Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.CCN(C(C)C)C(C)C.[C:28](O)(=[O:30])[CH3:29].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCOCC1.CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[CH:2][C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([NH:18][C:28](=[O:30])[CH3:29])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Nc1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc2nc(-c3ccccc3Cl)[nH]c2c1
Reaction time: 8 h

Procedure:
To a vial containing a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazol-5-ylamine in dioxane (0.2 M, 0.10 mL) was added DIPEA (0.5 M in toluene, 0.050 mL) and acetic acid (0.2 M in toluene, 0.12 mL), followed by BOP reagent (0.2 M in DMF, 0.15 mL). After overnight at ambient temperature, the mixture was then diluted by MeOH and the whole was loaded onto a solid phase extraction (SPE) cartridge that contained strong cation exchange (SCX) (1 g media in 6 mL cartridge, United Chemical Technology). Wash-to-waste (5 mL MeOH) was followed by elute-to-collect (5 mL 20:2:1 ethyl acetate-MeOH-Et3N) and, after evaporation of volatiles, the crude was further purified by silica gel column chromatography to N-[2-(2-Chloro-phenyl)-3H-benzoimidazol-5-yl]-acetamide: MS (m/z) 320.02 (M+1).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.[C:19]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH:31]=[C:30]([CH3:32])[C:29](=[O:33])[N:28]([CH2:34][CH2:35][CH2:36][Cl:37])[C:27]2=[O:38])[CH:20]=1>>[ClH:37].[C:19]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]2[CH:31]=[C:30]([CH3:32])[C:29](=[O:33])[N:28]([CH2:34][CH2:35][CH2:36][N:14]3[CH2:15][CH2:16][N:11]([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][C:2]([F:1])([F:17])[F:18])[CH2:12][CH2:13]3)[C:27]2=[O:38])[CH:20]=1
Reactant: FC(F)(F)COc1ccccc1N1CCNCC1
Reactant: Cc1cn(Cc2cccc(-c3ccccc3)c2)c(=O)n(CCCCl)c1=O
Product: Cc1cn(Cc2cccc(-c3ccccc3)c2)c(=O)n(CCCN2CCN(c3ccccc3OCC(F)(F)F)CC2)c1=O
Product: Cl

Procedure:
substituting 1-(2-(2,2,2-trifluoroethoxy)phenyl]piperazine and 1-biphenyl-3-ylmethyl-3-(3-chloropropyl)-5-methyl-2,4(1H,3H)-pyrimidinedione gave 1-biphenyl-3-ylmethyl-3-(3-{4-[2-(2,2,2-trifluoroethoxy)phenyl]piperazin-1-yl}-propyl)-5-methyl-2,4(1H,3H)-pyrimidinedione hydrochloride, m.p. 93°-94° C.; Anal.: Calcd. for C33H35F3N4O3.HCl: C, 63.06; H, 5.77; N, 8.92%; Found: C, 61.66; H, 5.90; N, 8.50%;
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][CH2:12][CH:13]=O)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[OH2:15].[CH2:16]1[CH2:20][O:19][CH2:18][CH2:17]1>>[Si:3]([O:10][C:11]1[CH:12]=[C:13](/[C:11](/[CH2:12][CH3:13])=[CH:17]/[C:18]([O:19][CH2:20][CH3:16])=[O:15])[CH:7]=[CH:6][CH:8]=1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: O
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C=C(\CC)c1cccc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
22.5 ml (113 mmol) of triethyl phosphono-acetate are dissolved in 100 ml of THF. 4.5 g (113 mmol) of 60% sodium hydride are then added, and the medium is stirred for 30 minutes at ambient temperature. A solution of 20 g (75.6 mmol) of 3-(tert-butyldimethylsilanyloxy)propan-1-one in 100 ml of THF is then added drop by drop. The medium is stirred for 6 hours, then treated with water and extracted with ethyl acetate. The residue obtained is purified by chromatography on silica gel (eluent ethyl acetate 10-heptane 90). A yellow oil is obtained (m=7.6 g; Y=30%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH:6]=[N:7]O)([O-])=O.C(O)(=O)C.[H][H].[OH-].[Na+]>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][NH2:7]
Reactant: O=[N+]([O-])c1ccccc1C=NO
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: NCc1ccccc1N
Reaction time: 7 h
Yield: 79.4 %

