Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][NH2:8])[CH:4]=[N:3]1.C(N(CC)C(C)C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[F:39][C:40]1[CH:41]=[C:42]([C:47]2[CH2:51][C:50]([CH3:55])([C:52](O)=[O:53])[O:49][N:48]=2)[CH:43]=[C:44]([F:46])[CH:45]=1.OS(O)(=O)=O>ClCCl>[F:46][C:44]1[CH:43]=[C:42]([C:47]2[CH2:51][C:50]([CH3:55])([C:52]([NH:8][CH2:7][C:5]3[CH:6]=[N:2][NH:3][CH:4]=3)=[O:53])[O:49][N:48]=2)[CH:41]=[C:40]([F:39])[CH:45]=1
Reactant: NCc1cn[nH]c1
Reactant: CC1(C(=O)O)CC(c2cc(F)cc(F)c2)=NO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C(=O)NCc2cn[nH]c2)CC(c2cc(F)cc(F)c2)=NO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-(1H-Pyrazol-4-yl)methanamine hydrochloride (609 mg, 4.56 mmol), N,N-diisopropylethylamine (1.61 g, 12.44 mmol), HOBt (506 mg, 4.15 mmol) and EDCI (1.59 g, 8.29 mmol) were added to a solution of 3-(3,5-difluorophenyl)-5-methyl-4,5-dihydro-1,2-oxazole-5-carboxylic acid (1.00 g, 4.15 mmol) in dichloromethane (30 ml), and the mixture was stirred at RT for 16 h. H2SO4 (0.5M, 10 ml) was then added, and the mixture was diluted with CH2Cl2 (20 ml). The aqueous phase was extracted with CH2Cl2 (2×20 ml), the combined organic phases were washed with saturated NaHCO3 solution (30 ml) and dried over Na2SO4, and the solvent was removed. This gave 1.2 g of 3-(3,5-difluorophenyl)-5-methyl-N-(1H-pyrazol-4-ylmethyl)-4,5-dihydro-1,2-oxazole-5-carboxamide which was used without further purification.
Reaction SMILES: ClS(C1C=CC(C(O)=O)=CC=1)(=O)=O.N1(C(OC(C)(C)C)=O)CCNCC1.[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][C:29]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1.C(OC([N:48]1[CH2:53][CH2:52][N:51]([S:54]([C:57]2[CH:65]=[CH:64][C:60]([C:61](O)=[O:62])=[CH:59][CH:58]=2)(=[O:56])=[O:55])[CH2:50][CH2:49]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[Cl:27][C:28]1[CH:34]=[CH:33][C:31]([NH:32][C:61](=[O:62])[C:60]2[CH:64]=[CH:65][C:57]([S:54]([N:51]3[CH2:52][CH2:53][NH:48][CH2:49][CH2:50]3)(=[O:56])=[O:55])=[CH:58][CH:59]=2)=[CH:30][C:29]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(=O)O)cc2)CC1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Agent: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)N2CCNCC2)cc1

Procedure:
1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 931 mg of tert-butyl piperazine-1-carboxylate via Procedure H. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 150 mg of 4-(4-(tert-butoxycarbonyl)piperazin-1-ylsulfonyl)benzoic acid via Procedure G. The crude product was subjected to basic workup conditions, treated with TFA to remove the Boc group and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(piperazin-1-ylsulfonyl)benzamide. MS (Q1) 457.1 (M)+.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[F:23])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[F:23])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: Fc1c(Cl)cccc1Cc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Cc2cccc(Cl)c2F)ncn1
Temperature: 25 °C
Yield: 101.7 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.05 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.07 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(3-chloro-2-fluorobenzyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.23 g of 4-(2-butynyloxy)-6-(3-chloro-2-fluorobenzyl)pyrimidine (the present compound (102)).
Reaction SMILES: [B:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([OH:3])[OH:2].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[F:44][C:45]1([F:50])[CH2:49][CH2:48][NH:47][CH2:46]1>C(#N)C>[F:44][C:45]1([F:50])[CH2:49][CH2:48][N:47]([C:8]([C:7]2[CH:6]=[CH:5][C:4]([B:1]([OH:2])[OH:3])=[CH:12][CH:11]=2)=[O:10])[CH2:46]1
Reactant: FC1(F)CCNC1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(B(O)O)cc1)N1CCC(F)(F)C1
Reaction time: 0.5 h
Yield: 0 %

