Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:17])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:24]([C:25](O)=[O:26])=[C:23]([F:28])[C:22]([CH2:29][NH:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:21][CH:20]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:25](=[O:26])[C:24]3[C:19]([Cl:18])=[CH:20][CH:21]=[C:22]([CH2:29][NH:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:34])[CH3:35])[C:23]=3[F:28])[CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([CH3:17])[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(NC(C)(C)C)c2cccc(N)c2n1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NC(C)(C)C)c2cccc(NC(=O)c3c(Cl)ccc(CNC(=O)C(C)(C)C)c3F)c2n1
Yield: 21.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)-2-methylquinazoline-4,8-diamine (Intermediate-58, 100 mg, 0.43 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 150 mg, 0.52 mmol), oxalyl chloride (82 mg, 0.65 mmol), DMF (1 drop) and DIPEA (166 mg, 1.29 mmol) in CH2Cl2 (3 mL) to afford 46 mg of the title product. 1H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 8.66 (d, J=7.4 Hz, 1H), 8.15 (t, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.44-7.33 (m, 4H), 4.31 (d, J=5.8 Hz, 2H), 2.48 (s, 3H), 1.14 (s, 9H); MS (m/z): 500.60 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(N(C(C)C)CC)(C)C>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH2:21][N:37]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccc2c([C@H](CBr)OC3CCCCO3)ccc(OCc3ccccc3)c2[nH]1
Reactant: c1ccc(CCCCOCCCCCCNCc2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1ccc2c([C@H](CN(CCCCCCOCCCCc3ccccc3)Cc3ccccc3)OC3CCCCO3)ccc(OCc3ccccc3)c2[nH]1
Temperature: 25 °C
Yield: 54.3 %

Procedure:
8-(Benzyloxy)-5-[(1R)-2-bromo-1-(tetrahydro-2H-pyran-2-yloxy)ethyl]quinolin-2(1H)-one (100 mg), N-benzyl-6-(4-phenylbutoxy)hexan-1-amine (Tetrahedron Letters. 1994, 35, 9375) (112 mg) and diisopropylethylamine (77 μl) were heated in a reacti-vial at 120° C. for 4 h prior to cooling to room temperature. The mixture was purified by chromatography (Hexane-EtOAc 2:1, biotage) afforded the title compound (85 mg). LCMS RT=3.46 min
Reaction SMILES: [NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])([S:8][CH2:9][CH2:10][CH3:11])[C:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:3]1[NH:22][C:23]([NH:25][C:26]([O:28][CH3:29])=[O:27])=[S:24].[CH3:30]C(C)=O.[OH-].[Na+].CI>O>[NH:1]=[C:2]1[CH:7]=[CH:6][C:5]([N+:12]([O-:14])=[O:13])([S:8][CH2:9][CH2:10][CH3:11])[C:4]([CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:3]1[NH:22][C:23](=[N:25][C:26]([O:28][CH3:29])=[O:27])[S:24][CH3:30]
Reactant: CCCSC1([N+](=O)[O-])C=CC(=N)C(NC(=S)NC(=O)OC)=C1Cc1ccccc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CCCSC1([N+](=O)[O-])C=CC(=N)C(NC(=NC(=O)OC)SC)=C1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
A mixture of 1-imino-(4-nitro)phenylmethyl-2-(3-carbomethoxythioureido)-4-propylthiobenzene (4.3 g; 0.01 mole) acetone (50 ml), water (25 ml) and 50% aqueous sodium hydroxide (0.8 g; 0.01 mole) is stirred at room temperature for 15 min. and is cooled to 12° C. To the mixture there is added methyl iodide (1.4 g; 0.01 mole) and it is stirred at 13° C. to 20° C. for 2 hrs. The suspension that forms is vacuum filtered and the filter cake is washed with acetone and dried to afford 1-imino(4-nitro)phenylmethyl-2-(3-carbomethoxy-S-methylisothioureido)-4-propylthiobenzene (3.5 g; 78%), m.p. 135°-137° C. dec.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CN(C)C=O.[CH2:21](Br)[C:22]#[CH:23]>C(OCC)(=O)C.O>[CH2:3]([N:10]1[CH2:14][CH2:13][CH:12]([O:15][CH2:23][C:22]#[CH:21])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C#CCBr
Reactant: OC1CCN(Cc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOC1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
On an ice bath, 233 mg of sodium hydride was added to a mixture of 948 mg of 1-benzyl-3-pyrrolidinol and 10 ml of N,N-dimethylformamide and the mixture was stirred at room temperature for 1 hour. There action mixture was cooled to −40° C. and 495 μl of propargyl bromide was added thereto. The temperature was elevated to room temperature and water and ethyl acetate were added to the reaction mixture. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was purified by NH-silica gel column chromatography with 15% ethyl acetate/hexane, to give 507 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH2:15][CH3:16])[C:13]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[CH3:26][O:27][C:28]([CH3:32])([CH3:31])[CH2:29][NH2:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:26][O:27][C:28]([CH3:32])([CH3:31])[CH2:29][NH:30][C:21]([C:19]1[CH:18]=[CH:17][C:13]2[N:14]([CH2:15][CH3:16])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:25]=[CH:24][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:20]=1)=[O:23]
Reactant: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COC(C)(C)CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(C)(C)OC)ccc21
Yield: 39.6 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzoimidazole-5-carboxylic acid (2-methoxy-2-methyl-propyl)-amide (73.0 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-ethyl-1H-benzo-imidazole-5-carboxylic acid (150.0 mg), 2-methoxy-2-methyl-propylamine (61.0 mg), HBTU (190.0 mg) and DIEA (0.2 mL) in DMF (1.0 mL). LCMS: m/z 459; and 1H NMR (DMSO-d6, 400 MHz): δ 8.18-8.16 (1H, m), 8.08 (1H, m), 7.92-7.91 (1H, m), 7.79-7.77 (1H, m), 7.67-7.65 (1H, m), 7.54-7.52 (1H, m), 7.40-7.37 (1H, m), 4.21-4.20 (2H, m), 3.37-3.35 (2H, d), 3.18 (3H, s), 1.34-1.30 (3H, t), 1.14 (6H, s), —NH proton signal was not observed.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]2=[CH:7][S:8][N:9]=[C:5]2[CH:4]=1.O1CCCC1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[N:9]1[S:8][CH:7]=[C:6]2[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=12
Reactant: OCc1ccc2csnc2c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1ccc2csnc2c1

