Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[C:7]([Cl:12])[CH:6]=1)=[O:3].[H-].[Na+].[CH3:15]I>C1COCC1>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([N:4]([CH3:15])[C:2](=[O:3])[CH3:1])=[CH:6][C:7]=1[Cl:12]
Reactant: CI
Reactant: CC(=O)Nc1ccc(Br)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-3-chloroacetanilide (10.0 g, 40.2 mmol) in 50 mL THF is added 60% sodium hydride in mineral oil (2.40 g, 60.0 mmol) and the reaction mixture is stirred for 1 h at RT. The reaction mixture is cooled to 0° C., methyliodide (2.49 mL, 40.0 mmol) is added. After 2 h additional methyl iodide (0.25 mL, 4.0 mmol) is added and the reaction mixture is stirred at RT for 10 min. The reaction mixture is quenched with saturated aqueous ammonium chloride, filtered and extracted with diethyl ether. The organic phases are washed with brine, dried over Na2SO4 and evaporated to dryness. Yield: 10.3 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C@@H:9]([OH:12])[CH2:10][OH:11])=[CH:4][C:3]=1[CH3:13].O.[C:15]1(C)[CH:20]=CC(S(O)(=O)=O)=C[CH:16]=1>COC(OC)(C)C>[Cl:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([CH2:8][C@@H:9]2[CH2:10][O:11][C:15]([CH3:20])([CH3:16])[O:12]2)=[CH:6][N:7]=1
Reactant: Cc1cc(C[C@@H](O)CO)cnc1Cl
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: Cc1cc(C[C@@H]2COC(C)(C)O2)cnc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 970.4 %

Procedure:
A suspension of 52 (3.2 g, 16.2 mmol) in dimethoxypropane (33 mL) was cooled with an ice bath and treated with paratoluene sulfonic acid monohydrate (0.31 g, 1.62 mmol). The ice bath was removed and the solution was stirred at room temperature for 16 hrs, cooled to 5° C. and treated with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to afford 3.80 g (97%) of 53 as an oil. 1HNMR (CDCl3) δ 1.34 (3 H, s), 1.41 (3 H, s), 2.37 (3 H, s), 2.81 (2 H, m), 3.61 (1 H, t, J=7.0 Hz), 4.03 (1 H, m, J=6.0 Hz), 4.27 (1 H, m, J=6.0 Hz), 7.44 (1 H, s), 8.10 (1 H, s). LC/MS (M+1) 258.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C1(=O)NC(=O)CC1.[N:21]1([C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[NH:35][C:34](=[O:39])[CH2:33][CH2:32]3)=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:24]1[CH2:25][CH2:26][N:21]([C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[NH:35][C:34](=[O:39])[CH2:33][CH2:32]3)=[O:28])[CH2:22][CH2:23]1)=[O:8]
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: O=C1CCC(=O)N1
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Reaction time: 24 h

Procedure:
123 Grams of succinimide 3,4-dimethoxybenzoate and 137 mg of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril were dissolved in 2 ml of dimethylformamide and stirred for 24 hours. The water was added to the reaction mixture and extracted with chloroform, the chloroform extract was washed with water and a saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate. The solvent was removed by distillation and the residue was recrystallized from ethanol-chloroform to obtain 100 mg of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)([CH3:8])([CH3:7])[CH3:6].[F:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17]>O>[C:5]([C:15]1[CH:14]=[CH:13][C:12]([OH:17])=[C:11]([F:10])[CH:16]=1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)Cl
Reactant: Oc1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: CC(C)(C)c1ccc(O)c(F)c1
Temperature: 25 °C

