Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:6][C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][N:8]=2.[H-].[Na+].[CH3:16]I>CN(C)C=O>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:6]([CH3:16])[C:7]2[C:12]([N:13]=1)=[CH:11][CH:10]=[CH:9][N:8]=2
Reactant: CI
Reactant: OCCCc1nc2cccnc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CCCO)nc2cccnc21

Procedure:
A procedure similar to that described in Preparation 15 was repeated, except that 3.40 g of 2-(3-hydroxypropyl)-3H-imidazo[5,4-b]pyridine (prepared as described in Preparation 33), 0.81 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 1.2 ml of methyl iodide and 100 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatograpy through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent. The product was crystallized by trituration with ethyl acetate, to give 3.10 g of the title compound, melting at >300° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:9]=[C:10]([CH2:11][CH3:12])[C:5]2=[CH:4][N:3]=1.[CH:19]([N:32]1[CH2:35][CH:34]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)[CH2:33]1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>>[CH:19]([N:32]1[CH2:35][CH:34]([N:36]2[CH2:41][CH2:40][N:39]([C:2]3[N:7]=[C:6]4[N:8]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)[N:9]=[C:10]([CH2:11][CH3:12])[C:5]4=[CH:4][N:3]=3)[CH2:38][CH2:37]2)[CH2:33]1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: c1ccc(C(c2ccccc2)N2CC(N3CCNCC3)C2)cc1
Reactant: CCc1nn(-c2ccccc2)c2nc(Cl)ncc12
Solvent: CCN(CC)CC
Product: CCc1nn(-c2ccccc2)c2nc(N3CCN(C4CN(C(c5ccccc5)c5ccccc5)C4)CC3)ncc12

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 6-chloro-3-ethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (420 mg, 1.63 mmol, 1.00 equiv) in C7H8 (15 mL) at room temperature. To the resulting mixture was then added 1-(1-benzhydrylazetidin-3-yl)piperazine (500 mg, 1.63 mmol, 1.00 equiv), in portions at room temperature, followed by triethylamine (490 mg, 4.85 mmol, 3.00 equiv), in portions at room temperature. The resulting solution was heated to reflux overnight. The resulting mixture was concentrated under vacuum. The residue was dissolved in DCM (20 mL). The resulting mixture was washed with sodium chloride (2×15 mL). The resulting mixture was concentrated under vacuum. The resulting mixture was washed with methanol (1×5 mL). The solids were collected by filtration to yield 6-(4-(1-benzhydrylazetidin-3-yl)piperazin-1-yl)-3-ethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine as a yellow solid. MS (m/z): 530 [MH+].
Reaction SMILES: O.NN.[C:4]([NH:7][C:8]1[CH:29]=[CH:28][C:11]([O:12][CH2:13][CH:14]([OH:27])[CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)=[CH:10][CH:9]=1)(=[O:6])[CH3:5].[ClH:30]>C(O)C>[ClH:30].[NH2:16][CH2:15][CH:14]([OH:27])[CH2:13][O:12][C:11]1[CH:28]=[CH:29][C:8]([NH:7][C:4](=[O:6])[CH3:5])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(OCC(O)CN2C(=O)c3ccccc3C2=O)cc1
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(OCC(O)CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydrazine hydrate (3.6 g, 0.071 mol) was dissolved in 50 ml ethanol and added slowly to a suspension of Compound XVII (25 g, 0.071 mol) in 300 ml boiling ethanol. After 30 min., all the material dissolved. The temperature of the reaction mixture was reduced to 75° C. and maintained for an additional 1.5 hr. At the end of this time, the mixture was cooled to room temperature and concentrated hydrochloric acid added dropwise to pH 1 (pH paper) to destroy the hydrazide intermediate. Since not all of the material dissolved, the mixture was filtered to remove undissolved phthalhydrazide and the filtrate stored at 4° C. overnight. Filtration of the newly precipitated material gave 10.6 g of the title compound m.p. 192°-197° C. Recrystallization from ethanol/ether yielded 9.0 g of small white cluster crystals which were homogenous by thin layer chromatography (30:10:3:12 butanol/pyridine/acetic acid/water, Rf =0.46) m.p. 198.5°-200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[NH:20][C:19](=[O:21])[CH:18]=[N:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:20]([CH3:23])[C:19](=[O:21])[CH:18]=[N:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CI
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cncc(=O)[nH]1
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cncc(=O)n1C

Procedure:
The title compound, yellow cristalline solid, MS: m/e=326.1, 328.2 (M+H+), was prepared in accordance with the general method of example 3 from 6-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-1H-pyrazin-2-one and methyl iodide, along with the O-alkylation product from which it was separated by flash chromatography (gradient: EtOAc to EtOAc/MeOH 95:5).
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH:4]=[CH:3]1.[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].C(N(CC)CC)C>C(#N)C>[CH:2]1([O:7][N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])[CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: ClC1C=CCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1OC1C=CCC1
Temperature: 0 °C
Yield: 69.1 %

