Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]([Cl:10])(=[O:9])[CH:7]=[CH2:8]>>[CH:2]12[CH2:1][CH:5]([CH:7]([C:6]([Cl:10])=[O:9])[CH2:8]1)[CH:4]=[CH:3]2
Reactant: C1=CCC=C1
Reactant: C=CC(=O)Cl
Product: O=C(Cl)C1CC2C=CC1C2
Temperature: 0 °C

Procedure:
A 1-L, three-neck round-bottom flask equipped with a magnetic stirrer, digital thermometer, glass stopper, an addition funnel with a nitrogen gas purge, and a dry-ice cooling bath was charged with freshly distilled cyclopentadiene (248 g, 3.75 mol), which was cooled to 0° C. The addition funnel was charged with freshly distilled acryloyl chloride (317 g, 3.5 mol), which was added drop wise to the reaction over about three hours while maintaining the reaction temperature between 0-10° C. After the acryloyl chloride addition was complete, the cooling bath was removed and the reaction allowed to warm to room temperature overnight. The reaction mixture was distilled under vacuum, collecting 533 g of the title product distilling at 54-56° C. at a pressure of 300 milliTorr.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[C:12]([CH3:14])[N:11]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[CH:18][CH:17]=4)[C:8]=3[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccc(CO)cc1
Reactant: C1CCNC1
Product: Cc1cc2c(ccc3nnc(C)n32)n1Cc1ccc(CN2CCCC2)cc1
Reaction time: 8 h

Procedure:
The title compound was prepared according to the procedures of Example 45, using the alcohol of Example 49 as starting material and using pyrrolidine (0.016 mL, 0.20 mmol, Aldrich) in the displacement, which was performed overnight (11.2 mg, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[OH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:30]1[CH2:31][CH2:32][CH:27]([OH:26])[CH2:28][CH2:29]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Reactant: OC1CCNCC1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCC(O)CC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from rac.-2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 4-hydroxypiperidine, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.97 minutes; C22H22Cl2N4O3 (461.35); mass spectrum: (M−H)−=460/462/464 (chlorine isotope).
Reaction SMILES: Br[C:2](Br)=[CH:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1.C([Li])CCC>C1COCC1>[C:3]([C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1)#[CH:2]
Reactant: BrC(Br)=Cc1ccc2c(c1)OCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of 5-(2,2-dibromo-vinyl)-benzo[1,3]dioxole (1.47 g, 5.0 mmol) in THF (10 mL) at −78° C. was added 2.0 M solution of n-butyllithium (5.5 mL, in cyclohexane) over 5 minutes period. After the addition completed, the reaction was stirred for 1 h, and then quenched with saturated NH4Cl. The mixture was allowed to warm up to room temperature. THF was removed. The aqueous was extracted with ethyl acetate. The organic layer was washed with water, brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel, eluting with DCM/hexane (5 to 10%) to give the title compound (0.64 g, 95% yield) as an orange oil. 1H NMR (CDCl3) δ 7.02 (dd, 1H, J=1.6, 8.1 Hz), 6.93 (d, 1H, J=1.6 Hz), 6.75 (d, 1H, J=8.0 Hz), 5.98 (s, 2H), 2.97 (s, 1H).
Reaction SMILES: [C:1]([O:6]C)(=O)[C:2]([CH3:4])=[CH2:3].CC(C)(O)C#[N:11].[S:14](=[O:18])(=[O:17])([OH:16])[OH:15]>>[S:14]([OH:18])([OH:17])(=[O:16])=[O:15].[C:1]([NH2:11])(=[O:6])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(C)(O)C#N
Reactant: C=C(C)C(=O)OC
Agent: O=S(=O)(O)O
Product: C=C(C)C(N)=O

