Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@H:12]([OH:14])[CH2:11][N:10]2[C:15]([C:17]2([C:20]([F:23])([F:22])[F:21])[CH2:19][CH2:18]2)=[O:16])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.O>O1CCCC1.CN(C)C1C=CN=CC=1.CO>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[N:10]([C:15]([C:17]3([C:20]([F:23])([F:21])[F:22])[CH2:19][CH2:18]3)=[O:16])[CH2:11][C@@H:12]([O:14][S:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:32])=[O:31])[CH2:13]2)=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: N#CC1(NC(=O)[C@@H]2C[C@H](O)CN2C(=O)C2(C(F)(F)F)CC2)CC1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1(NC(=O)[C@@H]2C[C@H](OS(=O)(=O)c3ccccc3)CN2C(=O)C2(C(F)(F)F)CC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
(2S,4S)-4-Hydroxy-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (100.0 g, 301.8 mmol) was dissolved in tetrahydrofuran (500 mL). The mixture was cooled to 2° C. (ice bath), benzenesulfonyl chloride (99%, 48 mL, 370.5 mmol), 4-(dimethylamino)pyridine (98%, 2.0 g, 16.0 mmol), and triethylamine (75.0 mL, 539 mmol) were added subsequently and the mixture was stirred for 15 min. The reaction was allowed to warm to room temperature and stirred for 20 h. After cooling to 2° C. (ice bath), water (150 mL) and methanol (350 mL) were added. Tetrahydrofuran was distilled off carefully in vacuo (ca. 500 mL) and water (500 mL) was added slowly. After addition of 300 mL water, crystallization was induced by addition of seed crystals. The resulting suspension was stirred for 30 min at 2° C. (ice bath) and filtered. The solid was washed with methanol/water 1:2 (v/v, 300 mL) and heptane (300 mL) and dried in vacuo to afford the title compound as off-white crystals (140.8 g, 99%). 1H NMR (CDCl3, 400 MHz): δ 1.06-1.27 (m, 4H), 1.28-1.41 (m, 2H), 1.44-1.54 (m, 2H), 2.26 (ddd, J=5.9 Hz, 9.4 Hz, 14.2 Hz, 1H), 2.59 (ddd, J=3.8 Hz, 3.8 Hz, 14.2 Hz, 1H), 3.90 and 4.03 (ABX, JAB=12.5 Hz, JAx=4.0 Hz, JBX=5.2 Hz, each 1H), 4.57 (br d, J=5.1 Hz, 1H), 5.02-5.09 (m, 1H), 7.08 (br s, 1H), 7.61 (t, J=7.8 Hz, 2H), 7.71 (t, J=7.5 Hz, 1H), 7.95 (d, J=7.2 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[C:9](F)=[C:8]([F:11])[C:7]([F:12])=[C:4]([C:5]#[N:6])[C:3]=1[C:13]#[N:14].[OH:15][C:16]([C@H:19]1[CH2:23][CH2:22][NH:21][C@H:20]1[CH3:24])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Li+].[Li+]>>[F:12][C:7]1[C:8]([F:11])=[C:9]([N:21]2[CH2:22][CH2:23][C@H:19]([C:16]([OH:15])([CH3:18])[CH3:17])[C@@H:20]2[CH3:24])[C:2]([F:1])=[C:3]([C:13]#[N:14])[C:4]=1[C:5]#[N:6]
Reactant: C[C@@H]1NCC[C@@H]1C(C)(C)O
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1C#N
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@H]1[C@@H](C(C)(C)O)CCN1c1c(F)c(F)c(C#N)c(C#N)c1F

Procedure:
Using 3,4,5,6-tetrafluorophthalonitrile (464 mg), (2S,3S)-3-(1-hydroxy-1-methylethyl)-2-methylpyrrolidine 1/2 oxalate (480 mg) and lithium carbonate (362 mg), the title compound was obtained as a pale-yellow solid (yield: 250 mg) by an operation similar to that in Example 3.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)[N:16]=[C:15]3[CH2:32][CH2:33][CH2:34][C:14]=23)=[CH:8][CH:7]=1)C.[NH3:36]>CO>[NH2:36][C:4](=[O:3])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH2:20]3)[N:16]=[C:15]3[CH2:32][CH2:33][CH2:34][C:14]=23)=[CH:8][CH:7]=1
Reactant: N
Reactant: CCOC(=O)Cc1ccc(Nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)nc3c2CCC3)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Nc3ccc(CC(N)=O)cc3)c3c(n2)CCC3)CC1