Procedure:
A mixture of 3-chlorocyclopentene (36.9 g), N-hydroxyphthalimide (58.2 g) and triethylamine (53.9 g) in acetonitrile (370 ml) was refluxed for 2 hours. The reaction mixture was poured into ice-water. The precipitated crystals were collected by filtration, washed with water and dried over phosphorus pentoxide to give N-(2-cyclopenten-1-yl)oxyphthalimide (56.5 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].[N:16]1([C:22]2[S:23][C:24]([C:27]#[N:28])=[CH:25][N:26]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH:11]=1)[C:8]([N:19]1[CH2:20][CH2:21][N:16]([C:22]2[S:23][C:24]([C:27]#[N:28])=[CH:25][N:26]=2)[CH2:17][CH2:18]1)=[O:10])#[N:2]
Reactant: N#Cc1cnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(C#N)cc1C(=O)O
Product: CC(C)Oc1ccc(C#N)cc1C(=O)N1CCN(c2ncc(C#N)s2)CC1
Yield: 70 %

Procedure:
Prepared in analogy to example 1 (b) from 5-cyano-2-isopropoxy-benzoic acid (Example A28) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white solid (yield 70%). MS (m/e): 382.3 (M+H+, 100%).
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH2:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([CH3:27])[CH2:23][CH2:22]3)[C:9]([N:11]3[CH2:16][CH2:15][O:14][C@@H:13]4[CH2:17][CH2:18][CH2:19][C@@H:12]34)=[N:10][C:6]=2[CH:5]=[C:4]([Cl:28])[N:3]=1.[Cl:29][C:30]1[CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[C:33]([F:36])=[N:34][CH:35]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>CCOC(C)=O>[Cl:28][C:4]1[N:3]=[C:2]([C:32]2[C:33]([F:36])=[N:34][CH:35]=[C:30]([Cl:29])[CH:31]=2)[C:7]2[N:8]([CH2:20][C@H:21]3[CH2:22][CH2:23][C@H:24]([CH3:27])[CH2:25][CH2:26]3)[C:9]([N:11]3[CH2:16][CH2:15][O:14][C@@H:13]4[CH2:17][CH2:18][CH2:19][C@@H:12]34)=[N:10][C:6]=2[CH:5]=1
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(Cl)c32)CC1
Reactant: CC1(C)OB(c2cc(Cl)cnc2F)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H]1CC[C@H](Cn2c(N3CCO[C@@H]4CCC[C@H]43)nc3cc(Cl)nc(-c4cc(Cl)cnc4F)c32)CC1
Temperature: 90 °C

Procedure:
4,6-dichloro-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic, 422 mg, 1 mmol), 5-chloro-2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (340 mg, 2 mmol) and Cs2CO3 (980 mg, 3 mmol) were added to degassed dioxane:water (10 mL:2 mL), followed by the addition of [1,1′-bis(di-tert-butylphosphino)ferrocene]PdCl2 (130 mg, 0.2 mmol). The reaction was heated at 90° C. for 24 hours. Water and EtOAc were added. The aqueous layer was extracted with EtOAc several times. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified on a silica gel column (0 to 60% EtOAc/hexanes) to afford 6-chloro-4-(5-chloro-2-fluoropyridin-3-yl)-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (racemic). MS ES calc'd. for C26H30Cl2FN5O [M+H]+ 518. found 518.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH3:14])[C:5]=1[S:15]C(N(C)C)=O.O.Cl>CO>[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:14])[C:5]=1[SH:15]
Reactant: COC(=O)c1ccc(Cl)c(SC(=O)N(C)C)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1c(C(=O)O)ccc(Cl)c1S

Procedure:
6.61 g (85% by weight pure, 100.1 mmol) of potassium hydroxide were added to 4.80 g (16.7 mmol) of methyl 4-chloro-3-(dimethylaminocarbonylthio)-2-methylbenzoate in 150 ml of methanol, and the mixture was stirred under reflux for two days. The reaction mixture was freed from the solvent, water was added to the residue, the mixture was acidified with 1M HCl and the solid was removed by filtration. This gave 3.2 g of clean product.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1I.[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[N:7]([CH2:20][CH2:21][O:22][CH3:23])[C:6]=2[C:5]([O:24][CH3:25])=[CH:4][C:3]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(I)cc(OC)c21
Reactant: OB(O)c1ccccc1
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: Cc1ccccc1
Solvent: O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2c(Br)c(-c3ccccc3)cc(OC)c21
Temperature: 100 °C
Reaction time: 12 h
Yield: 29.5 %

