Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(OC(=O)C)(=O)C.N1C=CC=CC=1>COCCOC>[CH3:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:12])[O:13][C:8](=[O:10])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1cnc(C(=O)O)c(C(=O)O)c1
Solvent: CC(=O)OC(C)=O
Solvent: COCCOC
Solvent: c1ccncc1
Product: Cc1cnc2c(c1)C(=O)OC2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.1 %

Procedure:
A solution of 75.0 g (0.41 m) of 5-methyl-2,3-pyridinedicarboxylic acid in 500 mL of 1,2-dimethoxyethane is treated with 125 g acetic anhydride (1.2 m) and 81 g pyridine (1.02 m). The resulting solution is stirred for 18 hours at room temperature. The solution is stripped in vacuo to leave 70.3 g (100%) of 5-methyl-2,3-pyridinedicarboxylic acid anhydride. The anhydride is dissolved in 500 mL CCl4 and is treated with 1 g AIBN and 240 g (150 mL, 1.8 m) SO2Cl2 at room temperature. The solution is heated to reflux for 2 hours. An additional 1.0 g AIBN and 80 g (50 mL 0.6 m) SO2Cl2 are added and refluxing continued for an additional 2 hours. The solution, with some suspended solids, is cooled to 15° in an icebath and filtered to leave 56.0 g (69%) of a yellow solid: 5-chloromethyl-2,3-pyridinedicarboxylic anhydride (78% by nmr) mp (softens at 90° C.) 141°-145° C. Alternatively, the product can be hydrolyzed to give 5-chloromethyl-2,3-pyridinedicarboxylic acid, mp 170°-172°, from which the anhydride can be reformed by standard methods (see Example 6).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)=[C:15](Br)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[N:55]1[CH:60]=[C:59](B(O)O)[CH:58]=[N:57][CH:56]=1>>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:18]=[C:17]3[C:13]([C:14]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=4)=[C:15]([C:59]4[CH:60]=[N:55][CH:56]=[N:57][CH:58]=4)[C:16]3=[O:19])=[CH:12][CH:11]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1cncnc1
Reactant: O=C1C(Br)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCOCC3)cc21
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: O=C1C(c2cncnc2)=C(c2cc(F)cc(F)c2)c2ccc(OCCN3CCOCC3)cc21
Yield: 36 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 6-(2-morpholinoethoxy)-2-bromo-3-(3,5-difluorophenyl)-1H-inden-1-one obtained in Step 6 of Example 36 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 5-pyrimidinylboronic acid instead of 3-pyridinylboronic acid, and being purified by prep HPLC (CH3CN/H2O=7:3) to obtain the title compound (36%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](Cl)=O)=[CH:14][CH:13]=1.C(OCC)(=O)C.O1CCCC1.[OH-].[Na+]>O>[Br:9][C:5]1[CH:6]=[C:7]2[NH:8][C:19]([CH2:18][C:15]3[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=3)=[N:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: COc1ccc(CC(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cc2nc3ncc(Br)cc3[nH]2)cc1
Temperature: 170 °C
Reaction time: 1.5 h
Yield: 54.9 %

Procedure:
A mixture of 2,3-diamino-5-bromopyridine (Compound of Reference Example 1) (1.32 g) and 4-methoxyphenylacetyl chloride (1.29 g) was stirred in the absence of solvent at 170° C. for 1.5 hour. The mixture was distributed with ethyl acetate-tetrahydrofuran (3:1, v/v) and water (at that time, the water layer was neutralized with 1 N sodium hydroxide). The organic layer was washed with water, dried over MgSO4, and the solvent was distilled off under reduced pressure. The resulting crystals were collected by filtration to obtain 6-bromo-2-(4-methoxybenzyl)-1H-imidazo[4,5-b]pyridine (1.22 g, 55%).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13](=[O:16])[CH2:14][CH3:15])[CH:9]=2)[CH:4]=1.Br>C(O)(=O)C>[C:13]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]2)(=[O:16])[CH2:14][CH3:15]
Reactant: CCC(=O)c1ccc2cc(OC)ccc2c1
Agent: Br
Solvent: CC(=O)O
Product: CCC(=O)c1ccc2cc(O)ccc2c1
Temperature: 0 °C
Yield: 56.7 %

