Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][N:6]=1.C(=O)([O-])[O-:30].[K+].[K+].OO>CS(C)=O>[Cl:1][C:2]1[CH:16]=[C:15]([CH2:17][N:18]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19]2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]([NH2:10])=[O:30])=[CH:7][N:6]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cc2Cl)nc1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCC(c4ccccc4)C3)cc2Cl)nc1
Yield: 126.6 %

Procedure:
Using a similar method to Example 371, and using (±)-6-[2-chloro-4-(3-phenyl-pyrrolidin-1-ylmethyl)-phenoxy]-nicotinonitrile (step 2 above) (0.198 g, 0.508 mmol), potassium carbonate (0.0337 g, 0.244 mmol), and 30% hydrogen peroxide solution (aq) (0.180 mL, 1.59 mmol) in dimethylsulfoxide (5.0 mL) provides 0.126 g (61%) of the title compound as a yellowish syrup: high resolution mass spectrum (electrospray): m/z calc for C23H23ClN3O2 408.1479, found 408.1449; 1H NMR (methanol-d4): 8.61 (d, 1H, J=2.4 Hz), 8.32 (d, 1H, J=2.4, 8.8 Hz), 7.61 (d, 1H, J=2.0 Hz), 7.44 (dd, 1H, J=2.0, 8.3 Hz), 7.35-7.29 (m, 4H), 7.27 (d, 1H, J=8.3 Hz), 7.24-7.18 (m, 1H), 7.11 (d, 1H, J=8.8 Hz), 3.80 (d, 1H, J=13.2 Hz), 3.76 (d, 1H, J=13.2 Hz), 3.50-3.39 (m, 1H), 3.15 (dd, 1H, J=7.8, 9.3 Hz), 2.99-2.91 (m, 1H), 2.82 (td, 1H, J=6.3, 8.8 Hz), 2.60 (t, 1H, J=8.8 Hz), 2.45-2.34 (m, 1H), 2.03-1.92 (m, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2OC)[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:42]2[CH2:47][CH2:46][C@@H:45]([OH:48])[CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[OH:48][C@H:45]1[CH2:46][CH2:47][C@H:42]([C:34]2[CH:33]=[CH:32][C:31]([NH:30][C:2]3[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]4[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][CH:14]=4)[N:3]=3)=[C:39]3[C:35]=2[CH2:36][N:37]([CH3:41])[C:38]3=[O:40])[CH2:43][CH2:44]1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1Cc2c(c(N)ccc2[C@H]2CC[C@@H](O)CC2)C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@H](O)CC4)c4c3C(=O)N(C)C4)n2)cc1)OCC

Procedure:
This compound was prepared in a manner analogous to Example 87 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-amino-4-(cis-4-hydroxycyclohexyl)-2-methyl-2,3-dihydro-1H-isoindol-1-one. Purification: ISCO Combi-flash Rf system, eluting with 0 to 5% MeOH in EtOAc. 1H NMR (400 MHz, DMSO-d6) δ 10.58 (br. s., 1H), 9.87 (s, 1H), 8.46 (s, 1H), 7.37 (d, J=8.34 Hz, 1H), 7.25 (dd, J=2.53, 8.59 Hz, 3H), 4.52 (s, 3H), 4.40 (d, J=4.04 Hz, 2H), 3.89-4.02 (m, 5H), 3.17-3.26 (m, 2H), 3.08 (s, 3H), 1.91 (q, J=12.80 Hz, 1H), 1.78 (d, J=13.64 Hz, 2H), 1.48-1.62 (m, 4H), 1.18 (t, J=7.07 Hz, 6H). MS (ES+): m/z: 648.22 [MH+]. HPLC: tR=3.46 min (Micromass ZQ3: polar—5 min).
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.O.[OH-].[Li+]>C1COCC1.O.CO.Cl>[F:24][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a suspension of sodium hydride (55% dispersion in mineral oil, 852 mg, 20 mmol) in THF (27 mL) was added a solution of [3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methanol (3.68 g, 18 mmol) in THF (54 mL) at 0° C. and the reaction mixture warmed to room temperature over 30 min. Then a solution of methyl 6-chloronicotinate (3.35 g, 20 mmol) in THF (1.5 mL) was added dropwise at 0° C. and the reaction mixture was stirred at room temperature overnight. The reaction mixture was then poured into aqueous sodium chloride (saturated) and the mixture was extracted with ethyl acetate. The combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate=7:3) afforded 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (4.1 g, 68%) which was obtained as a white solid. To a solution of 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (1.1 mmol) in THF (5 mL) was added a solution of lithium hydroxide monohydrate (94 mg, 2.2 mmol) in water (5 mL) and methanol (1 mL) added and the resulting mixture stirred at room temperature overnight. The mixture was acidified to pH 4 with HCl (25%, 3 drops) and methanol (2 drops) added. A gum began to form and the mixture was cooled at 0° C. for 1.5 h and then the aqueous layer decanted off. Trituration with diethylether and hexane afforded the title compound (95%) which was obtained as an off white solid. MS: m/e=327.4 [M−H]−.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][C:5]#[CH:6])[CH3:2].C(N(CC)CC)C.Br[C:17]1[N:37](S(C2C=CC=CC=2)(=O)=O)[C:20]2=[N:21][CH:22]=[C:23]([CH2:25][CH2:26][C:27]3[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[C:29]([O:35][CH3:36])[CH:28]=3)[N:24]=[C:19]2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:34][O:33][C:31]1[CH:32]=[C:27]([CH2:26][CH2:25][C:23]2[N:24]=[C:19]3[CH:18]=[C:17]([C:6]#[C:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[NH:37][C:20]3=[N:21][CH:22]=2)[CH:28]=[C:29]([O:35][CH3:36])[CH:30]=1
Reactant: C#CCN(CC)CC
Reactant: COc1cc(CCc2cnc3c(cc(Br)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CC#Cc1cc2nc(CCc3cc(OC)cc(OC)c3)cnc2[nH]1
Temperature: 60 °C
Reaction time: 1 h
Yield: 19.2 %