Procedure:
A process for producing the α,β-unsaturated carboxylic acid esters, for example, methyl methacrylate on a commercial scale, comprises reacting acetone cyanohydrin with concentrated sulfuric acid to form methacrylamide sulfate and thereafter esterifying this with methanol.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13](O)[CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=O)C>Cl>[NH:4]1[C:12]2[C:7](=[CH:8][C:9](/[CH:13]=[CH:14]/[CH2:15][N:16]([CH3:18])[CH3:17])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCc2cc(C(O)CCN(C)C)ccc21
Agent: Cl
Product: CN(C)C/C=C/c1ccc2c(c1)CCN2
Temperature: 25 °C

Procedure:
A mixture of 3-[1-acetyl-2,3-dihydro-1H-indol-5-yl]-3-hydroxy-N,N-dimethyl-1-propanamine (3.3 g) obtained in 1) above and concd. hydrochloric acid (20 ml) was heated for 16 hours under reflux. The reaction solution was cooled to room temperature, then concentrated under reduced pressure, diluted with water, made basic with 2 N aqueous sodium hydroxide and extracted with ethyl acetate. The extract was washed with a saturated saline solution and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure, whereby the title compound (2.3 g) was obtained as oily matter.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:11]([CH3:12])[C:10]3[CH:13]=[C:14]([O:17][C:18]4[CH:19]=[C:20]([NH:24]C(=O)OC(C)(C)C)[CH:21]=[CH:22][CH:23]=4)[CH:15]=[CH:16][C:9]=3[N:8]=2)=[O:5])[CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[NH2:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][C:14]1[CH:15]=[CH:16][C:9]2[N:8]=[C:7]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[N:11]([CH3:12])[C:10]=2[CH:13]=1
Reactant: Cn1c(NC(=O)C2CC2)nc2ccc(Oc3cccc(NC(=O)OC(C)(C)C)c3)cc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(NC(=O)C2CC2)nc2ccc(Oc3cccc(N)c3)cc21
Yield: 87.9 %

Procedure:
Using tert-butyl [3-({2-[(cyclopropylcarbonyl)amino]-1-methyl-1H-benzimidazol-6-yl}oxy)phenyl]carbamate (1.52 g, 3.60 mmol) and trifluoroacetic acid (50 mL) as starting materials, and in the same manner as in Example C1(vi), the title compound (1.02 g, 88%) was obtained as a pink amorphous substance.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:16]2[CH2:19][CH:18]([NH:20][CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[CH2:17]2)=[CH:11][CH:10]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([CH:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)[N:16]2[CH2:17][CH:18]([N:20]([CH2:21][C:22]3[CH:27]=[C:26]([F:28])[CH:25]=[C:24]([F:29])[CH:23]=3)[S:38]([CH3:37])(=[O:40])=[O:39])[CH2:19]2)=[CH:31][CH:32]=1
Reactant: CS(=O)(=O)Cl
Reactant: Fc1cc(F)cc(CNC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N(Cc1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Temperature: 0 °C

Procedure:
347 mm3 of triethylamine are added, at room temperature under an argon atmosphere, to a solution of 433 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)amine in 30 cm3 of dichloro-methane. The mixture is cooled to around 0° C. before adding thereto a solution of 46.4 mm3 of methylsulfonyl chloride in 5 mm3 of dichloromethane, and then it is stirred at room temperature for 1 hour. The reaction mixture is diluted with 20 cm3 of dichloromethane and is then washed with twice 20 cm3 of distilled water. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is introduced into solution in methanol on a Bond Elut® SCX cartridge (10 g), eluting successively with methanol and with a 1 M solution of ammonia in methanol. The ammoniacal fractions are pooled and concentrated to dryness under reduced pressure (2.7 kPa). 0.44 g of N-{1-[bis(4-chloro-phenyl)methyl]azetidin-3-yl}-N-(3,5-difluorobenzyl)-methylsulfonamide is thus obtained in the form of a cream-colored foam [1H NMR spectrum (300 MHz, CDCl3, δ in ppm): 2.81 (s:3H); 3.02 (broad t, J=7.5 Hz: 2H); 3.38 (broad t, J=7.5 Hz:2H); 4.23 (s:1H); 4.40 (mt:1H); 4.54 (s:2H); 6.75 (tt, J=9 and 2 Hz:1H); 6.95 (mt:2H); 7.25 (mt:8H)].
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:12]1[CH:17]=[C:16]([CH2:18][CH2:19][CH3:20])[C:15]([OH:21])=[C:14](/[CH:22]=[CH:23]\[CH3:24])[CH:13]=1)([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]>[C].[Pd].CO>[CH2:18]([C:16]1[CH:17]=[C:12]([C:3]([O:8][CH2:9][O:10][CH3:11])([C:2]([F:1])([F:25])[F:26])[C:4]([F:5])([F:6])[F:7])[CH:13]=[C:14]([CH2:22][CH2:23][CH3:24])[C:15]=1[OH:21])[CH2:19][CH3:20]
Reactant: C/C=C\c1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc(CCC)c1O
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)cc(CCC)c1O
Reaction time: 20 h
Yield: 71.6 %

