Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[CH:9][C:8]=2[C:12]([OH:14])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.Cl.[CH3:35][N:36]([CH3:50])[C:37]([C:39]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:43][CH2:42][NH:41][CH2:40]1)=[O:38]>ClCCl>[CH3:35][N:36]([CH3:50])[C:37]([C:39]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:43][CH2:42][N:41]([C:12]([C:8]2[CH:9]=[N:10][O:11][C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:14])[CH2:40]1)=[O:38]
Reactant: O=C(O)c1cnoc1-c1ccccc1
Reactant: CN(C)C(=O)C1(c2ccccc2)CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)C1(c2ccccc2)CCN(C(=O)c2cnoc2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
To a solution of 5-phenylisoxazol-4-carboxylic acid (15 mg, 0.08 mmol) in dichloromethane (2 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (15 mg, 0.08 mol), triethylamine (33 μL, 0.24 mmol) and finally N,N-dimethyl-3-phenylpyrrolidine-3-carboxamide hydrochloride (15 mg, 0.06 mmol) and allowed to stir at ambient temperature overnight. The residue was purified using straight phaseHPLC (1:1 hexane/ethyl acetate) to afford the title compound (4 mg). HRMS (ESI, pos. ion) m/z calcd for C23H23N3O3: 389.1739, found 389.1744.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:37][CH2:36][O:35][CH:34]([CH2:38][OH:39])[CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:32]4[CH2:37][CH2:36][O:35][CH:34]([CH2:38][OH:39])[CH2:33]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: OCC1CNCCO1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Product: OCC1CN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)CCO1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and morpholin-2-ylmethanol (56.8 mg; 0.48 mmol) to give Example 143 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, dd, J=4.7, 1.6 Hz), 7.97 (2H, d, J=7.9 Hz), 7.94-7.87 (1H, m), 7.76-7.69 (1H, m), 7.61 (2H, dd, J=4.7, 1.6 Hz), 7.58-7.48 (4H, m), 4.65 (1H, t, J=5.6 Hz), 3.80 (1H, d, J=11.2 Hz), 3.62-3.50 (3H, m), 3.46-3.39 (2H, m), 3.34-3.28 (1H, m), 2.79 (1H, d, J=11.1 Hz), 2.66 (1H, d, J=11.4 Hz), 2.12 (1H, td, J=11.3, 3.3 Hz), 1.84 (1H, t, J=10.4 Hz). LC/MS (Method C): 514 (M+H)+. HPLC (Method E) Rt 2.12 min (Purity: 99.9%).
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:9])=[C:5]([Br:8])[C:6]=1[CH3:7].C([Li])CCC.[CH3:15][S:16]SC>C(OCC)C>[Br:8][C:5]1[C:6]([CH3:7])=[C:2]([S:16][CH3:15])[S:3][C:4]=1[CH3:9]
Reactant: CSSC
Reactant: Cc1sc(Br)c(C)c1Br
Agent: [Li]CCCC
Solvent: CCOCC
Product: CSc1sc(C)c(Br)c1C
Temperature: -70 °C

Procedure:
20.0 G. of 2,4-dibromo-3,5-dimethylthiophene was dissolved in 300 ml. of anhydrous ethyl ether. The resulting solution was cooled to -70° C. with stirring under argon. 32 Ml. of a 2.4 M solution of n-butyl lithium was added slowly and the solution was warmed to -32° C. for 10 minutes and then cooled again to -70° C. 7.5 G. of dimethyl disulfide was added slowly while the temperature was maintained at -70° C. The resulting solution was warmed to room temperature and stirred for 2 hours then poured into ice water, stirred for 15 minutes, and extracted with ethyl ether. The combined ether extracts were washed with water, 5% sodium carbonate, and saturated sodium chloride solution; dried over sodium sulfate, filtered and evaporated to yield 3-bromo-2,4-dimethyl-5-(methylthio)thiophene.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([OH:10])=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:11]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:11][O:10][C:7]1[N:6]=[C:5]2[NH:1][CH:2]=[CH:3][C:4]2=[CH:9][CH:8]=1
Reactant: Oc1ccc2cc[nH]c2n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A mixture of 1H-pyrrolo[2,3-b]pyridin-6-ol (0.200 g, 1.49 mmol) and K2CO3 (1 g, 7.45 mmol) in acetone (30 mL) was stirred under N2 at room temperature for 1 h. MeI (0.166 g, 1.192 mmol) was added. The reaction mixture was stirred under N2 at 50° C. for 12 h and then filtered. The filtrate was concentrated to half its volume, diluted with water, and extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4, and evaporated to give a residue, which was purified on a column of silica gel eluting with EtOAc/hexane (1:4) to give 6-methoxy-1H-pyrrolo[2,3-b]pyridine (159 mg, 89%).