Procedure:
1.65 g (10 mmol) of 10b are stirred analogously to Example 1b in 100 ml of CH2Cl2 and 30 ml of tetrahydrofuran with 5.5 g (63.4 mmol) of manganese(IV) oxide at room temperature overnight.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:23]O.[CH2:25]([SH:33])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[C:6]2[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH2:23][S:33][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: SCCc1ccccc1
Reactant: Cc1c(CO)oc2cccc(OCCCNCc3cccnc3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(CSCCc2ccccc2)oc2cccc(OCCCNCc3cccnc3)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97 %

Procedure:
To a solution of the compound in Example 11 (20 mg, 0.06 mmol) and phenethyl mercaptan (30 mg) in anhydrous CH2Cl2 (0.9 ml) was added trifluoroacetic acid (TFA, 0.2 ml). The mixture was stirred at room temperature for 2.5 hours. The solvent was removed under reduced pressure. The residue was purified over preparative TLC (CH2Cl2/MeOH=100/1) to give the desired compound (26 mg, 95%) as a colorless oil. FAB-MS: m/z 446 (MH+); 1H-NMR (CDCl3): δ 2.10 (2H, m), 2.32 (3H, s), 2.79-2.97 (6H, m), 3.54 (2H, s), 3.85 (2H, s), 3.90 (2H, s), 6.63 (1H, d, J=7.6 Hz), 7.09-7.30 (3H, m), 7.71 (1H, d, J=7.8 Hz), 8.55 (1H, d, J=2.0 Hz), 8.62 (1H, s).
Reaction SMILES: [CH3:1][N:2]([CH:14]1[CH2:18][CH2:17][O:16][CH2:15]1)[S:3]([NH:6]C(=O)OC(C)(C)C)(=[O:5])=[O:4]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH3:1][N:2]([CH:14]1[CH2:18][CH2:17][O:16][CH2:15]1)[S:3]([NH2:6])(=[O:5])=[O:4]
Reactant: CN(C1CCOC1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C1CCOC1)S(N)(=O)=O