Procedure:
A mixture of 4-boronobenzoic acid (500 mg, 3.01 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (866 mg, 4.52 mmol) and 1-hydroxybenzotriazole (554 mg, 3.62 mmol) in acetonitrile (25 mL) was sonicated until it became a solution. N,N-Diisopropylethylamine (1.579 mL, 9.04 mmol) and 3,3-difluoropyrrolidine (484 mg, 4.52 mmol) were added. After 30 min at room temperature, the mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3×). The combined extracts were washed with brine, water, dried (Na2SO4) and concentrated. Reverse phase HPLC purification gave the expected product (0.250 mg, 33% yield). MS (ES+) m/z: 256 (M+H); LC retention time: 1.87 min (analytical HPLC Method A).
Reaction SMILES: [Mg].[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6](Br)[CH:7]=[CH:8][CH:9]=1.[OH:13][C:14]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=1[C:21](=[O:24])[CH2:22][CH3:23].[Cl-].[NH4+]>O1CCCC1>[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6]([C:21]([C:15]2[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:14]=2[OH:13])([OH:24])[CH2:22][CH3:23])[CH:7]=[CH:8][CH:9]=1
Reactant: CCC(=O)c1ccc(O)cc1O
Reactant: FC(F)(F)c1cccc(Br)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(c1cccc(C(F)(F)F)c1)c1ccc(O)cc1O

Procedure:
To a Grignard reactant prepared from 14.6 g. of magnesium turnings and 135 g. of 3-trifluoromethylbromobenzene in 330 ml. of tetrahydrofurane a solution of 16.6 g. of 2',4'-dihydroxy-propiophenone in 83 ml. of tetrahydrofurane is added dropwise, at 50° C., and the mixture is stirred at this temperature for 30 additional minutes. After cooling, the reaction mixture is decomposed with a cold 20% aqueous ammonium chloride solution, with stirring. The phases are separated, the aqueous phase is extracted with tetrahydrofurane, the combined organic phases are washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent is distilled off in vacuo. The residue is decolored with activated carbon in methanol, the solvent is filtered off, and distilled off under reduced pressure. If desired, the product is crystallized from a mixture of ethyl acetate and n-hexane to yield 26.6 g. of the named compound, melting at 137° to 138° C.
Reaction SMILES: [N+](=[C:3]([C:17](=[O:41])[CH2:18][C@@H:19]1[C@@H:22]([C:23]([CH3:39])([O:25][C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=2)=[O:27])[CH3:24])[C:21](=[O:40])[NH:20]1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>C1C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[O:41]=[C:17]1[CH2:18][C@H:19]2[N:20]([C:21](=[O:40])[C@@H:22]2[C:23]([CH3:39])([O:25][C:26]([O:28][CH2:29][C:30]2[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=2)=[O:27])[CH3:24])[C@H:3]1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N[C@@H]1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Temperature: 25 °C
Yield: 86.7 %

Procedure:
A mixture of 4-nitrobenzyl 2-diazo-4-{(2R,3S)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-4-oxoazetidine-2-yl}-3-oxobutanoate (58.0 mg) and rhodium (II) acetate (0.1 mg) in benzene (3.4 ml) was refluxed for 30 minutes. After cooling to ambient temperature, the mixture was filtered with a diatomaceous earth and evaporated to give 4-nitrobenzyl(2R,5R,6S)-3,7-dioxo-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-azabicyclo[3.2.0]-heptane-2-carboxylate (47.8 mg) as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][C:13]2[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-])=O)=[CH:15][C:14]=2[CH3:23])=[CH:4][CH:3]=1.[H][H]>C1(C)C=CC=CC=1.[Pt]>[Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([O:12][C:13]2[C:14]([CH3:23])=[CH:15][C:16]([NH2:20])=[CH:17][C:18]=2[CH3:19])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Oc1ccc(Cl)c2c1CCCC2
Agent: [Pt]
Solvent: Cc1ccccc1
Product: Cc1cc(N)cc(C)c1Oc1ccc(Cl)c2c1CCCC2
Yield: 99.5 %