Procedure:
A solution of N,N-diethylprop-2-yn-1-amine (10.6 mg, 95.5 μmol), bis(triphenylphosphine)palladium(II) chloride (2.8 mg, 4.0 μmol), copper(I) iodide (1.2 mg, 6.4 mmol), triethylamine (17.0 μL, 120 μmol), and 6-bromo-2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-5H-pyrrolo[2,3-b]pyrazine (from Example 1, Step 4, 40.0 mg, 79.7 μmol) in N,N-dimethylformamide (1.0 mL) was stirred at ambient temperature overnight. The reaction was quenched with saturated aq. NH4Cl, then extracted with methylene chloride. The combined organic layers were dried over MgSO4, and then concentrated. The residue was dissolved in methanol (2.0 mL) and potassium carbonate (22.0 mg, 0.159 mmol) was added. The reaction mixture was then warmed up to 60° C. After 1 hour, the crude mixture was allowed to warm to room temperature and was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (6.0 mg, 20%) as its TFA salt. LCMS calculated for C23H29N4O2 (M+H)+: m/z=393.2. Found: 393.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1.Cl.[CH2:26]([NH:33][NH2:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][NH:34][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:22])([F:24])[F:23])=[CH:16][CH:15]=2)[CH:5]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NNCc1ccccc1
Reactant: COc1ccc(C(=O)O)cc1/C=C/c1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: COc1ccc(C(=O)NNCc2ccccc2)cc1/C=C/c1ccc(OC(F)(F)F)cc1

Procedure:
The captioned compound was synthesized from 4-methoxy-3-[(E)-2-(4-trifluoromethoxyphenyl)vinyl]benzoic acid obtained in step B of Example 2-2-1 and benzylhydrazine hydrochloride in accordance with the same procedure as in the methods described in step C of Example 1-2-3.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([O:19]C)[CH:10]=[CH:9][C:8]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24].[CH2:26](Cl)Cl>>[OH:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]([OH:19])[CH:10]=[CH:9][C:8]=1[CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24]
Reactant: ClCCl
Reactant: COc1ccc(CCC(=O)O)c(OC)c1-c1ccccc1
Agent: BrB(Br)Br
Product: COC(=O)CCc1ccc(O)c(-c2ccccc2)c1O
Reaction time: 8 h
Yield: 94 %

