Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.[Cl:16][C:17]1[N:25]=[C:24]2[C:20]([NH:21][CH:22]=[N:23]2)=[C:19]([NH2:26])[N:18]=1>CN(C=O)C>[Cl:16][C:17]1[N:25]=[C:24]2[C:20]([N:21]=[CH:22][N:23]2[CH2:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[C:19]([NH2:26])[N:18]=1
Reactant: Nc1nc(Cl)nc2nc[nH]c12
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)nc2c1ncn2Cc1cccnc1
Temperature: 80 °C

Procedure:
Potassium carbonate (1.1 g, 8 mmol) and 3-chloromethylpyridine hydrochloride (660 mg, 5 mmol) were added to a DMF solution (30 ml) comprising 2-chloroadenine (520 mg, 3 mmol), and the resultant was stirred while heating at 80° C. for 3 hours. The reaction solution was concentrated under reduced pressure, water was added thereto, and the precipitated solid was collected by filtration. Thus, 2-chloro-9-(3-pyridylmethyl)adenine was obtained (yield: 759 mg). Sodium (750 mg, 30 mmol) was added to butanol (50 ml), and the temperature of the mixture was raised to 90° C. to completely dissolve sodium therein. Subsequently, 2-chloro-9-(3-pyridylmethyl)adenine (430 mg, 1.5 mmol) was added thereto, and the resultant was heated under reflux for 2 hours. The solvent was concentrated under reduced pressure, water was added to the residue, and concentrated hydrochloric acid was added dropwise under ice cooling to neutralize the solution. Liquid separation was carried out with the addition of methylene chloride, and the organic layer was concentrated under reduced pressure. Acetic acid (30 ml) was added to the residue to dissolve it, bromine (660 mg, 5.5 mmol) was added thereto, and the resultant was allowed to react at room temperature all day and night. The reaction solution was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1). Thus, 310 mg of 8-bromo-2-butoxy-9-(3-pyridylmethyl)adenine was obtained. Subsequently, the title compound was obtained in the same manner as in Reference Example 3 and Example 1.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[C:22](=[O:28])[CH2:21][CH2:20]3)[CH:16]=1)(C)(C)C.[ClH:30].O1CCOCC1>CO>[ClH:30].[NH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH3:27])[C:22](=[O:28])[CH2:21][CH2:20]3)[CH:14]=[N:13][CH:12]=1
Reactant: CN1C(=O)CCc2cc(-c3cncc(OCCNC(=O)OC(C)(C)C)c3)ccc21
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CN1C(=O)CCc2cc(-c3cncc(OCCN)c3)ccc21
Temperature: 25 °C
Yield: 91 %

Procedure:
To a solution of {2-[5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-yloxy]-ethyl}-carbamic acid tert-butyl ester (example 39, 0.06 g, 0.151 mmol) in MeOH (1 mL) was added 4M HCl in dioxane (0.151 mL, 0.604 mmol) and the reaction mixture was stirred at room temperature over night. The resulting suspension was filtered off and the solid material was triturated in diethyl ether, filtered off and further dried in a high vacuum to give the title compound (0.046 g, 91%) as a white solid. MS: 298.3 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:16]3[N:15]=2)[C:5]([OH:8])=[N:6][CH:7]=1.[H-].[Li+].Br[CH2:30][C@H:31]([CH3:44])[CH2:32][N:33]1[C:41](=[O:42])[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]1=[O:43]>CN(C=O)C.CCOC(C)=O>[O:43]=[C:34]1[C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41](=[O:42])[N:33]1[CH2:32][C@@H:31]([CH3:44])[CH2:30][N:6]1[CH:7]=[C:2]([F:1])[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:16]3[N:15]=2)[C:5]1=[O:8]
Reactant: C[C@@H](CBr)CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cnc3O)nc12
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(C[C@H](C)CN4C(=O)c5ccccc5C4=O)c3=O)nc12
Temperature: 70 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
To a solution of (R)-methyl 5-(2-(5-fluoro-2-hydroxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (202 mg, 0.565 mmol) in DMF (5 mL) was added lithium hydride (22.5 mg, 2.83 mmol) and (R)-2-(3-bromo-2-methylpropyl)isoindoline-1,3-dione (prepared according to the procedure described in Euro. J. Med. Chem. 2000, 147-156) (239 mg, 0.848 mmol). The reaction was stirred for 2 hours at 70° C., and then cooled to ambient temperature. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (2×10 mL). The organic layer was dried with Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica column chromatography, eluting with 66% EtOAc/Hexanes to afford the product (110 mg, 34.8% yield). MS (apci) m/z=559.0 (M+H).
Reaction SMILES: [C@H:1]1([NH2:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CO[CH:13]=[CH:14][CH:15]=[C:16]([C:21]([O:23][CH3:24])=[O:22])[C:17]([O:19][CH3:20])=[O:18]>C1COCC1>[C@H:1]1([NH:10][CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:21]([O:23][CH3:24])=[O:22])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: COC=CC=C(C(=O)OC)C(=O)OC
Solvent: C1CCOC1
Product: COC(=O)C(=CC=CN[C@@H]1CCc2ccccc21)C(=O)OC
Temperature: 65 °C
Yield: 97.4 %

