Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([OH:11])[CH:3]=1.[Cl-].[C:13]([C:15]1[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][NH2+:22][CH3:23])[CH:16]=1)#[N:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:13]([C:15]1[N:19]([CH3:20])[N:18]=[C:17]([CH2:21][N:22]([CH3:23])[C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=2[OH:11])[CH:16]=1)#[N:14]
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: C[NH2+]Cc1cc(C#N)n(C)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(Cc1cc(C#N)n(C)n1)C(=O)c1ccc(F)cc1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 40.1 %

Procedure:
To a solution of 4-fluoro-2-hydroxybenzoic acid 136 (500 mg, 3.2 mmol), (5-cyano-1-methyl-1H-pyrazol-3-yl)-N-methylmethanaminium chloride 137 (600 mg, 3.2 mmol), and HATU (1.4 g, 3.5 mmol) in DMF (21 mL) was added DIEA (2.8 mL, 16 mmol). After stirring at room temperature for 14 hours, the solution was concentrated and purified by column chromatography over silica gel eluting with heptane/ethyl acetate(0-75%) to afford compound 138 (370 mg, 40%) as a semi-solid. 1H NMR (400 MHz, 80° C., DMSO-d6) δ 10.08 (s, 1H) 7.19 (m, 1H) 6.94 (s, 1H) 6.70-6.59 (m, 2H) 4.52 (s, 2H) 3.98 (d, J=0.8 Hz, 3H) 2.86 (s, 3H). LCMS APCI m/z 298 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([NH:19][S:28]([CH:27]=[CH2:26])(=[O:30])=[O:29])=[CH:20][CH:21]=3)=[CH:10][C:9]=2[CH3:22])=[O:7])=[CH:23][CH:24]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cc(Cc2ccc(N)cc2)n(C)c1C(=O)c1ccc(Cl)cc1
Solvent: c1ccncc1
Product: C=CS(=O)(=O)Nc1ccc(Cc2cc(C)c(C(=O)c3ccc(Cl)cc3)n2C)cc1
Reaction time: 1.5 h
Yield: 92.5 %

Procedure:
4-[5-(4-Chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]aniline (1.1 g, 3.25 mmol) was dissolved in pyridine (16.5 ml) and 2-chloroethanesulfonyl chloride (1.02 ml, 9.74 mmol) was added to the solution. The mixture was stirred for 1.5 h and then concentrated to dryness. The residue was filtered through a pad of silica gel (ethyl acetate) to give N-{4-[5-(4-chloro-benzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]phenyl}ethenesulfonamide, (1.29 g, 93%) as a solid.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]([NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:5]([OH:7])=[O:6])[CH3:3].N1C=CC=C[CH:20]=1.Cl.COC(=O)[C@H](C(C)C)N>C(Cl)(Cl)Cl>[NH:8]([C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[C@H:4]([C:5]([O:7][CH3:20])=[O:6])[CH:2]([CH3:1])[CH3:3]
Reactant: c1ccncc1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C

Procedure:
5.61 g of the resin 6a obtained according to Instruction (5b) are stirred in 40 ml of chloroform with 0.50 ml of pyridine and 0.350g of L-valine methyl ester hydrochloride for 130 minutes. The resin is filtered off and washed with 200 ml of chloroform and the filtrate is worked up as described in the previous Example. The yield is 0.300 g of Z-Val-Val-OMe and the melting point of the crude product is 120° C.; according to the IR and NMR spectrum, this product is identical to the authentic comparative preparation.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=2)=[N:2]1.ClCCl.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:17](=[O:18])[O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8][CH:7]=2)=[N:2]1
Reactant: Nc1ccc(-c2ccon2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccon2)cc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
4-Isoxazol-3-ylphenylamine (Intermediate 5, 4 g, 24.69 mmol) was added to dichloromethane (20 ml) followed by pyridine (4.6 ml). The solution was cooled to 0° C. and benzyl chloroformate (5.27 ml, 37.02 mmol) was added drop wise. The solution was allowed to stir for 2 hours at room temperature and then concentrated under vacuum. The residue was added to 30 ml of 1:1 hexane:EtOAc mixture. The crystals were collected by filtration to yield the product (2.26 g).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[Br:13][CH2:14][CH2:15]Br>>[Br:13][CH2:14][CH2:15][O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[CH:7]=1
Reactant: BrCCBr
Reactant: CCCCOc1cccc(O)c1
Product: CCCCOc1cccc(OCCBr)c1
Yield: 84.6 %