Procedure:
BBr3 (4.72 g, 1.78 ml, 18.9 mmol) was carefully added through a syringe over 5 min to a stirred solution of dimethoxy acid 4c (1.35 g, 4.7 mmol) in anhydrous CH2Cl2 (20 ml). Resulted mixture was magnetically stirred for 8 h and concentrated under vacuum. The residue was co-evaporated with toluene (2×20 ml), dissolved in methanol (20 ml) and HCl gas was bubbled into the solution for 2 min. The material obtained after evaporation of the solvent was partitioned between cold water (30 ml) and ethyl acetate (100 ml). The organic phase was washed with saturated NaHCO3 (2×10 ml), brine (20 ml), dried over MgSO4 and concentrated. The resultant crude product was chromatographed on a short silica gel column eluting with ethyl acetate. Pure product fractions were concentrated to afford 1.2 g (94%) of 5c as a tan oil. 1H NMR(DMSO-d6): δ 8.95 (s, 1H), 7.82 (s, 1H), 7.24–7.36 (m, 5H), 6.83 (d, J=8.2 Hz, 1H), 6.38 (d, J=8.2 Hz, 1H), 3.59 (s, 3H), 2.75 (t, J=8.0 Hz, 2H), 2.52 (t, J=8.0 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12](OS(C(F)(F)F)(=O)=O)[N:11]([C@H:22]([C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)[CH3:23])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[CH:43]=[C:42](B(O)O)[CH:41]=[CH:40]2.C(N(CC)CC)C>C(COC)OC>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:13]=[C:12]([C:42]3[CH:41]=[CH:40][C:39]4[C:44](=[CH:45][CH:46]=[C:37]([O:36][CH3:35])[CH:38]=4)[CH:43]=3)[N:11]([C@H:22]([C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)[CH3:23])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2OS(=O)(=O)C(F)(F)F)cc1
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CCOC(=O)c1ccc([C@H](C)n2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc3cc(OC)ccc3c2)cc1
Temperature: 100 °C

Procedure:
Ethyl 4-[(1S)-1-(3-(3,5-dichlorophenyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazol-1-yl)ethyl]benzoate (2.15 g, 4.0 mmol), 6-methoxy-2-naphthylboronic acid (1.18 g, 6.0 mmol) and triethylamine (1.2 ml, 8.0 mmol) were dissolved in dimethoxyethane (40 ml) in a thick-wall tube. The reaction mixture was purged with N2 for 15 min. Catalyst Pd(PPh3)4 (350 mg, 8%) was added, and the test tube was heated in a microwave reactor to 100° C. for 15 min. The solvent was removed under reduced pressure, and the residue partitioned between ethyl acetate and IN HCl. The organic layer was washed with 0.5 NH4Cl 2×, brine 2×, dried over Na2SO4, and filtered through a Celite pad. The crude product was purified by column chromatography (SiO2, 10-15% ethyl acetate in hexanes) to give ethyl 4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxy-2-naphthyl)-1H-pyrazol-1-yl]ethyl}benzoate as a dry film. NMR (500 MHz, CDCl3) δ: 1.38 (t, J=7.1 Hz, 3H); 1.96 (d, J=7.0 Hz, 3H); 3.95 (s, 3H; 4.37 (q, J=7.1 Hz, 2H); 5.59 (q, J=7.0 Hz, 1H); 6.65 (s, 1H); 7.17 (d, J=2.6 Hz, 1H); 7.20 (dd, J=2.6, 8.9 Hz, 1H); 7.28 (d, J=8.4 Hz, 2H); 7.29 (dd, J=1.8, 8.5 Hz, 1H); 7.30 (t, J=1.9 Hz, 1H); 7.63 (d, J=1.8 Hz, 1H); 7.67 (d, J=8.9 Hz, 1H); 7.76 (d, J=8.5 Hz, 1H); 7.80 (d, J=1.9 Hz, 2H); 7.99 (d, J=8.4 Hz, 2H); MS C31H26Cl2N2O3 Cald: 544.13; Obsd: 545.15.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:88]=[CH:89][CH:90]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([C:71]5[CH2:72][CH2:73][N:74]([CH3:77])[CH2:75][CH:76]=5)=[CH:67][CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:88]=[CH:89][CH:90]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:66]=[CH:67][C:68]([C:71]5[CH2:72][CH2:73][N:74]([CH3:77])[CH2:75][CH:76]=5)=[CH:69][CH:70]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5=CCN(C)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN1CC=C(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2)CC1
Yield: 170.5 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (180 mg, 0.291 mmol) was hydrolyzed by lithium hydroxide (37 mg, 0.874 mmol) in THF/methanol/water (2/2/2 ml) to yield crude 230 mg of the titled compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH:13]1[CH2:16][CH:15]([NH:17][C:18](=[O:35])[CH2:19][NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:29]=3)[N:24]=[CH:23][N:22]=2)[CH2:14]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([NH:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:13]2[CH2:14][CH:15]([NH:17][C:18](=[O:35])[CH2:19][NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]([F:32])([F:34])[F:33])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH2:16]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: CCNC(=O)C1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCNC(=O)C1CCC(N2CC(NC(=O)CNc3ncnc4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
Reaction of N-ethyl-4-oxocyclohexanecarboxamide with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product. 1H NMR (DMSO-d6) δ: 0.97 (t, J=7.20 Hz, 3 H) 1.25 (d, J=16.93 Hz, 5 H) 1.48 (br. s., 2 H) 1.67 (br. s., 2 H) 1.97-2.08 (m, 1 H) 2.17 (br. s., 1 H) 2.74 (t, J=7.07 Hz, 2 H) 3.01 (m, J=7.07, 5.81 Hz, 2 H) 3.43 (t, J=7.20 Hz, 2 H) 4.12 (d, J=5.56 Hz, 2 H) 4.17-4.30 (m, 1 H) 7.61 (t, J=5.56 Hz, 1 H) 7.88 (d, J=8.59 Hz, 1 H) 8.05 (dd, J=8.97, 1.39 Hz, 1 H) 8.44 (d, J=7.33 Hz, 1 H) 8.55 (s, 1 H) 8.81 (s, 1 H) 9.05 (t, J=5.43 Hz, 1 H); ESI-MS (m/z): Calcd. For C23H29F3N6O2: 478.23. found: 479 (M+H).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=[CH2:4].[C:7]1([CH3:16])[CH:12]=[CH:11][C:10]([S:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.[Na+]>CO>[Cl:1][CH2:2][C:3]([CH2:5][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:16])=[CH:8][CH:9]=1)(=[O:15])=[O:14])=[CH2:4]
Reactant: C=C(CCl)CCl
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Na+]
Solvent: CO
Product: C=C(CCl)CS(=O)(=O)c1ccc(C)cc1
Yield: 44.1 %