Procedure:
A 500 ml round-bottom flask was charged with 5.0 g (1.0 eq.) (R)-2,3-dihydro-1H-inden-1-amine and 7.5 g (1.0 eq.) dimethyl 2-(3-methoxyallylidene)malonate in 120 ml dry THF. The mixture was heated at 65° C. under N2 for 3 hrs. Then the solvent was removed in vacuo, and the crude mixture was purified by silica gel flash column chromatography to afford (R)-dimethyl 2-(3-(2,3-dihydro-1H-inden-1-ylamino)allylidene)malonate as a yellow solid (11.0 g) in 97% yield.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH:9]1(O)[CH2:13][CH2:12][CH2:11][CH2:10]1.P(=O)(O)(O)O>O.C(OCC)(=O)C>[CH:9]1([C:6]2[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=2[OH:5])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OC1CCCC1
Reactant: Oc1cccc(O)c1
Agent: O=P(O)(O)O
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(C2CCCC2)c(O)c1
Temperature: 120 °C
Reaction time: 2.5 h

Procedure:
A round bottom flask equipped with stirrer bar was charged with resorcinol (150 g, 1.36 moles), cyclopentanol (125 ml, 1.38 moles) and phosphoric acid (85% in water) 500 ml. The flask was fitted with a reflux condenser, purged with nitrogen and the mixture heated at 120° C. (oil bath temperature) for 26 h. After this time, TLC analysis indicated that starting resorcinol was still present. Further cyclopentanol (25 ml, 0.28 moles) was added to the reaction mixture and heating continued for 2.5 hours. On cooling, the mixture was diluted with water (500 ml) and ethyl acetate (600 ml). The organic layer was separated, and the aqueous layer extracted with ethyl acetate (3×500 ml). The combined organic layers were neutralized by careful addition of an excess of saturated aqueous sodium hydrogen carbonate solution, washed with brine (300 ml), dried (magnesium sulfate) and concentrated. The residue was dissolved in toluene (500 ml) and water (20 ml, 1.11 moles, 0.8 eq) added. The solution was stirred for ca. 30 s and cooled in an ice/water batch with periodic stirring. After 4 h the solid was filtered and left to air dry in a crystallizing dish for 16 h to give colored crystals. Recrystallization in toluene afforded the monohydrate form of 4-cyclopentylresorcinol as white plates. An anhydrous toluene solution of 4-cyclopentylresorcinol was prepared via azeotropic distillation. The solution was cooled, and pentane added. Anhydrate A was obtained by filtration. MPt 65-66.5° C. Selected IR Data (υmax/cm−1): 1108.3 s, 1094.7 m, 977.8 s, 971.1 s, 930.4 w, 838.3 m, 826.7 s, 799.8 w, 748.1 w and 628.0 w.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C@H:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C@H:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[NH:15][S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])=[CH:8][CH:9]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)S(=O)(=O)N[C@@H]1CCC[C@@H]1c1ccc(N)cc1

