Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([NH:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH:21]([OH:25])[CH2:20]4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:5][CH:4]=1>O.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][C@H:21]([OH:25])[CH2:20]4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:7][CH:8]=1.[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:16]([NH:18][C@@H:19]4[CH2:24][CH2:23][CH2:22][C@H:21]([OH:25])[CH2:20]4)=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(NC4CCCC(O)C4)c23)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(N[C@@H]4CCC[C@H](O)C4)c23)cc1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(N[C@H]4CCC[C@H](O)C4)c23)cc1
Yield: 14.3 %
Yield: 50 %

Procedure:
Separate 300 mg (0.72 mmol) of (+/−)-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclohexanol (cis/trans mixture) by preparative HPLC into the pure cis- and trans isomers [column: Phenomenex Gemini, C-18, 5 μm, 250 mm×21.2 mm; flow rate: 20 ml/min; temperature: 25° C.; eluent: water/THF 60:40]. 43 mg (14.3% of theory) of (+/−)-trans-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclohexanol (Example 58A) and 150 mg (50.0% of theory) of (+/−)-cis-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]amino}cyclohexanol (Example 59A) are obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:18].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.[N:31](OCCC(C)C)=O>C1(C)C=CC=CC=1>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][C:6]2[CH:7]=[C:2]3[C:3](=[CH:4][CH:5]=2)[NH:18][N:31]=[CH:1]3)=[N:10][CH:11]=1)([O-:17])=[O:16]
Reactant: CC(C)CCON=O
Reactant: Cc1cc(Oc2ccc([N+](=O)[O-])cn2)ccc1N
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ncc3c2)nc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 20.9 %

Procedure:
To a mixture of 2-methyl-4-(5-nitro-pyridin-2-yloxy)-phenylamine (10 g, 41 mmol), potassium acetate (17 g, 160 mmol), acetic anhydride (17 g, 160 mmol) and toluene (140 mL) at 80° C. was added isoamyl nitrite (9.6 g, 82 mmol) dropwise via an addition funnel. After stirring for 24 h at 80° C., the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was treated with methanol (120 mL) containing 12 mL of concentrated ammonium hydroxide. After refluxing for 2 h, the mixture was cooled to room temperature and was concentrated in vacuo. The residue was purified by silica gel chromatography eluting with ethyl acetate-hexane to afford 2.2 g of 5-(5-Nitro-pyridin-2-yloxy)-1H-indazole as an orange solid. 1H NMR (CD3OD, 400 MHz): δ 8.96 (d, 1H, J=2.4 Hz), 8.56 (dd, 1H, J=2.8, 9.2 Hz), 8.05 (s, 1H), 7.60 (1H, d, 8.8 Hz), 7.56 (m, 1H), 7.21 (dd, 1H, J=2.0, 8.8 Hz), 7.13 (d, 1H, 9.2 Hz) ppm.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH3:12][NH2:13]>O>[F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:13][CH3:12]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: O
Product: CNc1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 3,4-difluoro-nitrobenzene (13, 5.0 g, 31.4 mmol) taken in dimethyl sulfoxie (30 mL) was added 40% aqueous methylamine in portions. The reaction was stirred at room temperature for 30 minutes. The reaction was diluted with 150 mL of water and the resulting precipitate was filtered and dried under vacuum to obtain solid (5.34 g) in 98% isolated yield.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.C([Li])CCC.CN([CH:18]=[O:19])C>C(OCC)C>[F:9][C:4]1[CH:3]=[C:2]([CH:7]=[C:6]([Br:8])[CH:5]=1)[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)cc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: O=Cc1cc(F)cc(Br)c1
Yield: 100 %

