Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].C([O:5][C:6]([C:8]1[C:9](=[O:33])[C:10]2[CH:15]=[N:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)=[N:12][C:11]=2[N:25]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:26]=1)=O)C>>[CH3:1][NH:2][C:6]([C:8]1[C:9](=[O:33])[C:10]2[CH:15]=[N:14][C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH:24]=[CH:23][N:22]=[CH:21]3)=[N:12][C:11]=2[N:25]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:26]=1)=[O:5]
Reactant: CCOC(=O)c1cn(C2CCCCC2)c2nc(NCCCn3ccnc3)ncc2c1=O
Reactant: CN
Product: CNC(=O)c1cn(C2CCCCC2)c2nc(NCCCn3ccnc3)ncc2c1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methylamine (1N, 1 ml in methanol) was added to 2-(3-imidazol-1-yl-propylamino)-8-cyclohexyl-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (Example 28, Step F, 7.0 mg, 0.015 mmol). The mixture was kept in a sealed tube at 110° C. with stirring for 2 days. The solution, after cooling down to room temperature, was loaded to hplc for purification. 8-Cyclohexyl-2-(3-imidazol-1-yl-propylamino)-5-oxo-5,8-dihydro-pyrido[2,3-d]pyrimidine-6-carboxylic acid methylamide was obtained as a white solid (5.5 mg, 80%). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.67 (br, 1H), 9.26 (s, 1H), 8.79 (s, 1H), 7.51 (br, 1H), 7.10 (s, 1H), 6.93 (br, 1H), 5.95 (br, 1H), 5.06 (m, 1H), 4.10 (t, J=6.8 Hz, 2H), 3.50 (m, 2H), 2.98 (d, J=4.9 Hz, 3), 2.20-1.20 (m, 12H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C21H27N7O2: 410.22 (M+H). Found: 410.2.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[N:21]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=5)[CH:19]=[CH:18][CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:32][CH:33]1[CH2:37][CH2:36][CH2:35][NH:34]1>CCN(C(C)C)C(C)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][CH:19]=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([S:28]([N:34]6[CH2:35][CH2:36][CH2:37][CH:33]6[CH3:32])(=[O:30])=[O:29])=[CH:24][CH:23]=5)[N:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC1CCCN1
Reactant: O=C(Nc1cccc(-c2ccc(S(=O)(=O)Cl)cc2)n1)C1(c2ccc3c(c2)OCO3)CC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCN1S(=O)(=O)c1ccc(-c2cccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)n2)cc1
Reaction time: 1 h

Procedure:
4-(6-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)pyridin-2-yl)benzene-1-sulfonyl chloride (˜35 μmol, 400 μl solution in chloroform) was treated with 2-methylpyrrolidine followed by the addition of DIEA (100 μl). The reaction mixture was kept at room temperature for 1 h, concentrated, then diluted with DMSO (400 μl). The resulting solution was subjected to HPLC purification. Fractions containing the desired material were combined and concentrated in vacuum centrifuge at 40° C. to provide the trifluoroacetic salt of target material (ESI-MS m/z calc. 505.0, found 505.9 (M+1), retention time 4.06 min). 1H NMR (250 MHz, DMSO-d6) δ 1.15 (m. 2H), δ 1.22 (d, 3H, J=6.3 Hz), δ 1.41-1.47 (m, 2H), δ 1.51 (m, 2H), δ 1.52-1.59 (m, 2H), δ 3.12 (m, 1H), δ 3.33 (m, 1H), δ 3.64 (m, 1H), δ 6.07 (s, 2H), δ 6.96-7.06 (m, 2H), δ 7.13 (d, 1H, J=1.3 Hz), δ 7.78 (d, 1H, J=8.2 Hz), δ 7.88 (d, 2H, J=8.5 Hz), δ 7.94 (t, 1H, J=8.2 Hz), δ 8.08 (d, 1H, J=8.2 Hz), δ 8.16 (d, 2H, J=8.5 Hz), δ 8.53 (s, 1H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([C:9]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:10])[NH:6][C:7]=1[CH3:8].Br[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[N:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:9]([C:5]2[NH:6][C:7]([CH3:8])=[C:3]([Br:2])[CH:4]=2)=[O:10])[CH2:17][CH2:16]1
Reactant: Cc1[nH]c(C(=O)NC2CCNCC2)cc1Br
Reactant: Brc1nc2ccccc2s1
Agent: Cl
Product: Cc1[nH]c(C(=O)NC2CCN(c3nc4ccccc4s3)CC2)cc1Br