Procedure:
Following general procedure C, tert-butyl 4-(4-((4-(2-ethoxy-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)piperazine-1-carboxylate (0.034 g, 0.071 mmol) was reacted with ammonia in methanol (7.0 M, 5 mL) to afford crude product (0.031 g) as an orange oil. MW=451.56. APCI MS m/z 452 [M+H]+.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[CH2:11][CH2:12][CH2:13][OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:48][C:49]1[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=1)[O:52][C:53]1[C:58](O)=[CH:57][CH:56]=[CH:55][N:54]=1>C1COCC1>[Br:48][C:49]1[CH:50]=[C:51]([CH:60]=[CH:61][CH:62]=1)[O:52][C:53]1[C:58]([O:14][CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[OH:4])=[CH:57][CH:56]=[CH:55][N:54]=1
Reactant: COCOc1cnccc1CCCO
Reactant: Oc1cccnc1Oc1cccc(Br)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Oc1cnccc1CCCOc1cccnc1Oc1cccc(Br)c1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
3-(3-Methoxymethoxypyridin-4-yl)-1-propanol (2.50 g, 12.7 mmol) obtained in Example 2 and triphenylphosphine (4.50 g, 17.0 mmol) are dissolved in THF (40 ml), and thereto are successively added with stirring diisopropyl azodicarboxylate (3.00 g, 15.0 mmol) and 2-(3-bromophenoxy)-3-pyridinol (2.50 g, 9.4 mmol) obtained in Reference Example 11 under ice-cooling. The mixture is further stirred at 40° C. for 30 minutes, and the reaction solution is concentrated under reduced pressure. To the residue is added ethyl acetate (50 ml), and the mixture is extracted with a 10% aqueous hydrochloric acid solution (50 ml×2). The pH value of the aqueous layer is adjusted to pH 12 with potassium carbonate, and the mixture is extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue are added ethanol (200 ml) and a 47% aqueous hydrobromic acid solution (20 ml), and the mixture is heated under reflux for 30 minutes. The reaction solution is concentrated under reduced pressure, and neutralized with a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate (100 ml×2). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: hexane/ethyl acetate/ethanol), recrystallized from ethanol/diethyl ether to give the title compound (3.10 g) as colorless crystals, m.p. 116-118° C.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]3[CH2:16][CH2:15]3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:20]1.C(N(CC)CC)C>CCCCO>[Br:1][C:2]1[C:3]([N:19]2[CH2:24][CH2:23][CH2:22][C@@H:21]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[CH2:13][CH:14]3[CH2:16][CH2:15]3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(CC1CC1)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)CC4CC4)c23)C1
Yield: 26.4 %

Procedure:
A mixture of N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopropylacetamide (204 mg, 0.654 mmol), (R)-tert-butyl piperidin-3-ylcarbamate (393 mg, 1.96 mmol), and triethylamine (182 μL, 1.31 mmol) in n-BuOH (5 mL) was processed as in Example 56. The crude was purified by C-18 reverse phase chromatography (Biotage 25M+) on Biotage SP4 unit eluting with a gradient of 15-85% CH3CN/water (25 CV) to provide (R)-tert-butyl 1-(5-bromo-3-(2-cyclopropylacetamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (85 mg, 26% yield) as a solid. LCMS (APCI+) m/z 492, 494 (M+H)+, Retention time=3.75 min (Method 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].Br.[CH2:11]([NH:13][CH2:14][CH2:15][CH2:16]Br)[CH3:12]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][CH2:16][CH2:15][CH2:14][NH:13][CH2:11][CH3:12])[CH:8]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: CCNCCCBr
Agent: Br
Solvent: ClCCl
Product: CCNCCCNc1cc(Cl)ccc1C
Yield: 92.5 %