Reaction SMILES: Cl.[NH2+:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14][C@@H:3]12.C(N(CC)CC)C.Br[CH2:23][CH2:24][CH3:25]>CN(C)C=O>[CH2:23]([N:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14][C@@H:3]12)[CH2:24][CH3:25]
Reactant: c1ccc2c(c1)C[C@H]1[NH2+]CCC[C@H]21
Reactant: CCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCN1CCC[C@@H]2c3ccccc3C[C@H]21
Temperature: 25 °C
Reaction time: 18 h
Yield: 378.7 %

Procedure:
A solution of trans-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridinium hydrochloride (3.00 g, 14.3 mmol) and triethylamine (4.36 g, 43.1 mmol) in 95 ml of N,N-dimethylformamide was stirred at room temperature and bromopropane (1.85 g, 15.04 mmol) added dropwise. After the mixture was stirred for 18 h at room temperature, the solvent was removed and ethyl acetate/water were added. The organic layer was washed with water and dried over MgSO4. The filtrate was concentrated to give a yellow oil (11.66 g, 82%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[Cl:18][C:19]1[C:20](B(O)O)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1.C(Cl)Cl>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].COCCOC>[Cl:18][C:19]1[C:20]([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([NH:8][CH2:9][C:10]3([C:16]#[N:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:7]=2)=[CH:21][C:22]([F:25])=[N:23][CH:24]=1
Reactant: N#CC1(CNc2cccc(Br)n2)CCOCC1
Reactant: OB(O)c1cc(F)ncc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: N#CC1(CNc2cccc(-c3cc(F)ncc3Cl)n2)CCOCC1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
A mixture of 4-((6-bromopyridin-2-yl-amino)methyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate S, 410 mg, 1.384 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (362.2 mg, 2.07 mmol), PdCl2(dppf).CH2Cl2 adduct (113 mg, 0.14 mmol), DME (5 Ml) and 2 M aqueous Na2CO2 (1.75 Ml, 3.5 mmol) was sealed and stirred at 110° C. for 20 min using microwave reactor. After cooling to room temperature the mixture was extracted with EtOAc (35 Ml), filtered and concentrated in vacuo. The crude material was purified by column chromatography [silica gel, 24 g, EtOAc/hexane=5/100 to 50/50] to provide 4-((5′-chloro-2′-fluoro-2,4′-bipyridin-6-ylamino)methyl)tetrahydro-2H-pyran-4-carbonitrile (360 mg, 75% yield). LCMS (m/z): 347 [M+H]+; retention time=0.814 min.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:25])=[N:5][C:6]2[N:7]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16].[N-:26]=[N+:27]=[N-:28].[Na+]>CN(C=O)C.CCOC(C)=O>[N:26]([CH2:2][C:3]1[C:4]([CH3:25])=[N:5][C:6]2[N:7]([CH:17]=[C:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:19]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])=[N+:27]=[N-:28]
Reactant: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CCl)c(C)nc2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(CN=[N+]=[N-])c(C)nc2n1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
To a stirred solution of crude ethyl 6-(chloromethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (448 mg, 1.12 mmol) in DMF (5 mL) was added NaN3 (110 mg, 1.69 mmol). The reaction was heated to 50° C. for 1 h. After cooling, the reaction was diluted with EtOAc and extracted with H2O and brine before drying over MgSO4. Filtration and concentration under reduced pressure gave ethyl 6-(azidomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxylate (450 mg, 100% crude yield) as a yellow oil.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:9])=[CH:6][CH:5]=1>C(OCC)C>[Br:1][CH:10]([C:8](=[O:9])[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:16][CH:15]=1)[CH2:11][C:12]([OH:14])=[O:13]
