, 0.33H), 4.48-4.42 (m, 0.67H), 4.42-4.36 (m, 1.33H), 3.06-2.98 (m, 1.33H), 2.88-2.82 (m, 0.67H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl>O1CCOCC1>[ClH:13].[C:1]1([C:7]2[CH:8]=[C:9]([O:14][CH2:15][C@H:16]3[CH2:20][CH2:19][CH2:18][NH:17]3)[CH:10]=[N:11][C:12]=2[Cl:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(-c2ccccc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ncc(OC[C@H]2CCCN2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To the 5-phenyl-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine compound from Example 69b (164 mg) was added HCl in dioxane (3 mL). The mixture was stirred at room temperature for 40 hours. The solvent was removed under vacuum at 50° C., and the residue was triturated with ether. The solid was dried under high vacuum to afford the title compound. mp 178°-180° C. MS (DCI/NH3) m/z 289 (M+H)+. 1 H NMR (D2O, 300 MHz) δ: 1.27-2.10 (m, 1H), 2.03-2.18 (m, 2H), 2.22-2.31 (m, 1H), 3.41 (t, J=7.5 Hz, 2H), 4.13 (m, 1H), 4.26 (m, 1H), 4.46 (dd, J=3.4, 10.8 Hz, 1H), 7.54 (m, 6H), 8.12 (d, J=3.0 Hz, 1H). Anal. Calcd for C16H17N2OCl·1.2 HCl: C, 57.79; H, 5.52; N, 8.42. Found: C, 57.73; H, 6.5.58; N, 8.27. [α]25D =-10.94° (c 0.64, MeOH).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=3)[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: Nc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(N2C(=O)c3ccc([N+](=O)[O-])cc3C2=O)cc1
Yield: 81.3 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and p-aminobenzoic acid (0.18 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.33 g (81%) 145 as a very pale dull yellow powder: mp=331-332° C.; Rf0.86 (A): Rf0.92 (C): Rf0.56 (D): IR (cm−1): 2750-3150 (OH), 3116 (C═CH), 2684 (C—H), 1780 (C═O), 1730 (bs, C═O), 1622 (C═C), 1608 (C═C), 1543 (N═O), 1510 (C═C), 1434 (C═C), 1383 (C—O), 1350 (N═O), 1103 (C—O), 727 (C═CH); MS m/z (rel intensity) 311 (100), 267 (87).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([O:6][C:7]1[CH:17]=[CH:16][C:10]2[C:11](=[O:15])[CH:12]=[CH:13][O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.N1CCCC1>CO>[F:19][C:2]([F:1])([F:18])[S:3]([O:6][C:7]1[CH:17]=[CH:16][C:10]2[C:11](=[O:15])[C:12](=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:13][O:14][C:9]=2[CH:8]=1)(=[O:5])=[O:4]
Reactant: O=Cc1ccccc1
Reactant: O=c1ccoc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Solvent: C1CCNC1
Solvent: CO
Product: O=C1C(=Cc2ccccc2)COc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a stirred solution of the product of Step C (27 g, 91.2 mmole) in 183 mL of methanol was added benzaldehyde (11.1 mL, 109 mmole) followed by pyrrolidine (9.1 mL, 109 mmole). The mixture was stirred at room temperature overnight, cooled to 0° C. and filtered. The solid was washed once with 50 mL of ice-cold methanol and then dried in vacuo; 35.2 g, (75% yield) of the title product was recovered.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:9]=[N:8][NH:7][C:6]=1[NH2:10])([O-:4])=[O:3].C(O[CH:14]=[CH:15][C:16]#[N:17])C>C(O)(=O)C>[ClH:1].[N+:2]([C:5]1[CH:9]=[N:8][N:7]2[C:16]([NH2:17])=[CH:15][CH:14]=[N:10][C:6]=12)([O-:4])=[O:3]
Reactant: CCOC=CC#N
Reactant: Nc1[nH]ncc1[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ccnc2c([N+](=O)[O-])cnn12
Temperature: 40 °C
Yield: 93 %

Procedure:
50 g of 4-nitro-2H-pyrazole-3-ylamine hydrochloride (prepared according to H. Dorn and H. Dilcher, Liebigs Ann. Chem., 707, 141, 1967) 35 g of β-ethoxyacrylonitrile and 250 cc of acetic acid were introduced into a 500 cc three-necked round-bottomed flask fitted with a mechanical stirrer and equipped with a condenser and a thermometer. The medium was refluxed for 4h30'. The mixture was cooled to about 40° C. and the precipitate was then filtered off. This precipitate was taken up in 300 cc of ethyl ether with stirring. The precipitate was filtered off again, washed on the filter with 100 cc of ethyl ether and the product was dried under vacuum over phosphorus pentoxide. 61.3 g of 3-nitropyrazolo[1,5-a]pyrimidin-7-ylamine hydrochloride were obtained in the form of a yellow powder. (Yield=93%).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([NH:23][C@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:30]([O:37][C:38]([NH:40][C:41]1([C:44](O)=[O:45])[CH2:43][CH2:42]1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>ClCCl>[CH2:16]([N:23]([C:44]([C:41]1([NH:40][C:38]([O:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])[CH2:42][CH2:43]1)=[O:45])[C@H:24]([C:26]([O:28][CH3:29])=[O:27])[CH3:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](C)NCc1ccccc1
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COC(=O)[C@H](C)N(Cc1ccccc1)C(=O)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
N,N′-dicyclohexylcarbodiimide (6.0 g, 29.0 mmol) was added to a dichloromethane (150 ml) solution of methyl N-benzyl-L-alaninate (5.20 g, 26.9 mmol) and 1-{[(benzyloxy)carbonyl]amino}cyclopropanecarboxylic acid (6.30 g, 26.7 mmol) under ice cooling and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and then diluted with ethyl acetate, insoluble matter was removed by filtration and then the filtrate was washed with 1 N aqueous hydrochloric acid solution and saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography [n-hexane:ethyl acetate=1:3 (v/v)] to give the title compound (7.80 g, 71%) as a colorless oil.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([Cl:19])=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(-c2ccc(I)cc2)cc1
Product: O=C(Cl)c1ccc(-c2ccc(I)cc2)cc1