Procedure:
tert-butyl {[methyl(tetrahydrofuran-3-yl)amino]sulfonyl}carbamate (1.47 g, 5.23 mmol) was dissolved in 70 mL of CH2Cl2 and 45 mL of trifluoroacetic acid. After 1 h the solution was concentrated in vacuo, diluted in CH2Cl2, washed with saturated aqueous NaHCO3 and brine, then dried over Na2SO4. The solution was concentrated in vacuo to afford the title compound. 1H NMR (600 MHz, DMSO-d6) δ 4.25-4.31 (m, 1H); 3.79-3.84 (m, 1H); 3.58-3.66 (m, 2H); 3.47-3.52 (m, 1H); 2.56 (s, 3H), 2.04-2.10 (m, 1H); 1.81-1.88 (m, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[N-:12]=[N+:13]=[N-:14].[Na+]>CS(C)=O.O>[N:12]([CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5])=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: O[C@H](CCCl)c1ccccc1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NCC[C@@H](O)c1ccccc1
Temperature: 40 °C
Yield: 78.7 %

Procedure:
(R)-α-(2-Chloroethyl)benzenemethanol (0.73 g, 4.3 mmol) and sodium azide (417 mg, 1.5 eq.) in DMSO (3 ml) was stirred and heated at 40° C. for 1.5 h. The reaction mixture was diluted with water (50 ml) and the products extracted into ethyl acetate(2×75 ml). The combined extracts were dried (magnesium sulphate) and concentrated to an oil. Purification was achieved on silica gel eluting with 50% diethyl ether/isohexane to afford the azide as a colourless oil (0.6 g, 79%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2S(C2C=CC=CC=2)(=O)=O)=[C:4]([C:20]2[O:21][C:22]([CH2:25][N:26]3[CH2:31][C@H:30]([CH3:32])[N:29]([CH:33]([CH3:35])[CH3:34])[C@H:28]([CH3:36])[CH2:27]3)=[N:23][N:24]=2)[CH:3]=1.[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1[S:45]([NH:48][C:49]1[C:50]([O:64][CH3:65])=[N:51][CH:52]=[C:53](B2OC(C)(C)C(C)(C)O2)[CH:54]=1)(=[O:47])=[O:46].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH-].[Na+]>O1CCOCC1.O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:36][C@H:28]1[N:29]([CH:33]([CH3:35])[CH3:34])[C@@H:30]([CH3:32])[CH2:31][N:26]([CH2:25][C:22]2[O:21][C:20]([C:4]3[CH:3]=[C:2]([C:53]4[CH:54]=[C:49]([NH:48][S:45]([C:39]5[CH:40]=[CH:41][C:42]([F:44])=[CH:43][C:38]=5[F:37])(=[O:47])=[O:46])[C:50]([O:64][CH3:65])=[N:51][CH:52]=4)[CH:10]=[C:9]4[C:5]=3[CH:6]=[N:7][NH:8]4)=[N:24][N:23]=2)[CH2:27]1
Reactant: CC(C)N1[C@H](C)CN(Cc2nnc(-c3cc(Br)cc4c3cnn4S(=O)(=O)c3ccccc3)o2)C[C@@H]1C
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cc(-c3nnc(CN4C[C@@H](C)N(C(C)C)[C@@H](C)C4)o3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 100 °C
Yield: 2.5 %

