Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=3[N:16]=[C:15]2[CH:25]([F:27])[F:26])[N:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([S:35]([C:38]2[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:27][CH:25]([F:26])[C:15]1[N:14]([C:4]2[N:3]=[C:2]([C:41]3[CH:42]=[CH:43][C:38]([S:35]([N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)(=[O:36])=[O:37])=[CH:39][CH:40]=3)[N:7]=[C:6]([N:8]3[CH2:9][CH2:10][O:11][CH2:12][CH2:13]3)[N:5]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH3:24])[C:17]=2[N:16]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CN1CCN(S(=O)(=O)c2ccc(B(O)O)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(-c2ccc(S(=O)(=O)N3CCN(C)CC3)cc2)nc(N2CCOCC2)n1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A mixture of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-4-methoxy-1H-benzimidazole (Example 2) (200 mg, 0.504 mmol), 4-[(4-methyl-1-piperazinyl)sulfonyl]phenylboronic acid (186 mg, 0.655 mmol), PdCl2(dppf) (29 mg, 0.0355 mmol), and aq. K2CO3 (2M, 3 mL) in 1,4-dioxane (20 mL) was refluxed under nitrogen for 1 hr. The mixture was cooled to room temperature and diluted with H2O, and the aqueous phase extracted with CH2Cl2 (9×). The combined organic extracts were dried (Na2SO4), and the solvent was removed under vacuum. Chromatography on alumina, eluting with CH2Cl2/MeOH (100:0 to 99.75:0.25), followed by chromatography on silica, eluting with CH2Cl2/MeOH (100:0 to 98:2), and recrystallization from CH2Cl2/MeOH/hexanes gave 2-(difluoromethyl)-4-methoxy-1-[4-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (93 mg, 31%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].N>C(OCC)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C1CCCN1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: N
Solvent: CCOCC
Product: COc1ccc(C(=O)N2CCCC2=O)cc1

Procedure:
20 g. of p-methoxybenzoyl chloride and 20 g. of 2-pyrrolidinone are boiled at reflux in 20 ml. of diethyl ether for 16 hours and then diethyl ether, ice and 2-N aqueous ammonia are added to the mixture. The insoluble constituents are filtered off and washed ion-free with diethyl ether and water. The filter cake is dried and there is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone having a melting point of 119.5°-120.5° C.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][C:26]=1[O:27]C)[CH2:7][C:8]1[C:21]([CH3:22])=[CH:20][C:11]([NH:12][C:13](=[O:19])[C:14]([O:16]CC)=[O:15])=[CH:10][C:9]=1[CH3:23])([CH3:3])[CH3:2].B(Br)(Br)Br>ClCCl>[OH:27][C:26]1[CH:25]=[CH:24][C:6]([CH2:7][C:8]2[C:9]([CH3:23])=[CH:10][C:11]([NH:12][C:13](=[O:19])[C:14]([OH:16])=[O:15])=[CH:20][C:21]=2[CH3:22])=[CH:5][C:4]=1[CH:1]([CH3:3])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1cc(C)c(Cc2ccc(OC)c(C(C)C)c2)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc(NC(=O)C(=O)O)cc(C)c1Cc1ccc(O)c(C(C)C)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 99.4 %

Procedure:
128 mg (0.33 mmol) of ethyl 2-[4-(3-isopropyl-4-methoxybenzyl)-3,5-dimethyl-anilino]-2-oxoacetate (Example 1) in 5 ml of dichloromethane at −78° C. under argon are treated dropwise with 167 mg (0.66 mmol) of boron tribromide. The reaction mixture is stirred at room temperature for 2.5 hours. It is poured into buffer of pH 7, the phases are separated, the aqueous phase is acidified with buffer of pH 4 and, after extraction with dichloromethane, the organic phases are combined. The solution is dried over sodium sulphate and the solvent is removed in vacuo. 112 mg (98%) of 2-[4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylanilino]-2-oxoacetic acid are obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[NH:2]=[C:1]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: C1CCNC1
Product: N=C(c1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1)N1CCCC1
Yield: 16 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 2 equivalents of pyrrolidine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [C:1]([CH:4]([CH2:17][C:18]1[CH:23]=[C:22]([F:24])[C:21]([O:25][Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[C:20]([F:36])[CH:19]=1)[CH2:5][CH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)(O)=[O:2].[Cl-].[NH4+]>C1COCC1>[F:36][C:20]1[CH:19]=[C:18]([CH:23]=[C:22]([F:24])[C:21]=1[O:25][Si:26]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:33]([CH3:34])[CH3:35])[CH2:17][CH:4]([CH2:1][OH:2])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(CCC(Cc2cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c2)C(=O)O)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC(CO)Cc2cc(F)c(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c2)cc1
Temperature: -10 °C