Procedure:
A mixture of 5-chloro-2-methylaniline (12.3 g) and the N-ethyl-1-amino-3-bromopropane hydrobromide salt of Example 3, Step C (8.6 g) was heated at 100° C. under nitrogen for 20 minutes. After cooling, a solid mass formed which was partitioned between dichloromethane and 1 N sodium hydroxide. The organic phase was washed with brine, dried over anhydrous potassium carbonate, filtered and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with a solvent gradient (from 100% dichloromethane to 9:1 dichloromethane-methanol containing 0.2% ammonium hydroxide) provided the title compound (7.3 g, 92.8%) as a brown oil, which was used as such in the next step.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(O)C.[CH3:21][N:22]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:38][C:39]4[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][CH2:48][O:49]C5CCCCO5)=[CH:41][N:40]=4)[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[N:23]1>O>[CH3:21][N:22]1[CH:26]=[CH:25][C:24]([NH:27][C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:38][C:39]4[N:40]=[CH:41][C:42]([O:45][CH2:46][CH2:47][CH2:48][OH:49])=[CH:43][CH:44]=4)[CH:36]=3)[N:31]=[CH:30][N:29]=2)=[N:23]1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(OCCCOC5CCCCO5)cn4)cc23)n1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CCO
Product: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(OCCCO)cn4)cc23)n1
Temperature: 25 °C
Yield: 69.5 %

Procedure:
Pyridinium p-toluenesulfonate (243 mg, 0.97 mmol) was added to an ethanol solution (2 ml) of N-(1-methyl-1H-pyrazol-3-yl)-6-({5-[3-(tetrahydro-2H-pyran-2-yloxy)propoxy]pyridin-2-yl}oxy)quinazoline-4-amine (230 mg, 0.48 mmol) obtained in the above reaction, and stirred under reflux for 2 hours. The reaction solution was cooled to room temperature, saline water was added, and extracted with chloroform/methanol (9:1), the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Biotage, chloroform:methanol=100:5) to obtain 3-{[6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-yl]oxy}propan-1-ol (131 mg, yield: 69%) as a pale yellow amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:42][CH:43]([F:45])[F:44])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26](=[O:41])[N:27]3[CH2:32][CH2:31][N:30]([CH:33]([C:35]4[CH:40]=CC=C[CH:36]=4)C)[CH2:29][CH2:28]3)[N:9]=2)[CH:7]=1.ClC1C=CC(OC(F)F)=C(C2C(NC(C3C=NN4C=CC=NC=34)=O)=CN(CC(O)=O)N=2)C=1.CC(C)CN1CCNCC1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:42][CH:43]([F:45])[F:44])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]([N:27]3[CH2:28][CH2:29][N:30]([CH2:33][CH:35]([CH3:36])[CH3:40])[CH2:31][CH2:32]3)=[O:41])[N:9]=2)[CH:7]=1
Reactant: CC(c1ccccc1)N1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Agent: CC(C)CN1CCNCC1
Agent: O=C(O)Cn1cc(NC(=O)c2cnn3cccnc23)c(-c2cc(Cl)ccc2OC(F)F)n1
Product: CC(C)CN1CCN(C(=O)Cn2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1

Procedure:
Using synthetic method analoguous to that of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[2-oxo-2-[4-(1-phenylethyl)piperazin-1-yl]ethyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide, the title compound was prepared from {3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}acetic acid and 1-(2-methylpropyl)piperazine. LCMS (Method 25) [M+H]+=587.1, RT=1.80 min. 1H NMR (300 MHz, DMSO-d6) δ: (ppm) 9.75 (s, 1H), 9.33 (dd, 1H, J=1.8, 6.9 Hz), 8.68 (dd, 1H, J=1.5, 3.9 Hz), 8.67 (s, 1H), 8.31 (s, 1H), 7.62 (dd, 1H, J=3.0, 8.7 Hz), 7.55 (d, 1H, J=2.7 Hz), 7.45 (d, 1H, J=9.0 Hz), 7.28 (dd, 1H, J=4.2, 7.2 Hz), 7.02 (t, 1H, J=73.2 Hz), 5.23 (s, 2H), 3.57-3.42 (m, 4H), 2.40-2.21 (m, 4H), 2.05 (d, 2H, J=7.2 Hz), 1.81-1.76 (m, 1H), 0.86 (d, 6H, J=6.3 Hz).
Reaction SMILES: [CH2:1]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]1[CH:24]=[CH:23][C:22]([O:25]C)=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:27]([C:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][C:33]=1[C:41]1[CH:50]=[CH:49][C:48]([OH:51])=[C:47]2[C:42]=1[CH:43]=[CH:44][CH:45]=[N:46]2)[CH2:28][CH2:29][CH2:30][CH3:31].Br[CH2:53][C:54]#[N:55]>>[CH2:1]([C:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[C:15]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2)[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:27]([C:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[O:34][C:33]=1[C:41]1[CH:50]=[CH:49][C:48]([O:51][CH2:53][C:54]#[N:55])=[C:47]2[C:42]=1[CH:43]=[CH:44][CH:45]=[N:46]2)[CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: N#CCBr
Reactant: CCCCCc1c(-c2ccc(OC)c3ncccc23)oc2ccccc12
Agent: CCCCCc1c(-c2ccc(O)c3ncccc23)oc2ccccc12
Product: CCCCCc1c(-c2ccc(OCC#N)c3ncccc23)oc2ccccc12
Yield: 48 %