Procedure:
Methanol (30 mL) was added to 4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethyl)oxypropan-2-yl]-2-[(1Z)-1-propenyl]-6-propylphenol (1.29 g, 3.34 mmol). A 10% palladium-carbon catalyst (130 mg) was added to the mixed solution, followed by hydrogenation for 20 hours. The catalyst was separated from the reaction solution by filtration, followed by concentration under reduced pressure to obtain 929 mg of 2,6-dipropyl-4-[1,1,1,3,3,3-hexafluoro-2-(methoxymethyl)oxypropan-2-yl]phenol (yield: 72%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12]Br.[Cl:14][C:15]1[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=1[CH3:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][NH:21][C:19]1[CH:18]=[CH:17][C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][C:23]=2[CH3:32])=[C:15]([Cl:14])[CH:20]=1
Reactant: Cc1cc(C(F)(F)F)ccc1-c1ccc(N)cc1Cl
Reactant: FC(F)(F)c1ccc(CBr)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(C(F)(F)F)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2Br)cc1Cl
Temperature: 80 °C

Procedure:
2-Bromo-1-(bromomethyl)-4-(trifluoromethyl)benzene, prepared as described in Example 34 (2.5 g, 7.9 mmol), 2-chloro-2′-methyl-4′-(trifluoromethyl)-[1,1′-biphenyl]-4-amine (2.5 g, 8.7 mmol), and K2CO3 (1.6 g, 11.8 mmol) were diluted with DMF (20 mL) and heated to 80° C. After 3 h the resulting mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH:34]([NH2:36])[CH3:35]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:14])([F:15])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:36][CH:34]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[F:27])[CH3:35]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(N)c1ccccc1F
Solvent: Cc1ccccc1
Product: CC(Nc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccccc1F
Yield: 34.6 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (250 mg, 0.6 mmol) with (±)-1-(2-fluorophenyl)-ethylamine (206 mg, 1.5 mmol) in toluene (5 mL). Purify the residue by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) followed by SCX chromatography [pre-wash column with methanol followed by DCM, load material dissolved in DCM, then elute with DCM/2M ammonia in methanol (1:1) and concentrate in vacuo] to obtain (±)-7-chloro-6-[1-(2-fluorophenyl)-ethylamino]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (86 mg, 35%). GC-MS m/z: 414 (M30 ).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3]([O:5][NH:6][C@H:7]([C:25]([OH:27])=[O:26])[CH2:8][S:9][C:10]1[C:15]([N+:16]([O-])=O)=[CH:14][CH:13]=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:4]>[Pd].CO>[NH2:16][C:15]1[C:10]([S:9][CH2:8][C@@H:7]([C:25]([OH:27])=[O:26])[NH:6][O:5][C:3](=[O:4])[C:2]([CH3:28])([CH3:29])[CH3:1])=[C:11]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)C(=O)ON[C@@H](CSc1c(-c2ccccc2)cccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)C(=O)ON[C@@H](CSc1c(N)cccc1-c1ccccc1)C(=O)O
Yield: 77.1 %