Procedure:
4.2 g (8.07 mmol) of methyl 4-[3-carboxy-4-(3,5-difluoro-4-triisopropylsilanyloxyphenyl)butyl]-benzoate are dissolved in 200 ml of THF and cooled to −10° C. under argon. Then 16.13 ml (16.13 mmol) of a 1 M borane-THF complex solution are added dropwise, and the mixture is stirred at 0° C. until reaction is complete. The mixture is hydrolyzed with saturated ammonium chloride solution and extracted with diethyl ether, and the combined organic phases are concentrated. The resulting crude product is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1→10:1→4:1). 2.92 g (71% of theory) of the title compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][S:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.Cl.[CH:18](=O)/[CH:19]=[CH:20]/[CH3:21].N>>[CH3:18][C:19]1[CH:20]=[CH:21][C:14]2[C:13](=[CH:12][CH:11]=[C:10]([S:9][S:8][C:5]3[CH:4]=[C:3]4[C:2](=[CH:7][CH:6]=3)[N:1]=[C:3]([CH3:4])[CH:2]=[CH:7]4)[CH:15]=2)[N:16]=1
Reactant: Nc1ccc(SSc2ccc(N)cc2)cc1
Reactant: C/C=C/C=O
Agent: Cl
Agent: N
Product: Cc1ccc2cc(SSc3ccc4nc(C)ccc4c3)ccc2n1

Procedure:
To a stirred slurry of 4-aminophenyl disulfide (5.0 g, 0.02 mol) in refluxing 6M HCl (65 ml) was added crotonaldehyde (4.2 g, 0.06 mol) dropwise over 90 minutes. The resulting mixture was refluxed for an additional 2 hours, then cooled to ambient. Conc aqueous ammonia was added to adjust the pH to neutral and the mixture extracted with ethyl acetate. The combined extracts were washed with water, then saturated aqueous brine, dried (MgSO4), filtered and concentrated. The crude was purified on silica gel, eluting with 50 to 100% ethyl acetate/petrol. The product was an oil (2.57 g, 37%); MS ES+ 349.17.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[C:17](=[O:24])[N:16]2[CH3:25])=[CH:11][CH:10]=1)C1C=CC=CC=1.S(=O)(=O)(O)O>O.[OH-].[Na+]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[CH:22][CH:23]=[C:18]3[C:17](=[O:24])[N:16]2[CH3:25])=[CH:13][CH:14]=1
Reactant: Cn1c(=O)c2cccnc2n1-c1ccc(OCc2ccccc2)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)c2cccnc2n1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.6 %

Procedure:
A mixture of 1-[4-(benzyloxy)phenyl]-2-methyl-1,2-dihydro-3H-pyrazolo[3,4-b]pyridin-3-one (0.28 g) obtained in Example 6, step D) and concentrated sulfuric acid (5.0 ml) was stirred at room temperature for 10 min. The obtained reaction mixture was diluted with water (10 ml), sodium hydroxide in m solid was added to pH 10, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (0.15 g).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[CH:22]=1.OO.[O-:32]Cl=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>CC#N>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([C:10](=[O:11])[NH:12][CH:13]3[CH2:15][CH2:14]3)[CH:16]=[CH:17][C:18]=2[CH3:19])[N:5]=[CH:4][C:3]=1[C:20]([C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[C:27]([OH:32])=[O:28])=[O:29]
Reactant: [O-][Cl+][O-]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C=O)c2)c1N
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C(=O)O)c2)c1N
Yield: 36.8 %