Procedure:
Title compound was synthesized by an analogous method to Example 123 by coupling 4-bromo-5-methyl-N-piperidin-4-yl-1H-pyrrole-2-carboxamide hydrochloride (Intermediate 57) with 2-bromo-1,3-benzothiazole (commercially available).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[NH:8])=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:14]=[C:15]([S:20](Cl)(=[O:22])=[O:21])[CH:16]=[CH:17][C:18]=1[F:19]>>[Cl:12][C:13]1[CH:14]=[C:15]([S:20]([NH:8][C:7](=[NH:9])[C:6]2[CH:10]=[CH:11][C:3]([Cl:2])=[CH:4][CH:5]=2)(=[O:21])=[O:22])[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: N=C(N)c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)c(Cl)c1
Agent: Cl
Product: N=C(NS(=O)(=O)c1ccc(F)c(Cl)c1)c1ccc(Cl)cc1

Procedure:
4-chlorobenzamidine hydrochloride (0.025 g, 0.133 mmol) and 3-chloro-4 fluorophenyl sulfonylchloride (0.0304 g, 0.133 mmol); were used essentially as described in Example 114 to prepare the title compound. ES Positive Ion MS [M+H]+ ions observed: m/z 347 (35Cl, 35Cl), m/z 349 (37Cl, 37Cl) and m/z 351 (37Cl, 37Cl).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][P:6](=[O:18])([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[ClH:19].[H][H]>C(O)C.[Pd]>[ClH:19].[CH2:1]([N:3]1[CH2:4][CH2:5][P:6]([C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)(=[O:18])[CH2:7][CH2:8]1)[CH3:2]
Reactant: [H][H]
Reactant: CCN1CCP(=O)(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCN1CCP(=O)(c2ccc(N)cc2)CC1
Reaction time: 5 h

Procedure:
1-Ethyl-4-(4-nitro-phenyl)-perhydro-1,4-azaphosphorine 4-oxide (269.80 mg, 1.0058 mmol) dissolved in Ethanol (50 mL) and treated with palladium on carbon 10% (90:10, carbon black:Palladium, 30 mg, 2 mmol), 2.5 M of hydrogen chloride in ethanol (1.21 mL, 3.02 mmol) and 50 PSI of hydrogen gas. The mixture was shaken on a Parr apparatus for 5 hours. The mixture was degassed and backflushed with nitrogen. The mixture was filtered through a plug of diatomaceous earth and washed with ethanol. The filtrate was evaporated. 4-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)aniline hydrochloride was isolated (401 mg, 145%). MS=238 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]([CH3:7])[N:6]=1.C([Li])CCC.CN(C)[CH:15]=[O:16].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[Cl:1][C:2]1[S:3][C:4]([CH:15]=[O:16])=[C:5]([CH3:7])[N:6]=1
Reactant: CN(C)C=O
Reactant: Cc1csc(Cl)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1nc(Cl)sc1C=O
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 2-chloro-4-methylthiazole (0.3 g) in tetrahydrofuran (3 ml) was added a solution of n-butyllithium in n-hexane (1.63M, 1.52 ml) dropwise at −70° C. under a nitrogen atmosphere, and the mixture was stirred for 20 minutes at −70° C. To the resultant mixture was added N,N-dimethylformamide (0.21 ml) at −70° C., and the mixture was stirred for 40 minutes. The mixture was poured into a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography (silica gel 10 g, n-hexane:ethyl acetate=10:1) to give 2-chloro-5-formyl-4-methylthiazole (231 mg).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH3:9][C:10]1[O:14][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:12][C:11]=1[CH2:21][CH2:22]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH3:9][C:10]1[O:14][C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[N:12][C:11]=1[CH2:21][CH2:22][O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1
Reactant: Cc1cccc(O)c1
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cccc(OCCc2nc(-c3ccccc3)oc2C)c1
Temperature: 22 °C
Reaction time: 24 h
Yield: 78.3 %

