Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][C:9]=1[N:10]([S:19]([C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Cl:29])=[CH:24][C:23]=1[CH3:30])(=[O:21])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=1)=[O:4].[O:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[CH:39]=[C:38]1B(O)O>COCCOC.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.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>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][C:9]=1[N:10]([CH:11]([C:38]1[O:37][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[CH:39]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[S:19]([C:22]1[CH:27]=[C:26]([CH3:28])[C:25]([Cl:29])=[CH:24][C:23]=1[CH3:30])(=[O:21])=[O:20])=[O:4]
Reactant: OB(O)c1cc2ccccc2o1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(Cc1cccc(I)c1)S(=O)(=O)c1cc(C)c(Cl)cc1C
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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1sc(-c2ccccc2)cc1N(C(c1ccccc1)c1cc2ccccc2o1)S(=O)(=O)c1cc(C)c(Cl)cc1C
Yield: 98.6 %

Procedure:
To a degassed solution of 3-[(4-Chloro-2,5-dimethyl-benzenesulfonyl)-(3-iodo-benzyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (110 mg, 0.169 mmol) and benzofuran-2-boronic acid (55 mg, 0.185 mmol) in a mixture of DME (8 mL) and 2M aqueous Na2CO3 (4 mL), Pd(PPh3)4 (9 mg) was added and the reaction mixture was stirred at reflux conditions for 2 h under a N2 atmosphere. The reaction mixture was diluted with ethyl acetate and water. The organic layer was separated, dried (Na2SO4) and concentrated. 3-[(3-Benzofuran-2-yl-benzyl)-(4-chloro-2,5-dimethyl-benzenesulfonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (107 mg, 100%) was isolated as a thick syrup and used for the next reaction without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:20][S:21]([C:24]1[C:32]2[C:27](=[CH:28][N:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1)(=[O:23])=[O:22].CS(N1C2C(=CC=CC=2)C=N1)(=O)=O>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[N:6]([CH2:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:7]([CH2:9][N:26]3[C:27]4=[CH:28][N:29]=[CH:30][CH:31]=[C:32]4[C:24]([S:21]([CH3:20])(=[O:22])=[O:23])=[N:25]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: FC(F)(F)CCCn1c(CCl)nc2cc(Cl)ccc21
Agent: CS(=O)(=O)n1ncc2ccccc21
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2CCCC(F)(F)F)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 4-1 by using 5-chloro-2-chloromethyl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazole and 3-methanesulfonyl-1H-pyrazolo[3,4-c]pyridine instead of 5-chloro-2-chloromethyl-1-(4,4,4-trifluoro-butyl)-1H-benzoimidazole and methanesulfonyl-1H-indazole.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C(#N)C.C1C(=O)N([Br:24])C(=O)C1>>[Br:24][C:9]1[C:10]([NH2:13])=[N:11][CH:12]=[C:7]([CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:8]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccc(C2CCOCC2)cn1
Solvent: CC#N
Product: Nc1ncc(C2CCOCC2)cc1Br
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To 5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine/acetonitrile solution (1.4 g, 7.85 mmol/30 mL) at 0-5° C. was added portionwise NBS (1.4 g, 7.85 mmol) with internal temperature controlled below 5° C. The resulting mixture was stirred at 0° C. for 1 hour 40 min. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with dilute aqueous NaOH/H2O (1 g/30 mL). The solid suspension was collected via filtration. The filtercake was washed with ice cold water (˜10 mL), and the filtrates were combined, and extracted with EtOAc (20 mL). The EtOAc extract was washed with brine (20 mL), dried over Na2SO4, and concentrated. A light yellow solid was combined with the filter cake, and dried under high vacuum as crude 3-bromo-5-(tetrahydro-2H-pyran-4-yl)pyridin-2-amine. LCMS (m/z) 257.1/259.1 (MH+) 0.39 min. 1H NMR (CDCl3) δ ppm 7.90 (d, J=1.6 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 4.80 (br. s., 1H), 4.12-4.02 (m, 2H), 3.54-3.44 (m, 2H), 2.71-2.61 (m, 1H), 1.78-1.68 (m, 4H).
Reaction SMILES: [CH3:1][N:2]1[CH2:10][O:9][CH2:8][CH:7]2[CH:3]1[CH2:4][N:5](C(OCC)=O)[CH2:6]2>O>[CH3:1][N:2]1[CH2:10][O:9][CH2:8][CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2COCN(C)C2C1
Solvent: O
Product: CN1COCC2CNCC21

