Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][NH2:15])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:38][C:39]([NH:41][C:42]1[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([O:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH:50]=2)[CH:45]=[CH:44][CH:43]=1)=[O:40]>C(#N)C>[CH3:56][S:53]([O:52][C:49]1[CH:50]=[C:51]2[C:46]([CH:45]=[CH:44][CH:43]=[C:42]2[NH:41][C:39](=[O:40])[CH2:38][NH:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][N:8]([C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:12]=2)=[CH:47][CH:48]=1)(=[O:55])=[O:54]
Reactant: NCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CCl)c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)Oc1ccc2cccc(NC(=O)CNCCc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the product from Step B (25.6 g, 72.7 mmol) in 200 mL of acetonitrile was added diisopropylethylamine (50 mL, 303 mmol), followed by the product from Step D (19.0 g, 60.5 mmol). The reaction was stirred at room temperature overnight, then concentrated in vacuo. The resulting material was partitioned between EtOAc and water, washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH2:7][N:8]([C:14](=[O:26])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=1[S:22][C:23](=[O:25])[CH3:24])[CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)(C)(C)C.[I-].[Na+].Cl[Si](C)(C)C>CC#N>[C:23]([S:22][C:16]1[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]([N:8]([CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1)[CH2:7][C:6]([OH:27])=[O:5])=[O:26])(=[O:25])[CH3:24]
Reactant: CC(=O)Sc1c(C)cccc1C(=O)N(CC(=O)OC(C)(C)C)C1CCCC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)Sc1c(C)cccc1C(=O)N(CC(=O)O)C1CCCC1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
N-(2-Acetylthio-3-methylbenzoyl)-N-cyclopentylglycine t-butyl ester (16.7 g, 0.047 mole) was dissolved in 100 ml CH3CN. Sodium iodide (9.6 g, 0.064 mole) was then added. The resulting slurry was covered with a nitrogen atmosphere and warmed slowly to 55° C. Chlorotrimethylsilane (6.9 g, 0.0641 mole) was then added in one portion. The reaction was stirred 30 minutes at 50°-55° C. The heat source was then removed and the reaction cooled to room temperature with an ice bath. Water (60 ml) and CH2Cl2 (100 ml) were then added. The reaction mixture was transferred to a separatory funnel and the aqueous layer quickly withdrawn. The organic was washed 2×50 ml H2O, 3×75 ml Na2S2O3, 2×100 ml brine, dried (MgSO4), filtered and concentrated in vacuo to give 15.9 g of an orange oil.
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:19][C@H:20]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[CH3:21])=[O:18])[CH:10]=[CH:9]2)=[CH:3][CH:2]=1.CO.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:1]1([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[C:17]([NH:19][C@H:20]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[CH3:21])=[O:18])[CH:10]=[CH:9]2)=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(Cc4ccc(-c5ccccc5)cc4)c23)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](NC(=O)c1cccc2ccn(Cc3ccc(-c4ccccc4)cc3)c12)c1ccc(C(=O)O)cc1
Temperature: 65 °C
Reaction time: 2 h
Yield: 85.8 %

Procedure:
To methyl 4-[(1S)-1-({[1-(biphenyl-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoate (0.30 g) were added methanol (4.0 mL), THF (4.0 mL), and a 1 M aqueous sodium hydroxide solution (3.0 mL), followed by stirring at 65° C. for 2 hours and then at room temperature for 3 days. To the reaction mixture was added a 10% aqueous citric acid solution (4.0 mL), and the precipitated solid was collected by filtration, washed with water and a mixture of diethyl ether/hexane (1/1), and dried at 60° C. under reduced pressure to obtain 4-[(1S)-1-({[1-(biphenyl-4-ylmethyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid (0.25 g).
Reaction SMILES: [N:1]12CCC(CC1)C(CO)[CH2:2]2.[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[C:13](=[O:19])[CH2:12]2>>[C:2]([C:13]1([OH:19])[CH:14]2[CH2:17][CH2:18][N:11]([CH2:16][CH2:15]2)[CH2:12]1)#[N:1]
Reactant: OCC1CN2CCC1CC2
Reactant: O=C1CN2CCC1CC2
Product: N#CC1(O)CN2CCC1CC2