Procedure:
Prepared analogously to the method described in Example D above from 3-(n-butoxy)phenol (16.6 g; 0.1 mol; from Example B above) and 1,2-dibromoethane (100 ml; 1.16 mol). Following work up, the residue was chromatographed on silica gel with diisopropyl ether as eluent. The resultant oil was distilled to to yield 23.1 g (85%) of the title compound as an oil which subsequently crystallised (98% purity). bp 105-108° C. (0.01 mm Hg) mp 32-34° C. MW=273 (GC-MS)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[NH:17][CH2:16][CH2:15][CH2:14][N:10]3[C:11](=[O:13])[CH:12]=2)=[CH:3][CH:2]=1.[H-].[Na+].[C:20]1([CH2:26][CH2:27][C:28](Cl)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[C:20]1([CH2:26][CH2:27][C:28]([N:17]2[C:9]3=[N:8][C:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)=[CH:12][C:11](=[O:13])[N:10]3[CH2:14][CH2:15][CH2:16]2)=[O:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: O=c1cc(-c2ccncc2)nc2n1CCCN2
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=C(CCc1ccccc1)N1CCCn2c1nc(-c1ccncc1)cc2=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 0.2 g (0.87 mmol) of 2-pyridin-4-yl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 5 ml of chloroform was treated with 26 mg (1.14 mmol) of sodium hydride (60% suspension in mineral oil) and the resulting mixture was stirred at room temperature for 15 min and then cooled to 0° C. 0.148 g (0.964 mmol) of 3-phenylpropionyl chloride was added and the reaction mixture was stirred at room temperature during 18 h.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[BH4-].[Na+]>C(O)C>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cc1nc(C=O)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(CO)ccc1[N+](=O)[O-]
Yield: 21.7 %

Procedure:
A solution of 6-methyl-5-nitropicolinaldehyde (50 g, 329 mmol) in ethanol (200 mL) was cooled to 10° C. and sodium borohydride (5.9 g, 157 mmol) was added portion-wise. The solution was allowed to stir for one half hour, the ethanol was removed and the residue partitioned between ethyl Acetate and water, the organic phase washed with brine, and dried with magnesium sulfate and stripped. The residue was purified by column chromatography (10-40% ethyl acetate/hexanes) to give (6-methyl-5-nitropyridin-2-yl)methanol (12 g, 91%), a pale white solid. 1HNMR (CDCl3, 400 MHz) δ 2.89 (s, 3H), 3.55 (t, J=5.05, 1H), 4.83 (d, J=4.55, 2H), 7.31 (d, J=8.34, 1H), 8.31 (d, J=8.34, 1H); Exact mass calculated for C7H8N2O3: 168.05. found: 169.10 MS m/z (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[N:19]=[CH:20][NH:21][C:22]=1[C:23]#[N:24]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[CH:20]=[N:21][C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1[nH]cnc1N
Reactant: Cc1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Product: Cc1ccc(-c2cc(C(F)(F)F)n3cnc(C#N)c3n2)cc1
Yield: 44 %

Procedure:
Reaction of 1-(4-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (230 mg, 1.0 mmol), prepared from commercially available 4-methyl-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (133 mg, 44%). MS (ISP) 303.1 [(M+H)+]; mp 197° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:15]2[CH:20]=[C:19](O)[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[N:2].C([C:27]1[CH:32]=[CH:31][C:30]([NH:33]C(C2C=C(OS(C(F)(F)F)(=O)=O)C=C(OCC)C=2)C(OC)=O)=[CH:29][CH:28]=1)#N.NC1C=C(B(O)O)C=CC=1>>[NH2:33][C:30]1[CH:29]=[C:28]([C:19]2[CH:18]=[C:17]([O:22][CH2:23][CH3:24])[CH:16]=[C:15]([CH:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[C:11]([O:13][CH3:14])=[O:12])[CH:20]=2)[CH:27]=[CH:32][CH:31]=1
Reactant: CCOc1cc(OS(=O)(=O)C(F)(F)F)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Reactant: CCOc1cc(O)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1
Agent: Nc1cccc(B(O)O)c1
Product: CCOc1cc(-c2cccc(N)c2)cc(C(Nc2ccc(C#N)cc2)C(=O)OC)c1