Procedure:
3.30 g of 4-iodo-4'-biphenylcarboxylic acid and 10 ml of thionyl chloride were heated for 6 hours under reflux, followed by distilling off excess thionyl chloride to obtain 4-iodo-4'-biphenylcarboxylic acid chloride. This was used without purification in the following step, as a solution in toluene. Into 1.80 g of 1-trifluoromethylheptanol dissolved in 20 ml of pyridine and cooled with ice bath, was added drop-wise over 30 minutes the toluene solution of the above acid chloride, followed by stirring for 5 hours under heating with 90° C. water bath. After cooling, the resulting solution was acidified with addition of 6N hydrochloric acid and ice, and the organic layer was separated and washed with water, then with saturated aqueous solution of sodium bicarbonate, and again with water, followed by distilling off toluene under reduced pressure. Hexane-soluble matter of the resulting crude product was purified with silica gel column to obtain 2.85 g of oily optically active 1-trifluoromethylheptyl ester of 4-iodo-4'-biphenylcarboxylic acid.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=[O:8].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C)C1C=CN=CC=1>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:8]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: CCCCCCCCCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCCCCCCCOC(=O)[C@@H]1CCC(=O)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cold suspension of pyroglutamic acid (1.3 g) and n-decanol (1.6 g) in dichloromethane (50 ml), dicyclohexylcarbodiimide (2.1 g) and 4-dimethylaminopyridine (0.1 g) were added. After stirring at ice bath temperature for 2 hours, the cooling bath was removed and the mixture was stirred at room temperature overnight. The dichloromethane was evaporated off. The residue was taken in ether and filtered. The filtrate was washed with 1N HC1, water, aqueous bicarbonate and water. It was then dried over Na2SO4 and evaporated. The residue weighed 2.75 g. It was chromatographed over silica gel. The pure decyl ester was eluted with ethylacetate-chloroform (1:4), 2.3 g m.p. 34-35%.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([CH:14]([N:18]3[CH:22]=[C:21]([C:23]4[C:24]5[CH:31]=[CH:30][NH:29][C:25]=5[N:26]=[CH:27][N:28]=4)[CH:20]=[N:19]3)[CH2:15][C:16]#[N:17])[CH2:10][CH2:9]2)[C:3]=1[CH3:32].[F:33][C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36]>O>[N:26]1[C:25]2[NH:29][CH:30]=[CH:31][C:24]=2[C:23]([C:21]2[CH:20]=[N:19][N:18]([CH:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:4]4[C:3]([CH3:32])=[C:2]([NH:36][C:35]5[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=5[F:33])[N:7]=[CH:6][N:5]=4)[CH2:9][CH2:10]3)[CH2:15][C:16]#[N:17])[CH:22]=2)=[N:28][CH:27]=1
Reactant: Nc1ccccc1F
Reactant: Cc1c(Cl)ncnc1N1CCC(C(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Solvent: O
Product: Cc1c(Nc2ccccc2F)ncnc1N1CCC(C(CC#N)n2cc(-c3ncnc4[nH]ccc34)cn2)CC1
Yield: 27.8 %

Procedure:
A solution of 3-[1-(6-chloro-5-methylpyrimidin-4-yl)piperidin-4-yl]-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]propanenitrile (0.010 g, 0.022 mmol from step 3 in example 146) and 3 mg TSA.H2O in 2-fluoro-aniline (95 microL, 1.0 mmol) was heated at 160° C. for 1.7 hours. The reaction was purified by preparative-LCMS (pH 10) to give 3.2 mg white solid (50% yield). 1H NMR (400 MHz, DMSO): δ 12.07 (1H, s); 8.78 (1H, s); 8.61 (1H s); 8.37 (1H, s); 8.02 (1H, s); 7.99 (1H, s); 7.55 (1H, d); 7.38 (1H, m); 7.1.5 (1H, m); 7.06 (2H, m); 6.95 (1H, s); 4.57 (1H, m); 3.61 (1H, m); 3.45 (1H, m); 3.27 (2H, m); 2.7 (1H, m); 2.58 (1H, m); 2.02 (1H, m); 1.98 (3H, s); 1.82 (1H, m); 1.3 (2H, m); (1.01 (1H, m). LCMS (M+1): 523.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15]2)[C:8]2[N:13]=[N:12][NH:11][C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:31])=[O:24].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([C:5]1[N:6]=[C:7]([N:14]2[CH2:18][CH2:17][C:16]([F:19])([F:20])[CH2:15]2)[C:8]2[C:9](=[N:11][N:12]([CH2:22][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])=[O:24])[N:13]=2)[N:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Reactant: O=C(CBr)c1ccccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(CC(=O)c3ccccc3Cl)nc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 10.6 %

Procedure:
A mixture of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (11.6 mg, 41.1 μmol), 2-bromo-1-(2-chlorophenyl)ethanone (11.5 mg, 7.19 μl, 49.3 μmol) and DIPEA (10.6 mg, 14.4 μl, 82.2 μmol) were combined with DCM (250 μl) to give a light yellow solution. The reaction mixture was stirred at r.t. for 4 h and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3. The product containing fractions were evaporated to yield 1.9 mg (11%) of the title compound as yellow gum. MS (m/e): 435.3 (MH+).