Procedure:
The novel process of the invention for the preparation of quinuclidine-3-methanol comprises reacting quinuclidine-3-one acid addition salt with an alkali metal cyanide in an aqueous meda to obtain 3-cyano-3-hydroxy-quinuclidine, reacting the latter with anhydrous methanol in the presence of hydrogen chloride gas followed by treatment with aqueous alkali to obtain methyl 3-hydroxy-quinuclidine-3-carboxylate, reacting the latter with thionyl chloride to form methyl 1-azabicyclo(2,2,2)oct-2-ene-3-carboxylate, hydrogenating the latter with Raney nickel to obtain methyl 1-azabicyclo(2,2,2)octane-3-carboxylate and reducing the latter to obtain quinuclidine-3-methanol.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(O[Cl:17])(C)(C)C.CCOCC>CC(O)=O>[Cl:17][C:4]1[C:5]([OH:6])=[C:7]([O:8][CH3:9])[CH:10]=[CH:11][C:3]=1[CH:2]=[O:1]
Reactant: COc1ccc(C=O)cc1O
Reactant: CC(C)(C)OCl
Solvent: CC(=O)O
Solvent: CCOCC
Product: COc1ccc(C=O)c(Cl)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
41.2 g (0.271 mol) of isovanillin was dissolved in 160 ml of 90% AcOH under heating. 29.41 g of t-BuOCl was added dropwise to the solution while it was kept at 35° to 40° C. The solution was stirred at room temperature for 3 hours and then 200 ml of ether was added thereto. The mixture was left to stand overnight and crystals thus formed were separated by filtration and washed with ether. 42.0 g of the crude crystals were recrystallized from acetonitrile to obtain 35 g of 2-chloro-3-hydroxy-4-methoxybenzaldehyde (69%).
Reaction SMILES: CS([CH2:5][CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)(=O)=O.[CH2:16]([NH:18][CH2:19][CH3:20])[CH3:17]>C1COCC1>[CH2:16]([N:18]([CH2:19][CH3:20])[CH2:5][CH2:6][C:7]1[CH:15]=[C:14]2[C:10]([CH:11]=[CH:12][NH:13]2)=[CH:9][CH:8]=1)[CH3:17]
Reactant: CS(=O)(=O)CCc1ccc2cc[nH]c2c1
Reactant: CCNCC
Solvent: C1CCOC1
Product: CCN(CC)CCc1ccc2cc[nH]c2c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of 6-(2-(Methanesulfonyl)ethyl)-indole (107 mg, 0.45 mmol) and diethylamine (0.4 ml) in 2 ml of THF was stirred at 65° C. overnight. The reaction mixture was concentrated in vacuo and passed through a silica gel column, eluting with 2% 2M ammonia/methanol in dichloromethane, to give the title compound, 42 mg (43% yield).
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:34])[N:24]([CH2:30][CH2:31][C:32]#[N:33])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=[C:19]([Cl:35])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[C:32]([CH2:31][CH2:30][N:24]([CH2:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:23](=[O:34])[C:21]1[CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:18]=[C:19]([Cl:35])[CH:20]=1)(=[O:40])[NH2:33]
Reactant: CC(C)(C)CN(CCC#N)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CN(CCC(N)=O)C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1
Reaction time: 18 h

Procedure:
A solution of (2-{3-chloro-5-[(2-cyano-ethyl)-(2,2-dimethyl-propyl)-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.052 g) in a mixture of dichloromethane (5 ml) and trifluoroacetic acid (2 ml) was stored at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.02 g) was obtained as a colourless oil by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: C([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH:18]2[CH2:20][O:19]2)[CH:11]=1)(=O)C1C=CC=CC=1.[C:21]1([C:27]2[C:35]3[C:34]([N:36]4[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]4)=[N:33][CH:32]=[N:31][C:30]=3[S:29][CH:28]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(O)C.CS(C)=O>[OH:19][CH:18]([CH2:20][NH:42][CH:39]1[CH2:40][CH2:41][N:36]([C:34]2[C:35]3[C:27]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:28][S:29][C:30]=3[N:31]=[CH:32][N:33]=2)[CH2:37][CH2:38]1)[CH2:17][O:16][C:12]1[CH:11]=[C:10]([OH:9])[CH:15]=[CH:14][CH:13]=1
Reactant: NC1CCN(c2ncnc3scc(-c4ccccc4)c23)CC1
Reactant: O=C(Oc1cccc(OCC2CO2)c1)c1ccccc1
Solvent: CS(C)=O
Solvent: CC(C)O
Product: Oc1cccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5ccccc5)c34)CC2)c1
Yield: 20 %

