Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[CH3:22].[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(CC)CC>CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:16]1(=[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:25]=[CH:24]/[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:3]([CH3:22])[CH:4]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Cc1cc(C(=C2CCCCC2)c2ccc(O)cc2)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=C2CCCCC2)c2ccc(O)cc2)ccc1/C=C/C(=O)OC(C)(C)C
Temperature: 140 °C
Yield: 51.3 %

Procedure:
A mixture of 67 (380 mg, 1.06 mmol), tert-butyl acrylate (0.369 mL, 2.55 mmol), Pd(OAc)2 (15.0 mg, 0.067 mmol), P(o-tolyl)3 (40.0 mg, 0.131 mmol), and Et3N (0.520 mL, 3.73 mmol) were heated under microwave irradiation at 140° C. for 30 min. Water (30 mL) was added and the mixture was extracted with Et2O (3×20 mL). The combined ethereal extracts were washed with water (30 mL), brine (30 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 220 mg (51%) of 68. 1H NMR (400 MHz, CDCl3): δ 1.52 (s, 9H), 1.58 (m, 6H), 2.22 (m, 4H), 2.34 (s, 3H), 4.85 (s, 1H), 6.25 (d, J=16.0 Hz, 1H), 6.74 (d, J=8.4 Hz, 2H), 6.90-6.97 (m, 4H), 7.44 (d, J=8.1 Hz, 1H), 7.84 (d, J=16.0 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)=[CH:10][C:9]=2[O:19][CH3:20])=[CH:6][CH:7]=1.[N:21]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.C(O)CCC>CCOC(C)=O>[CH3:20][O:19][C:9]1[CH:10]=[C:11]([N:14]2[CH:18]=[CH:17][CH:16]=[N:15]2)[CH:12]=[CH:13][C:8]=1[C:5]1[N:4]=[N:3][C:2]([N:24]2[CH2:23][CH2:22][N:21]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][CH2:25]2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(-n2cccn2)ccc1-c1ccc(Cl)nn1
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-n2cccn2)ccc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nn1
Temperature: 120 °C

Procedure:
Following GENERAL METHOD 6-1 for SNAr, Intermediate 2-1 (50 mg, 0.174 mmol), tert-butyl piperazine-1-carboxylate (59 mg, 0.314 mmol), DIPEA (0.06 mL, 0.349 mmol), and n-butanol (0.1 mL) were combined in a 4 mL reaction vial and heated at 120° C. overnight. The reaction was cooled to RT and EtOAc was added. The white solid that formed was filtered off and washed with EtOAc, dissolved in DCM and washed with H2O. The organic layer was dried with sodium sulfate, filtered, and concentrated in vacuo to afford the desired product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([CH2:10][N:11]([CH3:25])[S:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:6][CH2:5]1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>>[CH3:25][N:11]([CH2:10][C@H:7]1[CH2:8][CH2:9][C@H:4]([CH2:3][CH2:2][O:1][S:27]([CH3:26])(=[O:29])=[O:28])[CH2:5][CH2:6]1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C[C@H]1CC[C@H](CCO)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Product: CN(C[C@H]1CC[C@H](CCOS(C)(=O)=O)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 3.4, trans-N-[4-(2-hydroxy-ethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was treated with methanesulfonyl chloride to yield trans-methanesulfonic acid 2-(4-{[methyl-(4-trifluoromethyl-benzenesulfonyl)-amino]-methyl}-cyclohexyl)-ethyl ester as colorless solid, MS: 358 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][C:8](Cl)=O)[CH2:6][CH2:5][CH2:4][CH2:3]1.[NH2:11][C:12]1[CH:17]=[C:16]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])[CH:15]=[CH:14][C:13]=1[NH:24][CH2:25][CH:26]1[CH2:28][CH2:27]1>>[CH:26]1([CH2:25][N:24]2[C:13]3[CH:14]=[CH:15][C:16]([S:18]([CH:21]([CH3:23])[CH3:22])(=[O:20])=[O:19])=[CH:17][C:12]=3[N:11]=[C:8]2[CH2:7][C:2]2([CH3:1])[CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:27][CH2:28]1
Reactant: CC(C)S(=O)(=O)c1ccc(NCC2CC2)c(N)c1
Reactant: CC1(CC(=O)Cl)CCCC1
Product: CC(C)S(=O)(=O)c1ccc2c(c1)nc(CC1(C)CCCC1)n2CC1CC1