Procedure:
6-Bromo-4-(5-{[(3R,5S)-3,5-dimethyl-4-(1-methylethyl)-1-piperazinyl]methyl}-1,3,4-oxadiazol-2-yl)-1-(phenylsulfonyl)-1H-indazole (172 mg, 0.300 mmol), 2,4-difluoro-N-[2-(methyloxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (128 mg, 0.300 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium dichloride (43.9 mg, 0.060 mmol) and potassium phosphate tribasic (191 mg, 0.900 mmol) were added to a microwave vial and dissolved in 1,4-dioxane (2.5 ml) and water (0.25 ml). The mixture was heated under microwave irradiation at 100° C. for 20 mins. The mixture was passed through a 1 g silica SPE cartridge, washing with MeOH. The solvent was removed under a stream of nitrogen and the residue was partitioned between DCM (10 ml) and water (10 ml), separated with a hydrophobic frit and the solvent again removed under a stream of nitrogen. The protected compound was dissolved in 1,4-dioxane (1 ml) and sodium hydroxide (1 ml, 2.000 mmol) and stirred at room temperature for 4 h. The mixture was evaporated to dryness under a stream of nitrogen. The residue was partitioned between ethyl acetate (5 ml) and saturated ammonium chloride (2 ml) and separated with a hydrophilic frit. The solvent was removed under a stream of nitrogen and the residue was dissolved in DMSO (1 ml) and purified by purified by Mass Directed Automated Preparative HPLC. The appropriate fraction was blown down under a stream of nitrogen to give the title compound as a pale yellow solid (4.9 mg).
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)(O)[C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[CH2:3]1.Cl>C(O)(C)C>[CH3:1][CH:2]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[C:6](=[C:13]2[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]2)[C:5]2[CH:20]=[CH:21][CH:22]=[CH:23][C:4]=2[CH2:3]1
Reactant: CC1Cc2ccccc2C(O)(C2CCN(C)CC2)c2ccsc21
Agent: Cl
Solvent: CC(C)O
Product: CC1Cc2ccccc2C(=C2CCN(C)CC2)c2ccsc21

Procedure:
A solution of 17.0 g of 9,10-dihydro-10-methyl-4-(1-methyl-4-piperidyl)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-4-ol in 350 cc of isopropanol and 350 cc of a 7 N solution of hydrogen chloride in isopropanol is heated to the boil for 4 hours, is evaporated to dryness, the residue is taken up in 150 cc of water, is made alkaline with concentrated caustic soda solution and extracted with methylene chloride. The extracts are washed with water, dried over potassium carbonate, decolourized with animal charcoal and concentrated by evaporation. The title compound, obtained as oily residue, is converted into the hydrochloride form in ethanol. M.P. of the hydrochloride form of the title compound: decomp. from 210° (from acetone/ethanol). M.P. (hydrogen malonate 191°-2° C.)
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([O:34][CH3:35])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[C:17]=23)=[CH:20][C:21]=1[O:34][CH3:35]
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Reactant: C1CCNC1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCN4CCCC4)c23)ccc1OCc1cccc(F)c1
Yield: 30 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate (prepared as described in Example 22) and pyrrolidine to give the title compound in 30% yield; NMR Spectrum: 1.66 (s, 4H), 2.55 (s, 4H), 2.88 (t, 2H), 3.80 (s, 3H), 4.42 (t, 2H), 5.11 (s, 2H), 7.00 (d, 1H), 7.16 (m, 2H), 7.29 (m, 2H), 7.38 (d, 1H), 7.45 (q, 1H), 8.25 (s, 1H), 8.52 (s, 1H); Mass Spectrum: 479 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl>CCOCC.Cl>[Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOCC
Product: Nc1cc(Cl)cnc1Br
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
2-Bromo-5-chloro-3-nitro-pyridine (11.87 g, 50 mmol) was dissolved in 100 mL ether. Tin(II) chloride dihydrate (56.4 g, 0.5 mol) was dissolved in 100 mL of concentrated hydrochloric acid and added drop wise over 15 minutes to the stirring ethereal solution of the nitro compound. The exothermic reaction brought the ether to boiling and it was allowed to evaporate off. After the addition was complete the reaction mixture was placed on a 50° C. oil bath and stirred for 30 minutes to boil of the remaining ether. The flask was then cooled on in an ice bath. The precipitate formed was collected and by filtration and dissolved in 100 mL of water. The pH was adjusted to 9-10 by the addition of concentrated ammonium hydroxide solution and the product was extracted with ethyl acetate (2×100 mL). The organic layer was washed with diluted ammonium hydroxide, water and brine and dried over Na2SO4 and the solvent was evaporated to afford 7.4 g of tan crystalline solid. MS m/z: 208.9 (M+H).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.Cl[C:22]1[N:27]=[CH:26][C:25]([CH2:28][C:29]#[N:30])=[CH:24][CH:23]=1>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]1([C:22]2[N:27]=[CH:26][C:25]([CH2:28][C:29]#[N:30])=[CH:24][CH:23]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: N#CCc1ccc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: N#CCc1ccc(-c2ccccc2)nc1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
Phenylboronic acid (4630.9 mg, 37.98 mmol), K3PO4 (20129 mg, 94.95 mmol), and PdCl2(dppf).CH2Cl2 (1291 mg, 1.58 mmol) was added to a solution of 2-(6-chloropyridin-3-yl)acetonitrile (5000 mg, 31.65 mmol) in dioxane (100 mL) and H2O (10 mL). The resulting mixture was stirred at 75° C. under argon overnight. The mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation and purification by column chromatography afforded 2-(6-phenylpyridin-3-yl)acetonitrile: LCMS tR=1.15 Min (5 min run, UV254nm), Mass calculated for, M+194.0, observed LC/MS m/z 195.0 (M+H).
Reaction SMILES: CC([O-])(C)C.[K+].Cl[CH:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28].Cl>CN(C=O)C.O>[F:20][C:21]1[CH:26]=[C:25]([CH:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:24]=[CH:23][C:22]=1[N+:27]([O-:29])=[O:28]
Reactant: CCOC(=O)C(Cl)c1ccccc1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: -45 °C
Reaction time: 0.33 h
Yield: 44.4 %