Procedure:
Aluminum chloride and tert-butyl chloride were added under ice-cooling to 2-fluorophenol and stirred at room temperature. By adding water to the reaction liquid, concentrating the organic layer under a reduced pressure and crystallizing from hexane, 4-tert-butyl-2-fluorophenol was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][C:17](=[O:19])[CH3:18])[C:3]([Cl:9])=[N:4][CH:5]=1
Reactant: CC(=O)Cl
Reactant: Nc1cc(Br)cnc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 3-amino-5-bromo-2-chloropyridine (stage 152.1.2, 3.59 mmol) and triethylamine (1 ml) in dichloromethane (20 ml) was added acetyl chloride (Aldrich, Buchs, Switzerland, 0.312 ml). The RM was stirred for 17 h at rt then was added acetyl chloride (0.3 ml), the RM was stirred for 3 h at rt. Acetyl chloride (0.1 ml) was added and the RM was stirred for 1 h at rt. The RM was quenched with aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (heptane/EtOAc 0% to 40%). The fractions containing product were evaporated together to give the title compound as a white solid. (HPLC: tR 2.46 min (Method A); M+H=249, 251 MS-ES)
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[N:5]=[C:6]2[CH:12]=[N:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]2=[N:8][CH:9]=1>C1(O)C=CC=CC=1.C(Cl)(Cl)Cl>[O:1]([C:4]1[N:5]=[C:6]2[CH:12]=[N:11][N:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7]2=[N:8][CH:9]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [OH-]
Reactant: Clc1cnc2c(cnn2-c2ccccc2)n1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: Oc1ccccc1
Product: c1ccc(Oc2cnc3c(cnn3-c3ccccc3)n2)cc1
Temperature: 150 °C
Yield: 92 %

Procedure:
In 5.0 (0.053 mole) of phenol was dissolved 0.34 g (0.0085 mole) of sodium hydroxide, and 1.00 g (0.0043 mole) of 5-chloro-1-phenyl-1H-pyrazolo[3,4-b]pyrazine was added to the solution. The mixture was maintained at 150° C. for 2 hours. The reaction mixture was dissolved in chloroform, and the resulting solution was washed with an aqueous 10% solution of sodium hydroxide and then dried. The solvent was removed by distillation, and the residue was recrystallized from a benzene-hexane mixed solvent to obtain 1.20 g (the yield was 92%) of 5-phenoxy-1-phenyl-1H-pyrazolo[3,4-b]pyrazine in the form of a colorless needle crystal.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][C:11]2=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][CH:16](O)[CH:17]=[CH2:18].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:15]([CH:10]1[CH2:9][C:8]2[C:12](=[CH:13][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)[C:11]1=[O:14])[CH:16]=[CH:17][CH3:18]
Reactant: CC(C)(C)c1ccc2c(c1)C(=O)CC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2ccc(C(C)(C)C)cc2C1=O
Yield: 53 %

Procedure:
A solution of 11.0 g of 6-tert-butyl-1-indanone, 12.5 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 41 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 6:1). 7.35 g (53%) of (RS)-2-(2-buten-1-yl)-6-tert-butyl-1-indanone was obtained as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C1(C)C=CC=CC=1>[CH2:11]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCBr
Reactant: c1ccc2c(c1)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCN1CCc2ccccc21
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A mixture of indoline (17 parts), 1-bromoheptane (31 parts), potassium carbonate (24 parts) and N,N-dimethylformamide (30 parts) was stirred at 100° C. for 3 days. The cooled mixture was diluted with toluene, washed with water (×4), dried (MgSO4) and evaporated to leave 1-heptyl-2,3-dihydro-1H-indole (30 parts).
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[C:6]([C:14]([O:16][CH3:17])=[O:15])=[N:7][C:8]([N+:11]([O-])=O)=[CH:9][N:10]=1>C(=O)([O-])[O-].[Ca+2].[Pd+2].C(=O)([O-])[O-].C(O)(=O)C>[NH2:11][C:8]1[N:7]=[C:6]([C:14]([O:16][CH3:17])=[O:15])[C:5]([O:4][CH3:3])=[N:10][CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)c1nc([N+](=O)[O-])cnc1OC
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Product: COC(=O)c1nc(N)cnc1OC
Yield: 71.8 %