Procedure:
Analogously to Example 155, from methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-hydroxy-phenyl)-acetate via methyl (RS)-(4-cyano-phenylamino)-(3-ethoxy-5-trifluoromethanesulphonyloxy-phenyl)-acetate by reaction with 3-aminophenylboronic acid there was obtained the compound methyl (RS)-(3′-amino-5-ethoxy-biphenyl-3-yl)-(4-cyano-phenyl-amino)-acetate, which was converted into methyl (RS)-(3′-amino-5-ethoxy-biphenyl-3-yl)-(4-carbamimidoyl-phenylamino)-acetate hydrochloride; MS: 419 ([M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][C:26]1=[O:40]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([C:28]4[CH:29]=[CH:30][N:25]([CH3:24])[C:26](=[O:40])[CH:27]=4)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: Cn1ccc(B2OC(C)(C)C(C)(C)O2)cc1=O
Product: Cn1ccc(-c2cc3c(cn2)OC(C2CCN(C(=O)OC(C)(C)C)CC2)C3)cc1=O

Procedure:
The title compound is prepared from 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester and 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one following a procedure analogous to that described in Example 28. LC (method 10): tR=1.61 min; Mass spectrum (ESI+): m/z=412 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:22]=[C:21]([NH:23][CH3:24])[N:20]=[CH:19][C:10]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1.N1C[CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:22]=[C:21]([N:23]4[CH2:28][CH2:27][CH2:26][CH2:24]4)[N:20]=[CH:19][C:10]=3[C:11]3[C:17]([CH3:18])=[N:16][O:15][C:12]=3[CH2:13][N:14]=2)=[CH:4][CH:3]=1
Reactant: CNc1cc2c(cn1)-c1c(C)noc1CN=C2c1ccc(Cl)cc1
Reactant: C1CCNC1
Product: Cc1noc2c1-c1cnc(N3CCCC3)cc1C(c1ccc(Cl)cc1)=NC2

Procedure:
A procedure similar to 6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[3,4-e]azepin-8-amine was followed, except that pyrrolidine was used instead of methylamine (33% in EtOH). LC/MS m/z 379 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.56 (d, J=0.62 Hz, 1H), 7.48 (ddd, J=1.70, 2.50, 8.20 Hz, 2H), 7.44 (ddd, J=1.70, 2.50, 8.20 Hz, 2H), 6.23 (d, J=0.62 Hz, 1H), 4.66 (br. s, 2H), 3.36-3.32 (m, 4H), 2.49 (s, 3H), 1.98-1.83 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[Mg].[B:10](OC)([O:13]C)[O:11]C.S(=O)(=O)(O)O>CCOCC>[C:4]1([CH3:8])[CH:5]=[CH:6][CH:7]=[C:2]([B:10]([OH:13])[OH:11])[CH:3]=1
Reactant: Cc1cccc(Br)c1
Reactant: COB(OC)OC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: Cc1cccc(B(O)O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of m-bromotoluene (25 g. 0.146 mol) in ether (200 ml) was added dropwise to magnesium (4.0 g, 0.17 mol) in ether (50 ml) at room temperature over a period of 3 hours under a nitrogen atmosphere. After the addition, the reaction mixture was stirred for 12 hours at room temperature. The Grignard reagent was added slowly to a solution of trimethyl borate (15.6 g, 17 ml, 0.15 mol) in ether (500 ml) over a period of 4hours at -78° C. and stirred for 12 hours at room temperature. The reaction mixture was hydrolyzed with 30% sulfuric acid (50 ml). The ether layer was separated, washed with water (3×250 ml) and dried over Na2SO4. The solvent was removed on a rotary evaporator and the solid obtained was recrystallized from water. M.P. 160°-161° C.
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:27](=[O:28])[CH2:26][Cl:25])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN1CCC(OC(=O)CCl)N(c2nnc(C3CC3)s2)C1=O