Procedure:
A solution of 2-(chloromethyl)-3-chloropropene (3.13 g, 25 mmol) and sodium p-toluenesulfmate (4.60 g, 25 mmol) in methanol (50 mL) was heated under reflux for 24 hours. The solvent was evaporated on a rotary evaporator and the residue was extracted between dichloromethane and water. The organic layer was dried (anhydrous MgSO4) and evaporated to give crude product (4.7 g) which, after purification by column chromatography on a silica-gel column using ethyl acetate/n-hexane 1:9 as eluent, gave pure product (2.7 g, 44% yield). 1H-NMR (CDCl3) δ (ppm): 2.46 (s, 3H, CH3Ar); 3.92 (s, 2H, CH2SO2); 4.19 (s, 2H, CH2Cl); 5.02 (s, 1H, vinylic-H); 5.45 (s, 1H, vinylic-H); 7.37 and 7.77 (2d, 4H, ArH).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:38])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[CH3:38][C:23]1[C:22]([CH2:21][O:19][C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)=[C:4]([CH3:3])[CH:5]=2)=[CH:27][CH:26]=[C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:36])([F:37])[F:35])[CH:29]=2)[N:24]=1
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)ccc1CCl
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(-c3cccc(C(F)(F)F)c3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.8 %

Procedure:
30 mg (0.74 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 162 mg (0.70 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.70 mmol) 3-chloromethyl-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, n-heptane, and ether. The residue was dried at 40° C. in vacuum to give 255 mg (76%) of the title compound as slightly pink powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][CH3:11].[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].P.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CCOC(C)=O.CCCCCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[CH2:10][CH3:11])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1cc(OC)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCc1cc(OC)ccc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 120 °C

