Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:14]([OH:16])=O)[C:10]([CH3:13])([CH3:12])[CH3:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[CH3:40][C:41]1[N:45]2[C:46](=[O:56])[N:47]([CH2:49][CH:50]3[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]3)[CH2:48][C:44]2=[CH:43][N:42]=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:13][C:10]([CH3:11])([CH3:12])[C@@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])[C:14]([N:53]1[CH2:54][CH2:55][CH:50]([CH2:49][N:47]2[CH2:48][C:44]3=[CH:43][N:42]=[C:41]([CH3:40])[N:45]3[C:46]2=[O:56])[CH2:51][CH2:52]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Reactant: Cc1ncc2n1C(=O)N(CC1CCNCC1)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ncc2n1C(=O)N(CC1CCN(C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)(C)C)CC1)C2
Yield: 90.5 %

Procedure:
To a solution of Boc-D-tert-leucine (0.69 g), HOBt (0.69 g) and WSC (0.86 g) in acetonitrile (20 ml) was added a solution of 5-methyl-2-(4-piperidinylmethyl)-1,2-dihydro-3H-imidazo[1,5-c]imidazol-3-one dihydrochloride (0.91 g) as described above, DBU (0.6 ml) and triethylamine (0.61 ml) in acetonitrile (20 ml), and mixed for 15 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in dichloromethane. The dichloromethane solution was washed with an aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified with basic silica gel column (ethyl acetate/methanol=10/1) to obtain the title compound as colorless powder (1.2 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[C:6]([N+:9]([O-])=O)[CH:5]=[CH:4][C:3]=1[OH:12].CO.[NH4+].[Cl-]>[Zn].C1COCC1>[NH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[C:2]([Cl:1])[C:7]=1[F:8]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(O)c(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
A 0° C. solution of 2-chloro-3-fluoro-4-nitrophenol (25 g, 130.9 mmol) in 1:1 MeOH and THF (400 mL) was treated with NH4Cl (70 g, 1.3 mol), followed by the portion-wise addition of zinc (83.2 g, 1.3 mol), then warmed to RT and stirred for 2 h. The solids were removed via filtration, the filtrate concentrated to dryness and the residue was dissolved in EtOAc, washed with brine, dried over Na2SO4 and concentrated to afford 4-amino-2-chloro-3-fluorophenol (16 g, 76%). 1H-NMR (400 MHz, DMSO-d6): δ 9.41 (s, 1 H), 6.59-6.51 (m, 2 H), 4.65 (s, 2H); MS (ESI): m/z 162.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[N:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[F:13][C:14]([F:26])([F:25])[O:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[F:13][C:14]([F:25])([F:26])[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[N:7][NH:8][C:9]3=[O:12])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: O=c1[nH]ncc2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=c1[nH]ncc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Temperature: 90 °C

Procedure:
A mixture of 7-bromophthalazinone (1.09 g, 4.84 mmol), 4-trifluoromethoxyphenyl boronic acid (1.20 g, 5.81 mmol), dppf(Pd)Cl2 (177 mg, 0.242 mmol), potassium carbonate (1.34 g, 9.68 mmol) in degassed toluene (4 mL), degassed water (2 mL) and degassed isopropanol (2 mL) was heated at 90° C. for 12 hours. The layers were separated, the organic layer was concentrated and the residue was purified by trituration with hexanes/ethyl acetate to provide 7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one as a white powder. C15H9F3N2O2. 307.2 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][C:18]([O:20]C2C=CC([N+]([O-])=O)=CC=2)=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][C:18](=[O:20])[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][OH:37])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCCCCO
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCO)OC1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of the carbonate (128.826 g, 0.322 moles) produced in Example 21 in 450 ml of methylene chloride was added dropwise under nitrogen to a solution of 6-amino-1-hexanol (56.6 g, 0.483 moles) and triethylamine (224.2 ml, 1.61 moles) in 2 L of methylene chloride at room temperature. After the addition the reaction was stirred overnight at room temperature. By TLC the reaction was not complete. An additional 37.7 g (0.322 moles) of 6-amino-1-hexanol and 224.2 ml (1.61 moles) of triethylamine were added and the stirring continued overnight. By TLC the reaction was complete. The reaction was extracted two times with 1N HCl, multiple times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 95.0 g (78%) of a yellow oil which crystallized on standing, mp 50-52° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=[O:20])[CH:6]=[C:7]([O:12]C)[C:8]=1[CH:9]([CH3:11])[CH3:10].Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][C:16]2[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=2)[C:19]([OH:21])=[O:20])[CH:6]=[C:7]([OH:12])[C:8]=1[CH:9]([CH3:11])[CH3:10]
Reactant: COc1cc(C=Cc2cccc(C(=O)O)c2)cc(OC)c1C(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1c(O)cc(C=Cc2cccc(C(=O)O)c2)cc1O
Yield: 86 %