Procedure:
To a solution of 10 g of 2-methoxy-6-propionylnaphthalene, prepared according to J. Chem. Soc. (1934), p. 864, in acetic acid (45 ml) and kept under reflux, 47 ml of aqueous HBr (48% by weight) is added during a three-hour time period. The resulting suspension is poured onto 500 g of crushed ice; the formed tars are left in the reaction flask. A suspension is obtained which is filtered on a Buchner filter. The solid material is washed with 100 ml of water, 50 ml of saturated aqueous solution of NaHCO3, and then with 50 ml of water. After drying in air and in oven at 60° C. for 10 hours, 5.3 g of pink-white product is obtained with the following characteristics:
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([NH:11][C:12]1[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[C:14]([C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)[CH:13]=1)=[O:10].CN(C)C=O.[Cl:40][C:41]1[CH:49]=[CH:48][CH:47]=[C:46]2[C:42]=1[CH2:43][CH2:44][NH:45]2.Cl.CCOCC>Cl>[NH2:19][CH2:18][CH2:17][O:16][C:15]1[CH:27]=[CH:28][C:12]([NH:11][C:9]([N:45]2[C:46]3[C:42](=[C:41]([Cl:40])[CH:49]=[CH:48][CH:47]=3)[CH2:43][CH2:44]2)=[O:10])=[CH:13][C:14]=1[C:29]1[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=1
Reactant: Clc1cccc2c1CCN2
Reactant: Cn1nccc1-c1cc(NC(=O)ON2C(=O)CCC2=O)ccc1OCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)N2CCc3c(Cl)cccc32)ccc1OCCN
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.5 %

Procedure:
A 1 mL aliquot of tert-butyl {2-[4-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}amino)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]ethyl}carbamate in dimethylformamide (78.8 μmol) was added to 4-chloroindoline (14.52 mg, 1.2 eq) and stirred at room temperature for 18 hr. To this was added 2.0M hydrochloric acid in ether (197 μL, 5 eq) and the reaction was stirred at room temperature for 24 hr (2-3 drops of concentrated hydrochloric acid was added if the deprotection was incomplete and the resulting mixture was stirred for another 24 hr). The ether and hydrochloric acid were evaporated under a stream of nitrogen and the resulting material was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 43.5% yield. LCMS m/z (%)=412 (+H35Cl, 100), 414 (M+H 37Cl, 36). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.10-3.24 (m, 4 H), 3.71 (s, 3 H), 4.13-4.21 (m, 4 H), 6.34 (d, J=2.02 Hz, 1 H), 6.96 (d, J=8.08 Hz, 1 H), 7.13-7.21 (m, 2 H), 7.48-7.50 (m, 2 H), 7.64 (dd, J=8.84, 2.78 Hz, 1 H), 7.81 (d, J=7.58 Hz, 1 H), 7.92 (s, 2 H), 8.63 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[O:10])[CH2:5][C:6]([O:8][CH3:9])=[O:7].S(Cl)([Cl:14])(=O)=O>ClCCl>[CH3:9][O:8][C:6](=[O:7])[CH:5]([Cl:14])[C:4](=[O:10])[CH2:3][O:2][CH3:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: COCC(=O)CC(=O)OC
Solvent: ClCCl
Product: COCC(=O)C(Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
46.0 g Methyl 4-methoxyacetoacetate were dissolved in 500 ml dichloromethane. 28.1 ml Sulfuryl chloride were added in one portion. The reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, the resulting residue was dissolved in 300 ml ethyl acetate and washed with 100 ml water and 100 ml brine. The organic layer was dried over MgSO4 and the solvent removed under reduced pressure. The resulting residue was purified by chromatography on silica gel with the eluent n-heptane:ethyl acetate=5:1=>2:1 to obtain 45.0 g 2-Chloro-4-methoxy-3-oxo-butyric acid methyl ester as a yellow oil.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH3:32][CH2:33][CH:34]([NH2:37])[CH2:35][CH3:36].[BH4-].[Na+]>>[CH2:33]([CH:34]([NH:37][CH2:27][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]2)[CH:26]=[CH:25][CH:24]=1)[CH2:35][CH3:36])[CH3:32]
Reactant: CCC(N)CC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)NCc1cccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)c1
Yield: 80.5 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (20 mg, 0.045 mmol), 3-pentanamine (32 uL, 0.27 mmol) and NaBH4 (10 mg, 0.27 mmol) were reacted to give the title compound (18.5 mg, 80%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][NH2:8]>C(O)(C)C>[OH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][NH:5][CH2:6][CH2:7][N:8]=[CH:4][C:3]1[CH:9]=[CH:10][CH:11]=[CH:12][C:2]=1[OH:1]
Reactant: NCCNCc1ccccc1O
Solvent: CC(C)O
Product: Oc1ccccc1C=NCCNCc1ccccc1O
Yield: 156.2 %