Procedure:
9 g (42 mmol) of ethyl 2-methyl-4-oxa-2,8-diazabicyclo[4.3.0]nonane-8-carboxylate are heated under reflux with 28 g of Ba(OH)2.8H2O in 280 ml of water overnight. The BaCO3 is filtered off with suction, the filtrate is concentrated and the residue is boiled up with dioxane. The dioxane solution is concentrated and the residue is distilled.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO>[OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O[C@H]1CCCN[C@H]1c1ccccc1
Solvent: CO
Product: OC1CCCNC1c1ccccc1

Procedure:
cis-3-Hydroxy-2-phenylpiperidine (Description 3b) and (-)dibenzoyltartrate were dissolved in methanol and crystallized by addition of ethyl acetate. The solid was recrystallised from hot methanol to give the hemi dibenzoyltartrate salt: mp 223°-224° C. This was liberated from the salt as described above to give the single enantiomer (+)-cis-3-hydroxy-2-phenylpiperidine, mp 93°-95° C. [a]23D =+98.5° (c=1, MeOH). The mother liquors were converted to the free base as described in Description 3b and crystallization using (+)dibenzoyltartrate in an analogous manner to that described above gave (-)-3-hydroxy-2-phenylpiperidine, mp 93°-95° C. [a]23D =-97.2° (c=1, MeOH).
Reaction SMILES: Cl[C:2]([F:32])([F:31])[C:3]1[N:8](N)[CH:7]([C:10]([F:13])([F:12])[F:11])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5](CC2C=CC=CC=2)[C:4]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27].C([N:35](CC)CC)C.Cl>C(O)C.[Pd]>[F:31][CH:2]([F:32])[C:3]1[N:8]=[C:7]([C:10]([F:13])([F:12])[F:11])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([NH2:35])[C:4]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)C1=C(C(F)(F)Cl)N(N)C(C(F)(F)F)C(C(=O)OCC)=C1Cc1ccccc1
Reactant: CCN(CC)CC
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(=O)OCC)c1N
Reaction time: 18 h