Procedure:
To a solution of 3,5-dibromofluorobenzene in diethyl ether (100 cm3) at −78° C. was added n-butyl lithium (2.5 M, 8 cm3, 20 mmol) dropwise. After 30 min. the mixture was treated with DMF (20 cm3) in diethyl ether (10 cm3) and stirring was continued at −78° C. After 30 min. the mixture was quenched with dilute HCl aq., separated and the aqueous layer was extracted with EtOAc. The combined organic layers were combined, washed with water, brine, dried (MgSO4) and evaporated to give 3-fluoro-5-bromobenzaldehyde (4.0 g, 19.7 mmol, 100%) as an oil: 1H NMR (CDCl3) δ inter alia 7.50-7.53 (m, 2H), 7.82 (s, 1H) and 9.93 (m, 1H); MS (EI) m/z 202, 204 [M+].
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH2:37])[CH:29]=3.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[N:46]=[C:47]=[O:48]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:38]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[C:30]([NH:37][C:47]([NH:46][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=1[F:39])=[O:48])[CH:29]=3
Reactant: O=C=Nc1ccccc1F
Reactant: Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc2cc(c1)Nc1nc(ncc1Cl)Nc1cccc(c1)CC2)Nc1ccccc1F
Yield: 43 %

Procedure:
The desired compound was prepared according to the procedure of Example B83, using 6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaen-11-amine bis(trifluoroacetate) and 1-fluoro-2-isocyanatobenzene as the starting materials in 43% yield. LCMS for C25H21ClFN6O (M+H)+: m/z=475.2.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1C1C=NN(C)C=1)=O.[F:25][C:26]1[CH:27]=[CH:28][C:29]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)=[C:30]([CH:34]=1)[C:31]([OH:33])=O>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:31]([C:30]1[CH:34]=[C:26]([F:25])[CH:27]=[CH:28][C:29]=1[N:35]1[N:39]=[CH:38][CH:37]=[N:36]1)=[O:33]
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-n2nccn2)[C@@H]1CN

Procedure:
The title compound was prepared following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1 using 5-fluoro-2-(2H-1,2,3-triazol-2-yl)benzoic acid. MS (ESI) 318 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](I)[CH2:18][CH2:19][CH3:20]>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:17][CH2:18][CH2:19][CH3:20])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][N:14]=2)=[CH:6][CH:7]=1
Reactant: Brc1ccc(Nc2ncccn2)cc1
Reactant: CCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(c1ccc(Br)cc1)c1ncccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere, N-(4-bromophenyl)pyrimidin-2-amine (160 mg) was added to a suspension of sodium hydride (33 mg) in anhydrous DMF (3 ml), and the resulting mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled to 0° C. and n-butyl iodide (0.080 ml) was added thereto, followed by stirring the resulting mixture at room temperature for 1 hour. Saturated brine was added to the reaction solution and the resulting mixture was extracted 3 times with ethyl acetate. Organic layers were washed 3 times with water and once with saturated brine, and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: ethyl acetate/hexane=1/10) to obtain N-(4-bromophenyl)-N-butylpyrimidin-2-amine (194 mg).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[C:15]([CH3:17])([CH3:16])[O:14][C:13](=[O:18])[NH:12]2)[CH:7]=[CH:8][C:9]=1[F:10].Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:21]>C1COCC1>[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[C:15]([CH3:16])([CH3:17])[O:14][C:13](=[O:18])[N:12]2[C:20]([O:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)=[O:21])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC1(C)OC(=O)NC1c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OC(=O)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
Into a stirred suspension of sodium hydride (60% suspension in paraffin 203 mg, 1.4 eq.) in THF (20 mL) at 0° C., a solution of 4-(3,4-difluorophenyl)-5,5-dimethyl-2-oxo-oxazolidine (870 mg, 3.622 mmol) in THF (5 mL) was added followed by stirring for 30 minutes. This suspension was added to a solution of 4-nitrophenyl chloroformate (950 mg, 4.71 mmol) in THF (20 mL) at −78° C. under argon and the stirring was continued for 2 h. It was slowly warmed to room temperature and after 4 h the solvent was evaporated. The residue was mixed with dichloromethane (150 mL), washed with 0.05 N sodium hydroxide (3×10 mL), and dried (sodium sulfate). The solvent was evaporated and the residue was purified by column chromatography on silica gel using chloroform/ethyl acetate (9:1) as the eluent to give the product as a white powder (860 mg, 59% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[OH:22].[CH3:23][O:24][C:25]1[N:30]=[C:29](S(C)(=O)=O)[N:28]=[C:27]([O:35][CH:36]([C:38]([O:40][CH3:41])=[O:39])[CH3:37])[CH:26]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:18])([F:19])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])=[CH:4][C:3]=1[O:22][C:29]1[N:28]=[C:27]([O:35][CH:36]([C:38]([O:40][CH3:41])=[O:39])[CH3:37])[CH:26]=[C:25]([O:24][CH3:23])[N:30]=1
Reactant: COC(=O)C(C)Oc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(O)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(OC)nc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.2 %