Reactant: BrBr
Reactant: O=C(O)CCC(=O)c1ccc(Cl)cc1
Solvent: CCOCC
Product: O=C(O)CC(Br)C(=O)c1ccc(Cl)cc1

Procedure:
Bromine (2.6 ml) was added dropwise to a solution of 3-(4-chlorobenzoyl)propionic acid (10.6 g) in ethyl ether (200 ml) under stirring. The ethyl ether was distilled off to give 3-bromo-3-(4-chlorobenzoyl)propionic acid. Acetamide (30 g) was added thereto, and the mixture was heated with stirring on an oil bath at 140° C. for an hour. Water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off and the resulting crystalline precipitate was collected by filtration and washed with ethyl ether to give crystals of 4-(4-chlorophenyl)-2-methyloxazole-5-acetic acid, yield 3.9 g (31.1%). Recrystallization from ethanol gave needles, yield 3.5 g (27.9%), m.p. 215°-216° C.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][O:6][CH2:5][C:4]([C:9]2[CH:10]=[C:11]([NH:16][C:17](=O)[C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH:12]=[CH:13][C:14]=2[F:15])([CH3:8])[N:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>COCCOC>[NH2:1][C:2]1[CH2:7][O:6][CH2:5][C:4]([C:9]2[CH:10]=[C:11]([NH:16][C:17](=[S:35])[C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[CH:12]=[CH:13][C:14]=2[F:15])([CH3:8])[N:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(c2cc(NC(=O)c3ccc(Cl)cc3)ccc2F)COCC(N)=N1
Solvent: COCCOC
Product: CC1(c2cc(NC(=S)c3ccc(Cl)cc3)ccc2F)COCC(N)=N1
Temperature: 70 °C
Reaction time: 16 h
Yield: 7.9 %

Procedure:
A solution of (RS)-N-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-benzamide (0.056 g, 0.2 mmol) in 1,2-dimethoxyethane (2 ml) was treated with Lawesson's reagent (0.083 g, 0.2 mmol). After heating to 70° C. the dispersion turned into solution; the temperature was kept during 16 hours. Another 0.5 eq of Lawesson's reagent were added to complete the reaction and heating was continued at 80° C. After 2 days the reaction was still incomplete. For the workup, the reaction mixture was evaporated to dryness and the residue directly purified by chromatography on an Isolute flash NH2 column using a gradient of dichloromethane/methanol=100/0 to 90/10 as the eluent. There were obtained 0.006 g (10% of theory) of (RS)-N-[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-4-chloro-thiobenzamide (27) as a yellow solid. Mass (calculated) C18H17ClFN3OS [377.87]; (found) [M+H]+=378.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH2:21]O)[CH:18]=[N:19][CH:20]=1.S(Cl)([Cl:25])=O>>[Cl:25][CH2:21][C:17]1[CH:18]=[N:19][CH:20]=[C:15]([O:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])[CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cncc(CO)c1
Reactant: O=S(Cl)Cl
Product: Cc1oc(-c2ccccc2)nc1COc1cncc(CCl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of 5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethanol (1.33 g) and thionyl chloride (4 ml) was stirred at room temperature for 1 hour. After the reaction mixture was concentrated, saturated aqueous sodium bicarbonate solution was added to the mixture, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain 3-chloromethyl-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (911 mg, yield 64%) as colorless crystals from the fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). This was recrystallized from tetrahydrofuran-hexane. Melting point: 98–99° C.