Procedure:
A mixture of 340 g (0.722 mol) of product from Example 99, 87.67 g (0.866 mol) of triethylamine and 10.00 g of 5% Pd/C (50% water coated) in 700 ml of ethanol was hydrogenated at 50° C. under 446 kPa of H2 pressure for 18 hours. Then 150 ml of 18% HCl (0.722 mol) was added, and the mixture was hydrogenated at 50° C. under 446 kPa of H2 pressure for 2 hours. The reaction mixture was filtered through celite, and concentrated in vacuo to remove the ethanol. The resie was taken up in H2O, and extracted with diethyl ether. The ether phase was dried (MgSO4) and concenrated in vacuo to 161.7 g (65%) of a brown oil, 90% pure by GC analysis. Then 5.0 g were purified by HPLC in 5% ethyl acetate/cyclohexane affording 3.9 g of product as a yellow solid; mp 29°-30° C.
Reaction SMILES: [Cl:1][C:2]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:11]([OH:13])=O)[C:7](=[O:18])[CH:6]=1.[NH2:24][C:25]1[CH:29]=[CH:28][N:27]([CH2:30][C:31]([CH3:34])([OH:33])[CH3:32])[N:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[OH:33][C:31]([CH3:34])([CH3:32])[CH2:30][N:27]1[CH:28]=[CH:29][C:25]([NH:24][C:11](=[O:13])[C@@H:10]([N:8]2[CH2:9][C:5]([O:4][C:3]3[CH:19]=[CH:20][CH:21]=[C:22]([Cl:23])[C:2]=3[Cl:1])=[CH:6][C:7]2=[O:18])[CH2:14][CH:15]([CH3:17])[CH3:16])=[N:26]1
Reactant: CC(C)C[C@@H](C(=O)O)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)Nc1ccn(CC(C)(C)O)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methy-1-pentanoic acid (130 mg, 0.36 mmol) in N,N-dimethylformamide (4 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 80 mg, 0.51 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (340 mg, 0.76 mmol) and N,N-diisopropylethylamine (120 mg, 0.93 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 40% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide as a fluffy material. This material was dissolved in dichloromethane (4 mL) and treated with 1M hydrogen chloride in diethyl ether (4 mL). Solvents were evaporated and the residue was triturated with diethyl ether. Solid was filtered to give (S)-2-[4-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochloride (60 mg, 31%): HR-ES-MS m/z calculated for C23H28Cl2N4O4 [M+H]+ 495.1561, observed 495.1564; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.90 (d, J=6.3 Hz, 3H) 0.94 (d, J=6.3 Hz, 3H) 1.04 (s, 3H) 1.06 (s, 3H) 1.35-1.65 (m, 2H) 1.67-1.86 (m, 1H) 3.89 (s, 2H) 4.22 (d, J=18.5 Hz, 1H) 4.63 (d, J=18.5 Hz, 1H) 4.86-4.91 (m, 1H) 4.92 (s, 1H) 6.44 (d, J=2.1 Hz, 1H) 7.44-7.59 (m, 3H) 7.64 (dd, J=7.5, 1.8 Hz, 1H) 10.82 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=O)#[N:2].C(Cl)(=O)C(Cl)=O.[F:35][C:36]([F:45])([F:44])[C:37]1[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=1.N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:41][C:40]1[CH:42]=[CH:43][C:37]([C:36]([F:35])([F:44])[F:45])=[CH:38][CH:39]=1)=[O:28])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)Nc3ccc(C(F)(F)F)cc3)n([C@H]3CCCc4ccccc43)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 4-trifluoromethylaniline (0.121 ml, 0.968 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 1 hour and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the objective product as a solid material.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:9])([F:8])[C:5]([OH:7])=[O:6].[CH3:10][N:11]1[CH2:25][C:16]2=[C:17]3[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]2[O:14][CH2:13][CH2:12]1)[NH:20][CH:19]=[CH:18]3.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C=O)C>[F:3][C:4]([F:9])([F:8])[C:5]([OH:7])=[O:6].[CH3:10][N:11]1[CH2:25][C:16]2=[C:17]3[C:21](=[C:22]([CH3:24])[CH:23]=[C:15]2[O:14][CH2:13][CH2:12]1)[N:20]([S:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:34])=[O:33])[CH:19]=[CH:18]3
Reactant: Cc1cc2c(c3cc[nH]c13)CN(C)CCO2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccn(S(=O)(=O)c4ccccc4)c13)CN(C)CCO2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.5 %

Procedure:
Sodium hydride (60% in mineral oil, 14 mg, 0.54 mmol, 95%) was added to a solution of 2,7-dimethyl-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole trifluoroacetate (Intermediate 13, 0.060 g, 0.18 mmol) in DMF (2 mL) and stirred at room temperature for 5 minutes before benzenesulfonyl chloride (0.035 mL, 0.27 mmol) was added. The mixture was stirred at room temperature for 10 minutes and quenched with ice/water and extracted with DCM. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a brown oil (14 mg) in the form of the trifluoroacetate salt. MS m/z 357 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[N:9]2[C:21](=[O:38])[CH2:22][NH:23][C:24](=[O:37])[NH:25][C:26]2[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=2)[C:29]([O:31]CC)=[O:30])[CH:5]=[CH:6][CH:7]=1>CO>[OH:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][C@@H:10]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[N:9]2[C:21](=[O:38])[CH2:22][NH:23][C:24](=[O:37])[NH:25][C:26]2[CH:27]=[C:28]([CH:34]=[CH:35][CH:36]=2)[C:29]([OH:31])=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NCC(=O)N2C(c3cccc(O)c3)CCC2c2cccc(OC)c2)c1
Solvent: CO
Product: COc1cccc([C@@H]2CC[C@H](c3cccc(O)c3)N2C(=O)CNC(=O)Nc2cccc(C(=O)O)c2)c1
Yield: 58.7 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 1.8 g of ethyl (2RS,5SR)-3-{3-{2-[2-(3-hydroxyphenyl)-5-(3-methoxyphenyl)-1-pyrrolidinyl]-2-oxoethyl}ureido}benzoate in solution in 30 cm3 of methanol and 0.29 g of potassium hydroxide in solution in 6 cm3 of water and after treatment and recrystallization in diethyl ether, 1 g of (2R*,5S*)-3-{3-{2-[2-(3-hydroxyphenyl)-5-(3-methoxy-phenyl)-1-pyrrolidinyl]-2-oxoethyl}ureido}benzoic acid, melting at 172° C., is obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])(C)(C)C.C(O[C:27](=[O:50])[CH2:28][C:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[S:37][CH:38]=[C:39]([CH2:41][O:42]C3CCCCO3)[N:40]=2)[CH:31]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:13][C:8]2[N:7]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[S:37][CH:38]=[C:39]([CH2:41][OH:42])[N:40]=4)[CH:31]=3)[CH2:28][C:27](=[O:50])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2nc(COC3CCCCO3)cs2)c1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3nc(CO)cs3)c1)=N2