Procedure:
9.8 g of potassium tert-butylate were dissolved in 90 mL of DMF and cooled to −45° C. To this, a mixture of ethyl 2-chloro-2-phenylacetate (43.8 mmol, 8.7 g) and 1-fluoro-2-nitrobenzene (43.8 mmol, 4.6 mL) was gently added dropwise and stirring was continued for a further 20 minutes. The reaction mixture was set to pH 4 with aq. 16% strength. HCl, diluted with 25 mL of water, and extracted with EA (3×50 mL). Following combination of the organic phases, they were washed with water and sat. aq. NaCl solution, dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by column chromatography (silica gel: mesh 100-200, eluent: 10% EA in cyclohexane) and yielded 5.9 g (44.9%) of the desired product.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][CH:14]([CH2:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:13][CH2:12]1)C1C=CC=CC=1>C(O)C.[Pd]>[CH3:21][S:18]([CH2:17][CH:14]1[CH2:15][CH2:16][CH:11]([NH2:10])[CH2:12][CH2:13]1)(=[O:19])=[O:20]
Reactant: CS(=O)(=O)CC1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CS(=O)(=O)CC1CCC(N)CC1
Reaction time: 16 h
Yield: 100.8 %

Procedure:
(4-Methanesulfonylmethyl-cyclohexyl)-carbamic acid benzyl ester (0.54 g, 1.66 mmol) in ethanol (15 mL, IMS grade) under nitrogen was treated with 10% palladium/carbon (0.18 g, 0.17 mmol). The mixture was purged with hydrogen gas and was stirred under an atmosphere of hydrogen (balloon) for 16 hours. The catalyst was filtered off through Celite® and the filter cake rinsed several times with ethanol. The filtrate was concentrated and then purified by column chromatography on Isolute® SCX-2 cartridge (eluting with MeOH then 2M NH3 in MeOH). The relevant fractions were combined concentrated under vacuum to afford 0.32 g (95%) 4-methanesulfonylmethyl-cyclohexylamine as clear oil that was used without further purification. LCMS (Method I, ESI): RT=0.35 min, m+H=191.9.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[O:14].[CH3:27][O-:28].[Na+].[NH4+].[Cl-]>CO>[CH3:27][O:28][C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[O:14]
Reactant: C[O-]
Reactant: Cc1nc2ncccc2c(Cl)c1C(=O)NCc1cccc(C(F)(F)F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: COc1c(C(=O)NCc2cccc(C(F)(F)F)c2)c(C)nc2ncccc12
Yield: 20 %

Procedure:
4-Chloro-2-methyl-N-(3-(trifluoromethyl)benzyl)-1,8-naphthyridine-3-carboxamide (60.0 mg, 0.16 mmol) was dissolved in anhydrous MeOH (1.0 ml). NaOMe was added and the mixture refluxed for 15 h. The mixture was allowed to cool. NH4Cl (5.0 ml (sat)) was added and the product extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated. Purification was done by flash chromatography (EtOAc/MeOH 98:2) giving 12.0 mg (20%) of the title compound.