Reaction SMILES: C([N:9]1[C:14](=[O:15])[C:13]([C:16]2[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:12][N:11]([CH2:23][CH2:24][CH2:25][CH2:26][Cl:27])[C:10]1=[O:28])(=O)C1C=CC=CC=1>N.CO>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][N:11]1[CH:12]=[C:13]([C:16]2[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=2)[C:14](=[O:15])[NH:9][C:10]1=[O:28]
Reactant: O=C(c1ccccc1)n1c(=O)c(-c2cccnc2F)cn(CCCCCl)c1=O
Agent: N
Solvent: CO
Product: O=c1[nH]c(=O)n(CCCCCl)cc1-c1cccnc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Benzoyl-1-(4-chloro-butyl)-5-(2-fluoro-pyridin-3-yl)-1H-pyrimidine-2,4-dione (310 mg, 0.77 mmol) was dissolved in a solution of 3% NH3 in MeOH (10 ml). The mixture was stirred at room temperature for 3 hours, the solvent was then evaporated under vacuum to give 260 mg of a crude that was used without further purification in the next step.
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[C:7]([C:8](Cl)=[O:9])=[CH:6][N:5]([CH3:11])[N:4]=1.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[NH2:28])[CH:17]=[CH:18][C:19]=1[Cl:20]>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[NH:28][C:8]([C:7]2[C:3]([CH:2]([F:12])[F:1])=[N:4][N:5]([CH3:11])[CH:6]=2)=[O:9])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: Cn1cc(C(=O)Cl)c(C(F)F)n1
Reactant: Nc1ccc(F)cc1-c1ccc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)Nc2ccc(F)cc2-c2ccc(Cl)c(Cl)c2)c(C(F)F)n1
Temperature: 85 °C
Reaction time: 0.08 h

Procedure:
5.6 g (0.029 mol, 98% pure) of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carbonyl chloride were dissolved at 25° C. in 10.4 g of toluene. The solution was evacuated to 400 mbar and heated to 85° C. Subsequently, within 5 minutes, 7.8 g (0.030 mol, approx. 92% pure) of 3′,4′-dichloro-5-fluorobiphenyl-2-ylamine, dissolved in 28 g of toluene, were metered in and the reaction mixture was stirred for a further 1 hour. After venting and cooling to 25° C. overnight, the mixture was cooled further to 0° C., and the solids were filtered off, washed with cold toluene and dried at 80° C. under reduced pressure. The yield (without further processing of the mother liquor) was 8.1 g (71%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:25])[C@H:19]([OH:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([CH3:26])=[CH:7][CH:8]=2)[N:3]=1.[F:27][C:28]1[CH:29]=[CH:30][C:31]([O:37][CH3:38])=[C:32](B(O)O)[CH:33]=1.C([O-])([O-])=O.[K+].[K+].C(#N)C>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.O>[F:27][C:28]1[CH:33]=[CH:32][C:31]([O:37][CH3:38])=[C:30]([C:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:25])[C@H:19]([OH:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][C:6]([CH3:26])=[CH:7][CH:8]=3)[N:3]=2)[CH:29]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)C)CC3)nc(Cl)nc2c1
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: CC#N
Product: COc1ccc(F)cc1-c1nc(N2CCN(C(=O)[C@H](O)CC(C)C)CC2)c2ccc(C)cc2n1
Temperature: 160 °C
Yield: 70 %

Procedure:
(R)-1-(4-(2-Chloro-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one (50 mg, 0.13 mmol), 5-fluoro-2-methoxyphenylboronic acid (27 mg, 0.16 mmol), Pd(Ph3P)4 (9.2 mg, 0.008 mmol), and K2CO3 (37 mg, 0.27 mmol) were placed into a microwave tube charged with a stir bar. Acetonitrile (2 mL) and H2O (400 μL) were added, and the vessel was capped and heated at 160° C. for 12 minutes in the microwave reactor. The reaction was partitioned between EtOAc and H2O, the layers were separated, and the aqueous layer was extracted once more with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered, and concentrated to an orange gel. The reaction was purified by silica gel chromatography using 10%-30% EtOAc in CH2Cl2/hexanes (2:1) to afford (R)-1-(4-(2-(5-fluoro-2-methoxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one as a white foam (70%). LC/MS: m/z 467.30 (M+H)+ at 2.38 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=1.[CH3:24][S:25]([O-:27])=[O:26].[Na+]>CN(C=O)C>[CH:18]([NH:17][C:15]([C@H:12]1[CH2:13][CH2:14][C@@H:9]([NH:8][C:6]2[C:5]([N+:21]([O-:23])=[O:22])=[CH:4][N:3]=[C:2]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:7]=2)[CH2:10][CH2:11]1)=[O:16])([CH3:20])[CH3:19]
