Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].C(O[C:18]1[C:22]([NH2:23])=[C:21]([S:24]([CH3:27])(=[O:26])=[O:25])[S:20](=[O:28])[N:19]=1)C>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:18]2[C:22]([NH2:23])=[C:21]([S:24]([CH3:27])(=[O:26])=[O:25])[S:20](=[O:28])[N:19]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: CCOC1=NS(=O)C(S(C)(=O)=O)=C1N
Reactant: CN(C)Cc1ccc(CSCCN)o1
Solvent: CC#N
Product: CN(C)Cc1ccc(CSCCNC2=NS(=O)C(S(C)(=O)=O)=C2N)o1
Reaction time: 15 h

Procedure:
To a solution of 2-[(5-dimethylaminomethyl-2furanyl)methylthio]ethylamine (440 mg, 2 mmol) in acetonitrile (6 ml) there was added 3-ethoxy-4-amino-5-methylsulfonylisothiazole-1-oxide (480 mg, 2 mmol). This mixture was stirred under a nitrogen atmosphere for 15 hours as product slowly crystallized out. Precipitate was collected by filtration, washed with acetonitrile, diethyl ether and air dried to give 650 mg, of title compound, mp 134°-137°.
Reaction SMILES: [NH2:1][C:2]1[C:12](I)=[CH:11][C:10]([Br:14])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6].C([Sn](CCCC)(CCCC)[C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)CCC>C1COCC1.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>[NH2:1][C:2]1[C:12]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][C:10]([Br:14])=[C:4]2[C:5]([NH:7][C:8](=[O:9])[C:3]=12)=[O:6]
Reactant: Nc1c(I)cc(Br)c2c1C(=O)NC2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Nc1c(-c2ccco2)cc(Br)c2c1C(=O)NC2=O
Yield: 52.5 %

Procedure:
In a similar manner to Step 1 of Example 10, 3-amino-4-iodo-6-bromophthalimide (100 mg, 0.273 mmol) was dissolved in THF (5 mL), and the solution was treated with 2-(tributylstannyl)furan (0.129 mL, 0.410 mmol) and bis(triphenylphosphine)dichloropalladium (15 mg, 0.022 mmol), followed by purification by preparative thin-layer chromatography (chloroform/acetonitrile=50/1, 40/1) to obtain 3-amino-4-(furan-2-yl)-6-bromophthalimide (44 mg, yield 52%).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:13])[CH3:12]>C(OCC)C>[Br:1][CH2:12][C:11]([C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[Cl:3])=[O:13]
Reactant: BrBr
Reactant: CC(=O)c1ccc(Cl)cc1Cl
Solvent: CCOCC
Product: O=C(CBr)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Bromine (4.23 g, 26.4 mmol) was slowly added dropwise to a solution of 1-(2,4-dichlorophenyl)ethanone (5.00 g, 26.4 mmol) in diethyl ether (100 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was distilled off under reduced pressure to give 2-bromo-1-(2,4-dichlorophenyl)ethanone as an oil quantitatively.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:26]2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: Nc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1ccc2c(c1)CN(c1c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 42.3 %

Procedure:
200 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 99 mg of 5-aminoisoindoline, 200 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 117 mg of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].C(N(CC)CC)C.[Cl:16][CH2:17][C:18](Cl)=[O:19]>ClCCl>[Cl:16][CH2:17][C:18]([NH:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])=[O:19]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccncc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccncc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 3-fluoro-pyridin-4-ylamine (0.2 g) in dry dichloromethane (2 mL) under nitrogen at 0° C. was treated with triethylamine (0.28 mL) followed by slow addition of chloroacetyl chloride (0.16 mL). The reaction mixture was allowed to warm up to room temperature. After 2 h, the mixture was partitioned between dichloromethane and water The phases were separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated to give the crude product which was purified by silica gel chromatography eluting with 0-100% EtOAc/cyclohexane. The relevant fractions were combined and evaporated to give the title compound (0.11 g) as a pink solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:36]=[CH:35][C:14]([CH2:15][C:16]23[C:24](=[O:25])[N:23]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=4)[C:22](=[O:34])[N:21]2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:13][CH:12]=1)=[O:4].[OH-].[Na+].Cl>CO.O>[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]23[C:24](=[O:25])[N:23]([C:26]4[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=4)[C:22](=[O:34])[N:21]2[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:35][CH:36]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Temperature: 50 °C
Yield: 83.1 %