Procedure:
(+,−) Cis propane-2-sulfonic acid [2-(4-nitro-phenyl)-cyclopentyl]-amide (200 mg, 0.64 mmol, prepared in example 22) was dissolved in 25 mL of ethanol and hydrogenated over 25 mg of 5% Pd/C at room temperature overnight at 413.69 kPa (60 psi). The solution was filtered through celite and concentrated in vacuo to 142 mg (78%) of a colorless oil which was used directly.
Reaction SMILES: [NH2:1][C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[C:14]([OH:17])(=[O:16])C>>[CH2:3]([O:17][C:14]([O:10][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][C@H:2]([C:11]([OH:13])=[O:12])[NH2:1])=[CH:9][CH:8]=1)=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)O
Reactant: N[C@H](Cc1ccc(O)cc1)C(=O)O
Product: N[C@H](Cc1ccc(OC(=O)OCc2ccccc2)cc1)C(=O)O

Procedure:
This compound was prepared from D-tyrosine (1.02 g) in the same manner as the L-isomer as described by Overell and Petrow, J. Chem. Soc. 232 (1955); yield, 0.73 g (40%); mp 208°-210° decn; tlc (BAW) Ff 0.55; [α]D24 +9.1 (c 2.14, 80% acetic acid).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:31]=[CH:30][C:9]([CH2:10][N:11]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1)=[O:4].[CH3:32][NH:33][CH3:34]>C(Cl)Cl.C1COCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:11]([CH2:10][C:9]2[CH:30]=[CH:31][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:33]([CH3:34])[CH3:32])=[CH:7][CH:8]=2)[C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CNC
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(NC(=O)CBr)cc1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(NC(=O)CN(C)C)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (2R)-2-[[4-(2-bromo-acetylamino)-benzyl]-(4-chlorobenzenesulfonyl)-amino]-4-methyl-pentanoic acid amide (41 mg, 0.77 mmol) in CH2Cl2 (2 mL) was added excess 2.0 M dimethylamine in THF. The reaction mixture was stirred overnight. The solvent was removed in vacuo. Purification by flash chromatography (SiO2, 10% MeOH/CH2Cl2) afforded the title compound (24 mg) in 63% yield. MS (ESI), (M+H)+ 495.14, 1H NMR (CDCl3, 400 MHz) δ 8.85 (s, 1H), 8.02 (d, 2H, J=8.0), 7.75 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 7.29 (d, 2H, J=8.0), 6.23 (br s, 1H), 5.39 (br s, 1H), 4.62 (m, 4H), 3.25 (t, 1H, J=6.0), 2.95 (s, 6H), 1.95 (m, 1H), 1.60 (m, 2H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0)
Reaction SMILES: N.C([O:5][CH2:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:12][CH:11]=1)=[O:8])(=O)C>CO>[OH:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:17]([CH3:23])[NH:18][C:19](=[O:22])[NH:20][N:21]=2)=[CH:14][CH:15]=1)=[O:8]
Reactant: CC(=O)OCC(=O)Nc1ccc(C2=NNC(=O)NC2C)cc1
Agent: N
Solvent: CO
Product: CC1NC(=O)NN=C1c1ccc(NC(=O)CO)cc1
Reaction time: 2 h
Yield: 51.5 %