Procedure:
810 mg of 38 (1.936 mmol), 69.84 mg of Pd/C (10%) and 20 mL of MeOH are hydrogenated at 5 bar for 10 hours at 20° C. in an autoclave. After filtering off the catalyst through Celite, the solvent is evaporated off and 580 mg of expected product 39 are obtained, which product is used directly in the following step.
Reaction SMILES: Cl.C([N:4]=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[CH3:24][C:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]([CH3:35])[O:27][C:26]=1[C:36]([OH:38])=O.N>O.N1C=CC=CC=1>[CH3:24][C:25]1[C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:28]([CH3:35])[O:27][C:26]=1[C:36]([NH2:4])=[O:38]
Reactant: CCOC(=O)c1c(C)oc(C(=O)O)c1C
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)c1c(C)oc(C(N)=O)c1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (248 mg, 1.30 mmol) and 1-hydroxybenzotriazole monohydrate (199 mg, 1.30 mmol) were added to a pyridine (4 ml) solution of the 3,5-dimethyl-4-ethoxycarbonylfuran-2-carboxylic acid (250 mg, 1.18 mmol) obtained in Example 2 (1). After a 28% aqueous ammonia solution (0.19 ml, 11.8 mmol) was added, heated to 80° C. and stirred for 4 hours. The mixture was cooled to room temperature with stirring, and after addition of water to reaction mixture, precipitate was collected by filtration, thereby giving 3,5-dimethyl-4-ethoxycarbonylfuran-2-carboxamide (176 mg, 71%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:6]=1[OH:13])=[O:4].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1F)([O-:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:13][C:6]1[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=1[C:3]([O:2][CH3:1])=[O:4])([O-:16])=[O:15]
Reactant: COC(=O)c1ccc(OC)cc1O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)cc1Oc1ccccc1[N+](=O)[O-]
Yield: 100.5 %

Procedure:
A solution of 2-methoxycarbonyl-5-methoxyphenol (34.1 g, 0.187 mol), 2-nitrofluorobenzene (19.7 mL, 0.187 mol), and K2CO3 (65 g, 0.467 mol) in DMF (200 mL) was heated at 110° C. for 18 h. The solution was diluted with water (200 mL) and extracted with EtOAc. The EtOAc layer was concentrated to give the crude title compound (57 g)which was used as is for the next step without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C@@H:5]([NH2:7])[CH3:6])[CH3:2].[N:11]1[S:12][N:13]=[C:14]2[C:19]([CH:20]=O)=[CH:18][CH:17]=[CH:16][C:15]=12>>[N:11]1[S:12][N:13]=[C:14]2[C:19]([CH2:20][NH:7][C@@H:5]([CH3:6])[CH:4]([O:8][CH2:9][CH3:10])[O:3][CH2:1][CH3:2])=[CH:18][CH:17]=[CH:16][C:15]=12
Reactant: O=Cc1cccc2nsnc12
Reactant: CCOC(OCC)[C@H](C)N
Product: CCOC(OCC)[C@H](C)NCc1cccc2nsnc12
Yield: 93.6 %

Procedure:
According to the procedure described in the synthesis method of Compound IX-5, (S)-1,1-diethoxypropan-2-amine (Compound XVIII-1) (883 mg, 6.0 mmol) was reacted with benzo[c][1,2,5]thiadiazole-4-carbaldehyde (837 mg, 5.1 mmol) to obtain the title compound (1.41 g, 95%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2([C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:21]([N:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1)([CH3:23])[CH3:22].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[CH:21]([N:24]1[CH2:29][CH2:28][CH:27]([O:20][C:17]2[CH:16]=[CH:15][C:14]([C:8]3([CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:19][CH:18]=2)[CH2:26][CH2:25]1)([CH3:23])[CH3:22]
Reactant: Oc1ccc(C2(CN3CCOCC3)CCOCC2)cc1
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2ccc(C3(CN4CCOCC4)CCOCC3)cc2)CC1
Yield: 12 %