Procedure:
At room temperature and under a pressure of 1 atmosphere, hydrogen gas was introduced into a mixture of 24.3 g of methyl 3-methoxy-6-nitro-2-pyrazinecarboxylate, 480 mL of acetic acid and 1.2 g of lead-poisoned palladium-calcium carbonate until the mixture became showing no further absorption of hydrogen. After filtering off insoluble matter from the reaction mixture, the solvent was removed under reduced pressure, and the solid product thus obtained was washed with ethyl acetate and diethyl ether. Thus, 15.0 g of methyl 6-amino-3-metoxy-2-pyrazinecarboxylate was obtained as a solid product. Furthermore, the solvent was removed from the filtrate under reduced pressure to obtain a solid product, and the solid product was washed with ethyl acetate to obtain 2.3 g of methyl 6-amino-3-methoxy-2-pyrazinecarboxylate as a solid product.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:35]1[N:36]=[C:37]([NH:40]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[S:38][CH:39]=1)\[C:7]([NH:9][C@@H:10]1[C:33](=[O:34])[N:12]2[C:13]([C:21]([O:23]CC3C=CC(OC)=CC=3)=[O:22])=[C:14](/[CH:17]=[CH:18]\[CH2:19]Cl)[CH2:15][S:16][C@H:11]12)=[O:8].[I-].[Na+].[CH3:62][N:63]([CH2:65][C:66]1[S:70][CH:69]=[N:68][C:67]=1[CH3:71])[CH3:64]>>[NH2:40][C:37]1[S:38][CH:39]=[C:35](/[C:6](=[N:5]/[O:4][CH2:3][CH2:2][F:1])/[C:7]([NH:9][C@@H:10]2[C:33](=[O:34])[N:12]3[C:13]([C:21]([O-:23])=[O:22])=[C:14](/[CH:17]=[CH:18]/[CH2:19][N+:63]([CH3:64])([CH3:62])[CH2:65][C:66]4[S:70][CH:69]=[N:68][C:67]=4[CH3:71])[CH2:15][S:16][C@H:11]23)=[O:8])[N:36]=1
Reactant: COc1ccc(COC(=O)C2=C(/C=C\CCl)CS[C@@H]3[C@H](NC(=O)/C(=N\OCCF)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C(=O)N23)cc1
Reactant: Cc1ncsc1CN(C)C
Agent: [I-]
Agent: [Na+]
Product: Cc1ncsc1C[N+](C)(C)C/C=C/C1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OCCF)c3csc(N)n3)[C@H]2SC1
Yield: 32.3 %

Procedure:
p-methoxybenzyl 7β[(Z)-2-fluoroethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]3-[(Z)-3-chloro-1-propen-1-yl]3-cephem-4-carboxylate (1.3 g), sodium iodide(0.68 g) and 5-dimethylaminomethyl-4-methylthiazole(0.27 g) were reacted in the same manner as described in Example 1 to obtain the target product (300 mg).
Reaction SMILES: C(O[C:9](=O)[N:10]([CH:12]([C:14](=[O:48])[NH:15][CH:16]([CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[C:17]([N:19]1[CH2:23][CH2:22][CH:21]2[N:24]([S:38]([CH3:41])(=[O:40])=[O:39])[CH2:25][CH:26]([C:27](=[O:37])[NH:28][CH:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:30])[CH:20]12)=[O:18])[CH3:13])C)C1C=CC=CC=1>CO.C(#N)C.O.[Pd]>[C:31]1([CH:29]([NH:28][C:27]([CH:26]2[CH2:25][N:24]([S:38]([CH3:41])(=[O:40])=[O:39])[CH:21]3[CH2:22][CH2:23][N:19]([C:17](=[O:18])[CH:16]([CH:42]4[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47]4)[NH:15][C:14](=[O:48])[CH:12]([NH:10][CH3:9])[CH3:13])[CH:20]23)=[O:37])[CH3:30])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(NC(=O)C1CN(S(C)(=O)=O)C2CCN(C(=O)C(NC(=O)C(C)N(C)C(=O)OCc3ccccc3)C3CCCCC3)C12)c1ccccc1
Agent: [Pd]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: CNC(C)C(=O)NC(C(=O)N1CCC2C1C(C(=O)NC(C)c1ccccc1)CN2S(C)(=O)=O)C1CCCCC1
Reaction time: 2.5 h