Procedure:
Synthesis followed SP6 (iPrOH:DMSO 3:1, 24 h), using 150 μmol 3-(oxiran-2-ylmethoxy)phenyl benzoate and 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine. The benzoic acid moiety was already lost during purification by prep. TLC (1 mm silica gel, PE/CH2Cl2/MeOH 4:6:1) and subsequent prep. HPLC (reversed phase) to give the title compound with 20% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li]CCCC.[Li]C(C)(C)C.[CH2:20]([N:22]([CH2:37][CH3:38])[CH2:23][CH2:24][N:25]1[C:35]2[C:30](=[C:31]([Br:36])[CH:32]=[CH:33][CH:34]=2)[C:28](=[O:29])[C:26]1=[O:27])[CH3:21].[NH4+].[Cl-]>C1COCC1.O>[CH2:37]([N:22]([CH2:20][CH3:21])[CH2:23][CH2:24][N:25]1[C:35]2[C:30](=[C:31]([Br:36])[CH:32]=[CH:33][CH:34]=2)[C:28]([OH:29])([C:2]2[NH:1][C:9]3[C:4]([CH:3]=2)=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:26]1=[O:27])[CH3:38]
Reactant: c1ccc2[nH]ccc2c1
Reactant: CCN(CC)CCN1C(=O)C(=O)c2c(Br)cccc21
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCN(CC)CCN1C(=O)C(O)(c2cc3ccccc3[nH]2)c2c(Br)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To indole (39.7 mg, 1.1 eq) in anhydrous THF (2 mL) under a nitrogen atmosphere and with stirring was added n-BuLi (0.22 mL, 1.1 eq, 1.53 M in hexanes) at −78° C. (bath temperature). Stirring was continued for 1 hour after which CO2 (g) was bubbled through the solution for ca. 30 minutes. The reaction mixture was then allowed to warm to room temperature and stirred at room temperature for a further 30 minutes. The solvent was removed in vacuo to give a white/light yellow solid which was left under vacuum (10 mmHg) for 17 hours. To the thus dried solid under a nitrogen atmosphere was added anhydrous THF (2 mL). The resulting clear solution was cooled to −78° C. (bath temperature) and t-BuLi (0.20 mL, 1.1 eq, 1.7 M in pentane) added dropwise. The colourless solution was stirred for 1 hour and 1-(2-diethylaminoethyl)-4-bromoisatin (100.0 mg, 3.08×10−4 mol) in anhydrous THF (2 mL) was added dropwise. The resulting red coloured solution was stirred at −40° C. for 7.5 hours. To the solution was added H2O (1.5 mL) and the mixture allowed to warm to room temperature. Saturated aqueous NH4Cl (1.5 mL) was then added. The mixture was extracted with EtOAc and the combined extracts were dried (anhydrous Na2SO4). After filtration the solvent was removed in vacuo. Purification was carried out by column chromatography (silica gel, eluting 1% to 1.5% MeOH in CHCl3) to give the title compound as a red oil (39.4 mg, 29%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH2:18][CH:19]([C:21]([O:23]C(C)(C)C)=[O:22])[CH3:20])[C:15]([CH3:17])=[N:16][C:12]=2[CH:11]=1.[OH-].[Li+].Cl>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH2:18][CH:19]([C:21]([OH:23])=[O:22])[CH3:20])[C:15]([CH3:17])=[N:16][C:12]=2[CH:11]=1
Reactant: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CC(C)C(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CC(C)C(=O)O
Reaction time: 5 h
Yield: 86.5 %