Procedure:
The title compound (52 mg, 12%) was prepared using 4-[4-(morpholin-4-ylmethyl)tetrahydro-2H-pyran-4-yl]phenol, 1-isopropyl-4-hydroxypiperidine (step 1 of intermediate 21), PPh3 and DIAD similarly to the procedure used for intermediate 55. 1H NMR (400 MHz, CD3OD) δ 1.09 (d, 6H), 1.74-1.80 (m, 2H), 1.83-1.90 (m, 2H), 1.98-2.04 (m, 2H), 2.12-2.18 (m, 6H), 2.40 (s, 2H), 2.47 (t, 2H), 2.75 (m, 1H), 2.80-2.85 (m, 2H), 3.47-3.54 (m, 6H), 3.71-3.77 (m, 2H), 4.36 (m, 1H), 6.90 (d, 2H), 7.28 (d, 2H). HRMS ESI+ m/z 403.2951 [MH]+.
Reaction SMILES: N1C=CC=CC=1.Cl.CN(C)CCCN=C=NCC.[S:19]1[CH:23]=[CH:22][C:21]2[C:24]([NH2:28])=[CH:25][CH:26]=[CH:27][C:20]1=2.[N:29]1([C:35]2[N:36]=[C:37]([CH2:42][C:43]([O-])=[O:44])[NH:38][C:39](=[O:41])[CH:40]=2)[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[Na+]>CN(C)C=O>[S:19]1[C:20]2[CH:27]=[CH:26][CH:25]=[C:24]([NH:28][C:43](=[O:44])[CH2:42][C:37]3[NH:38][C:39](=[O:41])[CH:40]=[C:35]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:36]=3)[C:21]=2[CH:22]=[CH:23]1
Reactant: Nc1cccc2sccc12
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc2sccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.9 %

Procedure:
2 ml of pyridine, 257 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 223 mg of benzo[B]thiophen-4-ylamine are added to a solution of 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 2 of example 1, in 2 ml of N,N-dimethylformamide. The reaction mixture is stirred at ambient temperature for 15 hours, and then concentrated under reduced pressure. Water and ethyl acetate are added and the resulting mixture is thus stirred for 30 minutes. The precipitate formed is filtered off, and rinsed with water, ethyl ether and petroleum ether. The solid obtained is dried under vacuum. 262 mg of N-(1-benzothiophen-4-yl)-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the formed of an off-white solid, the characteristics of which are the following:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13][C@H:14]2[CH2:18][N:17]([C@@H](C3C=CC=CC=3)C)[C:16](=O)[CH2:15]2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].C(O)C>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:13][C@H:14]2[CH2:15][CH2:16][NH:17][CH2:18]2)[CH2:10][CH2:11][CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1C[C@H](CC2(NC(=O)OC(C)(C)C)CCC2)CC1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C[C@H]2CCNC2)CCC1
Temperature: 50 °C
Yield: 99.9 %

Procedure:
To an ethanol (30 ml) solution of 3-(R)-[1-(tert-butoxycarbonyl)amino-1-cyclobutyl]methyl-1-[1-(R)-phenylethyl]pyrrolidine (isomer B1) (516 mg, 1.44 mmol) was added a 10% palladium-carbon catalyst (water content 53.8%, 500 mg) and catalytic hydrogenation was carried out under heating at an outer temperature of 50° C. at normal pressure for 5 hours. The reaction solution was filtered and the solvent was removed under reduced pressure to obtain the title compound (366 mg, quantitative) as colorless crystals.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][NH:22][C:23](=[O:25])[CH3:24])[CH2:11][CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[N:12]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][NH:22][C:23](=[O:25])[CH3:24])[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1
Reactant: CC(=O)NCc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CC(=O)NCc1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
Methanolic hydrogen chloride (4M, 5 mL) was added to a stirred, cooled (0° C.) suspension of N-[2-(4-t-butoxycarbonylpiperazin-1-yl)phenylmethyl]acetamide (668 mg, 2 mmol) in methanol (2 mL) and the mixture was stirred at room temperature for 4 h. The solvent was evaporated under reduced pressure to give the title compound as a colorless foam (536 mg, 99%), δH (360 MHz, d6 -DMSO) 9.20 (2H, br s), 8.26 (1H, br t, J 5.8 Hz), 7.26 (2H, m), 7.12 (2H, m), 4.33 (2H, d, J 5.8 Hz), 3.22 (4H, m), 3.04 (4H, m), and 1.89 (3H, s). m/e (ES+) 234 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[S:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([OH:14])=[O:13].[CH:16](NC(=NC(C)C)OC)(C)C>C(O)C>[CH3:1][C:2]1([CH3:15])[C@@H:4](/[CH:5]=[C:6]2/[C:7](=[O:11])[S:8][CH2:9][CH2:10]/2)[C@H:3]1[C:12]([O:14][CH3:16])=[O:13]
Reactant: COC(=NC(C)C)NC(C)C
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C1\CCSC1=O
Solvent: CCO
Product: COC(=O)[C@@H]1[C@H](/C=C2\CCSC2=O)C1(C)C
Yield: 46 %