Procedure:
16.6 g (0.1 mol) of this o-nitrobenzaldoxime, 0.83 g of a 5% Pd-C catalyst, 12 g (0.2 mol) of glacial acetic acid and 100 ml of tetrahydrofurane were charged into a hermetically sealed glass container and stirred vigorously while charging hydrogen. Reaction was continued at temperatures of 25°-35° C. for 7 hours. After the reaction, the resulting mixture was filtered to remove the catalyst, was added with 8 g (0.2 mol) of sodium hydroxide and was subject to distillation. Thus, 9.7 g of o-aminobenzylamine was obtained. Yield 79.4%; Purity 99.4%; B.P. 91°-93° C./1 mmHg. M.P. 58°-61° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1B(O)O>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:22]1[CH:21]=[CH:20][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc4ccccc4c3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-naphthaleneboronic acid to give (6-methoxy-1-naphthalen-2-yl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 367(MH+).
Reaction SMILES: [C:1]([C@@H](C)C(N)(N)C(O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.[OH2:23].O[N:25]1[C:29]2C=C[CH:32]=[CH:33][C:28]=2[N:27]=N1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:27][C@H:28]1[CH2:33][CH2:32][NH:25][C:29]1=[O:23])([CH3:5])([CH3:6])[CH3:7]
Reactant: O
Reactant: C[C@H](C(=O)OC(C)(C)C)C(N)(N)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCNC1=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
(S)-Boc-Diaminobutyric acid (25 g, 115 mmol), triethylamine (35 g, 344 mmol), and 1-hydroxybenzotriazole hydrate (19.3 g, 143 mmol) are dissolved in 300 mL of THF. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (27.4 g, 143 mmol) is added to the solution. The solution is heated at 60° C. over 15 min. A white precipitate forms and the solution is kept at 60° C. for 4 h. After this time, the solution is filtered and the collected liquid is concentrated. The crude product is purified by column chromatography eluting with a gradient of 1% MeOH/CH2Cl2 to 3% MeOH/CH2Cl2 to afford the title compound (19.6 g, 98 mmol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[CH:10]=[C:9]([CH2:11][N:27]3[CH2:28][CH2:29][CH:24]([N:23]([CH2:22][CH2:21][O:20][CH3:19])[CH3:30])[CH2:25][CH2:26]3)[S:8][C:6]=2[N:7]=1
Reactant: COCCN(C)C1CCNCC1
Reactant: O=Cc1cc2c(N3CCOCC3)nc(Cl)nc2s1
Product: COCCN(C)C1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1

Procedure:
(2-Chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidine-6-carboxaldehyde) was reacted with (2-methoxy-ethyl)-methyl-piperidin-4-yl-amine using standard reductive amination conditions to give [1-(2-chloro-4-morpholin-4-yl-thieno[2,3-d]pyrimidin-6-ylmethyl)-piperidin-4-yl]-(2-methoxy-ethyl)-methyl amine as a solid, which was reacted with 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine according to General Procedure A. The resulting solid was triturated with diethyl ether and methanol to give 366 as an off white solid (53% yield). NMR (CDCl3, 400 MHz), 1.59-1.70 (2H, m), 1.78-1.81 (2H, m), 2.10 (2H, t, J=12.3), 2.37 (3H, s), 2.42-2.48 (1H, m), 2.70 (2H, t, J=5.9), 3.07 (2H, d, J=11.3), 3.41 (3H, s), 3.49-3.54 (2H, m), 3.78 (2H, s), 3.92-3.94 (4H, m), 3.97-4.00 (4H, m), 4.67 (2H, br s), 6.60 (1H, d, J=8.9), 7.13 (1H, s), 8.51 (1H, dd, J=8.6 and 2.2), 9.20 (1H, d, J=1.6). MS: (ESI+): MH+=498
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].C(N(CC)CC)C.[Br:12][C:13]([CH3:18])([CH3:17])[C:14](Br)=[O:15].O>O1CCCC1>[Br:12][C:13]([CH3:18])([CH3:17])[C:14]([O:3][CH2:2][CH2:1][OH:4])=[O:15]
Reactant: CC(C)(Br)C(=O)Br
Reactant: OCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(Br)C(=O)OCCO
Reaction time: 16 h
Yield: 85.3 %