Procedure:
5-(3-Pentyl-1-benzofuran-2-yl)-8-hydroxy-quinoline was prepared as a solid (0.113 g, 99%) from 5-(3-pentyl-1-benzofuran-2-yl)-8-methoxy-quinoline according to the procedure described in the first part of Step 4 of Example 2. Mass spectrum (+ESI, [M+H)+) m/z 332. Reaction of 5-(3-Pentyl-1-benzofuran-2-yl)-8-hydroxy-quinoline with bromoacetonitrile according to the procedure described in Step 2 of Example 1 afforded the title compound as a solid (0.059 g, 48%). Mass spectrum (+ESI, [M+H)+) m/z 371. 1H NMR (500 MHz, DMSO-d6): δ 8.94-9.02 (m, 1H), 8.20 (d, 1H, J=9.5 Hz), 7.72-7.83 (m, 2H), 7.60-7.70 (m, 2H), 7.53 (d, 1H, J=8.6 Hz), 7.28-7.42 (m, 2H), 5.52 (s, 2H), 2.68 (t, 2H, J=7.4 Hz), 1.50-1.67 (m, 2H), 1.03-1.26 (m, 4H), and 0.67 ppm (t, 3H, J=7.0 Hz).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.CN(C=O)C.C(Cl)(=O)[C:15]([Cl:17])=O.[N+](=C)=[N-]>C(Cl)Cl.CCOCC>[Cl:17][CH2:15][C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:8]
Reactant: O=C(O)c1ccoc1
Reactant: O=C(Cl)C(=O)Cl
Agent: C=[N+]=[N-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CCl)c1ccoc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under N2, 3-furoic acid (25 g, 0.22 mmol) was dissolved in CH2Cl2 (200 mL) and DMF (few drops) then oxalyl chloride (23.9 mL, 0.27 mmol) was added at 0° C. The resulting solution was stirred at 0° C. for 15 min. and at r.t. for 30 min. The solvent was evaporated. To the acid chloride (3.1 g, 24 mmol) in Et2O (20 mL) at r.t. was added an ethereal solution of diazomethane until the reaction was completed by T.L.C. The reaction mixture was cooled to 0° C. and HCl (g) was bubbled in for 20 min.. Excess HCl (g) was removed by bubbling N2 into the solution for 2 h. The resulting solution was washed with a saturated solution of NaHCO3 (2×), brine, dried over MgSO4 and then concentrated. Flash chromatography of the residue with hexane:EtOAc 9:1 as eluent afforded the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:36]=[C:35]([CH3:37])[C:20]([O:21][S:22]([C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[C:27]([OH:34])[CH:26]=3)(=[O:24])=[O:23])=[C:19]([CH3:38])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.ClC(Cl)(Cl)C(=N)O[C:43]([CH3:46])([CH3:45])[CH3:44]>CCOC(C)=O.C1CCCCC1>[C:43]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([S:22]([O:21][C:20]2[C:35]([CH3:37])=[CH:36][C:17]([C:9]3[C:10]4[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][C:11]=4[C:2]([Br:1])=[C:3]4[C:8]=3[CH:7]=[CH:6][CH:5]=[CH:4]4)=[CH:18][C:19]=2[CH3:38])(=[O:24])=[O:23])=[CH:26][C:27]=1[OH:34])([CH3:46])([CH3:45])[CH3:44]
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Product: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Reaction time: 24 h
Yield: 69 %