Procedure:
The title compound was prepared according to the procedure described in Step C of Example 5 from (1-methylcyclopentyl)acetyl chloride (Step A) and 2-amino-1-(N-cyclopropylmethylamino)-4-(isopropylsulfonyl)benzene (Step E of Example 1).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[N:18]=2)[CH2:13]1)C1C=CC=CC=1>[Pd].CO>[NH2:10][CH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[N:18]=2)[CH2:13]1
Reactant: Cc1ccc2c(N3CC[C@H](CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc2c(N3CC[C@H](CN)C3)nc(-c3ccccc3O)nc2c1
Yield: 45.9 %

Procedure:
A solution of benzyl((R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate (0.19 g, 0.41 mmol) and MeOH (5 mL) was stirred with Pd/C (20 mg, 10% weight of Pd on carbon) under an H2 atmosphere at ambient pressure overnight. Purification via silica gel chromatography using MeOH in CH2Cl2 (0-10%) gave 2-(4-((R)-3-(aminomethyl)pyrrolidin-1-yl)-7-methylquinazolin-2-yl)phenol (63 mg, 45%). LC/MS: m/z 335.7 (M+H)+ at 1.23 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C(Cl)Cl.FC(F)(F)C([N:8]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=[O:14])=[CH:11][CH:10]=1)=O.[S:36]([OH:46])(=[O:45])([C:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=1)=[O:37].[OH-].[Na+:48]>>[CH2:18]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:44][C:41]2[CH:42]=[CH:43][C:38]([S:36]([O-:46])(=[O:37])=[O:45])=[CH:39][CH:40]=2)=[O:14])=[CH:16][CH:17]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].[Na+:48]
Reactant: CCCCCCCCCCCCCCCCN(C(=O)C(F)(F)F)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)Nc2ccc(S(=O)(=O)[O-])cc2)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
A methylene chloride solution of N-trifluoroacetyl-4-(hexadecylamino)benzoyl chloride (4.8 g.) is added to a solution of 1.8 g. of sulfanilic acid in 1 N sodium hydroxide at 0° C. After 3 hours, the solution is warmed to 60° C. briefly and the whole evaporated to dryness. The residue is extracted with a small amount of cold water and the resulting white solid crystallized from aqueous ethanol.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([N:15]1[C:19](=[O:20])[C:18]([NH:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[C:17]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[S:16]1(=[O:35])=[O:34])([CH3:14])([CH3:13])[CH3:12]>>[C:11]([N:15]1[C:19](=[O:20])[C:18]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:24][CH2:23]2)=[C:17]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[S:16]1(=[O:35])=[O:34])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)N1C(=O)C(NC2CCNCC2)=C(c2ccccc2)S1(=O)=O
Reactant: O=C(Cl)Cc1ccccc1
Product: CC(C)(C)N1C(=O)C(NC2CCN(C(=O)Cc3ccccc3)CC2)=C(c2ccccc2)S1(=O)=O
Yield: 78 %