Procedure:
Concentrated ammonia (1.5 ml) was added to a stirred solution of 6-(4-acetoxyacetylaminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.85 g) in methanol (15 ml) and the stirring was continued for 2 hours at room temperature. The resulting precipitates were collected by filtration and recrystallized from 70% aqueous ethanol to give 6-[4-(2-hydroxyacetylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.377 g).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[CH3:30][O:31][C:32](=[O:37])[CH2:33][CH2:34][CH2:35][NH2:36].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>O1CCCC1>[CH3:30][O:31][C:32](=[O:37])[CH2:33][CH2:34][CH2:35][NH:36][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])[CH2:10][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:28])=[CH:20][CH:21]=1
Reactant: COC(=O)CCCN
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: COC(=O)CCCNC(=O)c1ccc(C(CC(=O)c2ccc(=O)n(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with methyl-4-aminobutyrate hydrochloride using BOP reagent in tetrahydrofuran to give the title compound as a colorless foam, MS (ESI+): m/z=475.1 [M+H]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][NH2:12].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.CCN(C(C)C)C(C)C.C([N:44]=[C:45]=[S:46])(=O)C1C=CC=CC=1>ClCCl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][NH:12][C:45]([NH2:44])=[S:46]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: NCCc1nc2ccccc2[nH]1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=S)NCCc1nc2ccccc2[nH]1
Reaction time: 1 h
Yield: 86 %

Procedure:
{2-(1H-Benzimidazol-2-yl)ethylamine was made as the dihydrochloride salt according to a procedure described by Nicolaou et al. Bioorg. Med. Chem., 1998, 6, 1185-1208 and pretreated with DIPEA (2.07 mL, 11.86 mmol) for 5 minutes.} To a suspension of 2-(1H-benzimidazol-2-yl)ethylamine (1.39 g, 5.93 mmol) in dichloromethane (20 mL) was added benzoyl isothiocyanate (0.88 mL, 6.52 mmol). After 1 h, the reaction mixture was concentrated in vacuo. Ammonia in methanol (7N, 30 mL) was then added and the reaction stirred another 4 h. The excess ammonia and methanol were removed in vacuo and dichloromethane (15 mL) was added. The solid was removed by filtration and the filtrate concentrated in vacuo and purified by flash chromatography (methanol/dichloromethane, 5% then 10%) to give the title compound as a solid (1.12 g, 86% yield).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3]1.Cl[CH2:26][C:27]1[CH:28]=[CH:29][C:30]2[O:35][CH2:34][C:33](=[O:36])[N:32]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:31]=2[CH:42]=1>>[CH3:17][O:16][C:14]([C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:3][CH:2]2[O:1][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][C:33](=[O:36])[N:32]([CH2:37][CH2:38][CH2:39][O:40][CH3:41])[C:31]=3[CH:42]=2)=[CH:13][CH:12]=1)=[O:15]
Reactant: COCCCN1C(=O)COc2ccc(CCl)cc21
Reactant: COC(=O)c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(C(=O)OC)cc3)cc21

Procedure:
Analogously to Method D, 1.180 g of tert-butyl 3-hydroxy-4-(4-methoxycarbonylphenyl)piperidine-1-carboxylate and 1.016 g of 6-chloromethyl-4-(3-methoxypropyl)-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as a colourless oil. Rf=0.20 (3:1 EtOAc-heptane); Rt=5.12.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[CH:4][C:5]2[CH2:10][O:9][CH:8]([CH2:11][NH:12][CH2:13][CH2:14][CH3:15])[O:7][C:6]=2[CH:16]=1.[CH3:18][S:19]([O-:21])=[O:20].[Na+].N1CCC[C@H]1C(O)=O>[Cu](I)I.CS(C)=O>[F:17][C:3]1[C:2]([S:19]([CH3:18])(=[O:21])=[O:20])=[CH:16][C:6]2[O:7][CH:8]([CH2:11][NH:12][CH2:13][CH2:14][CH3:15])[O:9][CH2:10][C:5]=2[CH:4]=1
Reactant: CS(=O)[O-]
Reactant: CCCNCC1OCc2cc(F)c(Br)cc2O1
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCNCC1OCc2cc(F)c(S(C)(=O)=O)cc2O1
Yield: 45 %