Procedure:
Anhydrous ethylene glycol (301.3 g, 4.85 mol) and triethylamine (28 mL, 200 mmol) were diluted with dry tetrahydrofuran (100 mL). The reaction mixture was cooled in an ice-water bath and a solution of α-bromoisobutyryl bromide (12 mL, 97.1 mmol) in dry tetrahydrofuran (50 mL) was slowly added while stirring. The mixture was stirred in the cooling bath for 1 h and then at room temperature for 16 h. The reaction mixture was then poured into water (800 mL) and extracted with dichloromethane (6×100 mL). The organic fractions were combined, washed with acidic water (pH=4), dried over MgSO4 and evaporated to dryness to afford 17.477 g (yield=85.3%) of a very pale yellow liquid. 1H NMR (CDCl3, δ, ppm): 4.30-4.19 (m, 2H), 3.86-3.75 (m, 2H), 2.86-2.47 (broad peak, 1H, OH), 1.89 (s, 6H). 13C NMR (CDCl3, δ): 171.95, 67.40, 60.63, 55.89, 30.72.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[C:36]([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:38]2=[O:51])=[CH:35][C:31]2[CH2:32][CH2:33][O:34][C:30]=2[CH:29]=1>>[OH:27][C:28]1[C:36]([C:37]2([CH2:5][OH:16])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])[C:38]2=[O:51])=[CH:35][C:31]2[CH2:32][CH2:33][O:34][C:30]=2[CH:29]=1
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCC3)c2ccccc21
Product: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCC3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 3-(6-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (46%): MS (ES+) m/z 368.3 (M+1), 380.4 (M+23).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:27]1[CH:31]=[CH:30][S:29][C:28]=1[C:32]([O:34][CH3:35])=[O:33]>C1COCC1.C(Cl)Cl.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:35][O:34][C:32]([C:28]1[S:29][CH:30]=[CH:31][C:27]=1[C:11]1[CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][CH:10]=1)=[O:33]
Reactant: COC(=O)c1sccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnc(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1sccc1-c1cnnc(-c2ccccc2)c1
Temperature: 150 °C
Yield: 12 %

Procedure:
3-Phenyl-5-(tri-n-butylstannyl)pyridazine (50 mg, 0.11 mmol), methyl 3-bromothiophene-2-carboxylate (30 mg) and Pd(PPh3)4 (5 mg) in THF (2 ml) were combined and heated to 150° C. for 600 seconds in a Smith Synthesizer microwave reactor. The reaction was diluted with CH2Cl2 (6 ml) and H2O (2 ml) then poured into PTFE (5 μM) fritted syringe barrels. The organic phase was collected and concentrated to leave 85 mg of crude product. Part of the sample was purified by HPLC with mass triggered collection of fractions to give the title compound (3.9 mg). δH (400 MHz, d6 DMSO) 3.73 (3H, s), 7.52-7.62 (4H, m), 8.10 (1H, d, J 8.0), 8.22 (2H, dd, J 1.6 and 8.0), 8.35 (1H, d, J 4.0), 9.33 (1H, d, J 4.0); m/z (ES+) (MH+) 297.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([OH:21])=[CH:18][CH:19]=4)[C:14]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:13]3[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:30](Cl)=[C:31](Cl)Cl.[CH3:35]N(C)C=O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[C:20]4[C:15](=[CH:16][C:17]([O:21][CH2:35][CH2:30][CH3:31])=[CH:18][CH:19]=4)[C:14]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:13]3[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: ClC(Cl)=C(Cl)Cl
Reactant: CCOC(=O)Cc1c(C)n(-c2ncnc3cc(Cl)ccc23)c2ccc(O)cc12
Reactant: CN(C)C=O
Product: CCCOc1ccc2c(c1)c(CC(=O)OCC)c(C)n2-c1ncnc2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of ethyl 1-(7-chloroquinazolin-4-yl)-5-hydroxy-2-methylindol-3-ylacetate (1.0g.) in dry dimethyl-formamide (10ml.); dried by distillation from calcium hydride, and stored over sodium alumino-silicate) was added to sodium hydride (0.068g.), and the mixture was stirred under a slight vacuum (ca 150mm. Hg) at room temperature for 15 minutes. n-Propyl iodide (0.9g.) was added to the resulting clear solution, and the mixture stirred at room temperature overnight. The solution was added to water (300ml.) and extracted with ethyl acetate (3 × 40ml.). The combined extracts were washed with a saturated solution of sodium chloride (30ml.), dried (MgSO4), and then evaporated in vacuo. The yellow oil thus obtained was treated with tetrachloroethylene (100ml.) and the solution evaporated in vacuo. This process was then replaced with ethanol (50ml.) to give ethyl 1-(7chloroquinazolin-4-yl)-2-methyl-5-n-propoxyindol-3-ylacetate as a stiff yellow syrup [NMR: 2-CH3 at 7.65 τ; pure by TLC (systems A and D)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])[N:13]=1.C(N(CC)CC)C.[CH3:38][CH:39]([CH3:46])[CH2:40][CH2:41][S:42](Cl)(=[O:44])=[O:43].O>ClCCl>[CH3:38][CH:39]([CH3:46])[CH2:40][CH2:41][S:42]([O:30][C:27]1[CH:26]=[CH:25][C:24]([N:10]2[C:11]([CH3:23])=[C:12]([C:14]([NH:16][N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:15])[N:13]=[C:9]2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])=[CH:29][CH:28]=1)(=[O:44])=[O:43]
Reactant: CC(C)CCS(=O)(=O)Cl
Reactant: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(OS(=O)(=O)CCC(C)C)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
2-(2,4-Dichlorophenyl)-1-(4-hydroxyphenyl)-5-methyl-N-piperidin-1-yl-1H-imidazole-4-carboxamide, prepared as described in Ex. 2, Step 1 (50 mg, 0.11 mmol) was dissolved in dichloromethane (3.0 ml), cooled to 0° C. and triethylamine (20 μl, 0.13 mmol) was added to the mixture. The resulting mixture was cooled to −78° C. and 3-methylbutane-1-sulfonyl chloride (23 mg, 0.13 mmol) was carefully added. The reaction was stirred at −78° C. for 1.5 h. Water was added to the reaction, the product extracted with dichloromethane and dried. The solvent was removed under reduced pressure and separation by preparatory HPLC gave the title compound (46 mg, 71%) as a solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=[CH2:7].CC[C@H]1[C@H]2C[C@H]([C@H](OC3C4C(=CC=CC=4)C(O[C@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:38]C)C=C4)N(CC2)C1.S([O-])([O-])=O.[Na+].[Na+].[OH2:81]>CC(O)(C)C>[F:1][C:2]([F:15])([F:16])[C:3]1[CH:4]=[C:5]([C@H:6]([OH:38])[CH2:7][OH:81])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1
Reactant: CC[C@@H]1CN2CC[C@@H]1C[C@@H]2[C@H](Oc1nnc(O[C@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: C=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: OC[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C