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Chloroacetyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-chloroacetyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:20]([O-])=O)=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[NH2:20][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH3:9])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]
Reactant: CN(Cc1ccc([N+](=O)[O-])c(C(=O)O)c1)C(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(Cc1ccc(N)c(C(=O)O)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 80 mL of methanol, there were added 8.3 g of 5-(N-tert-butoxycarbonyl-N-methyl-aminomethyl)-2-nitrobenzoic acid prepared in the foregoing Step 2 and 500 mg of 10% Pd/C (wet product), then hydrogen gas was introduced into the resulting dispersion and the mixture was then stirred at room temperature. After 1.5 hours, additional 500 mg of 10% Pd/C was further added to the mixture and the latter was stirred over 7 hours in a hydrogen gas atmosphere. The catalyst was removed by the filtration through Celite and the Celite was washed with methanol. The filtrate was concentrated to dryness to thus give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH3:11])[N:5]=[C:4](Cl)[N:3]=1.[C@H:13]1([NH2:23])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15]C1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][CH3:11])[N:5]=[C:4]([NH:23][C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]2)[N:3]=1
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: CCc1nc(Cl)nc(N)c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCc1nc(N[C@@H]2CCc3ccccc32)nc(N)c1C#N
Yield: 92 %

Procedure:
0.25 g (1.09 mmol) of 4-amino-2-chloro-6-ethylpyrimidine-5-carbonitrile, 0.19 g (1.31 mmol) of (1R)-1,2,3,4-tetrahydronaphthalen-1-amine and 0.45 g (3.28 mmol) of potassium carbonate in 2 ml of N,N-dimethylacetamide are heated at 140° C. in a closed cell in a microwave for 30 minutes. The crude mixture obtained in this way is absorbed on silica gel and purified by means of column chromatography using heptane/ethyl acetate as eluent. Following concentration by evaporation, 0.28 g of 4-amino-2-[(1R)-2,3-dihydro-1H-inden-1-ylamino]-6-ethylpyrimidine-5-carbonitrile is obtained (yield 82% at 95% purity).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3]([NH2:5])=[S:4].[O-]S([O-])(=O)=O.[Mg+2].[Cl:13][CH2:14][C:15]([CH2:17]Cl)=O>CC(C)=O>[Cl:13][CH2:14][C:15]1[N:5]=[C:3]([N:2]([CH3:6])[CH3:1])[S:4][CH:17]=1
Reactant: O=C(CCl)CCl
Reactant: CN(C)C(N)=S
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CN(C)c1nc(CCl)cs1
Yield: 55 %

Procedure:
A mixture of 15 g (144 mmol) of N,N-dimethylthiourea and excess MgSO4 in 350 ml of acetone was heated to reflux and treated dropwise with a solution of 18.3 g (144 mmol) of 1,3-dichloroacetone in 35 ml of acetone. The resulting mixture was heated at reflux for 1.5 h, allowed to cool, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography using 20% ethyl acetate in hexane to provide 14.0 g (70%) of the desired compound.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[N:4]=1.C([O:17][C:18]([CH:20]1[CH2:22][CH:21]1[C:23]1[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([F:30])[CH:24]=1)=[O:19])C>>[CH:10]1([S:9][C:5]2[N:4]=[C:3]([CH2:2][O:29][C:26]3[CH:27]=[CH:28][C:23]([CH:21]4[CH2:22][CH:20]4[C:18]([OH:19])=[O:17])=[CH:24][C:25]=3[F:30])[CH:8]=[CH:7][CH:6]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: ClCc1cccc(SC2CCCC2)n1
Reactant: CCOC(=O)C1CC1c1ccc(O)c(F)c1
Product: O=C(O)C1CC1c1ccc(OCc2cccc(SC3CCCC3)n2)c(F)c1
Yield: 92.6 %

Procedure:
2-Chloromethyl-6-cyclopentylsulfanyl-pyridine (0.040 g, 0.17 mmol) obtained in Step C of Preparation Example 27 and 2-(3-fluoro-4-hydroxy-phenyl)-cyclopropane carboxylic acid ethyl ester (0.040 g, 0.17 mmol) obtained in Step C of Preparation Example 44 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.061 g, 89%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:25])[C:3]=1[CH3:26].[CH3:27][O:28][C:29]1[C:34](B(O)O)=[CH:33][C:32]([CH3:38])=[CH:31][N:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:34]5[C:29]([O:28][CH3:27])=[N:30][CH:31]=[C:32]([CH3:38])[CH:33]=5)[C:3]([CH3:26])=[C:4]([CH3:25])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C
Reactant: COc1ncc(C)cc1B(O)O
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: COCCOC
Product: COc1ncc(C)cc1-c1nc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc(C)c1C
Temperature: 120 °C
Yield: 57 %