Procedure:
A solution of 3.50 g of m-cresol, 9.87 g of 2-(5-methyl-2-phenyl-oxazole-4yl)-ethanol and 12.73 g of triphenylphosphine in 190 ml of THF was treated at 0° C. with a solution of 8.45 g of diethyl azodicarboxylate (DEAD) in 75 ml of THF over 20 min and the brown solution was stirred at 22° C. for 24 h. The solution was evaporated and the residue partitioned between CH2Cl2 (300 ml) and 0.1 N aqueous NaOH (100 ml). The organic layer was washed twice with water (2×100 ml), dried, the organic solvent was evaporated and the residue was chromatographed on silica (n-hexane/AcOEt, 20:1) to give 7.43 g (78%) of the title compound as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[C:5]([CH2:27][CH:28]=C)([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][B:10]1[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]1)[CH3:2].[O:31]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:30])[C:5]([NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])([CH2:27][CH:28]=[O:31])[CH2:6][CH2:7][CH2:8][CH2:9][B:10]1[O:11][C:12]([CH3:17])([CH3:18])[C:13]([CH3:15])([CH3:16])[O:14]1)[CH3:2]
Reactant: C=CCC(CCCCB1OC(C)(C)C(C)(C)O1)(NC(=O)OC(C)(C)C)C(=O)OCC
Reactant: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C(CC=O)(CCCCB1OC(C)(C)C(C)(C)O1)NC(=O)OC(C)(C)C
Reaction time: 4 h
Yield: 93 %

Procedure:
A solution of Ethyl-2-allyl-2-(tert-butoxycarbonylamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (650 mg, 1.53 mmol) in dichloromethane (30 mL,) was cooled to −78° C. and treated with ozone until a pale blue-gray color appeared. After TLC indicated the absence of starting material, the ozone inlet tube was replaced with nitrogen and nitrogen was bubbled through the solution for 20 min to remove any excess ozone. Triphenylphosphine (1.20 g, 4.59 mmol, 3 equiv) was added in one portion, the cooling bath was removed and the mixture was stirred for 4 h. The solution was concentrated and purified by MPLC (0-40% ethyl acetate in heptane) gave the title compound as a colorless oil (608 mg, 93%). Rf 0.25 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz): δ 9.64 (s, CHO, 1H), 5.60 (br, s, NH, 1H), 4.19 (q, J=7.5 Hz, 2H), 3.56 (d, J=17 Hz, 1H), 2.93 (d, J=17.5 Hz, 1H), 2.20 (m, 1H), 1.62 (m, 1H), 1.38 (s, 9H), 1.28-1.43 (m, 4H), 1.23 (t, J=7 Hz, 3H), 1.21 (s, 12H) and 0.72 (t, J=7.5 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:18]=[C:17]([O:19]C)[N:16]=[C:15]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[CH:14]=1)=[O:12])[CH2:6][CH2:5]2.Cl.N1C=CC=CC=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([C:13]1[CH:14]=[C:15]([N:21]3[CH2:26][CH2:25][CH:24]([N:27]4[C:35]5[C:30](=[N:31][CH:32]=[CH:33][CH:34]=5)[NH:29][C:28]4=[O:36])[CH2:23][CH2:22]3)[NH:16][C:17](=[O:19])[CH:18]=1)=[O:12])[CH2:6][CH2:5]2
Reactant: COc1cc(C(=O)N2CCc3cc(F)ccc32)cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)n1
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)[nH]c(=O)c1)N1CCc2cc(F)ccc21
Reaction time: 0.12 h