Procedure:
The title compound was prepared as described for Example 105 from phenylacetic chloride and 2-tert-butyl-5-phenyl-4-(piperidin-4-ylamino)isothiazol-3(2H)-one 1,1-dioxide (Example 75) to give the title compound (0.103 g, 78%). 1H NMR (500 MHz CDCl3): δ 7.54-7.47 (m, 2H), 7.47-7.41 (m, 3H), 7.34-7.29 (m, 2H), 7.27-7.23 (m, 1H), 7.18 (d, 2H), 5.12 (d, 1H), 4.43-4.26 (m, 1H), 3.70-3.61 (m, 3H), 3.11-3.02 (m, 1H), 2.55-2.47 (m, 1H), 2.28-2.20 (m, 1H), 1.90-1.65 (m, 11H), 1.54-1.47 (m, 1H), 1.19 (dq, 1H), 0.91 (dq, 1H); 13C δ NMR (125 MHz CDCl3): 169.5, 159.7, 135.0, 133.9, 131.8, 130.2, 129.0, 128.9, 128.6, 127.2, 125.2, 107.5, 61.9, 50.2, 44.6, 41.3, 41.2, 40.4, 32.6, 32.1, 27.8; Mass Spectrum: M+H+ 482.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Br:9]Br.C(=O)(O)[O-].OS([O-])=O.[Na+]>C(Cl)(Cl)Cl>[Br:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1ncc(Cl)cc1Br
Yield: 88.1 %

Procedure:
A 250 mL round-bottomed flask was charged with 5-chloropyridin-2-amine (80 g, 622.3 mmol) and CHCl3 (100 mL). Added bromine (31.98 mL, 622.3 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was poured into saturated bicarbonate and NaHSO3 and extracted with CH2Cl2. The organic layer was dried with sodium sulfate, filtered and concentrated to afford the title compound (113.8 g, 88.1% yield) as a tan solid. 1H NMR (d6-DMSO) δ 7.97 (d, 1H), 7.90 (d, 1H), 6.44 (bs, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][CH2:12][C:13]1([CH2:26][CH2:27][C:28]2([CH2:41][CH2:42][C:43](OCC)=[O:44])[C:40]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:34]3[C:29]2=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)C.O.[OH-].[Na+]>CCOCC.C(OCC)(=O)C>[OH:9][CH2:10][CH2:11][CH2:12][C:13]1([CH2:26][CH2:27][C:28]2([CH2:41][CH2:42][CH2:43][OH:44])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:34]=3[C:35]3[C:40]2=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2
Reactant: CCOC(=O)CCC1(CCC2(CCC(=O)OCC)c3ccccc3-c3ccccc32)c2ccccc2-c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OCCCC1(CCC2(CCCO)c3ccccc3-c3ccccc32)c2ccccc2-c2ccccc21
Reaction time: 8 h
Yield: 91.8 %

Procedure:
A 2-neck 1-Liter round bottom flask was equipped with a condenser, a magnetic stir bar and an addition funnel. The flask was charged with 100 mL of anhydrous ether. Lithium aluminum hydride (2.30 g) was then carefully added to the flask. 3-(9-{2-[9-(2-Ethoxycarbonyl-ethyl)-9H-fluoren-9-yl]-ethyl}-9H-fluoren-9-yl)-propionic acid ethyl ester (11.3 g, 20.2 mmol) was suspended in 100 mL of anhydrous ether and added to the addition funnel. The suspension of diester was then added dropwise to the rapidly stirred lithium aluminum hydride suspension. The addition funnel was rinsed with additional portions of anhydrous ether to rinse all of the diester into the reaction flask. The reaction mixture was then refluxed for several hours and then left at ambient temperature overnight. The rapidly stirred reaction mixture was carefully treated by the dropwise addition of water (2.3 mL), followed by 15% NaOH solution (2.3 mL), and finally more water (6.9 mL). After stirring for 2 h, the ether solution was filtered from the aluminum salts. The salts were rinsed with additional portions of diethyl ether. The combined organic portions were concentrated under reduced pressure to give a white solid. The white solid was dissolved in 100 mL of ethyl acetate, washed with 1N HCl solution, water, and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting white solid was crystallized from hot toluene to give the title compound (2-d) (8.8 g) as white crystals. 1H NMR (CDCl3, 500 MHz) δ 7.73 (d, J=7.5 Hz, 4H), 7.36 (m, 4H), 7.28 (m, 4H), 7.00 (d, J=7.5 Hz, 4H), 3.15 (t, J=6.7 Hz, 4H), 1.65 (m, 4H), 1.24 (s, 4H), 0.64 (m, 4H).
Reaction SMILES: C([O:8][C:9](=O)[NH:10][C:11]1[CH:20]=[CH:19][C:14]2[O:15][CH2:16][CH2:17][O:18][C:13]=2[CH:12]=1)C1C=CC=CC=1.[C:22]([Si:26]([CH3:36])([CH3:35])[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]1[CH2:34][O:33]1)([CH3:25])([CH3:24])[CH3:23].C(O[Li])(C)(C)C.C1COCC1.Cl>CN(C=O)C>[C:22]([Si:26]([CH3:35])([CH3:36])[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]1[O:33][C:9](=[O:8])[N:10]([C:11]2[CH:20]=[CH:19][C:14]3[O:15][CH2:16][CH2:17][O:18][C:13]=3[CH:12]=2)[CH2:34]1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OCCCCC1CO1
Reactant: O=C(Nc1ccc2c(c1)OCCO2)OCc1ccccc1
Agent: Cl
Agent: [Li]OC(C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCCC1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Temperature: 25 °C
Reaction time: 22 h
Yield: 82.1 %