Procedure:
To a mixture of N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (114 mg, 0.3 mmol) and 2-methoxy-5-methylpyridin-3-ylboronic acid (75 mg, 0.45 mmol) in DME (3 mL) and Na2CO3 (2M, 0.3 mL, 0.6 mmol) was added Pd(PPh3)4 (17 mg, 0.015 mmol). The mixture was heated in microwave oven at 120° C. for 30 min. The reaction was re-partitioned between EtOAc and H2O and the aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (0-20% EtOAc-Hexane) to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(2′-methoxy-3,4,5′-trimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (80 mg, 57%). 1H NMR (400 MHz, CDCl3) 8.02 (s, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.59 (s, 1H), 7.31 (d, J=2.1 Hz, 1H), 7.20-7.16 (m, 2H), 7.04 (d, J=8.1 Hz, 1H), 3.85 (s, 3H), 2.33 (s, 3H), 2.26 (s, 3H), 1.95 (s, 3H), 1.73 (dd, J=3.8, 6.9 Hz, 2H), 1.14 (dd, J=3.9, 7.0 Hz, 2H). Retention time: 2.02 min; ESI-MS m/z calc. 467.5. found 468.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10](CC2C=C3C(C=CN=C3N)=CC=2)[C:9]1=[O:25])([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]1[C:33]2[CH:34]=[C:35]([CH2:37][NH2:38])[O:36][C:32]=2[CH:31]=[CH:30][N:29]=1>>[C:1]([O:5][C:6](=[O:26])[NH:7][C@H:8]1[CH2:12][CH2:11][N:10]([NH:38][CH2:37][C:35]2[O:36][C:32]3[CH:31]=[CH:30][N:29]=[C:28]([NH2:27])[C:33]=3[CH:34]=2)[C:9]1=[O:25])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(Cc2ccc3ccnc(N)c3c2)C1=O
Reactant: NCc1cc2c(N)nccc2o1
Product: CC(C)(C)OC(=O)N[C@H]1CCN(NCc2cc3c(N)nccc3o2)C1=O

Procedure:
Using the procedure described in example 85i 166 mg of 4-amino-2-(aminomethyl)furo[3,2-c]pyridine was transformed into 150 mg of the title compound. MS ESI+: 347 (M+H).
Reaction SMILES: C([O:4][C@H:5]1[C@@H:21]([O:22]C(=O)C)[C@H:20]([O:26]C(=O)C)[C@@H:19]([CH2:30][O:31]C(=O)C)[O:18][C@@H:6]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16]C)=[O:14])(=O)C.C[O-].[Na+]>CO>[O:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[C@H:6]1[O:18][C@H:19]([CH2:30][OH:31])[C@@H:20]([OH:26])[C@H:21]([OH:22])[C@@H:5]1[OH:4]
Reactant: CCOC(=O)CCCCCO[C@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCCO[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@@H]1O
Reaction time: 0.5 h
Yield: 90.2 %

Procedure:
To compound 1 (3.7 g, 7.55 mmol) dissolved in 35 mL of anhydrous methanol, sodium methylate (1.6 g, 30.20 mmol) was added. After 30 min under stirring, cation exchange resin (Dowex® 50WX2, H+ form, 13 g) was added. After 1 h the resin was filtered and washed with methanol. The filtrate was concentrated under reduced pressure yielding 2 (2.1 g, 100%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[O:20])[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=2)=[C:5]([CH3:27])[O:4][N:3]=1.[CH:28]1([Mg]Cl)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>C1COCC1>[CH:28]1([C:19]([C:9]2[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[NH:12][C:11]=3[CH:18]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:27])[CH:8]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[OH:20])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CCOc1nc2c(C(=O)c3ccccn3)cc(-c3c(C)noc3C)cc2[nH]1
Solvent: C1CCOC1
Product: CCOc1nc2c(C(O)(c3ccccn3)C3CCCCC3)cc(-c3c(C)noc3C)cc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanone (50 mg, 0.14 mmol) was dissolved in dry THF (1.4 mL) and cooled to 0° C. Cyclohexylmagnesium chloride (2.0 M, 0.21 mL, 0.41 mmol) was added dropwise and the reaction was allowed to stir for 10 mins and then quenched with water. Reaction was extracted three times with EtOAc and combined organic layers were washed once with water, concentrated, and purified by reverse-phase HPLC to give cyclohexyl(6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazol-4-yl)(pyridin-2-yl)methanol intermediate. The intermediate was taken up in EtOH (1.5 mL) and 0.2 mL concentrated HCl and heated to 65° C. for 2 hours and concentrated afford the desired product as a white powder.