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(S(C)(=O)=O)ncc2[N+](=O)[O-])CC1
Temperature: 100 °C

Procedure:
To a solution of cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide (0.100 g, 0.293 mmol) in DMF (0.6 mL) was added sodium methanesulfinate (0.042 g, 0.352 mmol), and the reaction mixture was heated at 100° C. for 2 hours. The reaction was conducted twice and the mixtures were combined and concentrated under reduced pressure and the yellow residue purified by flash chromatography, eluting with 0-80% 9:1 DCM/MeOH:DCM to afford cis-N-isopropyl-4-(2-(methylsulfonyl)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide as a yellow solid. MS (ESI pos. ion) m/z: 385.0 [M+H].
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[C:10](=O)[CH2:11][CH3:12].[N:14]([O-])=O.[Na+].Cl[Sn]Cl>OS(O)(=O)=O.O>[Br:9][C:5]1[CH:4]=[C:3]2[C:2](=[C:7]([Cl:8])[CH:6]=1)[NH:1][N:14]=[C:10]2[CH2:11][CH3:12]
Reactant: CCC(=O)c1cc(Br)cc(Cl)c1N
Reactant: O=N[O-]
Agent: Cl[Sn]Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCc1n[nH]c2c(Cl)cc(Br)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
1-(2-Amino-5-bromo-3-chloro-phenyl)-propan-1-one (130.0 mg, 0.50 mmol) dissolved in aqueous 50% H2SO4 (2.5 mL) and NaNO2 (43.1 mg, 0.59 mmol) was slowly added to this mixture at 0° C. The mixture was then stirred at room temperature for 1 hour. SnCl2 2H2O (342.0 mg, 1.48 mmol) was then added, and the mixture was stirred at 0° C. for 1 hour, and then diluted with water. White solid appeared and was collected by filtration and dried to afford 5-bromo-7-chloro-3-ethyl-1H-indazole as a solid (127.0 mg, 98.8%).
Reaction SMILES: [NH2:1][C:2](=[O:29])[C@@H:3]([NH:12][C:13]([C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1.[CH3:30][S:31]([O:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][CH:40]=1)(=[O:33])=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[CH3:30][S:31]([O:34][C:35]1[CH:36]=[C:37]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C@H:3]([NH:12][C:13]([C:15]3([NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:14])[C:2]([NH2:1])=[O:29])=[CH:6][CH:7]=2)[CH:38]=[CH:39][CH:40]=1)(=[O:33])=[O:32]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(I)cc2)C(N)=O)CCOCC1
Reactant: CS(=O)(=O)Oc1cccc(B(O)O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3cccc(OS(C)(=O)=O)c3)cc2)C(N)=O)CCOCC1
Reaction time: 20 h

Procedure:
(S)-tert-butyl 4-(1-amino-3-(4-iodophenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 1, step (iii), 300 mg), 3-(methylsulfonyloxy)phenylboronic acid (Example 12, step (i), 125 mg) and potassium carbonate (240 mg) in acetonitrile (10 mL) and water (5 mL) were stirred and heated at 90° C. under a nitrogen atmosphere with 1,1 bis(di-tert-butylphosphino)ferrocene palladium dichloride (11 mg). After 20 h the reaction was complete and the solvents were removed under reduced pressure. The residue was partitioned between water (100 mL) and ethyl acetate (100 mL), and the organic phase collected and dried over magnesium sulfate. The extract was concentrated to a gum and the crude material purified by chromatography on silica eluting with ethyl acetate to afford the sub-titled is compound (120 mg).