Procedure:
A solution of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-carbamic acid benzyl ester (0.75 g, 2.6 mmol) and rac-tert-butyl-dimethyl-(4-oxiranyl-butoxy)-silane (prepared according to Angew. Chem. (2007), 46, 5896; 0.91 g, 1.5 eq.) in DMF (8 mL) at 0° C. was treated with a 2.2M solution of t-BuOLi in THF (3.6 mL, 3 eq.). The mixture was stirred at rt for 22 h. HCl 1M (5.3 mL) was added and the mixture partitioned between EA and water. The org. phase was washed with water and brine, dried over MgSO4 and concentrated. The product was purified by FC (Hex/EA 1:1, 1:2) to give the title intermediate as a yellowish oil (0.87 g, 81% yield).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:15][C:16]1[N:21]=[CH:20][N:19]=[C:18]2[N:22]([C:38]3[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=3)[N:23]=[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:27][CH:26]=3)[C:17]=12.[CH3:46][N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClC(Cl)C.O>[CH3:46][N:47]1[CH2:52][CH2:51][N:50]([CH2:42][C:41]2[CH:44]=[CH:45][C:38]([N:22]3[C:18]4=[N:19][CH:20]=[N:21][C:16]([NH2:15])=[C:17]4[C:24]([C:25]4[CH:30]=[CH:29][C:28]([O:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[CH:27][CH:26]=4)=[N:23]3)=[CH:39][CH:40]=2)[CH2:49][CH2:48]1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccccc3)cc1)nn2-c1ccc(C=O)cc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc(-n3nc(-c4ccc(Oc5ccccc5)cc4)c4c(N)ncnc43)cc2)CC1
Temperature: 25 °C
Yield: 20.8 %