Procedure:
A well stirred mixture of 20 mg (0.041 mmol) 1-[4′-(5-fluoro-2,3-dihydroindole-1-carbonyl)-6′-methoxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 100 mg (0.865 mmol) pyridine hydrochloride was kept in a melt for 7 min using a hot air blower. After the reaction mixture had cooled it was dissolved in DMF and purified by preparative HPLC. The fractions containing the product were combined and lyophilised.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11](=[S:31])[NH:10]2)=[CH:5][CH:4]=1)#[N:2].IC.[C:34](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[C:11]([S:31][CH3:34])=[N:10]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=S)NC1c1ccc(C#N)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(SC)=NC1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 4-(4-cyanophenyl)-6-methyl-2-thioxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydro-5-pyrimidinecarboxylate (Example 3; 1000 mg, 2.24 mmol), iodomethane (350.5 mg, 2.47 mmol) and potassium carbonate (341 mg, 1.82 mmol) are dissolved in 20 ml acetone. The reaction mixture is stirred at room temperature overnight and the solvent is removed in vacuo. The product is purified by column chromatography (silica gel; eluent: cyclohexane-ethyl acetate, gradient 90:10 to 50:50).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)(=[O:4])=[O:3].[CH:15]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)([CH3:17])[CH3:16]>>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[C:21]1[CH2:22][CH2:23][N:18]([CH:15]([CH3:17])[CH3:16])[CH2:19][CH:20]=1)(=[O:3])=[O:4]
Reactant: CC(C)N1CCC(=O)CC1
Reactant: CS(=O)(=O)Nc1ccc2[nH]ccc2c1
Product: CC(C)N1CC=C(c2c[nH]c3ccc(NS(C)(=O)=O)cc23)CC1
Yield: 64.3 %

Procedure:
Beginning with 1.0 gm (4.76 mMol) 5-methanesulfonylamino-1H-indole and 0.873 gm (6.2 mMol) 1-isopropyl-4-piperidone, 1.02 gm (64.2%) of the title compound were recovered as a tan powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:5]=[N:6][C:7]1[CH:12]=[CH:11][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:9][CH:8]=1.C[Si]([C:26]#[N:27])(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]([NH:6][C:7]2[CH:8]=[CH:9][C:10]([S:13](=[O:16])(=[O:15])[NH2:14])=[CH:11][CH:12]=2)[C:26]#[N:27])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C=Nc2ccc(S(N)(=O)=O)cc2)cc1F
Reactant: C[Si](C)(C)C#N
Product: COc1ccc(C(C#N)Nc2ccc(S(N)(=O)=O)cc2)cc1F

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(3-fluoro-4-methoxybenzylidene)-4-sulfamoylaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a slightly yellow powder (yield 98%).
Reaction SMILES: [Na].CO[C:4](=[O:10])[CH:5]([CH3:9])[C:6]([OH:8])=O.[NH2:11][C:12]([NH2:14])=[O:13].O>C(O)C>[CH3:9][CH:5]1[C:4](=[O:10])[NH:14][C:12](=[O:13])[NH:11][C:6]1=[O:8]
Reactant: NC(N)=O
Reactant: COC(=O)C(C)C(=O)O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CC1C(=O)NC(=O)NC1=O
Reaction time: 0.08 h

Procedure:
46 g (2 mols) of sodium are dissolved in 1 liter of absolute ethanol in a 5-liter flask. To this solution are firstly added 348 g (2 mols) of methyl malonic acid methyl ester; and there is then added dropwise at 70° C. with stirring, within about 5 minutes, a solution of 120 g (2 mols) of urea in 1 liter of absolute ethanol. There is formed a thin suspension, which is diluted with 3.5 liters of ethanol, refluxed for 16 hours and afterwards cooled. There are subsequently added 2 liters of water and, for clearing, a filtering auxiliary (HiFlo) is introduced, and the suspension is filtered. Concentrated hydrochloric acid is then added until a Congo blue colour is indicated, and the mixture is left to stand for several hours in a cool place. A fine white crystalline precipitate is formed, which is filtered and dried. The mother liquor is concentrated by evaporation, diluted with water, and the precipitate is likewise filtered and dried. The crude yield is 263 g of material, which melts at 200°-215° C. After recrystallisation from water, there remain 144 g of white crystals (58% of theory), which melt at 203°-204° C.
Reaction SMILES: Br[C:2]([CH3:15])([CH3:14])[C:3]([NH:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].CCOC(C)=O.[CH2:22]([OH:27])[C:23]([F:26])([F:25])[F:24]>O1C=CC=C1>[CH3:14][C:2]([O:27][CH2:22][C:23]([F:26])([F:25])[F:24])([CH3:15])[C:3]([NH:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: OCC(F)(F)F
Reactant: CC(C)(Br)C(=O)NOCc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccoc1
Product: CC(C)(OCC(F)(F)F)C(=O)NOCc1ccccc1