Reaction SMILES: N1CCCCC1.[Br:7][C:8]1[CH:9]=[C:10]([C:13]#[CH:14])[S:11][CH:12]=1.I[C:16]1[CH:29]=[CH:28][C:19]([O:20][CH2:21][CH2:22][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1>C1COCC1.[Cu]I>[Br:7][C:8]1[CH:9]=[C:10]([C:13]#[C:14][C:16]2[CH:29]=[CH:28][C:19]([O:20][CH2:21][CH2:22][N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:18][CH:17]=2)[S:11][CH:12]=1
Reactant: C#Cc1cc(Br)cs1
Reactant: Ic1ccc(OCCN2CCCC2)cc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: C1CCNCC1
Product: Brc1csc(C#Cc2ccc(OCCN3CCCC3)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere 0.3 mL (3.13 mmol) piperidine, 14.9 mg (0.08 mmol) CuI and 90.3 mg (0.08 mmol) tetrakis-triphenylphosphane-palladium are added to a solution of 293 mg (1.56 mmol) 4-bromo-2-ethynyl-thiophene and 620 mg (1.56 mmol) 1-[2-(4-iodo-phenoxy)-ethyl]-pyrrolidine in 10 mL THF and the reaction mixture is stirred overnight at RT. To complete the reaction another 150 mg (0.8 mmol) 4-bromo-2-ethynyl-thiophene are added and the mixture is stirred for a further 24 h at RT. The mixture is evaporated down i. vac., the residue is triturated with EtOAc and the insoluble ingredients are filtered off. After the solvent has been eliminated the residue is purified by chromatography (silica gel, EtOAc/MeOH/NH3 8:2:0.2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23](=[O:31])[N:24]([CH3:30])[C:25](SC)=[N:26][CH:27]=2)=[CH:18][C:17]=1[F:32].C(O)(C(F)(F)F)=[O:34].OO.NC(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23](=[O:31])[N:24]([CH3:30])[C:25]([OH:34])=[N:26][CH:27]=2)=[CH:18][C:17]=1[F:32]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2nccc(Oc3ccc(-c4cnc(SC)n(C)c4=O)cc3F)c2cc1OC
Agent: NC(N)=O
Agent: OO
Solvent: CC#N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1cc2nccc(Oc3ccc(-c4cnc(O)n(C)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
5-(4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-3-methyl-2-methylthio-3H-pyrimidin-4-one (Step 1, 1.048 g, 2.3 mmol) was dissolved in CH3CN (15 mL) and TFA (1.7 mL) and cooled to 0° C. Urea hydrogen peroxide (290 mg, 3.09 mmol) was added, and the reaction was stirred for 5 min. trifluoroacetic anhydride (0.43 mL, 3.09 mmol) was added, and the reaction was warmed to RT and stirred for 40 min. The mixture was quenched with H2O (10 mL) and EtOAc (25 mL) and allowed to stand overnight. Saturated NaHCO3 (10 mL) and EtOAc were added, and the layers were separated. The aqueous layer was extracted with EtOAc, and the organic layers were combined, dried over Na2SO4, filtered, concentrated, and purified on silica gel (EtOAc→1:1 EtOAc/MeOH) to give title compound. MS (ESI pos. ion) m/z: 411. Calc'd for C21H17FN3O5: 410.39.