Procedure:
28.7 g of salicylicaldehyde were added to a solution of 39.2 g of N-(2-hydroxybenzyl)-1,2-diaminoethane [prepared in accordance with: A. Bottcher et al., Z. Naturforsch. 49b, 1089-1100 (1994)] in 100 ml of isopropanol, and the resulting solution was refluxed for two hours. Cooling the solution produced a solid, and recrystallization from isopropanol gave 49.8 g of N-(2-hydroxybenzyl)-N'-(2-hydroxybenzylidene)-1,2-diaminoethane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:27][CH3:28])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19]C(OC(C)(C)C)=O)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[Cu](C#N)[C:30]#[N:31].O.N>CN(C)C=O>[C:30]([C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:27][CH3:28])[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1)#[N:31]
Reactant: CCc1nc(-c2cccc(Br)c2)c(-c2ccnc(NC(=O)OC(C)(C)C)c2)s1
Reactant: N#C[Cu]C#N
Agent: N
Solvent: O
Solvent: CN(C)C=O
Product: CCc1nc(-c2cccc(C#N)c2)c(-c2ccnc(N)c2)s1
Temperature: 150 °C
Reaction time: 20 h
Yield: 56.4 %

Procedure:
To a solution of 4-(3-bromophenyl)-5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-1,3-thiazole (0.5 g, 1.1 mmol) in N,N-dimethylformamide (10 mL) was added copper cyanide (0.25 g, 1.6 mmol), and the mixture was stirred for 20 hours at 150° C. under argon atmosphere. Into the reaction mixture was poured ammonia water, and the deposit was removed, then, extracted with ethyl acetate. The extracts were washed with water, then, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:1) to obtain a crystal. This crystal was washed with hexane-ethyl acetate to obtain a title compound (0.19 g, yield 57%).
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:41]1[CH:42]=[N:43][C:44]([C:47]([OH:49])=[O:48])=[N:45][CH:46]=1>C1COCC1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.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>[CH3:31][C:2]1([CH3:1])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[C:19]([C:41]5[CH:42]=[N:43][C:44]([C:47]([OH:49])=[O:48])=[N:45][CH:46]=5)[CH:20]=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1
Reactant: O=C(O)c1ncc(Br)cn1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(B5OC(C)(C)C(C)(C)O5)cc43)sc2C(=O)N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)Cc2nc(N3CCOc4ccc(-c5cnc(C(=O)O)nc5)cc43)sc2C(=O)N1
Temperature: 120 °C
Yield: 16.1 %

Procedure:
To a solution of Example 292 (100 mg, 0.227 mmol) in THF (3 mL) and water (1 mL) was added tetra-n-butylammonium bromide (146 mg, 0.454 mmol), potassium phosphate (144 mg, 0.681 mmol), 5-bromopyrimidine-2-carboxylic acid (70 mg, 0.34 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol). The reaction was heated at 120° C. under microwave irradiation for 30 minutes then cooled to r.t. The mixture was partitioned between DCM (50 mL) and water (50 mL). The aqueous phase was acidified with 1M HCl and the resulting precipitate was collected, washed with water (2×10 mL), Et2O (3×10 mL) and dried in vacuo to yield the title compound (16 mg, 16%) as an off-white solid. δH (CD3OD) 9.06 (2H, br s), 8.57 (1H, br. s), 7.32 (1H, s), 7.31 (1H, d, J 8.5 Hz), 7.07 (1H, d, J 8.5 Hz), 4.41-4.34 (2H, m), 4.07-4.01 (2H, m), 2.83 (2H, s), 1.34 (6H, s). LCMS (ES+) 875.0 (2M+H)+, RT 2.43 minutes (Method 1).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:6]1=[O:20])[CH3:4].CC(C)=O>C(O)C>[CH2:3]([C:5]1[CH:6]([OH:20])[C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:10]=[CH:9][CH:8]=2)[CH3:4]
Reactant: CCC1Cc2c(cccc2-c2ccccc2)C1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCC1=Cc2c(-c3ccccc3)cccc2C1O
Reaction time: 3.5 h
Yield: 100.1 %