Procedure:
Produced as a by-product 56% from the reaction of 2-bromo-2-methyl-N-(phenylmethoxy)propanamide with TEA in furan and trifluoroethanol. Rf=0.26 (3:1, hexanes:EtOAc); 1H NMR (500 MHz, CDCl3) δ 8.88 (s, 1H), 7.56-7.31 (m, 5H), 4.94 (s, 2H), 3.68 (q, J=8.3 Hz, 2H), 1.43 (s, 6H); 13C NMR (125 MHz, CDCl3) 13C NMR (101 MHz, cdcl3) δ 170.8, 134.9, 129.4, 129.0, 128.7, 123.7 (q, J=278 Hz), 80.4, 78.3, 61.6 (q, J=35 Hz), and 23.6; FT-IR 3218 (br), 3036; 2942, 2886, 1663 (st), 1430, 1455, 1485, 1386, 1369, 1307, 1285, 1217, 1181, 1145, 1029, 1010 cm-1; HR-ESIMS calculated for C13H17F3NO3 (M+H)+ 292.1155, observed 292.1160.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:28]=[CH:27][C:9]3[C:10]([CH2:13][O:14][C:15]4[CH:23]=[CH:22][CH:21]=[C:20]5[C:16]=4[CH:17]=[C:18]([C:24](O)=[O:25])[NH:19]5)=[CH:11][O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[NH2:29][CH:30]1[CH2:35][CH2:34][C:33]([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[C@@H:41]([CH3:46])[CH2:40]2)([OH:36])[CH2:32][CH2:31]1>>[OH:36][C:33]1([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][C@H:42]([OH:45])[C@@H:41]([CH3:46])[CH2:40]2)[CH2:34][CH2:35][CH:30]([NH:29][C:24]([C:18]2[NH:19][C:20]3[C:16]([CH:17]=2)=[C:15]([O:14][CH2:13][C:10]2[C:9]4[CH:27]=[CH:28][C:6]([O:5][CH2:4][CH:1]5[CH2:2][CH2:3]5)=[CH:7][C:8]=4[O:12][CH:11]=2)[CH:23]=[CH:22][CH:21]=3)=[O:25])[CH2:31][CH2:32]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Reactant: O=C(O)c1cc2c(OCc3coc4cc(OCC5CC5)ccc34)cccc2[nH]1
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCc5coc6cc(OCC7CC7)ccc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(6-cyclopropylmethoxy-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid 30b and amine 14.
Reaction SMILES: [CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1)[CH3:2].[H-].[Na+].[F:13][C:14]([F:23])([F:22])[CH2:15][CH2:16][CH:17]([C:20]#[N:21])[C:18]#[N:19]>CN(C)C=O>[CH2:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:17]([CH2:16][CH2:15][C:14]([F:13])([F:22])[F:23])([C:18]#[N:19])[C:20]#[N:21])=[CH:5][CH:4]=1)[CH3:2]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: CCc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1ccc(CC(C#N)(C#N)CCC(F)(F)F)cc1
Yield: 48.3 %

Procedure:
Using 0.16 g of 4-ethylbenzyl chloride, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.17 g of (3,3,3-trifluoropropyl)malononitrile, and according to the process described in the Production Example 26, there was obtained 0.14 g of 2-(4-ethylbenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (31)).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:23])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[N:12]([CH:14]3[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]3)[N:13]=2)[CH:8]=1.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C1COCC1.CCN(C(C)C)C(C)C>[Cl:23][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([CH:14]2[CH2:15][CH2:16][C:17]([CH3:20])([CH3:21])[CH2:18][CH2:19]2)[N:13]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(C)CCC(n2nc(-c3cc(CN)ccc3Cl)[nH]c2=O)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)CCC(n2nc(-c3cc(CNC(=O)C(C)(C)C)ccc3Cl)[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.3 %