Procedure:
5-(Benzoxazol-2-yl)-2-methyl-1-(2-tert-butoxycarbonyl-n-propyl)benzimidazole (see Working Example 121-2) (0.4 g, 1.0 mmol) and THF/water=2:1 (40 mL) were charged, and lithium hydroxide (0.043 g, 1.0 mmol) was added at room temperature, and this was heated and stirred for 5 hours. After being kept cool, the liquid was brought to approximately pH 5 with dilute hydrochloric acid (1 M), the crystals obtained were filtered off and washed with distilled water, and then were dried with heating under reduced pressure to yield the title compound (0.29 g, 83% yield) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CC(C)=O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[O:1][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCCCCCCCCCCCCCBr
Reactant: COC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCOc1ccccc1C(=O)OC
Yield: 50.2 %

Procedure:
A mixture of 40 g of methyl 2-hydroxybenzoate, 45.4 g of powdered potassium carbonate, 700 ml acetone and 78.2 g of 1-bromotetradecane is heated at reflux temperature for 5 days. The reaction is cooled, filtered and concentrated in vacuo. The residue is dissolved in ethyl acetate; washed with water, saturated sodium bicarbonate, 10% sodium hydroxide, water and saturated sodium chloride; dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel:0-10% ethyl acetate/hexane) to give 46.0 g of the desired product.
Reaction SMILES: NC[C@@H]1C[C@H](O)C1.CS([O:12][C@H:13]1[CH2:16][C@@H:15]([CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH3:19])[CH2:14]1)(=O)=O.[F:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[C:32]([F:40])[C:33]=1[CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O.O>[F:27][C:28]1[CH:29]=[C:30]([CH:31]=[C:32]([F:40])[C:33]=1[CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)[O:12][C@H:13]1[CH2:16][C@H:15]([CH2:17][N:18]([CH3:19])[C:20](=[O:21])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:14]1
Reactant: Oc1cc(F)c(CN2CCCC2)c(F)c1
Reactant: CN(C[C@H]1C[C@@H](OS(C)(=O)=O)C1)C(=O)OC(C)(C)C
Agent: NC[C@H]1C[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C[C@H]1C[C@H](Oc2cc(F)c(CN3CCCC3)c(F)c2)C1)C(=O)OC(C)(C)C
Temperature: 92.5 °C

Procedure:
A mixture of intermediate 6, cis-3-{[(tert-butoxycarbonyl)(methyl)-amino]methyl}cyclobutyl methanesulfonate (2 g, 6.9 mmol), intermediate 21, 3,5-difluoro-4-(pyrrolidin-1-ylmethyl)phenol (3.47 g, 13.8 mmol) and Cs2CO3 (4.5 g, 13.8 mmol) in DMSO (20 mL) was heated at 90-95° C. for 4 h under vigorous stirring in a flow of argon, then cooled. Water (40 ml) and EtOAc (40 ml) were added, and the layers were separated. The water layer was extracted with ether (20 ml), the combined organic layers were washed with 1N NaOH (3×25 mL), brine, dried with Na2SO4, and evaporated to give the title compound (2.8 g, 98%) as a yellow oil. LC/MS data: 411.6, 412.6 (M+H) (calculated for C22H32F2N2O3 410.51). 1H NMR-data (DMSO-d6): 6.50-6.61 (m, 2H, Ar—H); 4.79-4.87 (m, 1H); 3.55 (s, 2H, CH2); 3.32 (d, 2H, J=8.1 Hz, CH2); 2.78 (s, 3H, NCH3); 2.52-2.62 (m, 1H); 2.38-2.50 (m, 4H); 2.20-2.28 (m, 2H); 2.05-2.17 (m, 2H); 1.58-1.73 (m, 4H); 1.41 (s, 9H, Boc).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1>CC(C)=O>[NH2:19][C:14]1[C:13]([Br:12])=[CH:18][CH:17]=[CH:16][N+:15]=1[O-:9]
Reactant: Nc1ncccc1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Product: Nc1c(Br)ccc[n+]1[O-]
Temperature: 23 °C
Reaction time: 1 h