Procedure:
To a stirred solution of 3-[5-amino-4-(3-formylbenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide (900 mg) in CH3CN (25 mL) were added NaH2PO4 (55 mg in 2 mL water) and H2O2 (1.3 g, 30% solution in water) followed by the dropwise addition of an aqueous solution of NaClO2 (365 mg) at 10° C. The mixture was stirred at this temperature for 4 h before Na2SO3 was added. Solvent was removed and residue was dissolved in EtOAc, the organic layer was washed with water and brine and concentrated. The crude product was purified by column chromatography on silica gel eluted with EtOAc followed by EtOAC:AcOH=100:1), to provide the desired intermediate as a beige foam (345 mg, 37%).
Reaction SMILES: [C:1](N1C=CN=C1)(=[O:3])[CH3:2].[F:9][C:10]([F:32])([F:31])[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:22]3[CH:23]=[C:24]([C:27]([NH:29][NH2:30])=[O:28])[CH:25]=[CH:26][C:21]=3[N:20]=[CH:19]2)=[CH:14][CH:13]=1>O1CCCC1>[C:1]([NH:30][NH:29][C:27]([C:24]1[CH:25]=[CH:26][C:21]2[N:20]=[CH:19][N:18]([C:15]3[CH:14]=[CH:13][C:12]([O:11][C:10]([F:9])([F:31])[F:32])=[CH:17][CH:16]=3)[C:22]=2[CH:23]=1)=[O:28])(=[O:3])[CH3:2]
Reactant: CC(=O)n1ccnc1
Reactant: NNC(=O)c1ccc2ncn(-c3ccc(OC(F)(F)F)cc3)c2c1
Solvent: C1CCOC1
Product: CC(=O)NNC(=O)c1ccc2ncn(-c3ccc(OC(F)(F)F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
A mixture of N-acetylimidazole (264 mg, 2.4 mmol), 1-[4-(trifluoromethoxy)phenyl]-1H-benzimidazole-6-carbohydrazide (672 mg, 2.0 mmol) and tetrahydrofuran (20 mL) was stirred overnight at room temperature, and at 50° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the precipitate was collected by filtration to give the title compound (614 mg, yield 81%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][OH:27])[CH2:24][O:23][C:22]3=[O:28])=[C:17]([F:29])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:33]I>CN(C)C=O.[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:30])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[C@H:25]([CH2:26][O:27][CH3:33])[CH2:24][O:23][C:22]3=[O:28])=[C:17]([F:29])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(N3C(=O)OC[C@H]3CO)c(F)c2)CC1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Yield: 56.8 %

Procedure:
(R)-4-[3-fluoro-4-(4-hydroxymethyl-2-oxooxazolidin-3-yl)benzoyl]piperazine-1-carboxylic acid tert-butyl ester (494 mg) described in Preparation Example 92 was dissolved in N,N-dimethylformamide (3.7 mL), sodium hydride (51 mg, 60% in oil) was added under ice-cooling and the mixture was stirred. Then, under ice-cooling, methyl iodide (182 mg) was added and the mixture was stirred at room temperature. The reaction mixture was added to saturated brine under ice-cooling and the mixture was extracted with ethyl acetate. The organic layer was washed twice with saturated brine, and dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (290 mg).
Reaction SMILES: [C:1]([O:9][CH:10]([C@H:13]1[O:22][C@@H:16]2[O:17][C:18](C)(C)[O:19][C@@H:15]2[CH2:14]1)CC)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.C([O-])(O)=O.[Na+]>CO>[C:1]([O:9][CH2:10][C@@H:13]1[CH2:14][C@H:15]([OH:19])[CH:16]([O:17][CH3:18])[O:22]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(OC(=O)c1ccccc1)[C@@H]1C[C@H]2OC(C)(C)O[C@H]2O1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC1O[C@H](COC(=O)c2ccccc2)C[C@@H]1O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 90.3 %

Procedure:
To a solution of [(3aS,5S,6aS)-2,2-dimethyl-3a,5,6,6a-tetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methyl benzoate (compound 32a, 5.1 g, 18 mmol) in MeOH (50 mL) was added H2SO4 (0.5 mL) at room temperature. After being stirred at 80° C. for 0.5 hour, the reaction mixture was cooled to room temperature, neutralized by solid NaHCO3 and concentrated in vacuo. The residue was re-dissolved in EtOAc, washed with water twice. The separated organic layer was dried over Na2SO4 and concentrated in vacuo to afford 4.1 g crude product of [(2S,4S)-4-hydroxy-5-methoxy-tetrahydrofuran-2-yl]methyl benzoate (compound 32b) as oil, which was used in next step directly. MS obsd. (ESI+) [(M+NH4)+]: 270.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.CCN(C1C=CC=CC=1)CC.P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:2]1[CH:11]=[CH:10][C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Oc1ccc2c(n1)CCCC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Clc1ccc2c(n1)CCCC2

Procedure:
A solution of 0.7 g of 2-hydroxy-5,6,7,8-tetrahydroquinoline (prepared according to the methods outlined by Meyers et al., J. Org. Chem., 29: 1435-1438, 1964) and 0.1 g of diethylaniline in 7 mL of phosphorus oxychloride is refluxed for 2 h, cooled and concentrated. The residue taken is up in chloroform, washed with excess 3 N NaOH solution and the organic layer dried and concentrated to provide crude 2-chloro-5,6,7,8-tetrahydro-quinoline (0.45 g) as an oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2([CH2:15][NH2:16])[CH2:14][CH2:13][CH:12]=[CH:11][O:10][CH2:9]2)[CH2:4][CH2:3]1.CC(O)=O.[CH3:21][N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH:32]=O)[C:23]1=[O:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.[OH-].[Na+]>[CH3:21][N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[C:24]([CH2:32][NH:16][CH2:15][C:8]2([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH2:14][CH2:13][CH:12]=[CH:11][O:10][CH2:9]2)[C:23]1=[O:34]
Reactant: CN1CCN(C2(CN)CCC=COC2)CC1
Reactant: Cn1c(=O)c(C=O)cc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN1CCN(C2(CNCc3cc4ccccc4n(C)c3=O)CCC=COC2)CC1
Yield: 69.3 %