Procedure:
A 1 L rocking Parr hydrogenator was charged with a solution containing 19.11 g of 4-(4-chloro-5,6,7,8-tetrahydro-1-naphthoxy)-3,5-dimethyl-1-nitrobenzene in 600 mL of toluene. To this was then added 1.0 g of 5% platinum on carbon. This was then placed under an atmosphere of hydrogen at 100 psi. The internal pressure was maintained between 80 and 100 psi while hydrogen uptake continued. When the hydrogen uptake ceased, the contents of the hydrogenator were removed and the vessel washed with toluene. The washings were combined with the reaction mixture. This was then filtered through celite. Removal of the solvents afforded 17.30 g of pale yellow solid. mp 126°-135° C. NMR(CDCl3): δ1.6-1.8 (m, 4H), 2.0 (S, 6H), 2.6-2.9 (m, 4H), 3.45 (S, 2H), 6.13 (d, J=9 Hz, 1H), 6.37 (S, 2H), 6.93 (d, J= 9 Hz, 1H).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([Cl:14])[C:7]([O:15][CH3:16])=[CH:6][C:5]=1[NH:17]C(=O)C>O.CCO>[Cl:3][C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[C:8]([Cl:14])[C:7]([O:15][CH3:16])=[CH:6][C:5]=1[NH2:17]
Reactant: COc1cc(NC(C)=O)c(Cl)c(C(F)(F)F)c1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(N)c(Cl)c(C(F)(F)F)c1Cl
Temperature: 80 °C
Reaction time: 3.5 h

Procedure:
A 2 M solution of KOH in water (1.87 mL) is added to a solution of N-(2,4-dichloro-5-methoxy-3-trifluoromethyl-phenyl)-acetamide (104 mg, 0.344 mmol) in EtOH (3 mL). After stirring for 3.5 h at 80° C. followed by cooling to RT, the solvent is evaporated and the residue is taken up in EtOAc and a saturated aqueous solution of NaHCO3. The separated aqueous layer is extracted twice with EtOAc. The organic phases are washed with brine, dried (Na2SO4), filtered and concentrated, providing the title compound: ESI-MS: 258/260 [M-H]−; tR=4.8 min (system 1); TLC: Rf=0.54 (EtOAc).
Reaction SMILES: C(OC(N1C[C@H](O)C[C@@H]1C(O)=O)=O)(C)(C)C.[F:17][C:18]1[CH:19]=[C:20]([CH:50]=[C:51]([F:53])[CH:52]=1)[CH2:21][C@H:22]1[C@@H:26]([C@H:27]2[CH2:31][C@@H:30]([O:32]CC=C)[CH2:29][N:28]2[CH:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:25][C:24](=[O:49])[NH:23]1.FC1C=C(C=C(F)C=1)C[C@H]1[C@@H]([C@H]2C[C@@H](OCC=C)CN2)OC(=O)N1.[Br-].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:53][C:51]1[CH:50]=[C:20]([CH:19]=[C:18]([F:17])[CH:52]=1)[CH2:21][C@H:22]1[C@@H:26]([C@H:27]2[CH2:31][C@@H:30]([OH:32])[CH2:29][N:28]2[CH:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:25][C:24](=[O:49])[NH:23]1
Reactant: C=CCO[C@@H]1C[C@H]([C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)N(C(c2ccccc2)c2ccccc2)C1
Agent: C=CCO[C@H]1CN[C@@H]([C@H]2OC(=O)N[C@H]2Cc2cc(F)cc(F)c2)C1
Agent: CC(C)(C)OC(=O)N1C[C@H](O)C[C@@H]1C(=O)O
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: O=C1N[C@@H](Cc2cc(F)cc(F)c2)[C@@H]([C@H]2C[C@@H](O)CN2C(c2ccccc2)c2ccccc2)O1
Temperature: 25 °C
Yield: 87 %