Procedure:
A solution of 32 (113 mg, 0.16 mmol) in MeOH (15 mL) was treated with 10% Pd/C (wet, 151 mg) and pressurized under H2 atmosphere (50 psi) using a Parr apparatus. After 2.5 h, the reaction mixture was filtered through a filter disc (Acrodisc-PSF-0.45 μM) and rinsed with MeOH. The filtrate was concentrated to afford the crude amine 33 which was diluted with ACN/H2O containing 0.1% HOAc and purified by reverse phase HPLC (2″ Dynamax® C18, 10% ACN/H2O to 100% ACN over 30 min). The product-containing fractions were combined, frozen, and lyophilized to afford 33 as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([NH:6][CH:7]([CH:9]1[CH2:11][CH2:10]1)[CH3:8])=[O:5].[H-].[Na+].[Br:19]Br.Cl>CN(C)C=O>[NH2:1][C:2]1[C:15]([Br:19])=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([NH:6][CH:7]([CH:9]1[CH2:11][CH2:10]1)[CH3:8])=[O:5]
Reactant: CC(NC(=O)c1cc(Cl)ccc1N)C1CC1
Reactant: BrBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(NC(=O)c1cc(Cl)cc(Br)c1N)C1CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
0.1 g of 2-amino-5-chloro-N-(1-cyclopropylethyl)benzamide was dissolved in 3 ml of N,N-dimethylformamide and cooled to 0° C. 0.02 g of sodium hydride was added, followed by stirring for one hour, and 0.09 g of bromine was added, followed by stirring for 2 hours. The reaction liquid was added to a 1 M-HCl aqueous solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 1/1) to obtain 0.08 g of the pale yellow desired produce (melting point: 177° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C@@H:16]3[C@@H:12]([CH2:13][O:14][CH2:15]3)[O:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[F:20][C:21]([F:34])([F:33])[CH2:22][O:23][C:24]1[N:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=1>>[NH2:17][C:10]1[O:11][C@H:12]2[C@@H:16]([C@:8]([C:6]3[CH:7]=[C:2]([NH:1][C:30]([C:27]4[CH:26]=[N:25][C:24]([O:23][CH2:22][C:21]([F:33])([F:34])[F:20])=[CH:29][N:28]=4)=[O:31])[CH:3]=[CH:4][C:5]=3[F:19])([CH3:18])[N:9]=1)[CH2:15][O:14][CH2:13]2
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21
Reactant: O=C(O)c1cnc(OCC(F)(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3cnc(OCC(F)(F)F)cn3)ccc2F)N=C(N)O[C@@H]2COC[C@@H]21

Procedure:
The coupling of (3aS,7S,7aS)-7-(5-amino-2-fluoro-phenyl)-7-methyl-3,3a,7,7a-tetrahydro-1H-2,4-dioxa-6-aza-inden-5-ylamine and 5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid (prepared as described in Suzuki Y. et al., WO 2009/091 016) following procedure G yielded the title compound as a colorless solid. MS: m/z=470.2 [M+H]+.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:38])[NH:16][C:17]2[C:18](=[O:37])[N:19]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[F:36])[C:20](=[O:28])[N:21]([CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:22]=2[NH2:23])=[CH:10][CH:9]=1)(C)(C)C.[ClH:40]>O1CCOCC1>[ClH:40].[NH2:23][C:22]1[N:21]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[C:20](=[O:28])[N:19]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[F:36])[C:18](=[O:37])[C:17]=1[NH:16][C:15](=[O:38])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([NH2:7])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CC(=O)Nc2c(N)n(CC3CC3)c(=O)n(Cc3ccccc3F)c2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(CC(=O)Nc2c(N)n(CC3CC3)c(=O)n(Cc3ccccc3F)c2=O)cc1
Temperature: 0 °C
Yield: 89 %