Procedure:
mCPBA (12.0 g, 69.3 mmol) was added portionwise over 5 min to a solution of 3-bromopyridin-2-amine (10 g, 58 mmol) in anhydrous acetone (150 mL) at 0° C. The resulting mixture was warmed to 23° C. and stirred for 1 h, then concentrated. The residue was partitioned between a solution of 5% methanol in chloroform and saturated aqueous sodium hydroxide solution (3×). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the title compound. MS: m/z=189.0 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([CH2:8][C:9]2[CH:10]=[N:11][CH:12]=[N:13][CH:14]=2)[C:5](=[O:15])[N:4]=[C:3]1SC.[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][CH3:33])=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:36]([F:39])([F:38])[F:37]>C(O)C>[Cl:18][C:19]1[CH:35]=[CH:34][C:22]([O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][N:32]([CH3:33])[C:3]3[N:2]([CH3:1])[CH:7]=[C:6]([CH2:8][C:9]4[CH:10]=[N:11][CH:12]=[N:13][CH:14]=4)[C:5](=[O:15])[N:4]=3)=[CH:26][CH:25]=2)=[CH:21][C:20]=1[C:36]([F:37])([F:38])[F:39]
Reactant: CSc1nc(=O)c(Cc2cncnc2)cn1C
Reactant: CNCCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Solvent: CCO
Product: CN(CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1)c1nc(=O)c(Cc2cncnc2)cn1C
Temperature: 130 °C
Reaction time: 48 h
Yield: 28.9 %

Procedure:
1-Methyl-2-methylsulfanyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (50 mg, 0.201 mmol, 1 eq) and {2-[4-(4-Chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-methyl-amine (99.4 mg, 0.302 mmol, 1.5 eq) were dissolved in dry ethanol (300 μl) and stirred at 130° C. for 48 h. Reaction mixture was evaporated and crude residue was purified via Biotage SP-1 Snap Si 10 g; 15 ml/min; UV Wavelength (Collection: 254 nm; Monitor: 290 nm) in the gradient of MeOH in DCM: 0% for 1 CV, 0-8% for 25 CV. The appropriate fractions were combined and product was not pure enough and it was sent to HPLC/MS Purification. After HPLC/MS purification combined fractions of desired product were collected and put on lyophilisation to obtain 2-({2-[4-(4-chloro-3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-methyl-amino)-1-methyl-5-pyrimidin-5-ylmethyl-1H-pyrimidin-4-one (0.058 mmol; yield: 28.9%, HPLC-MS/UV: [M+H]+=530.95; rt: 12.13 min; purity: 99%). 1H NMR (300 MHz; DMSO-d6) δ/ppm 1.38 (s, 3H), 2.81 (s, 3H), 2.87 (t, J=6.73 Hz, 2H), 3.38 (t, J=7.20 Hz, 2H), 3.50 (s, 2H), 7.02 (d, J=7.20, 2H), 7.18 (d, J=8.17, 1H), 7.31 (d, J=8.17, 2H), 7.37 (s, 1H), 7.50 (s, 1H), 7.67 (d, J=8.65, 1H), 8.67 (s, 2H), 8.97 (s, 1H)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:6][CH2:5][C:4]([CH3:7])=[C:3]1[CH:8]=[CH:9][C:10](=[O:13])[CH2:11][CH3:12].[OH:15]C1(C)CC(O)CC(C)(C)C1C=CC(O)C>>[OH:15][C:4]1([CH3:7])[CH2:5][CH2:6][C:2]([CH3:1])([CH3:14])[CH:3]1[CH:8]=[CH:9][CH:10]([OH:13])[CH2:11][CH3:12]
Reactant: CCC(=O)C=CC1=C(C)CCC1(C)C
Reactant: CC(O)C=CC1C(C)(C)CC(O)CC1(C)O
Product: CCC(O)C=CC1C(C)(C)CCC1(C)O