Procedure:
Preparation according to Example 18. N-[(7-bromo-6-fluoro-4H-1,3-benzodioxin-2-yl)methyl]propan-1-amine (0.30 g, 0.99 mmol), sodium methanesulfinate (0.15 g, 1.23 mmol, 85%), copperiodide (19 mg, 0.10 mmol), L-proline (56 mg, 0.49 mmol) and DMSO (6 ml) was heated at 140° C. for 1 h. Purification was made twice by flash column chromatography (ETOAc/MeOH 10:1) and afforded the title compound (135 mg, 45%). The amine was converted into the hydrochloric acid salt and crystallized from EtOH/DEE. M.p. 225° C. 1H-NMR (400 MHz, MeOH): δ 7.34 (1H, d, J 6.0 Hz), δ 7.13 (1H, d, J 9.6 Hz), δ 5.21 (1H, t, J 4.8 Hz), δ 5.02 (2H, dd, J1 45.2 Hz, J2 15.6 Hz), δ 3.23 (3H, s), δ 2.96 (2H, m), δ 2.64 (2H, t, J 7.6 Hz), δ 1.56 (2H, m), δ 0.95 (3H, t, J 7.2 Hz).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:11])([CH3:10])[CH:5]([C:8]#[N:9])[C:6]#[N:7].[F:13][C:14]1[CH:33]=[CH:32][CH:31]=[CH:30][C:15]=1[CH2:16][N:17]1[C:21]2=[N:22][C:23]([CH3:26])=[N:24][CH:25]=[C:20]2[C:19]([C:27](=[NH:29])[NH2:28])=[N:18]1.O>C(O)(C)(C)C>[NH2:7][C:6]1[C:5]2[C:4]([CH3:11])([CH3:10])[C:3](=[O:2])[NH:9][C:8]=2[N:29]=[C:27]([C:19]2[C:20]3[C:21](=[N:22][C:23]([CH3:26])=[N:24][CH:25]=3)[N:17]([CH2:16][C:15]3[CH:30]=[CH:31][CH:32]=[CH:33][C:14]=3[F:13])[N:18]=2)[N:28]=1
Reactant: Cc1ncc2c(C(=N)N)nn(Cc3ccccc3F)c2n1
Reactant: COC(=O)C(C)(C)C(C#N)C#N
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ncc2c(-c3nc(N)c4c(n3)NC(=O)C4(C)C)nn(Cc3ccccc3F)c2n1

Procedure:
3 ml tert.-butanol, a solution of 146 mg (0.70 mmol) of methyl-3,3-dicyano-2,2-dimethylpropanoate in 1.5 ml tert.-butanol and 94 mg (0.84 mmol) of potassium tert.-butylate were added to 200 mg (0.70 mmol) of 1-(2-fluorobenzyl)-6-methyl-1H-pyrazolo[3,4-d]pyrimidine-3-carboximidamide and it was heated under reflux for 48 h. Water was added and the precipitate was filtered off. The filtrate was extracted with dichloromethane, the organic phase was dried over sodium sulphate and concentrated in a rotary evaporator. The residue was mixed with water/ethanol. The solid was filtered off and dried under high vacuum. 102 mg (34% of theor.) of the target compound was obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1([OH:37])[CH2:17][N:16]([C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[C:20]=2[NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])[CH2:15]1)(C)(C)C.[ClH:39]>CO>[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1([OH:37])[CH2:17][N:16]([C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[C:20]=2[NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[O:36])[CH2:15]1.[ClH:39].[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[C:14]1([OH:37])[CH2:17][N:16]([C:18]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[C:20]=2[NH:27][C:28]2[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:29]=2[F:35])=[O:36])[CH2:15]1
Reactant: CC(C)(C)OC(=O)NC1CCCCC1C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: Cl
Solvent: CO
Product: NC1CCCCC1C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tert-butyl-2-(1-(3,4-difluoro-2-(2-fluoro-4-iodophenylamino)benzoyl)-3-hydroxyazetidin-3-yl)cyclohexylcarbamate was dissolved in a mixture of methanol (4 mL) and hydrogen chloride (4 M in dioxane) (3 mL). The solution was heated to reflux then cooled to room temperature and stirred for 16 hours. The reaction mixture was concentrated and purified by reverse phase HPLC. The purified fractions were evaporated to dryness and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford an oil. The residue was taken up in methanol (2 mL) and was added hydrogen chloride (4M in dioxane) (700 μL) and evaporated to dryness to afford the title compound 3-(2-aminocyclohexyl)-1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-ol hydrochloride (44.7 mg, 12%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(O[K])(C)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Brc1ccc2ccccc2n1
Reactant: Nc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: c1ccc(Nc2ccc3ccccc3n2)nc1
Yield: 45 %