Procedure:
Sodium triacetoxyborohydride (67 mg, 0.319 mmol) was added to a mixture of 4-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]benzaldehyde (100 mg, 0.245 mmol), 4-methylpiperazine (37 mg, 0.369 mmol), glacial acetic acid (35 mg, 0.589 mmol) in dichloroethane (4 mL). After stirring at room temperature over night, more sodium triacetoxyborohydride (67 mg, 0.319 mmol) was added and the reaction mixture was stirred over night. Water (2 mL) was added and followed by sodium bicarbonate (250 mg). After stirring vigorously for 1 hour, the layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichlromethane/methanol (97:3 to 80:20) as mobile phase to give 1-{4-[(4-methylpiperazino)methyl]phenyl}-3-(4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (25 mg, 21%). 1H NMR (DMSO-d6) δ 2.30 (s, 3H), 2.48 (bm, 8H), 3.56 (s, 3H), 5.75 (bs, 2H), 7.11 (d, J=8.50, 2H), 7.18 (m, 3H), 7.40 (m, 2H), 7.48 (d, J=8.50 Hz, 2H), 7.29 (d, J=8.63 Hz, 2H), 8.12 (d, J=8.50 Hz, 2H), 8.47 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=492.2, Rt=2.97 min.
Reaction SMILES: C[C:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)([CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[OH-].[Na+]>CO>[CH:7]1([CH2:6][CH:2]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[C:3]([OH:5])=[O:4])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(CC1CCCC1)(C(=O)O)c1ccc(S(C)(=O)=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of methyl 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid (2.8 g, 9.0 mmol), 1 N sodium hydroxide (19 mL), and methanol (25 mL) was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo to remove the methanol and 2 N HCl (9 mL) was slowly added at 0° C. to give white crystals of 3-cyclopentyl-2-(4-methanesulfonylphenyl)propionic acid. Yield: 2.3 g (87%). mp: 160-161° C. 1H-NMR (CDCl3, δ ppm): 7.90 (d, J=8.2 Hz, 2H); 7.54 (d, J=8.2 Hz, 2H); 3.72 (t, J=7.8 Hz, 1H); 3.05 (s, 3H); 2.15-2.08 (m, 1H); 1.9-1.45 (m, 8H); 1.05-1.20 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][CH2:12][C@H:13]([OH:15])[CH3:14])(=[O:10])=[O:9].[NH2:16][C:17]1[C:18]([C:39]#[N:40])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:24]=2[F:38])=[CH:21][N:22]=1>>[NH2:16][C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:2]3[C:3]([S:8]([NH:11][CH2:12][C@H:13]([OH:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:25][C:24]=2[F:38])=[N:19][C:18]=1[C:39]#[N:40]
Reactant: C[C@@H](O)CNS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)c(C#N)n3)c(F)c2)OC1(C)C
Product: C[C@@H](O)CNS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)c(C#N)n2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using (R)-2-bromo-N-(2-hydroxypropyl)benzenesulfonamide and 3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C20H18FN5O3S, 427.11; m/z found, 428.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.75 (d, J=2.1, 1H), 8.09 (dd, J=8.0, 1.3, 1H), 7.95 (m, 1H), 7.70 (m, 1H), 7.62 (m, 1H), 7.43 (dd, J=7.6, 1.4, 1H), 7.39-7.31 (m, 2H), 3.74-3.62 (m, 1H), 2.80-2.67 (m, 2H), 1.07 (d, J=6.3, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[Li].C[Si]([N-][Si](C)(C)C)(C)C>C1(C)C=CC=CC=1>[CH2:25]([O:24][C:22]([C:19]1([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=2)[CH2:20][CH2:21][N:16]([C:14]([O:13][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:15])[CH2:17][CH2:18]1)=[O:23])[CH3:26]
Reactant: Fc1ccc(Br)nc1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(c2ccc(F)cn2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 87 h

Procedure:
Under an inert atmosphere a 250 mL three necked round bottom flask (flame dried) with a magnetic stirring bar was charged with 4 g (22.7 mmol) 2-bromo-5-fluoropyridine, 11.7 g (45 mmol) ethyl 1-tert.-butyloxycarbonylpiperidine-4-carboxylate, 416 mg (0.04 mmol) tris(dibenzylideneacetone)palladium(0), 0.91 mL tri-tert-butylphosphine (1M in toluene) and 60 ml toluene. To the dark red solution, 50 mL lithium-bis-(trimethylsilyl)-amid (1M in hexane) was added dropwise during 1 h at 18 to 23° C. The dark brown reaction solution was stirred for 87 h at room temperature. The reaction was quenched with saturated aqueous NH4Cl-solution. The aqueous layer was separated and extracted once with 200 mL ethyl acetate. The organic layers were washed once with 150 mL brine, dried over Na2SO4, filtered off and concentrated under vacuum. The residue was purified on silica eluting with a gradient formed from heptane and TBME to yield after evaporation of the product fractions 4 g (50%) of the title compound as yellow viscous oil. MS ISP (m/e): 253.3 (M-Boc)/353.2 [(M+H)+].
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.S(Cl)([Cl:22])=O>>[ClH:22].[N:2]1([CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:14]([C:15]([Cl:1])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Product: O=C(Cl)c1ccc(OCCN2CCCCC2)cc1
Temperature: 25 °C