Procedure:
This material was prepared from 3-[2-(3,5-dimethoxy-4-i-propylphenyl)ethenyl]benzoic acid 2B and pyridine hydrochloride in 86% yield in the same way as described in example 3. 1HNMR (DMSO-d6, ppm): δ 1.22 (d, J=7.0 Hz, 6H), 6.48 (s, 2H), 7.03 (d, J=17 Hz, 1H), 7.12 (d, J=17 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.7-7.9 (m, 2H), 8.06 (s, 1H), 9.12 (s, 2H).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([OH:35])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[CH2:19][O:18]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:42][N:43]([CH3:47])[C:44](Cl)=[O:45].C1(C)C=CC=CC=1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)(=O)C.CCCCCC>[C:1]([O:4][C@H:5]1[C@@H:31]2[O:32][C@@H:30]2[C@@:29]2([CH3:33])[C:7](=[CH:8][C@@H:9]([O:35][C:44](=[O:45])[N:43]([CH3:47])[CH3:42])[C@@H:10]3[C@@H:28]2[CH2:27][CH2:26][C@@:25]2([CH3:34])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[CH:15]([CH:17]2[O:18][CH2:19][C:20]([CH3:23])([CH3:24])[CH2:21][O:22]2)[CH3:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CN(C)C(=O)Cl
Reactant: CC(=O)O[C@@H]1CC2=C[C@@H](O)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1CC2=C[C@@H](OC(=O)N(C)C)[C@H]3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@H]2O[C@@H]12
Temperature: 60 °C
Reaction time: 10 h
Yield: 5.1 %

Procedure:
A mixture of 49.0 mg (0.1 mole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxy-7α-hydroxypregna-5-en-3β-yl acetate, 0.24 ml (3 mmoles) of pyridine, 0.5 mg (0.004 mmole) of 4-(dimethylamino)pyridine, 0.12 ml (1.3 mmoles) of N,N-dimethylcarbamoyl chloride and 10 ml of dry toluene was stirred at a temperature of 60° C. for 10 hours. The reaction mixture thus obtained was cooled to room temperature, diluted with 50 ml of methylene chloride, washed with water 3 times and finally washed with aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. Finally the residue was purified by silica gel chromatography (eluent:ethyl acetate-hexane=1:10, v/v) to recover 37 mg of 7α-(N,N-dimethylcarbamoyloxy)-20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-en-3β-yl acetate (yield: 70%).
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][C:31]1([CH3:38])[NH:36][CH2:35][CH2:34][NH:33][C:32]1=[O:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:36]4[CH2:35][CH2:34][NH:33][C:32](=[O:37])[C:31]4([CH3:38])[CH3:30])[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: CC1(C)NCCNC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCNC(=O)C3(C)C)n(C)c2n1
Reaction time: 16 h
Yield: 10.5 %