Procedure:
3,5-Bis(trifluromethyl)styrene (13 g) was dissolved in a mixture of water (270 ml) and 2-methylpropan-2-ol (270 ml) and cooled to 0° C. AD-mix-α (76 g) was added in one portion and the reaction left to warm to room temperature over 72 hours. The mixture was then cooled to 0° C., sodium sulfite (81 g) added and the reaction mixture extracted into ethyl acetate (3×250 ml). The combined organics were dried (brine, MgSO4) and concentrated under reduced pressure to afford the product as a crude orange solid which was purified on silica eluting with 35% ethyl acetate/iso-hexane to afford the product as a crystalline white solid (chiral hplc, ee 92.2%). This was recrystallised from toluene to give the title compound as a white fibres (chiral hplc, ee 96.2%).
Reaction SMILES: O.[ClH:2].[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[C:10]([O:14][C:15](=[O:18])[NH:16][NH2:17])([CH3:13])([CH3:12])[CH3:11]>CO>[ClH:2].[C:10]([O:14][C:15]([NH:16][N:17]=[C:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1)=[O:18])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C1CCNCC1
Reactant: CC(C)(C)OC(=O)NN
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NN=C1CCNCC1
Temperature: 25 °C

Procedure:
A mixture of 4-piperidone hydrochloride monohydrate (31.2 g, 203 mmol) and tert-butylcarbazate (26.8 g, 203 mmol) in 100 mL MeOH is stirred over weekend at RT and then concentrated in vacuo. The residue is crystallized from ethyl acetate. Yield: 47.5 g.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24]Br)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:28]1([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:34][CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5]([C:7]1([CH2:21][CH2:22][CH2:23][CH2:24][N:31]2[CH2:32][CH2:33][CH2:34][N:28]([C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)[CH2:29][CH2:30]2)[C:20]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:14][C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2Oc2ccccc21
Reactant: c1ccc2nc(N3CCCNCC3)ccc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCCN(c3ccc4ccccc4n3)CC2)c2ccccc2Oc2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-xanthene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[1.4]diazepan-1-yl-quinoline.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH2:25]([NH:32][C:33]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][C:36]=1[O:44][CH3:45])=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:25]([NH:32][C:33](=[O:34])[C:35]1[CH:40]=[CH:39][C:38]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=2)=[CH:37][C:36]=1[O:44][CH3:45])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: COc1cc(B(O)O)ccc1C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1C(=O)NCc1ccccc1