Procedure:
Step J (1): (4S,5S)-4-(3,5-difluorobenzyl)-5-((2R,4R)-4-(allyloxy)-1-benzhydrylpyrrolidin-2-yl)oxazolidin-2-one. A mixture of (4S,5R)-4-(3,5-difluorobenzyl)-5-((2R,4R)-4-(allyloxy)pyrrolidin-2-yl)oxazolidin-2-one (Step C (8), 2.03 g, 6.0 mmol), benzylhydryl bromide (2.22 g, 9.0 mmol), and potassium carbonate (1.24 g, 9.0 mmol) in acetonitrile (40 mL) was stirred at reflux for 35 min. After cooling to rt, the mixture was filtered and concentrated in vacuo. The crude mixture was purified by Flash Chromatography (silica gel, 0-7.5% methanol/chloroform) to give a slightly yellow oil as the title compound (2.64 g, 87% yield): 1H NMR (CDCl3, 300 MHz) δ 1.95-2.23 (2H, m), 2.36 (1H, t, J=12 Hz), 2.70 (1H, m), 3.02 (2H, d, J=6 Hz), 3.48 (1H, m), 3.71-3.99 (4H, m), 4.70 (1H, s), 4.78 (1H, t, J=6 Hz), 4.93 (1H, s), 5.12 (1H, m), 5.22 (1H, dd, J=3, 18 Hz), 5.84 (1H, m), 6.49 (1H, d, J=6 Hz), 6.67 (1H, m), 7.20-7.39 (11H, m).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:33])([F:32])[O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([O:23][C:22]([F:21])([F:32])[F:33])=[CH:25][CH:26]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1)[CH3:20]
Reactant: CCOC(=O)C(C)CC(N)c1c(F)cccc1OCC
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Product: CCOc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2-ethoxy-6-fluorophenyl)-2-methylbutanoate with commercially available 4-(trifluoromethoxy)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.97 min.; [M+H]+: 411.97 g/mol.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8](=[O:19])[CH2:9][N:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH:12]=[C:11]3[C:4]=2[CH:3]=1.[CH2:22]1COCC1>>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8]([CH3:22])([OH:19])[CH2:9][N:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH:12]=[C:11]3[C:4]=2[CH:3]=1
Reactant: C1CCOC1
Reactant: O=C1COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Product: CC1(O)COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.6 %

Procedure:
MgBrCH3 (0.12 mL, 0.352 mmol) was added to the solution of 2-bromo-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7(8H)-one (60 mg, 0.176 mmol) in THF (1 mL) at 0° C. under N2. The mixture was stirred at room temperature for 30 minutes. The mixture was then quenched with saturated NH4Cl (10 mL) and extracted with ethyl acetate (10 mL×3). The organic layer was washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using p-TLC (petroleum ether:EA=3:1) to provide 2-bromo-7-methyl-7,8-dihydro-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7-ol (30 mg, yield: 47.6%). 1H-NMR(CDCl3, 400 MHz) δ 7.56˜7.59 (m, 2H), 7.36˜7.40 (m, 2H), 7.18˜7.22 (m, 1H), 7.08 (t, J=7.2 Hz, 1H), 6.93 (d, J=8.8 Hz, 1H), 6.61 (s, 1H), 3.81˜4.15 (m, 4H), 2.34 (s, 1H), 1.24 (s, 3H). MS (M+H)+: 358/360.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:17]2)=[O:15])[C@@H:10]([NH2:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:38]([C:41]1[CH:42]=[C:43]([N:47]=[C:48]=[O:49])[CH:44]=[CH:45][CH:46]=1)(=[O:40])[CH3:39]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]([N:16]2[CH2:21][CH2:20][CH2:19][C@@H:18]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:17]2)=[O:15])[C@@H:10]([NH:30][C:48]([NH:47][C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([C:38](=[O:40])[CH3:39])[CH:42]=2)=[O:49])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)[C@@H](N)C1
Reactant: CC(=O)c1cccc(N=C=O)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1cccc(NC(=O)N[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 16 h
Yield: 38.3 %

Procedure:
In a dry flask (3R,4S)-3-amino-4-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (77 mg, 0.18 mmol) was dissolved in tetrahydrofuran (2.5 mL) and triethylamine (20 μL, 0.143 mmol) and 3-acetylphenylisocyanate (50 μL, 0.36 mmol) were added. The reaction mixture was stirred for 16 hours. The reaction mixture was concentrated in vacuo and purified by preparative reverse-phase HPLC (10-90% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (40 mg, 38%). 1H NMR (300 MHz, CDCl3), δ: 7.98 (d, J=8, 1H), 7.83 (m, 2H), 7.74 (m, 1H), 7.65 (m, 2H), 7.56 (m, 1H), 7.46 (m, 1H), 7.01 (m, 2H), 6.87 (m, 1H), 3.09 (m, 1H), 2.51-2.77 (m, 7H), 2.42 (m, 1H), 1.23-1.78 (m, 1H), 1.42 (s, 9H). HRMS (ESI), C32H42FN4O5 m+/z: calc.=581.3139, found=581.3142.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1B1OC(C)(C)C(C)(C)O1)[O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=1.C([O-])(O)=O.[Na+].Br[C:32]1[CH:37]=[CH:36][N:35]([CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:34](=[O:42])[C:33]=1[C:43]#[N:44]>O1CCOCC1.CCOC(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>[CH:39]1([CH2:38][N:35]2[CH:36]=[CH:37][C:32]([C:16]3[CH:15]=[CH:14][C:4]([O:5][C:6]4[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[N:7]=4)=[CH:3][C:2]=3[F:1])=[C:33]([C:43]#[N:44])[C:34]2=[O:42])[CH2:40][CH2:41]1
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
Reactant: Cc1cc(C)nc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)c1
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: C1COCCO1
Product: Cc1cc(C)nc(Oc2ccc(-c3ccn(CC4CC4)c(=O)c3C#N)c(F)c2)c1