Procedure:
Using the procedure of Example 17, 4.5 g of (1R,cis) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylic acid and 3.5 g of methyl N,N'-diisopropylcarbamimidate were reacted to obtain 2.2 g of methyl (1R,cis) 2,2-dimethyl-3-[(E) (dihydro-2-oxo-3-(2H)-thienylidene)-methyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+63.5°±1.5° (c=1.1% in ethanol).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[OH:12])[NH:8][C:7]=12>C(Cl)Cl.O=[Mn]=O>[Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:12])[NH:8][C:7]=12
Reactant: OC(c1ccccc1)c1cc2ccnc(Cl)c2[nH]1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=C(c1ccccc1)c1cc2ccnc(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 82.8 %

Procedure:
A mixture of (7-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methanol (Example 26) (0.83 g, 3.2 mmol) and MnO2 (3.35 g, 38.5 mmol) in methylene chloride (64 mL) was stirred under a nitrogen atmosphere at room temperature overnight (20 h). The crude reaction mixture was filtered through diatomaceous earth and rinsed with methylene chloride. Concentration afforded (7-chloro-1H-pyrrolo[2,3-c]pyridin-2-yl)(phenyl)methanone (0.68 g, 82%) as an off-white solid: mp 152-153° C.; 1H NMR (300 MHz, CDCl3) δ7.18 (1H, d, J=2.1 Hz), 7.55-7.71 (4H, m), 7.99-8.05 (2H, m), 8.11 (1H, d, J=5.7 Hz), 9.55 (1H, br s); ESI MS m/z 257 [C14H9ClN2O+H]+; HPLC (Method A) >99% (AUC), tR=25.0 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][C:9]2[N:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=[N:11][C:10]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:4](=[O:25])[N:3]=1.[CH2:26]([NH2:28])[CH3:27]>C(O)C>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:10]2[N:11]=[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]3[C:9]=2[CH2:8][N:5]2[CH:6]=[CH:7][C:2]([NH:28][CH2:26][CH3:27])=[N:3][C:4]2=[O:25])=[CH:23][CH:22]=1
Reactant: CCN
Reactant: O=c1nc(Cl)ccn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12
Solvent: CCO
Product: CCNc1ccn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c(=O)n1
Temperature: 70 °C

Procedure:
A mixture of 4-chloro-1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2(1H)-one (50 mg, 0.13 mmol) and ethylamine (30 μl) in ethanol (2 ml) in a sealed tube was heated at 70° C. for 4 hours. Excess reagent was evaporated under reduced pressure. Crude product was dissolved in CH2Cl2 (10 mL) was washed with water, sat. NaHCO3 and brine, dried and evaporated. The crude product was purified by silica gel chromatography. M/e+ 380 for C20H19ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.42 (d, J=6.6 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.64 (d, J=9.1 Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.29 (d, J=7.7 Hz, 1H), 6.87 (t, J=6.9 Hz, 1H), 6.65 (d, J=7.3 Hz, 1H), 5.37 (d, J=7.3 Hz, 2H), 4.97 (s, 1H), 3.51 (m, 2H), 3.18 (s, 1H), 1.18 (t, J=7.3 Hz, 3H) ppm.