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (141 mg, 0.319 mmol), 4-[(benzylamino)carbonyl]-3-methoxyphenylboronic acid (100 mg, 0.351 mmol), palladium tetrakistriphenyphosphine (22 mg, 0.019 mmol) and sodium carbonate (81 mg, 0.765 mmol) were mixed with ethylene glycol dimethyl ether (4 mL) and water (2 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give cis-N1-benzyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxybenzamide (126 mg, 71%). 1H NMR (CDCl3) δ 1.83 (m, 6H), 2.34 (s, 3H), 2.45 (m, 11H), 4.02 (s, 3H), 4.43 (d, J=5.66 Hz, 2H), 4.95 (m, 1H), 5.52 (bs, 2H), 7.37 (m, 7H), 8.18 (m, 1H), 8.41 (m, 1H); LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+ =555.5, Rt=2.65 min.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([CH:16]([CH3:18])[CH3:17])=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7]>CO.O>[OH:3][C:4]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([CH:16]([CH3:18])[CH3:17])=[CH:10][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cc(C(C)C)c(OC)cc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(O)c(C(=O)O)cc1C(C)C
Temperature: 25 °C
Yield: 69.6 %

Procedure:
Aqueous potassium hydroxide (50% w/v, 0.2 ml) was added to a suspension of methyl 2-hydroxy-5-isopropyl-4-methoxybenzoate (420 mg, 1.88 mmol) in methanol (5 ml) and water (2 ml) and the mixture was stirred and held at reflux for 3 hours. Upon cooling to room temperature the organic solvent was removed in vacuo and the residue acidified by the addition of 2M hydrochloric acid (10 ml). The solid material was collected by suction filtration, rinsed with water (2×10 ml) and sucked dry under reduced pressure to afford 2-hydroxy-5-isopropyl-4-methoxybenzoic acid (275 mg, 70%) as a colourless solid. 1H NMR (DMSO-d6) 13.50 (1H, br s), 11.40 (1H, br s), 7.53 (1H, s), 6.51 (1H, s), 3.83 (3H, s), 3.12 (1H, m), 1.13 (6H, d). MS: [M+H]+ 211.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C@@H:7]2[CH2:12][CH2:11][CH2:10][N:8]2[CH3:9])[CH:4]=[CH:3][CH:2]=1.[Br:13][CH2:14][CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH3:21]>CC(O)=O>[Br-:13].[CH3:9][N:8]1[CH2:10][CH2:11][CH2:12][C@H:7]1[C:5]1[CH:6]=[N+:1]([CH2:14][CH2:15][C:16]#[C:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:2]=[CH:3][CH:4]=1
Reactant: CCCCC#CCCBr
Reactant: CN1CCC[C@H]1c1cccnc1
Solvent: CC(=O)O
Product: CCCCC#CCC[n+]1cccc([C@@H]2CCCN2C)c1
Product: [Br-]
Yield: 56.9 %

Procedure:
To a stirred solution of (S)-nicotine (0.41 g, 2.5 mmol) in AcOH (10 ml) was added 1-bromo-oct-3-yne (1.16 g, 6.14 mmol). The mixture was heated at reflux for 3 days. AcOH was evaporated and the residue was dissolved in CHCl3. The mixture was washed with saturated aqueous NaHCO3, water and brine successively and dried. Evaporation of the solvent followed by titration with ether afforded 0.50 g (56%) of (S)-3-(1-methyl-pyrrolidin-2-yl)-1-oct-3-ynyl-pyridinium bromide (NONB-3y) as a brown oil. 1H NMR (300 MHz, CDCl3) δ 9.74 (1H, d, J=5.1 Hz), 9.15 (1H, s), 8.43 (1H, d, J=7.8 Hz), 8.04 (1H, dd, J=7.8, 5.1 Hz), 5.13 (2H, m), 3.51 (1H, t, J=7.8 Hz), 3.23 (1H, m), 3.00 (2H, m), 2.42 (2H, m), 2.22 (3H, s), 2.01 (2H, m), 1.89 (2H, m), 1.64 (2H, m), 1.28 (4H, m), 0.82 (3H, t, J=7.2 Hz); 13C NMR (75 MHz, CDCl3) δ 145.97, 144.38, 144.10, 143.57, 128.00, 86.12, 74.07, 67.30, 60.72, 56.92, 40.74, 36.11, 30.94, 23.14, 22.50, 22.16, 18.54, 13.80; Anal. Calcd for C18H27BrN2.0.5H2O: C, 60.00; H, 7.83; N, 7.77. Found: C, 60.15; H, 7.92; N, 6.92.