Procedure:
To a solution of intermediate 8 (1.42 mmol) in 1,4-dioxane (6 ml) and a saturated solution of NaHCO3 (5 ml) was added intermediate 5 (0.329 g, 1.3 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.15 mg, 0.13 mmol). The reaction was then microwaved in a sealed tube at 140° C. for 5 minutes. The resulting cooled reaction mixture was then diluted with EtOAc and filtered through a pad of diatomaceous earth. The filtrate was washed with water, dried (Na2SO4) and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/EtOAc up to 10% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 1 that was washed with diethyleter and dried in vacuum (0.207 g, 41%). Melting point: 137.0° C.
Reaction SMILES: [Br:1][C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([O:11]C)=[N:4][CH:3]=1.Cl>CC(O)=O>[Br:1][C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5](=[O:11])[NH:4][CH:3]=1
Reactant: COc1ncc(Br)n2cnnc12
Agent: Cl
Solvent: CC(=O)O
Product: O=c1[nH]cc(Br)n2cnnc12
Temperature: 110 °C
Yield: 85.3 %

Procedure:
To a solution of 5-bromo-8-methoxy-[1,2,4]triazolo[4,3-a]pyrazine (Borchardt WO2011/112766) (500 mg, 2.18 mmol) in HOAc (3 mL) was added HCl (1 N, 5.00 mL). The mixture was heated at 110° C. for 4 h and concentrated to give the title compound (400 mg, yield: 85%) as a yellow solid which was carried on without purification. 1H NMR (DMSO-d6, 400 MHz): δ 11.78 (s, 1H), 9.25 (s, 1H), 7.25 (d, J=6.0 Hz, 1H). LCMS: 214.9 (M+H)+
Reaction SMILES: [CH2:1]([N:3]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]2[C:6](=[O:16])[C:5]([C:17](O)=[O:18])=[CH:4]1)[CH3:2].S(Cl)(Cl)=O>>[CH2:1]([N:3]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]2[C:6](=[O:16])[C:5]([C:17]([NH:7][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:10]=2)=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)n2c3ccccc3nc12
Solvent: O=S(Cl)Cl
Product: CCn1cc(C(=O)Nc2ccccc2)c(=O)n2c3ccccc3nc12
Yield: 73 %

Procedure:
0.05 mol. of 1-ethyl-1,4-dihydro-4-oxo-pyrimido-[1,2-a]benzimidazole-3-carboxylic acid is refluxed with stirring in 100 ml. of thionyl chloride. After this time, the chlorinating agent is removed by distillation, the remaining acid chloride is treated with 50 ml. of toluene and again evaporated to dryness. After addition of 100 ml. of toluene, 0.1 mol. of aniline are added and the solution is stirred overnight. The solvent is distilled off and the residue treated with water and filtered. The product 1-ethyl-1,4-dihydro-4-oxo-N-phenyl-pyrimido[1,2-a]benzimidazole-3-carboxamide, is recrystallized from DMF, yield 73%; m.p. 268°-270°.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.C(N(CC)CC)C.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>ClCCl>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CSc1nc(Cl)cc(Cl)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1nc(Cl)cc(N2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Yield: 101.3 %

Procedure:
4,6-Dichloro-2-methylsulfanylpyrimidine (10 g) was dissolved in dichloromethane (200 ml) and triethylamine (20.6 g) was added. The mixture was stirred at room temperature and piperazine-1-carboxylic acid tert-butyl ester (9.54 g) was added in portions. The mixture was stirred at room temperature overnight. Mixture was washed with water (200 ml) then brine (100 ml). The organic layer was dried (MgSO4) then evaporated under reduced pressure to afford 4-(6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (17.9 g) as a white solid. 1H NMR (CDCl3): δ 6.11 (s, 1H), 3.58 (m, 4H), 3.44 (m, 4H), 2.42 (s, 3H), 1.41 (s, 9H).