Procedure:
To a solution of 5-(5-(aminomethyl)-2-chlorophenyl)-2-(4,4-dimethylcyclohexyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-73, 0.070 g, 0.202 mmol) in dry THF (5.0 mL), DIPEA (2.0 mL) and pivaloyl chloride (0.30 g, 0.242 mmol) were added and the reaction mass was stirred at RT for 16 h. After completion of the reaction, the reaction mass was quenched with water and extracted with 10%.MeOH:DCM. The organic layer was washed with dilute HCl and concentrated. The obtained crude was purified with column chromatography on basic alumina by eluting with 2.0% MeOH:DCM to afford 0.040 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.44 (s, 6H), 1.47 (s, 9H), 1.81-1.94 (m, 8H), 3.86-3.90 (m, 1H), 4.40 (s, 2H), 7.33 (d, J=1.5 Hz, 1H), 7.45 (s, 7.50 (d, J=2.1 Hz, 1H), 8.16 (t, 1H), 11.93 (s, 1H); MS (m/z): 419.21 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:25]C(OC(C)C)=O)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].C(N(CC)CC)C.CO>C(Cl)Cl.CCOC(C)=O>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH2:25])[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](N)C[C@H](C)N3C(C)=O)cc1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 74 %

Procedure:
Ethyl 4-[(2S,4R)-1-acetyl-2-methyl-4-({[(1-methylethyl)oxy]carbonyl}amino)-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (for a preparation see intermediate 53) (25.33 g, 57.8 mmol) was added to a cold (ice/water bath) suspension of aluminum chloride (29.24 g, 219 mmol) in DCM (450 mL). The resulting solution was stirred at approximately 0° C. for 35 min then a solution of triethylamine (96 mL, 693 mmol) and methanol (50 mL) was added over 30 s. The resulting mixture was stirred for approximately 1 h in the ice bath, and then partitioned between AcOEt and a saturated NaHCO3 aqueous solution. The mixture was filtered through Celite, and the residue washed with AcOEt and a saturated NaHCO3 aqueous solution (several times each). The layers were separated and the aqueous phase was extracted with AcOEt (×2). The combined organic phases were washed with brine, dried using a hydrophobic frit and concentrated in vacuovacuo. The solid obtained was dissolved, with warming, in AcOEt, filtered through Celite in order to remove remaining inorganics and the insoluble material was washed with warm AcOEt. The combined filtrate and washings were concentrated in vacuo to give a first batch of ethyl 4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (15.0 g, 42.6 mmol, 74%) as a cream solid The solid residue on celite was further washed with acetone, and the filtrate concentrated in vacuovacuo. The residue was partially dissolved in AcOEt, filtered through a hydrophobic frit and the filtrate was concentrated vacuo to give a second batch of ethyl 4-[(2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydro-6-quinolinyl]benzoate (2.78 g, 7.9 mmol, 14%) as a cream foam.
Reaction SMILES: Cl.C(OC([NH:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[C:16]([C:27]2[NH:28][CH:29]=[CH:30][N:31]=2)=[CH:15][N:14]=1)=O)(C)(C)C>CC#N>[NH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=2)[C:16]([C:27]2[NH:31][CH:30]=[CH:29][N:28]=2)=[CH:15][N:14]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ncc(-c2ncc[nH]2)c(-c2ccc(C#N)cc2)n1
Agent: Cl
Solvent: CC#N
Product: N#Cc1ccc(-c2nc(NCCN)ncc2-c2ncc[nH]2)cc1
Reaction time: 16 h
Yield: 89 %

Procedure:
Aqueous 3M HCl (15-30 ml) was added to a stirred solution of (tert-butoxy)-N-(2-{[4-(4-cyanophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)carboxamide (0.15 M) in CH3CN (50 ml) at room temperature until the reaction became slightly turbid. After 16 hours, the reaction was partitioned between dichloromethane (200 ml) and 1M HCl (200 ml). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×200 ml). The aqueous layer was basified carefully with solid NaHCO3 to pH 7-8. A solid forms which can be filtered and dissolved in CH3CN (100 ml). The organic solution is washed with sat. aq. NaHCO3 (50 ml), brine (50 ml), dried with Na2SO4, filtered, and concentrated. The crude product was purified by flash chromatography over silica gel. The column was eluted first with a 1:1 mixture of dichloromethane/methanol followed by a mixture of 5% TEA/10% water/85% methanol to elute the product. The proper fractions were condensed. The dark yellow glass was dried overnight in vacuo giving 4-{2-[(2-aminoethyl)amino]-5-imidazolylpyrimidin-4-yl}benzenecarbonitrile in 89% yield.