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isopropyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (0.17 g) (Example J26) and 3-oxo-3-[3-[4-(tetrahydro-pyran-2-yloxymethyl)-thiazol-2-yl]-phenyl]-propionic acid tert-butyl ester (Example K27) (0.23 g) according to the general procedure M. The obtained material was deprotected and cyclized by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light-brown solid (0.05 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:29]=[CH:28][C:27](OS(C(F)(F)F)(=O)=O)=[CH:26][CH:25]=4)[CH2:22][CH2:21][N:20]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1.[NH:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([CH2:16][O:17][CH:18]3[CH:23]([C:24]4[CH:25]=[CH:26][C:27]([N:48]5[CH2:52][CH2:51][CH2:50][CH2:49]5)=[CH:28][CH:29]=4)[CH2:22][CH2:21][N:20]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH2:19]3)[CH:14]=[CH:15][C:10]=2[O:9][CH2:8][CH2:7]1
Reactant: C1CCNC1
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OS(=O)(=O)C(F)(F)F)cc3)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(N4CCCC4)cc3)cc21
Temperature: 100 °C
Reaction time: 20 h

Procedure:
The mixture of 0.300 g of benzyl 3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-(4-trifluoromethanesulphonyloxyphenyl)piperidin-1-carboxylate, 0.043 ml of pyrrolidine, 0.041 g of (±)-2,2′-bis(diphenylphosphine)-1,1′-binaphthyl, 0.194 g of caesium carbonate and 0.0099 g of palladium(II) acetate in 3.0 ml of dioxane is stirred under argon at 100° C. over 20 hours. The reaction mixture is cooled, admixed with water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed successively with water (20 ml) and brine (20 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.40 (2:1 EtOAc-heptane); Rt=4.68.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:14][CH2:13][C@H:12]([O:15][C:16]3[N:17]([CH3:29])[C:18](=[O:28])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][N:23]=4)[N:21]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[CH3:42][N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH3:29][N:17]1[C:18](=[O:28])[CH:19]=[C:20]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][N:23]=2)[N:21]=[C:16]1[O:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)=[CH:4][CH:5]=2)[CH2:10][CH2:11]1
Reactant: CN1CCNCC1
Reactant: Cn1c(O[C@H]2CC[C@H](c3ccc(CO)cc3)CC2)nc(-c2ccncn2)cc1=O
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CN1CCN(Cc2ccc([C@H]3CC[C@H](Oc4nc(-c5ccncn5)cc(=O)n4C)CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-[trans-4-(4-hydroxymethyl-phenyl)cyclohexyloxy]-1-methyl-1H-[4,4′]bipyrimidinyl-6-one (100 mg, 0.255 mmol) and triethylamine (51.6 mg, 0.510 mmol) in dichloromethane (1.3 ml) was added methanesulfonyl chloride (32.1 mg, 0.28 mmol) at 0° C. The mixture was warmed to room temperature and stirred overnight. The mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved into tetrahydrofuran (1.3 ml) and N,N-dimethylformamide (0.3 ml). 1-Methylpiperazine (30.6 mg, 0.306 mmol) and potassium carbonate (52.8 mg, 0.382 mmol) was added to the solution. The mixture was stirred at 60° C. for 3 hours. The mixture was poured into water, and extracted with chloroform. The organic layer was washed with water (three times), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by NH-silica gel column chromatography (eluent; ethyl acetate) to afford 1-methyl-2-{trans-4-[4-(4-methyl-piperazin-1-ylmethyl)phenyl]cyclohexyloxy}-1H-[4,4′]bipyrimidinyl-6-one as a colorless solid (51.1 mg, 0.108 mmol, 42%).
Reaction SMILES: C([Li])CCC.CN(C)CCN(C)C.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:22][O:23][CH3:24].[CH:25](=[O:34])[C:26]1[C:27]([O:32][CH3:33])=[CH:28][CH:29]=[CH:30][CH:31]=1.[Cl-].[NH4+]>O1CCCC1>[Cl:14][C:15]1[C:16]([O:21][CH2:22][O:23][CH3:24])=[C:17]([CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH3:33])[OH:34])[CH:18]=[CH:19][CH:20]=1
Reactant: COCOc1ccccc1Cl
Reactant: COc1ccccc1C=O
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1c(Cl)cccc1C(O)c1ccccc1OC
Temperature: 0 °C