Procedure:
To a mixture of 400 mg of 2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenol, 377 mg of 6-methoxy-4-{1-(methoxycarbonyl)ethoxy}-2-methylsulfonylpyrimidine and 3 ml of N,N-dimethylformamide, 196 mg of potassium carbonate was added, and the mixture was stirred for 1 hour at 80° C. The reaction solution was cooled to room temperature, then, this reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 630 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-methoxy-4-{1-(methoxycarbonyl)ethoxy}pyrimidine [present compound 1-42].
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:9]=1[CH3:10])=[O:4].C1C(=O)N([Br:35])C(=O)C1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O.CCCCCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[C:8]([C:11]2[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:15][CH:16]=2)[C:9]=1[CH2:10][Br:35])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)c1CBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
A solution of 404 mg of the product of Step 5, 200 mg of NBS, and 5 mg of benzoylperoxide in 10 mL of CCl4 was heated in a 80° C. oil bath under light from a W-lamp. After 30 min, the reaction mixture was cooled to room temperature, diluted with 10 mL of 3:1 EtOAc/hexane, and filtered through a pad of silica gel. The filtrate was concentrated in vacuo to give 400 mg of the crude title compound which was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1>C(O)(=O)C.C1COCC1>[Cl:20][C:21]1[N:22]=[CH:23][N:24]([C:26]2[CH:32]=[CH:31][C:29]([NH:30][C:2]3[N:3]=[C:4]([NH:18][CH3:19])[C:5]4[CH2:10][CH2:9][CH:8]([C:11]5[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=5)[C:6]=4[N:7]=3)=[CH:28][C:27]=2[O:33][CH3:34])[CH:25]=1
Reactant: COc1cc(N)ccc1-n1cnc(Cl)c1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNc1nc(Nc2ccc(-n3cnc(Cl)c3)c(OC)c2)nc2c1CCC2c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
2-Chloro-7-(4-chlorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (101 mg, 0.343 mmol) was added to a solution of 4-(4-chloro-1H-imidazol-1-yl)-3-methoxyaniline (77 mg, 0.343 mmol) in acetic acid (2 mL) and THF (2 mL). The reaction mixture was heated at 80° C. overnight. Partial conversion to the desired product was observed. The reaction was further heated at 120° C. for 6 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-chlorophenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (35.5 mg, 0.059 mmol, 17.19% yield). LC-MS (M+H)+=481.3. 1H NMR (500 MHz, CDCl3) δ ppm 11.08 (1H, s), 8.33 (1H, s), 7.48 (2H, d, J=2.1 Hz), 7.30 (2H, d, J=8.2 Hz), 7.20 (1H, d, J=1.5 Hz), 7.13 (2H, d, J=8.5 Hz), 5.83-5.93 (1H, m), 4.38-4.48 (1H, m), 3.97 (1H, s), 3.86 (3H, s), 3.22 (3H, d, J=4.9 Hz), 2.85-2.95 (1H, m), 2.77 (2H, dd, J=8.7, 5.3 Hz), 2.20-2.32 (1H, m).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([O:9]CC)=O)[CH:4]=[N:3][CH:2]=1.[OH-].[NH4+:13]>CO>[N:1]1[CH:6]=[C:5]([C:7]([NH2:13])=[O:9])[CH:4]=[N:3][CH:2]=1
Reactant: [NH4+]
Reactant: CCOC(=O)c1cncnc1
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1cncnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of ethyl pyrimidine-5-carboxylate (6.10 g, 40.0 mmol) in methanol (40 mL) was stirred with ammonium hydroxide (4.30 mL, 110 mmol) in a sealed tube at 50° C. for 10 hours. The reaction mixture was then concentrated and the residue was stirred in ethanol/ethyl acetate (v/v 1/4, 50 mL) at ambient temperature for 2 hours. The white precipitate was collected by filtration and dried to give the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 7.85 [s (broad), 1 H], 8.33 [s (broad), 1 H], 9.18 (s, 2 H), 9.32 (s, 1 H) ppm; MS (DCI/NH3) m/z 124 (M+H)+, 141 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:31]2[CH:32]=[N:33][NH:34][CH:35]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[NH:33]1[CH:32]=[C:31]([C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:3]=2)[CH:35]=[N:34]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Clc1nc(-c2ccc(N3CCOCC3)cc2)cc2nccn12
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: COCCOC
Solvent: O
Product: c1cn2c(-c3cn[nH]c3)nc(-c3ccc(N4CCOCC4)cc3)cc2n1
Temperature: 100 °C
Yield: 36.2 %