Procedure:
A 500 mL round-bottom flask is charged with 4-(2-piperidin-1-yl-ethoxy)-benzoic acid hydrochloride, (25 g, 0.08748 mol) and thionyl chloride (150 mL, 2.0564 mol). The mixture is brought to reflux for 15 minutes whereupon it becomes a clear solution. The reaction is cooled to room temperature and the excess thionyl chloride is removed to give a quantitative yield of the desired product. 1H NMR: ∂ 8.08 (app. d, J=8.8 Hz, 2H), 6.99 (app. d, J=9.2 Hz, 2H), 4.71 (t, J=4.6 Hz, 2H), 3.65 (d, J=12 Hz, 2H), 3.43 (quart., J=4.6 Hz, 2H), 2.76–2.85 (m, 2H), 2.22–2.32 (m, 2H), 1.87–1.94 (m, 3H), 1.37–1.49 (m, 1H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C=O)C.[NH2:18][C:19]1[N:23]([CH2:24][CH3:25])[N:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC([O-])=O.CC([O-])=O.[Cu+2].C(O)(=O)C.O>[CH2:24]([N:23]1[C:19]([NH:18][C:2]2[C:3](=[CH:7][C:8]([S:11][CH3:12])=[CH:9][CH:10]=2)[C:4]([OH:6])=[O:5])=[CH:20][CH:21]=[N:22]1)[CH3:25]
Reactant: CCn1nccc1N
Reactant: CSc1ccc(Cl)c(C(=O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: CCn1nccc1Nc1ccc(SC)cc1C(=O)O
Temperature: 25 °C
Yield: 37.7 %

Procedure:
A mixture of 2-chloro-5-(methylthio)benzoic acid (8.8 g, 0.043 mol), DMF (100 ml), 5-amino-1-ethylpyrazole (4.8 g, 0.043 mol), K2CO3 (5.94 g, 0.043 mol) and Cu(OAc)2 (0.5 g ) is refluxed overnight. The reaction mixture is cooled to room temperature, poured into water and acidified with acetic acid to a pH of about 4-5. The mixture is extracted with CH2Cl2 and then the CH2Cl2 layer is evaporated to afford 4.5 g of N-(1-ethylpyrazol-5-yl)-5-(methylthio)anthranilic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:17][C:18]3[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=4)[CH:20]=[N:21][CH:22]=3)[CH:15]=[N:16][C:10]=2[CH:9]1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Br:38])[CH:33]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:38][C:34]1[CH:33]=[C:32]([CH:9]2[C:10]3[N:16]=[CH:15][N:14]([CH2:17][C:18]4[N:19]([CH2:23][C:24]5[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=5)[CH:20]=[N:21][CH:22]=4)[C:11]=3[CH2:12][CH2:13][NH:8]2)[CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(ncn2Cc2cncn2Cc2ccc(C#N)cc2)C1c1cccc(Br)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Cn2cncc2Cn2cnc3c2CCNC3c2cccc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(3-bromophenyl)-1-[3-(4-cyanobenzyl)-3H-imidazol-4-ylmethyl]-1,4,6,7-tetrahydroimidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (0.045 g, 0.078 mmol) dissolved in CH2Cl2 (5 mL) was added TFA (1 mL) and the reaction mixture was stirred at room temperature under Ar for 2h. The solution was concentrated in vacuo and purified using reverse phase liquid chromatography (95/5 -5/95 H2O/CH3CN with 0.1% TFA over 60 min, flow rate =65 mL/min) to yield the title compound.