Procedure:
2-Bromoquinoline, I (500 mg, 2.40 mmol), 2-aminopyridine (249 mg, 2.64 mmol), tBuOK (404 mg, 3.60 mmol), (±)-BINAP (6 mg, 0.01 mmol) and Pd2(dba)3 (5.5 mg, 0.006 mmol) were stirred in toluene (10 mL) at 90° C. under Ar(g) for 21 h. The reaction mixture was then diluted with CH2Cl2 (10 mL) and silica was added, followed by the removal of the solvent under reduced pressure. The resulting dry load material was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:1 then 100:2) to furnish II as a colourless oil (344 mg, 45%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:27].CO>C1COCC1>[CH2:3]([O:10][C:11]([N:13]([C@H:14]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]1)[CH3:27])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C(=O)OCc1ccccc1)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
Sodium hydride (60% oil dispersion, 0.32 g) was added to a stirred solution of tert-butyl (S)-3-benzyloxycarbonylaminopyrrolidine-1-carboxylate (prepared according to Cheng et al, WO2007 142585, 1.73 g) in THF (20 mL) and the mixture was stirred for 15 minutes. Iodomethane (1.85 g) was added and the mixture was stirred at room temperature for 1 hour. Methanol was carefully added to destroy the excess sodium hydride then ethyl acetate and water were added and the organic layer was washed with brine, dried (Na2SO4), filtered. The filtrate was concentrated in vacuo to give tert-butyl (S)-3-(N-benzyloxycarbonyl-N-methylamino)pyrrolidine-1-carboxylate (1.66 g) as a pale coloured oil.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][N:15]=3)[CH:10]=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[S:21]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.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>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:4]3[O:3][C:2]([C:23]4[CH:24]=[CH:25][S:21][CH:22]=4)=[N:6][CH:5]=3)[N:12]=2)=[N:15][CH:16]=1
Reactant: Clc1ccc(Nc2cccc(-c3cnc(Cl)o3)n2)nc1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(Nc2cccc(-c3cnc(-c4ccsc4)o3)n2)nc1
Temperature: 100 °C
Yield: 88.7 %

Procedure:
A solution of [6-(2-chloro-oxazol-5-yl)-pyridin-2-yl]-(5-chloro-pyridin-2-yl)-amine (50 mg, 0.162 mmol) in THF (4 ml) and water (2 ml) was treated with 3-thiopheneboronic acid (25 mg, 0.195 mmol), Pd(PPh3)4 (19 mg, 0.0162 mmol) and K2CO3 (50 mg, 0.358 mmol) before heating to 100° C. for 60 h. The cooled mixture was treated with water and extracted with DCM. The combined organics were dried over MgSO4, filtered and evaporated under reduced pressure before purification by column chromatography on SiO2, eluting with 1% EtOH in DCM to afford the title compound as an off-white solid (51 mg, 89%). 1H NMR (400 MHz, DMSO-d6) δ 10.05 (s, 1H), 8.33-8.31 (m, 1H), 8.28 (d, J=2.5 Hz, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.89 (dd, J=9.0, 2.7 Hz, 1H), 7.85 (s, 1H), 7.83-7.77 (m, 2H), 7.69-7.65 (m, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.40 (d, J=7.4 Hz, 1H). (ESI+) m/z 355 (M+H)+. Retention time=4.28 mins (method 1).