Procedure:
4-(4-(5-Chloroimidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0400 g, 0.127 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.0370 g, 0.191 mmol) and potassium carbonate (0.0527 g, 0.381 mmol) were suspended in a mixture of DME (2 mL) and water (1 mL) and de-gassed with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.00734 g, 0.00635 mmol) was added and the reaction sealed and heated at 100° C. for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 and EtOAc. The organics were washed with brine, dried, MgSO4 and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 0.5%-6% (9:1 MeOH:NH4OH)/DCM) to furnish 4-(4-(5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-7-yl)phenyl)morpholine (0.0160 g, 0.046 mmol, 36.4% yield). MS (apci) m/z=347.1 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.CCN(CC)CC.[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1F>CCOC(C)=O>[F:14][C:15]1[CH:16]=[C:17]([N+:22]([O-:24])=[O:23])[CH:18]=[CH:19][C:20]=1[N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: C1CSCCN1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(N2CCSCC2)c(F)c1
Temperature: 25 °C
Yield: 72.2 %

Procedure:
To a solution of thiomorpholine (3.57 g, 34.56 mmol) and Et3N (3.50 g, 34.56 mmol) in EtOAc was added 3,4-difluoronitrobenzene (5.00 g, 31.43 mmol) dropwise over a period of 30 min in an ice bath. Upon the end of addition the reaction mixture was warmed to rt slowly, and solid was precipitated out. The mixture was filtered. The filter cake was washed with an appropriate amount of water, dried in vacuo to obtain the 1st crop of product. The filtrate was extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo to obtain the 2nd crop of product. The solids of 1st crop and 2nd crop were combined to give the title compound as a yellow solid (5.50 g, 72%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.CCN(C(C)C)C(C)C.[Cl:27]C(Cl)C(Cl)=O.[CH2:33]1C[O:36][CH2:35][CH2:34]1>C(OCC)(=O)C>[Cl:27][CH2:33][CH2:34][C:35]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:12]=1)=[O:36]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: C1CCOC1
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 28 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (128 mg, 0.578 mmol) and DIEA (115 μL, 0.694 mmol) in THF (5 mL), dichloroacetyl chloride (61 μL, 0.636 mmol) was added at room temperature. The reaction mixture was stirred at room temperature for 48 hrs, diluted with ethyl acetate (20 mL). The organic phase was washed with water (10 mL) and then brine (10 mL), dried over MgSO4, and the solvent was evaporated in vacuo to afford a light-yellow solid. The solid was triturated with Et2O, filtered, and submitted to preparative LCMS to afford 3-chloro-N-[3-(quinoxalin-2-yl)phenyl]propanamide (50 mg, 28% yield). LCMS calculated for C17H14ClN3O (M+H): 312.08. found 312.14. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.30 (1H, br. s), 9.50 (1H, s), 8.52 (1H, m), 6.65-8.60 (2H, m), 8.58 (1H, d, J=7 Hz), 7.95-7.84 (3H, m), 7.55 (1H, m), 3.91 (2H, t, J=7.1 Hz), 2.88 (2H, t, J=7.1 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[O:4].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=O.[CH3:21][NH2:22]>C(O)C(C)C>[CH3:21][N:22]1[CH:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=2)[CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:7])[CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH:19]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1
Reactant: CN
Reactant: O=Cc1ccccn1
Reactant: COC(=O)CC(=O)CC(=O)OC
Solvent: CC(C)CO
Product: COC(=O)C1C(=O)C(C(=O)OC)C(c2ccccn2)N(C)C1c1ccccn1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 880.3 %