Procedure:
At ambient temperature, to a stirred suspension of 4-[4-(9-bromo-2, 3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid (1.033 g, 1.689 mmol) in EtOAc (16.89 mL) was added a solution of t-butyl 2,2,2-trichloroacetimidate (0.7690 g, 3.379 mmol) in cyclohexane (3.379 mL). After 24 h, the reaction was concentrated in vacuo, suspended in CH2Cl2 (10 mL), filtered through a 1"silica gel pad and eluted with 10% acetone/hexane. The filtrate was concentrated to give 0.778 g (69%) of the title compound as an off white solid, mp 168-172° C. 1H NMR (DMSO-d6) δ 1.57 (s, 12 H), 2.15 (s, 6 H), 2.43 (s, 3 H), 7.18 (s, 2 H), 7.45-7.55 (m, 4 H), 7.65 (t, 1 H), 7.96 (d, 1 H), 8.19 (d, 1 H), 10.75 (s, 1 H). IR (KBr) 3400, 2900, 1680, 1380 and 1140 cm-1. mass spectrum (-ESI) m/z 665/667 (M-H). Anal. Calcd. for C33H31BrO6S2 : C, 59.37; H, 4.68; N, 0.00. Found: C, 59.33; H, 4.44; N, 0.10.
Reaction SMILES: [C:1]1([Si:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21][C:22]1[CH:27]=[C:26]([F:28])[C:25]([CH:29]=[CH2:30])=[CH:24][C:23]=1[N+:31]([O-:33])=[O:32].N(/C(C)(C)C#N)=N\C(C)(C)C#N>C1C=CC=CC=1>[F:28][C:26]1[CH:27]=[C:22]([F:21])[C:23]([N+:31]([O-:33])=[O:32])=[CH:24][C:25]=1[CH2:29][CH2:30][S:8][Si:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: S[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=Cc1cc([N+](=O)[O-])c(F)cc1F
Agent: CC(C)(C#N)/N=N/C(C)(C)C#N
Solvent: c1ccccc1
Product: O=[N+]([O-])c1cc(CCS[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(F)cc1F
Temperature: 25 °C
Yield: 100 %

Procedure:
A flask was charged with triphenylsilanethiol (12 g, 41 mmol), and 1,5-difluoro-2-nitro-4-vinylbenzene (5 g, 27 mmol) in benzene (80 mL), and then (E)-2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (1.3 g, 8.1 mmol) was added. The mixture was refluxed for 1 hour, then cooled to ambient temperature and concentrated. The residue was purified using silica gel column chromatography with 10% acetone in hexanes to provide (2,4-difluoro-5-nitrophenethylthio)triphenylsilane (13 g, 27 mmol, 100% yield).
Reaction SMILES: FC1N=C(C[N:9]2[C:13]3=[N:14][C:15]([NH:18][C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[N:16][CH:17]=[C:12]3[CH:11]=[N:10]2)C=CC=1>CN(C=O)C>[CH3:24][N:22]1[CH:23]=[C:19]([NH:18][C:15]2[N:14]=[C:13]3[NH:9][N:10]=[CH:11][C:12]3=[CH:17][N:16]=2)[CH:20]=[N:21]1
Reactant: Cn1cc(Nc2ncc3cnn(Cc4cccc(F)n4)c3n2)cn1
Solvent: CN(C)C=O
Product: Cn1cc(Nc2ncc3cn[nH]c3n2)cn1
Temperature: 180 °C
Yield: 67.3 %