Procedure:
1-Bromo-2-ethyl-4-methoxy-benzene (1 eq), piperazine-1-carboxylic acid tert-butyl ester (1.5 eq), Pd(OAc)2 (0.03 eq), phosphine ligand (0.06 eq), sodium t-butoxide (1.7 eq) are mixed in toluene and the resulting mixture is heated at 120° C. in microwave for 20 minutes. It is then diluted with EtOAc/hexane and filtered through celite. Flash column chromatography (20% EtOAc/hexane) gave 4-(2-Ethyl-4-methoxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. MS: (ES+): 321.2 (M+1)+.
Reaction SMILES: [Cl:1][CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[NH2:15][C:16]1[N:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[N:17]=1>ClCCl>[CH3:23][C:18]1[CH:19]=[C:20]([CH3:22])[N:21]=[C:16]([NH:15][C:13]([NH:12][S:9]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:2]2[Cl:1])(=[O:11])=[O:10])=[O:14])[N:17]=1
Reactant: Cc1cc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)C1CCCCCC1Cl
Solvent: ClCCl
Product: Cc1cc(C)nc(NC(=O)NS(=O)(=O)C2CCCCCC2Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
14.3 g (0.06 mole) of 2-chlorocycloheptylsulfonyl isocyanate in 100. ml of dichloromethane were initially introduced and 7.4 g (0.06 mole) of 2-amino-4,6-dimethylpyrimidine were added in portions at 0° C. The mixture was stirred initially at 0° C. for 2 hours and then at room temperature for 18 hours. The organic phase was then extracted with 3×40 ml of 2N H2SO4, washed to neutrality and the organic layer was dried over Na2SO4. Then 50 ml of n-hexane was added and the solvent was distilled off in vacuo. 13.3 g (61% of theory) of N-[(4,6-dimethylpyrimidin-2-yl)aminocarbonyl]-2-chlorocycloheptylsulfonamide were obtained (viscous oil).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>CN(C)C=O>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:31](=[O:33])[CH3:32])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: CC(=O)OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 50 mg (0.125 mmol) of trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine in 2 ml of anhydrous N,N-dimethylformamide is added 13 μl (0.138 mmol) of acetic anhydride (Fluka, Buchs, Switzerland). After stirring 1 h at RT, working-up is effected by partitioning between water and ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated to dryness to provide trans-N-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-acetamide. Analytical HPLC: tR=6.65 min (Grad 2); ES-MS: m/eo=442.0.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[C:4]=1[N:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.Cl.[NH+]1C=CC=CC=1>O>[CH:22]1[C:23]2[N:11]([C:4]3[C:5]([OH:9])=[CH:6][CH:7]=[CH:8][C:3]=3[OH:2])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(OC)c1-n1c2ccccc2c2ccccc21
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: O
Product: Oc1cccc(O)c1-n1c2ccccc2c2ccccc21
Temperature: 25 °C
Yield: 60.6 %

Procedure:
9-(2,6-Dimethoxyphenyl)-9H-carbazole (10.00 g) and pyridinium hydrochloride (50.0 g) were placed in the 250 ml round-bottom flask, equipped with magnetic stirrer and immersed in the pre-heated oil bath (230° C., 45 min). The reaction mixture was cooled down to room temperature, diluted with 400 ml water and extracted with ethyl acetate (3×150 ml). Organic fractions were combined, dried over sodium sulfate anhydrous, filtered and evaporated, providing 5.5 g of pure 2-carbazol-9-yl-benzene-1,3-diol. 2-Carbazol-9-yl-benzene-1,3-diol (5.5. g, 20 mmol) and pyridine (6.0 ml) were dissolved in 50 ml DCM (anhydrous) and cooled in the ice bath. Solution of triflic anhydride (6.0 ml) in 20 ml DCM was added dropwise upon intensive stirring, reaction mixture was warmed up to room temperature and stirred overnight. The reaction mixture was washed with water, dried over sodium sulfate, filtered and evaporated, providing crude triflate. Pure material (white solid, 6.0 g) was obtained by column chromatography on silica gel (eluent hexane/ethyl acetate 1/1 mixture).
Reaction SMILES: [OH-].[NH4+:2].F[C:4]1[C:9]([F:10])=[C:8]([F:11])[N:7]=[C:6]([C:12]#[N:13])[CH:5]=1>>[NH2:2][C:4]1[C:9]([F:10])=[C:8]([F:11])[N:7]=[C:6]([C:12]#[N:13])[CH:5]=1
Reactant: N#Cc1cc(F)c(F)c(F)n1
Reactant: [NH4+]
Agent: [OH-]
Product: N#Cc1cc(N)c(F)c(F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.4 %

Procedure:
Ammonium hydroxide (NH4OH) was added to crude 4,5,6-trifluoropicolinonitrile (2.5 g, 15.8 mmol) and stirred at room temperature for 2 h. A brown solid formed which was filtered, washed with water and dried to give 0.72 g. Analysis by gas chromatography-mass spectroscopy (GC-MS) indicated the presence of two isomeric products. The aqueous filtrate was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, and evaporated to give additional brown solid. The two crops were combined and purified by silica gel chromatography to give 4-amino-5,6-difluoro-picolinonitrile (0.60 g, 24.4%): 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J=5.3 Hz, 1H, aromatic), 6.62 (s, 2H, NH2); 13C NMR (101 MHz, CDCl3) δ 157.0 (dd, J=235, 12 Hz), 151.7 (dd, J=10, 7 Hz), 139.5 (dd, J=254, 29 Hz), 128.8 (d, J=19 Hz), 121.2 (s), 121.0 (s); 19F NMR (376 MHz, CDCl3) δ −85.29 (d, J=24.5 Hz), −156.98 (dd, J=24.5, 5.2 Hz).