Procedure:
A 200-ml three-necked round flask equipped with a stirring bar, a Dimroth condenser, a dropping funnel and a thermometer was charged with 0.85 g (22.6 mmol) of sodium borohydride and 28 ml of ethanol. To the mixture was dropwise added a solution containing 10.6 g (45.1 mmol) of the above-obtained 2-ethyl-4-phenyl-1-indanone dissolved in 20 ml of ethanol at room temperature under a nitrogen atmosphere. After the addition was completed, the temperature of was elevated to 50° C., and the reaction mixture was stirred for 3.5 hours. After the reaction was completed, the unreacted sodium borohydride was decomposed by acetone. Then, the reaction mixture was concentrated under reduced pressure, and then dissolved in 50 ml of water and extracted with 50 ml of ether. After the organic phase was separated, the aqueous phase was extracted with 50 ml of ether two times. The combined organic phase was washed with 100 ml of a saturated aqueous solution of sodium chloride, followed by drying over anhydrous Na2SO4. The solvent was evaporated under reduced pressure to obtain 10.67 g of the desired product as a pasty pale yellow liquid (mixture of two kinds of isomers) (yield: 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C[O:15][C:16]([C:18]1[N:19]=[CH:20][C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:22]=2)=O.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH:9][C:16]([C:18]1[N:19]=[CH:20][C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH:22]=2)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C(CN)C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)C(CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)C1CC1
Temperature: 150 °C
Yield: 97.8 %

Procedure:
A mixture of 3-amino-2-cyclopropyl-propionic acid tert-butyl ester (66 mg), 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (35 mg) and DBU (0.027 mL) in DMA (1 mL) was heated in an oil bath (150° C.) for 1 h. The reaction mixture was then partitioned between EtOAc and diluted HCl solution, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product as brown solid (52 mg). LC-MS ESI+: 449 (M+1)+.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH:3]=1.[CH3:24][CH:25]1[C:30](=[O:31])[CH2:29][CH2:28][NH:27][CH2:26]1>CN1C(=O)CCC1.CS(C)=O.CO>[OH:22][C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:12]([NH:11][C:4]2[CH:3]=[C:2]([N:27]3[CH2:28][CH2:29][C:30](=[O:31])[CH:25]([CH3:24])[CH2:26]3)[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:23])=[CH:14][CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccc(C(=O)Nc2cc(Cl)n3nccc3n2)cc1
Reactant: CC1CNCCC1=O
Solvent: CO
Solvent: CN1CCCC1=O
Solvent: CS(C)=O
Product: CC1CN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)CCC1=O
Temperature: 25 °C
Yield: 55.3 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 50 mg, 0.151 mmol) and 3-methylpiperidin-4-one (34 mg, 0.302 mmol) in NMP (0.950 mL) was stirred at 85° C. overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 30-55% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (34 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.02 (d, J=6.57 Hz, 3H) 1.46 (s, 6H) 2.74-2.97 (m, 2H) 3.30 (t, J=11.87 Hz, 1H) 3.57-3.69 (m, 1H) 4.56-4.70 (m, 2H) 6.38 (d, J=2.27 Hz, 1H) 7.48 (s, 1H) 7.60 (d, J=8.59 Hz, 2H) 8.00 (d, J=8.59 Hz, 2H) 8.13 (d, J=2.27 Hz, 1H) 10.93 (s, 1H). ESI-MS: m/z 408.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1)[CH3:2].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=1B(O)O>>[CH2:1]([O:3][C:4](=[O:14])[C@@H:5]([O:3][CH2:1][CH3:2])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:14][CH2:4]/[CH:5]=[CH:6]/[C:7]2[CH:12]=[CH:11][C:10]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=3[Cl:15])=[CH:9][CH:8]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: OB(O)c1cccc(Cl)c1Cl
Reactant: CCOC(=O)/C=C/c1ccc(Br)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C/c2ccc(-c3cccc(Cl)c3Cl)cc2)cc1)OCC