Procedure:
1-((6-fluoropyridin-2-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Example 170) (45 mg, 0.138 mmol) was dissolved in DMF (0.6 ml) in a microwave tube under Nitrogen. This was sealed and heated at 180° C. for 1 h. The mixture was concentrated and purified by prep HPLC to afford 1-46-(dimethylamino)pyridin-2-yl)methyl)-N-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine as yellowish solid (20 mg, 42% yield). 1H NMR (d6-Acetone) δ 8.88 (s and br s, 2H), 8.06 (s, 1H), 7.99 (s, 1H), 7.61 (s, 1H), 7.40 (t, 1H), 6.49 (d, 1H), 6.24 (br s, 1H), 5.51 (s, 2H), 3.83 (s, 3H), 3.02 (s, 6H); LC-MS method B, (ES+) 350.1, RT=5.06 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][C:6]([N:8]([CH2:28][CH2:29][N:30]1[CH2:34][CH2:33][CH2:32][C:31]1=[O:35])[C:9]1[C:10]([C:23]([O:25]CC)=O)=[N:11][CH:12]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH:14]=1)=[O:7])[CH3:2].C1CCN2C(=NCCC2)CC1>C(O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:13]2[CH:14]=[C:9]3[C:10]([C:23]([OH:25])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:36])[C:6](=[O:7])[N:8]3[CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][C:31]3=[O:35])=[N:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: CCOC(=O)CC(=O)N(CCN1CCCC1=O)c1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Reaction time: 0.33 h

Procedure:
A solution of ethyl 3-{[3-(ethyloxy)-3-oxopropanoyl][2-(2-oxo-1-pyrrolidinyl)ethyl]amino}-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylate (1.80 g, 3.98 mmol) in ethanol (20 mL) was treated with DBU (1.53 mL, 10.3 mmol). After stirring under nitrogen for 20 min., the reaction was quenched with 1N HCl (7.8 mL) and evaporated in vacuo. Trituration with water and filtration provided the product as a white solid: 1H NMR (CDCl3) δ 8.50 (1H, d, J=1.4 Hz), 8.11 (1H, s), 7.26 (2H, m), 7.00 (2H, ddd, J˜9, 9, 2 Hz), 4.52 (2H, q, J=7 Hz), 4.33 (2H, br t, J˜7 Hz), 4.14 (2H, s), 3.52-3.44 (4H, m), 2.35 (2H, t, J=8 Hz), 2.00 (2H, m), 1.48 (3H, t, J=7 Hz); ES+ MS: 476 (M+Na+).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]([C:14]3[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[CH2:22][C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)[N:15]=3)[C:10]([F:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1>C1COCC1.[OH-].[OH-].[Pd+2]>[F:13][C:10]1[C:9]([C:14]2[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:15]=2)=[CH:8][C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)=[CH:12][N:11]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4=CCOCC4)cnc3F)n2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C4CCOCC4)cnc3F)n2)cc1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
The solid 4-(5-(3,6-dihydro-2H-pyran-4-yl)-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (130 mg, 0.246 mmol) from step 1 was dissolved in THF (30 mL) and mixed with palladium hydroxide on carbon (20%, 80 mg). The mixture was purged with hydrogen through vacuum/back-fill (3×) and stirred under a hydrogen balloon. After 15 h, the mixture was heated to about 50° C. for 2 h. The mixture was cooled to room temperature and filtered through a pad of Celite® (diatomaceous earth). The filtrate was concentrated to a yellow film. m/z (ESI, positive ion): 530.2 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[S:7][C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:17]=2)=[C:9]([CH3:11])[N:10]=1)[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[NH3:31].O>O1CCOCC1>[CH2:1]([NH:3][C:4](=[O:24])[NH:5][C:6]1[S:7][C:8]([C:12]2[CH:13]=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18]([NH2:31])(=[O:20])=[O:19])[CH:17]=2)=[C:9]([CH3:11])[N:10]=1)[CH3:2]
Reactant: CCNC(=O)Nc1nc(C)c(-c2ccc(OC)c(S(=O)(=O)Cl)c2)s1
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1nc(C)c(-c2ccc(OC)c(S(N)(=O)=O)c2)s1
Reaction time: 2 h

Procedure:
To a stirred solution of 5-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy benzenesulfonylchloride (Example 28d) (0.2 g, 0.514 mmol) in dioxane (10 ml) is added 2 M Na2CO3 (0.515 ml) followed by 0.5 M NH3 in dioxane (2.06 ml). After 2 hours at room temperature, the reaction mixture is poured into water (200 ml) then extracted with ethyl acetate (3×50 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford 5-[2-(3-ethyl-ureido)-4-methyl-thiazol-5-yl]-2-methoxy-benzenesulfonamide as a yellow powder.