Procedure:
To a solution of 1-[3-(4-methylpiperazin-1-yl)-2,3,4,5-tetrahydrooxepin-3-yl]methanamine (250 mg, 1.109 mmole) in 1,2-dichloroethane (4 ml) was added AcOH (290 μL, 5.07 mmole) then 1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (190 mg, 1.015 mmole). After 20 min sodium triacetoxyborohydride (323 mg, 1.522 mmole) was added. After 16 hr the mixture was diluted with 1M aqueous NaOH and extracted with CH2Cl2 (3×). The combined organic layers were dried (MgSO4), filtered, and concentrated. Flash column chromatography (gradient, 0-10% MeOH/CH2Cl2) gave the title compound as a pale yellow oil (279 mg, 69%). 1H-NMR (CDCl3, 500 MHz) d 7.70 (s, 1 H), 7.56 (m, 2 H), 7.35 (d, J=8.30 Hz, 1 H), 7.25 (m, 1 H), 6.24 (d, J=6.6 Hz, 1 H), 4.59 (m, 1 H), 4.25 (dd AB, J=12.94 and 44.19 Hz, 2 H), 3.80 (m, 2 H), 3.74 (s, 3 H), 2.71-2.61 (m, 6 H), 2.44 (m, 4 H), 2.28 (s, 3 H), 2.21-2.06 (m, 4 H), 1.51 (m, 1 H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][C@H:12]([C:20]([NH:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:21])[CH2:11]2)[CH:3]=1.[C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][C:31]=1[F:39])#[N:29].C([O-])(O)=O.[Na+].N#N>O1CCOCC1.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>[C:28]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]3[C@H:15]([C:16]([F:19])([F:18])[F:17])[CH2:14][CH2:13][C@H:12]([C:20]([NH:22][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[O:21])[CH2:11]3)[CH:3]=2)=[CH:32][C:31]=1[F:39])#[N:29]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCC3)CC[C@H]2C(F)(F)F)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NC3CCCC3)CC[C@H]2C(F)(F)F)n1
Temperature: 100 °C
Yield: 66.8 %

Procedure:
To a mixture of cis-1-[6-chloro-2-(methylamino)-4-pyrimidinyl]-N-cyclopentyl-6-(trifluoromethyl)-3-piperidinecarboxamide (46 mg, 0.113 mmol) and (4-cyano-3-fluorophenyl)boronic acid (28.0 mg, 0.170 mmol) in 1,4-dioxane (1 mL) was added saturated aqueous NaHCO3 (0.5 mL), and N2 gas was bubbled through the resulting mixture for 10 minutes into a 5 mL sealable vial. Pd(Ph3P)4 (19.7 mg, 0.017 mmol) was added, and N2 was bubbled for an additional 5 minute. The vial was capped, and the reaction mixture was heated at 100° C. overnight. The reaction was diluted with water (5 mL) and then extracted with EtOAc (3×10 mL). The organics were dried over MgSO4, filtered and concentrated. The resulting yellow oil was then purified on Biotage SNAP column 10 g with gradient of 0 to 40% EtOAc in Hexane to afford the title compound (37 mg) as a yellow oil. LC-MS (ES) m/z=491 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][C@@H:6]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([Cl:32])=[N:12][C:13]=3[NH:17][CH2:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:5]([OH:33])[C@@H:4]1[OH:34].ClC1N=C2C(N=CN2)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1.C(N(C(C)C)CC)(C)C.[C:69]1([CH2:75][CH2:76][C:77](Cl)=[O:78])[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=1>C1COCC1>[Cl:32][C:11]1[N:10]=[C:9]2[C:14]([N:15]=[CH:16][N:8]2[C@@H:6]2[CH2:7][C@H:3]([NH:2][C:77](=[O:78])[CH2:76][CH2:75][C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[C@@H:4]([OH:34])[C@H:5]2[OH:33])=[C:13]([NH:17][CH2:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:12]=1
Reactant: N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: O=C(Cl)CCc1ccccc1
Agent: Cl
Agent: Clc1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCc1ccccc1)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of (1S,2R,3S,5R)-3-amino-5-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopentane-1,2-diol hydrochloride (an intermediate for preparing the compound of Example 22) (100 mg, 0.2 mmol) in dry THF (1 ml) is treated with diisopropylethylamine (0.17 ml, 1 mmol) and 3-phenyl-propionyl chloride (0.03 ml, 0.2 mmol) and the mixture is stirred at room temperature for 18 hours. The solvent is removed under reduced pressure and the residue is dissolved in dichloromethane (2 ml) and washed with dilute hydrochloric acid (2 ml). The organic layer is separated and evaporated under reduced pressure to afford the title compound. LCMS (electrospray): m/z [MH+] 597.32
Reaction SMILES: [CH:1]12[N:8]([C:9]([C:11]3[N:15]4[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:19](Br)[C:14]4=[N:13][CH:12]=3)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2.[NH:25]1[CH:29]=[N:28][CH:27]=[N:26]1.N1C2C(=CC=CC=2O)C=CC=1.C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O.[Cu]I>[CH:1]12[N:8]([C:9]([C:11]3[N:15]4[CH:16]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:19]([N:25]5[CH:29]=[N:28][CH:27]=[N:26]5)[C:14]4=[N:13][CH:12]=3)=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][O:3][CH2:2]2
Reactant: c1nc[nH]n1
Reactant: O=C(c1cnc2c(Br)cc(C(F)(F)F)cn12)N1C2CCC1COC2
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=C(c1cnc2c(-n3cncn3)cc(C(F)(F)F)cn12)N1C2CCC1COC2
Temperature: 170 °C
Reaction time: 0.5 h
Yield: 7.2 %