Procedure:
A solution of (4-{[6-amino-1-cyclopropylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-ylcarbamoyl]-methyl}-phenyl)-carbamic acid tert-butyl ester (2.20 g, 4.10 mmol) in a solution of a 4.0N aqueous hydrochloric acid solution in dioxane (37.0 mL) was stirred at 25° C. for 1 h. A suspension formed during this time. The reaction mixture was cooled to 0° C. The resulting solid was collected by filtration, washed with dioxane and cold diethyl ether, and dried in vacuo to afford N-[6-amino-1-cyclopropylmethyl-3-(2-fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]-2-(4-amino-phenyl)-acetamide, hydrochloride salt (1.73 g, 89%); LRMS for C23H23FN5O3 (M+H)+ at m/z=438.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][N:13]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][CH2:23][CH3:24])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH2:22]([C:19]1[CH:18]=[N:17][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([C:35]5[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=5)[CH:26]=[CH:25][C:5]=4[N:6]=3)[CH2:11][CH2:12]2)=[N:21][CH:20]=1)[CH2:23][CH3:24]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)nc1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: C1COCCO1
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a degassed solution of 6-bromo-2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazole (190 mg, 0.438 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (163 mg, 0.526 mmol) and K2CO3 (182 mg, 1.315 mmol) in dioxane (3 mL) and water (1 mL) was added Pd(Ph3P)4 (25.3 mg, 0.022 mmol). Upon completion of addition, the reaction mixture was heated to 100° C., where it stirred overnight. At the conclusion of this period, the reaction mixture was cooled to rt, diluted with water and then extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford Compound 1D as a white solid (166 mg, 0.310 mmol, 71% yield). 1H NMR (500 MHz, chloroform-d) δ ppm 8.17 (2H, s), 7.62-7.65 (1H, m), 7.62 (1H, s), 7.40 (1H, dd, J=8.5, 1.9 Hz), 6.00-6.09 (1H, m), 5.42-5.49 (1H, m), 4.23 (2H, ddd, J=13.3, 6.7, 3.9 Hz), 4.05-4.13 (2H, m), 3.63-3.76 (4H, m), 2.53-2.61 (2H, m), 2.41 (2H, t, J=7.6 Hz), 2.14-2.23 (2H, m), 1.95 (2H, dddd, J=12.8, 8.5, 8.4, 3.9 Hz), 1.57-1.64 (2H, m), 1.51 (9H, s), 0.95 (3H, t, J=7.3 Hz).
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([CH:20]4[CH2:22][CH2:21]4)[CH:13]=[C:14]([C:15]([O:17]CC)=[O:16])[C:9]=3[C:8]([CH3:23])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([CH:20]4[CH2:21][CH2:22]4)[CH:13]=[C:14]([C:15]([OH:17])=[O:16])[C:9]=3[C:8]([CH3:23])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nn(C2CCCC2)c2nc(C3CC3)cc(C(=O)O)c12
Reaction time: 1 h