Procedure:
The entitled compound was obtained from 1-(2,2,5-trimethylcyclopent-5-enyl)pent-1-en-3-one in the same manner as in Example 1-(4), (5), and (6).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:14]2[CH:19]=[C:18]([C:20]3[C:28]4[C:23](=[N:24][CH:25]=[C:26]([C:29]5[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=5)[N:27]=4)[NH:22][CH:21]=3)[N:17]=[C:16]([NH2:35])[N:15]=2)([O:10]COC)[CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl>CO>[NH2:35][C:16]1[N:15]=[C:14]([C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([OH:10])[CH3:9])[CH:19]=[C:18]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[C:26]([C:29]4[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=4)[N:27]=3)[NH:22][CH:21]=2)[N:17]=1
Reactant: COCOC(C)(c1cccc(F)c1)c1cc(-c2c[nH]c3ncc(-c4cnn(C)c4)nc23)nc(N)n1
Agent: Cl
Solvent: CO
Product: Cn1cc(-c2cnc3[nH]cc(-c4cc(C(C)(O)c5cccc(F)c5)nc(N)n4)c3n2)cn1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
4-[1-(3-Fluorophenyl)-1-methoxymethoxyethyl]-6-[2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]pyrimidin-2-ylamine (234 mg, 0.25 mmol) is dissolved in MeOH (10 ml), 25% HCl (1 ml, 5.14 mmol) is added, and the mixture is stirred at 50° C. for about 1.5 h. The solvent is evaporated in vacuo. The residue is purified by HPLC on RP-18e, giving 1-{2-amino-6-[2-(1-methyl-1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]pyrimidin-4-yl}-1-(3-fluorophenyl)ethanol (“A3”); (HPLC/MS Rt=1.53 min, [M+H] 431);
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[CH:25]=[N:24][C:23]([CH2:26][NH:27][CH3:28])=[CH:22][N:21]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>C(#N)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([CH2:26][N:27]([CH3:28])[S:38]([CH3:37])(=[O:40])=[O:39])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CNCc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)cn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1cnc(CN(C)S(C)(=O)=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.5 %

Procedure:
To a suspension of 3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-1-({5-[(methylamino)methyl]pyrazin-2-yl}methyl)pyridin-2(1H)-one (0.16 g, 0.34 mmol) in acetonitrile at 0° C. was added triethylamine (0.043 g, 0.42 mmol), followed by the addition of methane sulfonylchloride (0.047 g, 0.41 mmol) and stirred at room temperature for 1 h under argon atmosphere. The solvents were removed in vacuo and the residue was triturated with water and filtered. It was washed with water an, acetonitrile and dried in vacuo to afford 0.11 g of material. 1H NMR (CD3OD/400 MHz) δ 8.62 (s, 1H), 8.55 (s, 1H), 7.61 (m, 1H), 7.0 (m, 2H), 6.53 (s, 1H), 5.47 (s, 2H), 5.29 (s, 2H), 4.49 (s, 2H), 2.95 (s, 3H), 2.85 (s, 3H), and 2.55 (s, 3H); 19F NMR (CD3OD/400 MHz) −111.70 (m) and −116.07 (m); ES-HRMS m/z 543.0515 (M+H calcd for C21H22BrF2N4O4S requires 543.0508).
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([NH:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1.[OH-].[Na+]>CO>[NH2:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:24]([NH:23][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1)[C:3]([OH:33])=[O:2])=[O:32]
Reactant: COC(=O)C(Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)NC(=O)c1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccccc1C(=O)NC(Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the title H compound, 2-(2-amino-benzoylamino)-3-(3-benzyloxy-4-nitro-phenyl)-propionic acid methyl ester (388 mg, 0.863 mmol) in methanol (8 mL) is added 1N aqueous NaOH (1.73 mL, 1.73 mmol) and the mixture is stirred at RT for 2 h and evaporated. The residue is dissolved in water (20 mL) and the solution is washed twice with EtOAc. The aqueous layer is neutralized with 1N aqueous HCl (1.73 mL) and extracted three times with EtOAc. The organic extracts are washed with brine, dried over anhydrous MgSO4, decolorized with charcoal, filtered and evaporated to give 2-(2-amino-benzoylamino)-3-(3-benzyloxy-4-nitro-phenyl)-propionic acid as a viscous yellow oil: [M+1]+=436, [M−1]−=434.