Procedure:
A solution of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (250 mg, 0.64 mmol), 3,3-dimethylpiperazin-2-one (100 mg, 0.78 mmol) and molecular sieves (4 Å, powdered, 1 g) in DCE (15 mL) was stirred at ambient temperature for 4 h. Sodium triacetoxyborohydride (204 mg, 0.96 mmol) was added and the mixture stirred for 16 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH, 100:0 to 98:2 to 95:5) to afford 649 as a yellow solid (34 mg, 11%). LCMS (method I): RT=3.12 min, M+H+=504. 1H NMR (CDCl3, 400 MHz) δ 8.02 (m, 1 H), 7.79 (m, 1 H), 7.30 (m, 2 H), 5.75 (bs, 1 H), 4.34 (m, 4 H), 3.94 (s, 2 H), 3.92 (s, 3 H), 3.87 (m, 4 H), 3.38 (q, J=7.4 Hz, 2 H), 3.23 (m, 2 H), 2.80 (m, 2 H), 1.54 (s, 6 H) and, 1.47 (t, J=7.4 Hz, 3 H)
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](O)=[O:7].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C>>[CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([N:25]([O:26][CH3:27])[CH3:24])=[O:7]
Reactant: CNOC
Reactant: CN(C)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cccc(N(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
To a stirred solution of 3-(dimethylamino)benzoic acid (16.5 g, 100 mmol), cooled to 0° C. with a brine/ice bath, was added N,N-dimethylformamide (0.39 mL, 5 mmol) followed by oxalyl chloride (10.5 mL, 120 mmol). The resulting mixture was stirred 4 h at room temperature, until gas evolution stopped and a clear solution was obtained. The mixture was cooled to 0° C. with a brine/ice bath, N,O-Dimethylhydroxylamine (13.7 g, 140 mmol) was added at once, followed by dropwise addition of triethylamine (55.8 mL, 400 mmol) through a dropping funnel, while keeping the internal temperature under 20° C. The resulting suspension was stirred overnight at room temperature, then washed with brine. The aqueous layers were extracted with dichloromethane (2×50 mL), then the combined organic layers were dried over MgSO4 and concentrated in vacuo to afford 3-(dimethylamino)-N-methoxy-N-methylbenzamide as an oil [15.5 g, yield 67%; HPLC/MS: m/z=209 (M+H); logP(HCOOH)=0.95].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[CH:17][C:4]=1[C:5]([O:7][CH2:8][P:9]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[O:10])=[O:6].[Br:21]Br>C(Cl)(Cl)Cl>[Br:21][C:20]1[C:3]([O:2][CH3:1])=[C:4]([CH:17]=[CH:18][CH:19]=1)[C:5]([O:7][CH2:8][P:9]([O:11][CH2:12][CH3:13])([O:14][CH2:15][CH3:16])=[O:10])=[O:6]
Reactant: CCOP(=O)(COC(=O)c1ccccc1OC)OCC
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(COC(=O)c1cccc(Br)c1OC)OCC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of diethylphosphonomethyl 2-methoxybenzoate (1 mmol) and bromine (100 mmol) in 10 mL CHCl3 was stirred at rt for 16 h. Extraction and chromatography provided diethylphosphonomethyl 3-bromo-2-methoxybenzoate as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH2:25][O:26][CH2:27][CH2:28]O)[CH:3]=1.[C:30]1(=[O:36])[NH:34][C:33](=[O:35])[CH2:32][CH2:31]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:23])=[O:16])=[C:11]([Cl:24])[CH:10]=2)=[C:4]([CH:3]=1)[CH2:25][O:26][CH2:27][CH2:28][N:34]1[C:33](=[O:35])[CH2:32][CH2:31][C:30]1=[O:36]
Reactant: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCO)cc1Cl
Reactant: O=C1CCC(=O)N1
Product: Cc1ccccc1C(=O)c1ccc(Nc2ccc(Br)cc2COCCN2C(=O)CCC2=O)cc1Cl

Procedure:
Compound 158 (47 mg, 0.1 mmol), succinimide (14 mg, 0.14 mmol) were treated as described in the preparation of compound 219. Purification was done by flash chromatography (petroleum ether/ethyl acetate 1:1) to provide the title compound as yellow oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[C:8]([O:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17])=[N:9][CH:10]=[CH:11][CH:12]=1>N1C=CC=CC=1>[Cl:6][C:7]1[C:8]([O:13][CH2:14][CH:15]([OH:18])[CH2:16][O:17][S:2]([CH3:1])(=[O:4])=[O:3])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC(O)COc1ncccc1Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(O)COc1ncccc1Cl
Temperature: 0 °C

Procedure:
25.2 g of methanesulphonic acid chloride are added dropwise over the course of 1 hour to a solution of 40.6 g of 3-chloro-2-(2',3'-dihydroxy-propoxy)-pyridine in 100 ml of pyridine whilst stirring and cooling at 0°-5° C. The reaction mixture is then stirred further for 5 hours at room temperature and is subsequently poured onto 200 ml of ice water. The oil which separates out is isolated as in Example (1b). Crude 3-chloro-2-(3'-methanesulphonyloxy-2'-hydroxy-propoxy)-pyridine is thus obtained and is converted further in the crude state.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[B-](F)(F)(F)[CH:14]=[CH2:15].[K+].C(=O)([O-])[O-].[Na+].[Na+]>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]>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:2]([CH:14]=[CH2:15])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C[B-](F)(F)F
Reactant: COC(=O)c1c(Cl)cccc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cccc(Cl)c1C(=O)OC
Temperature: 100 °C
Yield: 113.6 %