Procedure:
The title compound was prepared in the same manner as described for intermediate 46 using ethyl 1-cyclopentyl-6-cyclopropyl-3-methyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (740 mg, 2.361 mmol), sodium hydroxide (4 ml, 4.00 mmol), and ethanol (30 mL), wherein the stir time was 1 h. The final product was collected as 0.530 g (79%). LCMS E-S (M+H)=286.3 1H NMR (400 MHz, DMSO-d6) δ ppm 0.96-1.12 (m, 4 H) 1.52-1.74 (m, 2 H) 1.82-2.13 (m, 6 H) 2.26-2.37 (m, 1 H) 2.55 (s, 3 H) 5.17-5.30 (m, 1 H) 7.43 (s, 1 H) 13.70 (br. s., 1 H).
Reaction SMILES: C[O-].[Na+].CO.[O:6]=[C:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[CH2:25][CH2:24][CH2:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH2:9][CH2:8]1.[CH2:26]([N:33]1[CH2:38][CH2:37][CH:36]([CH:39]=O)[CH2:35][CH2:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[O:6]=[C:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:18]4[CH2:25][CH2:24][CH2:23][C:19]=4[N:20]=[CH:21][N:22]=3)=[CH:13][CH:14]=2)[CH2:9][C:8]1=[CH:39][CH:36]1[CH2:35][CH2:34][N:33]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:38][CH2:37]1
Reactant: O=CC1CCN(Cc2ccccc2)CC1
Reactant: O=C1CCc2cc(Nc3ncnc4c3CCC4)ccc21
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C(=CC2CCN(Cc3ccccc3)CC2)Cc2cc(Nc3ncnc4c3CCC4)ccc21
Reaction time: 1.5 h
Yield: 40.6 %

Procedure:
Under ice cooling, 1.70 g of a 28% sodium methoxide·methanol solution was added to 1.96 g of 4-(1-oxoindan-5-yl)amino-5,6-dihydro-7H-cyclopenta[d]pyrimidine dissolved in tetrahydrofuran, and then 1.80 g of 1-benzyl-4-formylpiperidine was added dropwise thereto. After the mixture was stirred for 1.5 hours, a saturated saline solution was added to the reaction mixture, and the mixture was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and condensed under reduced pressure. The obtained residue was applied to silica gel column chromatography and then recrystallized from chloroform to obtain 1.35 g of the title compound as pale yellow crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=1)=[O:12].IC.[C:22](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]([C:13]1[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH3:22])[CH:18]=1)=[O:12]
Reactant: O=C(/C=C/c1cc(Cl)ccc1Cl)c1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)/C=C/c2cc(Cl)ccc2Cl)ccc1=O

Procedure:
In analogy to example 161, step 1, (E)-5-(3-(2,5-dichlorophenyl)acryloyl)pyridin-2(1H)-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:33][CH3:34])=[C:9]([NH:11][C:12]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28](Cl)[N:27]=3)=[CH:17][CH:16]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:35]N(C=O)C>COCCOC.O.CCO.C([O-])([O-])=O.[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:33][CH3:34])=[C:9]([NH:11][C:12]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([O:25][C:26]3[CH:31]=[CH:30][N:29]=[C:28]([CH3:35])[N:27]=3)=[CH:17][CH:16]=2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: COc1ccc(C(C)(C)C)cc1NC(=O)Nc1ccc(Oc2ccnc(Cl)n2)c2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: COc1ccc(C(C)(C)C)cc1NC(=O)Nc1ccc(Oc2ccnc(C)n2)c2ccccc12
Temperature: 160 °C
Yield: 23 %

Procedure:
1-(5-tert-Butyl-2-methoxy-phenyl)-3-[4-(2-chloro-pyrimidin-4-yloxy)-naphthalen-1-yl]-urea (50 mg, 0.1 mmol) was dissolved in 0.4 mL of DMF. To this was added PdCl2(PPh3)2 (10 mol %), o-methoxyboronic acid (32 mg, 0.2 mmol) in 2 mL of DME/H2O/EtOH (7:3:2) and 0.53 mL of Na2CO3 (2M). The reaction was heated in a Smith synthesizer microwave for 3 min at 160° C. The product was concentrated on silica and purified (15-30% EtOAc-hexanes) to provide 13 mg (23%) of the title compound as an off-white foam.