Procedure:
1st stage: 12.9 kg of dimethyl acetonedicarboxylate (97%; 72 mol) were dissolved in 52.5 l of isobutanol. The solution was cooled to 10° C. At this temperature, 15.4 kg of pyridine-2-aldehyde (14.4 mol) were added dropwise and the mixture was stirred for a further 10 minutes. Subsequently, 5.59 kg of methylamine (40% in water, 72 mol) were added dropwise to this mixture at such a rate that the temperature could be maintained with uniform cooling. The reaction mixture was stirred at 10° C. for a further 90 minutes. After the reaction time had ended, the mixture was heated to 40-45° C. and 6.6 kg of water phase were separated out under reduced pressure at internal temperature 40-45° C. with the aid of a water separator. The mixture was then vented and cooled to 5-10° C. The product was filtered off and washed with 7.5 l of isobutanol. The moist product was dried at 50° C. under reduced pressure. 24.3 kg (88%) of 1-methyl-2,6-dipyridyl-3,5-di(methoxy-carbonyl)-4-piperidone were obtained as a white-beige powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C1(B(O)[OH:19])C=CC=CC=1.[CH:21]1([NH:27][CH:28]2[CH2:33]CCCC2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.CCCCCCCCCCC>C1(C)C=CC=CC=1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:23]2[CH:24]=[CH:25][CH:26]=[C:21]([NH:27][C:28](=[O:19])[CH3:33])[CH:22]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: Cc1ccc(Br)c([N+](=O)[O-])c1
Reactant: OB(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCCCCCCC
Product: CC(=O)Nc1cccc(-c2ccc(C)cc2[N+](=O)[O-])c1
Yield: 42 %

Procedure:
1-Bromo-4-methyl-2-nitro-benzene (0.107 g, 0.49 mmol) was reacted as described in Example 215a substituting 3-acetamidophenylboronic acid (0.086 g, 0.49 mmol) for phenylboronic acid, dicyclohexylamine (4 mole %) for 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3.]undecane and substituting dioxane for toluene to give the title biphenyl (0.0552 g, 42%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[O:8][CH2:7][C@H:6]([CH:13]1[O:18][CH2:17][CH:16]([C:19]3[CH:28]=[C:27]4[C:22]([CH2:23][C@@H:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][O:26]4)=[CH:21][C:20]=3[F:34])[CH2:15][O:14]1)[CH2:5]2.C([Li])(CC)C.C1(C)C=CC(S([C:49]#[N:50])(=O)=O)=CC=1>C1COCC1.C1CCCCC1.CCOCC>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[C:11]=1[C:49]#[N:50])[O:8][CH2:7][C@H:6]([CH:13]1[O:18][CH2:17][CH:16]([C:19]3[CH:28]=[C:27]4[C:22]([CH2:23][C@@H:24]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:25][O:26]4)=[CH:21][C:20]=3[F:34])[CH2:15][O:14]1)[CH2:5]2
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: CCCCC[C@H]1COc2cc(C3COC([C@H]4COc5c(F)cc(F)cc5C4)OC3)c(F)cc2C1
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: C1CCCCC1
Product: CCCCC[C@H]1COc2cc(C3COC([C@H]4COc5c(cc(F)c(C#N)c5F)C4)OC3)c(F)cc2C1
Temperature: -25 °C
Reaction time: 2 h

Procedure:
800 mg (1.68 mmol) of (R)-6,8-difluoro-3-[5-((R)-6-fluoro-3-pentylchroman-7-yl)-1,3-dioxan-2-yl]chroman are dissolved in 30 ml of THF, and 1.7 ml (2.38 mmol) of a 1.4 M solution of s-butyllithium in cyclohexane are added at −50° C. The batch is warmed at −25° C. for 5 min, left to stir at −70° C. for 2 h, and a solution of 400 mg (2.21 mmol) of p-toluenesulfonyl cyanide in 10 ml of THF is subsequently added at such a rate that the temperature does not exceed −65° C. After 1 h, the batch is allowed to thaw, diluted with ether and washed with dil. hydrochloric acid. The org. phase is dried over sodium sulfate and evaporated, and the crude product is chromatographed on silica gel with toluene, giving (R)-6,8-difluoro-3-[5-((R)-6-fluoro-3-pentylchroman-7-yl)-1,3-dioxan-2-yl]chroman-7-carbonitrile as colourless crystals of m.p. 111° C.