Procedure:
A mixture of 3-oxa-8-azabicyclo[3.2.1]octan-8-yl(8-bromo-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)methanone (315 mg), 1H-1,2,4-triazole (108 mg), copper(I) iodide (44.5 mg), 8-quinolinol (33.9 mg) and potassium carbonate (215 mg) in DMSO (3.0 mL) was stirred with microwave irradiation at 170° C. for 30 min. To the reaction mixture was added 0.1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (22.0 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13]NC(=O)C2C=CC(N3CCCC3)=CC=2)=[CH:9][CH:8]=1)[CH3:2].OCC1C=CC(C[S:38]([NH:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)(=[O:40])=[O:39])=CC=1>>[CH2:1]([O:3][C:4](=[O:28])[CH:5]=[CH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][S:38](=[O:40])(=[O:39])[NH:41][C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[CH:11][CH:12]=1)[CH3:2]
Reactant: O=S(=O)(Cc1ccc(CO)cc1)Nc1cccnc1
Reactant: CCOC(=O)C=Cc1ccc(CNC(=O)c2ccc(N3CCCC3)cc2)cc1
Product: CCOC(=O)C=Cc1ccc(CS(=O)(=O)Nc2cccnc2)cc1
Yield: 53 %

Procedure:
The titled compound was prepared as described in the process (5-2) using the compound from the process (9-2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[Cl:9].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:16]([O:18][C:19](=[O:22])[C:20]#[CH:21])[CH3:17]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C1COCC1>[CH2:16]([O:18][C:19](=[O:22])[C:20]#[C:21][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([Cl:9])[CH:4]=1)[CH3:17]
Reactant: Clc1ccc(I)cc1Cl
Reactant: C#CC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc(Cl)c(Cl)c1
Temperature: 35 °C
Reaction time: 8 h

Procedure:
Under argon atmosphere, a four neck flask was charged with 1,2-dichloro-4-iodo-benzene (222.8 g, 0.80 mol), bis(triphenylphosphine) palladium(II) chloride (11.2 g, 16.0 mmol, 2 mol %), copper(I) iodide (6.09 g, 32.0 mmol, 4 mol %) and dry THF (2.4 l). At r.t., cesium carbonate (526.6 g, 1.60 mol, 2 eq.) was added over 5 minutes. Afterward, propynoic acid ethyl ester (168.6 ml, 1.60 mol, 2 eq.) was added, and the reaction mixture was stirred overnight at 35° C. An additional portion of propynoic acid ethyl ester (17.0 ml, 0.16 mol, 0.2 eq.) was added, and the reaction was stirred for another 4 h at 35° C. The reaction mixture was evaporated to dryness, and the residue was taken up in toluene (0.8 l) and heptane (1.6 l). The resulting suspension was stirred at 40° C. for 1 h and filtered over celite. The filtrate was concentrated, and the product was purified by silica gel filtration (toluene/heptane 1:2) to yield 175.0 g (89%) of Vb as a white solid.