Procedure:
The title compound was prepared from (E)-3-(4-bromo-phenyl)-acrylic acid ethyl ester and 2,3-dichlorobenzene boronic acid by a sequence analogous to that described in example 52a-c.
Reaction SMILES: [H-].[Na+].C1(C)C=CC(S(O[CH2:13][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[C:32]4[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=4)[N:26]=[CH:25][N:24]=3)[CH2:19][CH2:18]2)([OH:16])[CH3:15])(=O)=O)=CC=1>C1COCC1>[CH3:15][C:14]1([CH:17]2[CH2:18][CH2:19][N:20]([C:23]3[C:32]4[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=4)[N:26]=[CH:25][N:24]=3)[CH2:21][CH2:22]2)[CH2:13][O:16]1
Reactant: COc1cc2ncnc(N3CCC(C(C)(O)COS(=O)(=O)c4ccc(C)cc4)CC3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2ncnc(N3CCC(C4(C)CO4)CC3)c2cc1OC

Procedure:
Sodium hydride (2.5 g of a 50% dispersion in oil) was added to a stirred suspension of 1-[4-toluenesulphonyloxy]-2-[1-(6,7-dimethoxyquinazolin-4-yl)piperid-4-yl]-2-hydroxypropane (8.6 g) in THF (20 cm3) and the mixture was heated under reflux for 16 hours. Volatile material was removed in vacuo, the residue was partitioned between chloroform (50 cm3) and water (50 cm3) and the aqueous phase was further extracted with chloroform (2×50 cm3). The combined, dried (MgSO4) organic phase was evaporated and the residue was crystallized from ethyl acetate to afford 2-methyl-2-[1-(6,7-dimethoxy-quinazolin-4-yl)piperid-4-yl]oxirane, m.p. 125°-127.5° (5.0 g).
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.I[CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1.[Cl:24][C:25]1[C:30](Cl)=[N:29][CH:28]=[CH:27][N:26]=1>CC(N(C)C)=O.[Zn].[Cu]I>[Cl:24][C:25]1[C:30]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:29][CH:28]=[CH:27][N:26]=1
Reactant: Clc1nccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(I)CC1
Agent: [Cu]I
Agent: C[Si](C)(C)Cl
Agent: [Zn]
Solvent: CC(=O)N(C)C
Solvent: BrCCBr
Product: CC(C)(C)OC(=O)N1CCC(c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.5 %

Procedure:
To a suspension of activated zinc dust (84.4 g, 1.29 mol, 1.94 eq.) in anhydrous DMA (270 mL) was added 1,2-dibromoethane (9.1 mL, 0.106 mol, 0.16 eq.), followed by the slow addition of chlorotrimethylsilane (13.5 mL, 0.106 mol, 0.16 eq.) over a period of 5 min. The resulting mixture was stirred for 15 min under nitrogen. Then a solution of tert-butyl 4-iodopiperidine-1-carboxylate (329 g, 1.06 mol, 1.59 eq.) in anhydrous DMA (670 mL) was added to the above suspension over a period of 45 min keeping the internal temperature below 65° C. The resulting mixture was stirred for 1 hour while cooling back to room temperature. The prepared zinc reagent was allowed to stand and the upper clear solution was transferred to a degassed and well stirred solution of 2,3-dichloropyrazine (99 g, 0.664 mol, 1 eq.), PdCl2(dppf)CH2Cl2 (16.3 g, 19.9 mmol, 0.03 eq.) and CuI (7.8 g, 41.2 mmol, 0.062 eq.) in anhydrous DMA (670 mL) using a cannula. DMA (400 mL) was used to rinse the remaining zinc dust and added to the above mixture. The resulting mixture was heated to 80° C. under nitrogen and stirred overnight (19 hours). The mixture was cooled to room temperature and diluted with brine (1 L) and ethyl acetate (6 L). The aqueous phase was extracted with ethyl acetate (4 L) and organic extracts were combined, washed with brine (1 L), dried and concentrated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=9:1 to 6:1) to give 92 g of tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[NH:54][C:55]([CH:57]([NH2:65])[C:58]3[CH:63]=[CH:62][CH:61]=[C:60]([Cl:64])[CH:59]=3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.CO>[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[NH:54][C:55]([CH:57]([C:58]3[CH:63]=[CH:62][CH:61]=[C:60]([Cl:64])[CH:59]=3)[NH:65][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: NC(c1cccc(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC(c2cccc(Cl)c2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 48 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and C-(5-chloro-1H-benzimidazol-2-yl)-C-(3chlorophenyl)methylamine in tetrahydrofuran. Yield: 48%; Rf value: 0.33 (silica gel; dichloromethane/methanol=20:1); C27H24C12N4O2 (507.42); mass spectrum: (M+H)+=507/509/511 (chlorine isotope).