Procedure:
To a solution of methyl 2-bromo-6-chlorobenzoate (7.5 g, 0.03 mol) and potassium trifluoro(vinyl)borate (6.07 g, 0.045 mol) in dioxane and H2O (10:1, 100 mL) was added Pd(dppf)Cl2 (739 mg, 0.906 mmol), and sodium carbonate (6.4 g, 0.06 mol) at RT. The reaction mixture was heated at 100° C. for 12 hours under a nitrogen atmosphere. The mixture was subsequently concentrated in vacuo and diluted with water. The aqueous phase was extracted with EtOAc (3×100 mL). The organic layers were combined, washed with brine, dried over anhydrous Na2CO3, filtered, and concentrated. The crude product was purified by column chromatography eluting with a gradient of EtOAc (0-90%) and PE to give the title compound (6.7 g, 85%). 1H NMR (400 MHz, CDCl3) δ ppm 7.39-7.41 (m, 1H), 7.22-7.26 (m, 2H), 6.55-6.62 (m, 1H), 5.68 (d, J=17.2 Hz, 1H), 5.31 (d, J=11.2 Hz, 1H).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]([NH:15][C:16]1[N:21]=[C:20]([C:22]2[C:30]3[C:25](=[N:26][C:27]([NH:31][CH2:32][CH2:33][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)=[N:28][CH:29]=3)[NH:24][N:23]=2)[CH:19]=[CH:18][N:17]=1)[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)(C)(C)C.Cl>CCO>[N:34]1([CH2:33][CH2:32][NH:31][C:27]2[N:26]=[C:25]3[NH:24][N:23]=[C:22]([C:20]4[CH:19]=[CH:18][N:17]=[C:16]([NH:15][CH:9]([C:10]5[CH:14]=[CH:13][S:12][CH:11]=5)[CH2:8][NH2:7])[N:21]=4)[C:30]3=[CH:29][N:28]=2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1
Reactant: CC(C)(C)OC(=O)NCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1ccsc1
Agent: Cl
Solvent: CCO
Product: NCC(Nc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1)c1ccsc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(2-{4-[6-(2-Morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-ylamino}-2-thiophen-3-yl-ethyl)-carbamic acid tert-butyl ester (200 mg, 0.35 mmol) was dissolved in EtOH (4 mL), then conc. HCl (4 mL) was added. The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure to afford the crude product which was purified by prep-HPLC to afford N1-{4-[6-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-pyrimidin-2-yl}-1-thiophen-3-yl-ethane-1,2-diamine; hydrochloride. (Yield 17 mg, 8.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[C:16]([NH:23][CH3:24])[CH:15]=3)[C:10](=[O:25])[CH:9]=2)=[CH:4][CH:3]=1>CC(O)=O.[Zn]>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:9][C:10]2=[O:25])=[CH:15][C:16]=1[NH:23][CH3:24]
Reactant: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CNc1cc(-n2ccc(OCc3ccc(Cl)cc3)cc2=O)ccc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.7 %