Procedure:
A solution containing 69 ml of 1.6 N butyl lithium (0.11 mol) and 12.78 g (0.11 mol) of tetramethylethylenediamine was prepared under nitrogen and cooled to 0° C. To this was added, with stirring and cooling at 0° C., 16.83 g (0.098 mol) of 1-chloro-2-methoxymethoxybenzene. After 3 hours 13.34 g (0.098 mol) of o-anisaldehyde in 40 ml of anhydrous tetrahydrofuran was added slowly at 0°-5° C. and allowed to react. The product was then poured into a mixture of ice and saturated aqueous ammonium chloride and the resulting mixture was extracted with ether. The ether extract was dried over magnesium sulfate and then the volatiles were removed by evaporation under reduced pressure to obtain 29.3 g of crude title compound as a yellow solid. This was purified by preparative liquid chromatography eluting with a 10:90 mixture of acetone and hexane to obtain 21.1 g (70 percent of theory) of the title compound as a white solid melting at 89°-90° C. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:14]=[C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[S:12][C:4]=2[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.C(N(C(C)C)CC)(C)C.[N+:31]([C:34]1[CH:42]=[CH:41][CH:40]=[CH:39][C:35]=1[C:36](Cl)=[O:37])([O-:33])=[O:32]>O1CCCC1>[CH2:10]([O:9][C:7]([N:5]1[C:4]2[S:12][C:13]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])=[CH:14][C:3]=2[C:2]([NH:1][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][CH:41]=[CH:42][C:34]=2[N+:31]([O-:33])=[O:32])=[N:6]1)=[O:8])[CH3:11]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)n1nc(N)c2cc(C(=O)OC(C)(C)C)sc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)n1nc(NC(=O)c2ccccc2[N+](=O)[O-])c2cc(C(=O)OC(C)(C)C)sc21
Reaction time: 0.17 h
Yield: 69.2 %

Procedure:
To a solution of 5-tert-butyl 1-ethyl 3-amino-1H-thieno[2,3-c]pyrazole-1,5-dicarboxylate (500 mg, 1.606 mmol) and diisopropylethylamine (DIEA, 0.824 mL, 4.818 mmol) in tetrahydrofuran (THF, 20 mL) at 0° C., 2-nitro-benzoyl chloride (0.318 mL, 2.409 mmol) was added. The reaction mixture was kept at the same temperature for 10 minutes then allowed to reach room temperature and let react overnight. The solvent was removed under vacuum, the residue was dissolved in dichloromethane (DCM) and washed with a 10% solution of acetic acid (AcOH), water, saturated NaHCO3 and brine. The crude was purified on silica gel (eluant dichloromethane/methanol 96/4) yielding 512 mg (69%) of the title compound.