Procedure:
A solution of 6-[4-(2-methoxycarbonylphenyl)benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione (0.141 g) in MeOH/H2O (5/1 mL) containing NaOH (0.087 g) was heated at 50° C. for 2 h. The reaction mixture was cooled in ice and acidified with 0.5 N HCl. It was extracted with EtOAc and the extract was washed with water, brine, dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: CHCl3/MeOH: 100/1 to 50/1, Chromatotron) afforded the titled compound (114 mg). MS (m/z) 531(M++Na).
Reaction SMILES: Cl.[N:2]1([C:8]2[CH:9]=[C:10]([CH:14]3[N:18]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[F:26])[N:17]=[C:16]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:15]3)[CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:18]1[CH:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([N:2]3[CH2:3][CH2:4][N:5]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:6][CH2:7]3)[CH:9]=2)[CH2:15][C:16]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])=[N:17]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2cccc(N3CCNCC3)c2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
5-[3-(piperazin-1-yl)-phenyl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (100.0 mg, 0.2 mmol) prepared in Step 1, triethylamine (143.0 uL, 1.02 mmol) and methanesulfonyl chloride (35.0 mg, 0.30 mmol) were added to dichloromethane (2.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/1) to give 55.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [NH2:1][C:2]([C:11]1[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1)([CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>C(OCC)(=O)C>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29](=[O:30])[NH:1][C:2]([C:11]1[N:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[N:12]=1)([CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=C=Nc1ccccc1Cl
Reactant: CCOC(=O)C(N)(c1nc(OC)cc(OC)n1)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)C(NC(=O)Nc1ccccc1Cl)(c1nc(OC)cc(OC)n1)C(C)C
Yield: 88.6 %

Procedure:
A solution of ethyl 2-amino-3-methyl-2-(4,6-dimethoxypyrimidin-2-yl)butanoate (0.556 g) and 2-chlorophenylisocyanate (0.306 g) in ethyl acetate (30 ml) was refluxed for 5 hours, evaporated to dryness, and flash chromatographed on silica gel, eluting with ethyl acetate/60°-80° petroleum ether (1:2). The residual gum was triturated with 60°-80° petroleum ether, to give 0.76 g of the desired product as a white solid, mp 84°-87° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[CH3:20]O>>[CH3:20][O:18][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1]
Reactant: CO
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Product: COC(=O)CCCCCCCCCCCCCCCO
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 92 %

Procedure:
To a cooled (0° C.) solution of 16-hydroxyhexadecanoic acid (3000 mg, 10.79 mmol) in anhydrous methanol (27 ml) acetyl chloride (3.837 ml, 53.96 mmol) was added dropwise at 0° C. within 2 min, then the mixture was stirred at room temperature for 3.5 hrs under Ar-atmosphere. Subsequently the mixture was evaporated to dryness, the residue was dissolved in dichloromethane (100 ml), washed with saturated sodium bicarbonate solution (2×50 ml) and Brine solution (1×50 ml). After drying over sodium sulfate the collected organic layer was evaporated to dryness and vacuum dried at room temperature. Yield: 92% (white solid).
Reaction SMILES: [CH:1]1([C:4]2[CH:16]=[CH:15][C:7]([O:8][CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=1>>[Br:17][C:18]1[N:19]=[CH:20][C:21]([C:22]([N:12]2[CH2:13][CH2:14][CH:9]([O:8][C:7]3[CH:15]=[CH:16][C:4]([CH:1]4[CH2:2][CH2:3]4)=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[O:23])=[CH:25][CH:26]=1
Reactant: c1cc(C2CC2)ccc1OC1CCNCC1
Reactant: O=C(O)c1ccc(Br)nc1
Product: O=C(c1ccc(Br)nc1)N1CCC(Oc2ccc(C3CC3)cc2)CC1
Yield: 100.7 %

Procedure:
To a mixture of 1-Boc-4-(4-bromophenoxy)piperidine (5 g), dichlorobis(tricyclohexylphosphine)palladium(II) (725 mg), tripotassium phosphate (14.9 g) and cyclopropylboronic acid (1.81 g) was added toluene (70 mL), and the mixture was stirred with heating under reflux for 7 hr. The reaction mixture was cooled, water was added, and the insoluble material was collected by filtration. The filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography to give 4-(4-cyclopropylphenoxy)piperidine-1-carboxylic acid tert-butyl ester. The obtained 4-(4-cyclopropylphenoxy)piperidine-1-carboxylic acid tert-butyl ester was dissolved in ethyl acetate (3 mL), 4N hydrogen chloride/ethyl acetate (7 mL) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was washed with ethyl acetate. To the obtained aqueous layer was added 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(4-cyclopropylphenoxy)piperidine (2.49 g). Using the obtained 4-(4-cyclopropylphenoxy)piperidine (1.4 g) and 6-bromonicotinic acid (1.2 g) and by the reaction and treatment in the same manner as in Preparation Example 111, the title compound (2.4 g) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C=CC2C3N(CC(C)C)C(CCC)=NC=3C=[N:45]C=2C=1)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:20]([CH2:26][O:27][CH2:28][CH3:29])=[N:19][C:14]=3[C:15]([NH2:45])=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CC(C)C
Product: CCOCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CC(C)C