Procedure:
Zinc (20.34 g) was added to a suspension of 4-((4-chlorobenzyl)oxy)-1-(3-(methylamino)-4-nitrophenyl)pyridin-2(1H)-one (12 g) in AcOH (200 ml) at room temperature. The mixture was stirred at room temperature for 1 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was neutralized with saturated NaHCO3 at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by NH silica gel column chromatography (MeOH/EtOAc) to give the title compound (5.5 g) as a pale orange solid.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[C:9]1(=O)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11][CH2:10]1.Cl>O.C1C=CC=CC=1.O1CCCC1.CCCCCC>[NH2:8][CH2:6][CH2:7][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:10][CH:11]=1
Reactant: CC#N
Reactant: O=C1CCCc2ccccc21
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: O
Product: NCCC1=CCCc2ccccc21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 107 g. (1.67 mole) of n-butyl lithium in 288 ml. of hexane was cooled to -78°C. and 240 ml. of tetrahydrofuran was added. A solution of 24 ml. (0.46 mole) of acetonitrile in 360 ml. of tetrahydrofuran was added over 20 minutes. After stirring for 1 hour at -78°C., a solution of 58.5 g. (0.40 mole) of 1-tetralone in 400 ml. of tetrahydrofuran was added over 15 minutes. The cold bath was removed and stirring was continued for another 15 minutes. Lithium aluminum hydride, 18 g. (0.48 mole), was added and the mixture was stirred at 24°C. for 3 hours. After cooling to 0°C., 18 ml. of water was added cautiously, followed by 13.5 ml. of 20% by weight of an aqueous solution of NaOH and 63 ml. of water. After stirring at 24°C. for 15 minutes, the inorganic salts were filtered off. The ether solution was extracted twice with 500 ml. portions and once with a 100 ml. portion of 10% by weight aqueous HCl. The aqueous layers were made basic by the addition of 25% by weight of NaOH in water and extracted three times with 500 ml. portions of ether to give a yellow oil. A benzene solution of the oil was saturated with HCl gas and refluxed under a water separator until water ceased to pass over. After cooling to 10°C., the crystalline hydrochloride salt of the product was collected in approximately 70 percent overall yield.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:30](O)[CH3:31]>>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)([C:14]([O:16][CH2:30][CH3:31])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCO
Reactant: Cc1cccc(NC2(C(=O)O)CCN(Cc3ccccc3)CC2)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1(Nc2cccc(C)c2)CCN(Cc2ccccc2)CC1

Procedure:
A mixture of 1-benzyl-4-(3-methylphenylamino)piperidine-4-carboxylic acid (3.81 g, 11.7 mmol) and concentrated sulfuric acid (2 mL) in absolute ethanol (80 mL) was heated under reflux overnight. The resultant solution was concentrated under vacuum, and the residue was treated with chloroform saturated with ammonia gas. The mixture was filtered, and the filtrate concentrated. The residue was passed through a small plug of silica gel eluting with chloroform saturated with ammonia gas. Collection and concentration of the eluent under vacuum provided the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH2:12][CH2:13][CH2:14][OH:15]>C(O)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:12][CH2:13][CH2:14][OH:15])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: NCCO
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(Br)cc1NCCO
Reaction time: 8 h
Yield: 101 %

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitrobenzene (I-19, Aldrich, Wis.; 25 g, 0.11 mol) and 2-aminoethanol (13.9 g, 0.23 mol, 2.0 eq.) in n-butanol (300 mL) was refluxed for 1 hour. The reaction mixture was concentrated and the residue was dispersed in petrol ether (600 mL) and stirred overnight. The solids were removed by filtration to give I-20 as a yellow powder (29 g, 98%). MS (ESI): m/z 262 (M+H+).
Reaction SMILES: C(NC(C)C)(C)C.C(O[B:12]([O:17][CH:18]([CH3:20])[CH3:19])[O:13][CH:14]([CH3:16])[CH3:15])(C)C.C([Li])CCC.[Cl:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1.OC(C(O)(C)C)(C)C.C(O)(=O)C>C(OCC)C>[Cl:26][C:27]1[S:28][C:29]([B:12]2[O:13][C:14]([CH3:15])([CH3:16])[C:18]([CH3:19])([CH3:20])[O:17]2)=[CH:30][N:31]=1
Reactant: Clc1nccs1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)(O)C(C)(C)O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Product: CC1(C)OB(c2cnc(Cl)s2)OC1(C)C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
Diisopropylamine (0.66 mL, 4.6 mmol) and triisopropylborate (1.26 mL, 5.44 mmol) were dissolved in 52 mL of anhydrous diethyl ether and then cooled to −90° C. n-Butyllithium (2.6 M in toluene, 1.77 mL, 4.6 mmol) was added slowly to the reaction and the mixture was stirred for 30 min. 2-Chlorothiazole (0.5 g, 4.18 mmol) was added and the reaction was allowed to gradually reach room temperature over 3 h. A solution of pinacol (0.69 g, 5.85 mmol) in 5 mL of diethyl ether was added. After 15 min, acetic acid (0.26 mL, 4.6 mmol) was added and the mixture was then filtered through Celite, rinsing with more diethyl ether. The filtrate was evaporated and the residue was distilled using a Kugelrohr apparatus at a temperature of 120-130° C. to give 0.84 g (82%) of 2-chloro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-thiazole.