Procedure:
The general methods described in Parts H and I of Example 1 were followed using 7-benzyloxy-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline (29.2 g, 78.2 mmol) in lieu of 7-benzyloxy-1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c]quinoline. The crude product was triturated with acetonitrile, isolated by filtration, and dried for 18 hours in a vacuum oven at 68° C. to provide 16.3 g of 7-benzyloxy-2-ethoxymethyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine an off-white solid, mp 201.0-203.0° C.
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[S:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([NH:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:8]2[S:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2sc3cnccc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)sc2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(3-methylthieno[2,3-c]pyridin-2-yl)methyl]amino}phenyl)carbonyl]amino}propanoate (209 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 1 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (169 mg, 86%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[C:22]([O:24]C)=[O:23])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:27]1[S:28][C:29]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:30]=2[N:31]=1.[OH-].[Na+]>C(O)CCC>[Cl:36][C:34]1[CH:33]=[CH:32][C:30]2[N:31]=[C:27]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]5[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]5[C:22]([OH:24])=[O:23])=[O:15])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:28][C:29]=2[CH:35]=1
Reactant: COC(=O)[C@@H]1CCCC[C@@H]1C(=O)c1ccc(-c2ccc(N)cc2)cc1
Reactant: Clc1ccc2nc(Cl)sc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: O=C(O)[C@@H]1CCCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
To a solution of cis-methyl 2-[(4′-amino-1,1′-biphenyl-4-yl)carbonyl]cyclohexanecarboxylate (200 mg, 0.59 mmol) in n-butanol (8 mL) was added 2,6-dichloro-1,3-benzothiazole (241 mg, 1.19 mmol), and the resulting reaction mixture was heated at 90° C. overnight. The mixture was evaporated to dryness and the residue was combined with MeOH. Then 1 N NaOH (6.0 mL, 6.0 mmol) was added to the suspension, and the reaction mixture was stirred at 50° C. overnight. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in water. Concentrated aqueous HCl was added to adjust the acidity to pH 1, and the precipitate was collected by filtration, washed with water and MeOH, and dried in a vacuum oven to give trans-2-({4′-[(6-chloro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclohexanecarboxylic acid (45 mg, 15%). LC-MS m/z 491.1 (, ret. time 3.90 min; 1H NMR (400 MHz, DMSO-d6) δ 1.13 (m, 1H), 1.28-1.51 (m, 3H), 1.78 (m, 1H), 1.93 (m, 1H), 2.09 (m, 1H), 2.68 (m, 1H), 3.63 (m, 1H), 7.35 (m, 1H), 7.60 (m, 1H), 7.80 (m, 4H), 7.90 (d, 1H), 7.96 (m, 1H), 8.05 (d, 2H), 10.75 (s, 1H).
Reaction SMILES: [Na].[CH3:2]CN(C(C)C)C(C)C.[OH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[O:13].[F:18][C:19]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[CH:42][C:20]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[N:29]=[C:30]3[CH2:41][CH2:40][NH:39][CH2:38][C:31]3=[N:32][C:33]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:24][CH2:23]1.C=O>CO>[F:18][C:19]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[CH:42][C:20]=1[O:21][CH:22]1[CH2:23][CH2:24][N:25]([C:28]2[N:29]=[C:30]3[CH2:41][CH2:40][N:39]([CH3:2])[CH2:38][C:31]3=[N:32][C:33]=2[NH:34][CH:35]([CH3:37])[CH3:36])[CH2:26][CH2:27]1.[C:12]([OH:13])([C:14]([F:17])([F:16])[F:15])=[O:11]
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CNCC4)CC2)c(F)c1
Agent: C=O
Agent: [Na]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(OC2CCN(c3nc4c(nc3NC(C)C)CN(C)CC4)CC2)c(F)c1
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyhydroborate (9.7 mg, 0.046 mmol) was added to a solution of DIPEA (8 μL, 0.046 mmol), 2-(4-(2-fluoro-4-methoxyphenoxy)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (12.1 mg, 0.023 mmol) and formaldehyde (1.9 μL, 0.023 mmol) in MeOH (229 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (12.1 mg, 97%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (d, J=6.3 Hz, 6H), 1.88-1.99 (m, 2H), 2.04-2.14 (m, 2H), 2.93-3.04 (m, 3H), 3.08 (br s, 4H), 3.35-3.53 (m, 3H), 3.76 (br s, 4H), 4.10-4.19 (m, 1H), 4.20-4.40 (m, 3H), 6.64-6.69 (m, 1H), 6.74 (dd, J=12.8, 2.1 Hz, 1H), 7.07 (t, J=9.2 Hz, 1H); ESI-MS m/z [M+H]+ 430.4.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])(=O)[CH3:2].Cl.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>CO>[CH2:13]([O:20][N:21]=[C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8])[CH3:2])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)c1cccc(C#N)c1
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=NOCc1ccccc1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95 %

Procedure:
To a suspension of 14.52 g (0.10 mol) of 3-acetylbenzonitrile in 100 ml of methanol was added 17.56 g (0.11 mol) of O-benzylhydroxyamine hydrochloride and further added dropwise 9.49 g (0.12 mol) of pyridine. The mixture was stirred at room temperature for 2.5 hours, and most of the methanol was distilled off. To the residue was added ethyl acetate and resultant mixture was washed successively with about 5% aqueous hydrochloric acid twice, an about 5% aqueous solution of sodium bicarbonate once, and water once, then dried and concentrated to obtain 24.15 g (95.0 mmol) of crude 3-(1-(benzyloxyimino)ethyl)benzonitrile.
Reaction SMILES: Br[C:2]1[C:3]([N:11]2[CH2:16][CH2:15][N:14]([C:17](=[O:38])[C@@H:18]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH2:19][N:20]([CH:28]([CH3:30])[CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH2:12]2)=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:46]=1[O:47][CH3:48].C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:37][C:34]1[CH:33]=[CH:32][C:31]([C@H:18]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:3]3[C:2]([C:44]4[CH:43]=[CH:42][C:41]([O:40][CH3:39])=[C:46]([O:47][CH3:48])[CH:45]=4)=[CH:7][N:6]=[C:5]4[NH:8][CH:9]=[CH:10][C:4]=34)[CH2:16][CH2:15]2)=[O:38])[CH2:19][N:20]([CH:28]([CH3:29])[CH3:30])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:36][CH:35]=1
Reactant: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(Br)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: COc1ccc(B(O)O)cc1OC
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+]
Product: COc1ccc(-c2cnc3[nH]ccc3c2N2CCN(C(=O)[C@H](CN(C(=O)OC(C)(C)C)C(C)C)c3ccc(Cl)cc3)CC2)cc1OC
Temperature: 80 °C
Yield: 18.3 %

Procedure:
(S)-tert-Butyl 3-(4-(5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-2-(4-chlorophenyl)-3-oxopropyl(isopropyl)carbamate (0.100 g, 0.165 mmol, see Example 4), 3,4-dimethoxyphenylboronic acid (0.0361 g, 0.198 mmol), Pd(PPh3)4 (0.009 g, 0.0083 mmol) and 10% K2CO3 (aq., 0.344 mL, 0.248 mmol) were added to an Ar degassed solution of 2:1 toluene:EtOH (3 mL). The reaction was then heated to 80° C. for 24 hours. The reaction was then cooled to room temperature, diluted with water, and extracted with DCM. The organic fractions were dried, filtered, concentrated, and purified (500:10-500:15) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(3,4-dimethoxyphenyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (0.020 g, 18.2% yield).
Reaction SMILES: [CH3:1][C:2]1([CH2:9][S:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].[OH:28]OS([O-])=O.[K+].C(=O)(O)[O-].[Na+].O>CO>[CH3:1][C:2]1([CH2:9][S:10]([C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:25])([F:27])[F:26])=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[O:28])[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8]
Reactant: O=S([O-])OO
Reactant: CC1(CSc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)NC(=O)NC1=O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC1(CS(=O)c2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)NC(=O)NC1=O
Yield: 43.3 %

Procedure:
5-methyl-5-[({4′-[(trifluoromethyl)oxy]-1,1′-biphenyl-4-yl}thio)methyl]imidazolidine-2,4-dione (48 mg, 0.112 mmol) was stirred at room temperature with oxone (50 mg), sodium bicarbonate (50 mg), water (5 ml) and Methanol (10 ml) for 18 hours. The solid was filtered off and crystallized from ethanol to give 20 mg of the title compound.
Reaction SMILES: [CH:1]1([CH2:7][C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:12][C:13]1[C:17]([CH2:18][N:19]2[CH:23]=[C:22]([NH2:24])[CH:21]=[N:20]2)=[C:16]([CH3:25])[O:15][N:14]=1>>[CH:1]1([CH2:7][C:8]([NH:24][C:22]2[CH:21]=[N:20][N:19]([CH2:18][C:17]3[C:13]([CH3:12])=[N:14][O:15][C:16]=3[CH3:25])[CH:23]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C(O)CC1CCCCC1
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(NC(=O)CC2CCCCC2)cn1
Yield: 17 %

Procedure:
Prepared as in Example 4-8 from 2-cyclohexylacetic acid and 1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (Example 4-1a). Yield 17%. MS M+H calculated 317.6. Found 317.4.