Procedure:
A mixture of 150 mg (0.283 mmol) 4-bromo-5-iodo-2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole (example 30), 38 mg (0.312 mmol) phenylboronic acid, 60 mg (0.567 mmol) sodium carbonate and 16 mg (0.014 mmol) tetrakis(triphenylphosphine)palladium in 6 ml toluene/water (3:1) is stirred at 100° C. for 12 h. Then the reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=3:1) to afford 40 mg of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=[O:16])[CH2:6][C:7]([CH3:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])[CH3:2].[C:18]1([Mg]Cl)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1COCC1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([OH:16])[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:8])[CH3:15])[CH3:2]
Reactant: Cl[Mg]c1ccccc1
Reactant: CCOC(=O)C(=O)CC(C)(C)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1ccccc1)c1ccccc1

Procedure:
Analogously to Example 1, 1.0 g of 4-methyl-4-phenyl-2-oxopentanoic acid-ethyl ester is converted with 2.14 ml of a 2 M phenylmagnesium chloride-THF solution into 980 mg of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[NH:7][C:8](=[O:18])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:40]=[C:39]([CH3:41])[C:33]3[N:34]([CH3:38])[C:35](=[O:37])[O:36][C:32]=3[CH:31]=2)=[O:29])[CH:25]=[C:24]([O:42][CH3:43])[N:23]=1>CN1C(=O)CCC1>[CH3:38][N:34]1[C:33]2[C:39]([CH3:41])=[CH:40][C:30]([C:28]([C:26]3[CH:25]=[C:24]([O:42][CH3:43])[N:23]=[C:22]([N:15]4[CH2:14][CH2:13][CH:12]([N:9]5[CH2:10][CH2:11][C:5]6[CH:4]=[C:3]([O:2][CH3:1])[CH:20]=[CH:19][C:6]=6[NH:7][C:8]5=[O:18])[CH2:17][CH2:16]4)[CH:27]=3)=[O:29])=[CH:31][C:32]=2[O:36][C:35]1=[O:37]
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Reactant: COc1cc(C(=O)c2cc(C)c3c(c2)oc(=O)n3C)cc(Cl)n1
Solvent: CN1CCCC1=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)cc(OC)n3)CC1)C(=O)N2
Temperature: 120 °C
Reaction time: 12 h

Procedure:
991 mg (3.60 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-benzo[d][1,3]diazepin-2-one and 420 mg (1.26 mmol) 6-(2-chloro-6-methoxy-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one were combined in 3 mL NMP and stirred for 12 h at 120° C. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the acetonitrile was eliminated i. vac. The residue was diluted with water, the precipitated solid was suction filtered, washed with water and dried.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:13](=[O:21])[CH2:12]1)=O)C1C=CC=CC=1>CCO.[Pd]>[C:17]([N:14]1[CH2:15][CH2:16][NH:11][CH2:12][C:13]1=[O:21])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)N1CCN(C(=O)OCc2ccccc2)CC1=O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)N1CCNCC1=O
Reaction time: 18 h
Yield: 68.5 %

Procedure:
A 10 mL round-bottomed flask was charged with a solution of 4-tert-butyl-3-oxopiperazine-1-carboxylic acid benzyl ester (0.75 g, 2.58 mmol) in EtOH (5 mL). The reaction mixture was flushed with nitrogen and 10% Pd/C (67 mg, 0.13 mmol) was added. The reaction mixture was stirred under a hydrogen atmosphere for 18 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the desired product was eluted using 2 M NH3 in MeOH to give 1-tert-Butylpiperazin-2-one as grey oil (0.276 g, 69%). 1H NMR (300 MHz, CDCl3): δ 3.50 (s, 2H), 3.37 (t, J=5.5 Hz, 2H), 3.06 (t, J=5.5 Hz, 2H), 1.48-1.41 (m, 9H)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].C(OC(=O)[NH:32][CH2:33][CH2:34][NH:35][S:36]([C:39]1[S:40][C:41](Br)=[CH:42][CH:43]=1)(=[O:38])=[O:37])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:32][CH2:33][CH2:34][NH:35][S:36]([C:39]1[S:40][C:41]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:42][CH:43]=1)(=[O:38])=[O:37]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(Br)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and [2-(5-bromo-thiophene-2-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (example B.51) (193 mg, 0.5 mmol) according to general procedure II and subsequent cleavage of the protecting group with TFA in dichloromethane at 0° C. Obtained as an orange solid (158 mg, 56%). MS (ISN) 558.0 [(M−H)−]; mp 161° C.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[N:14]=[CH:13][C:12]=1[C:26]([NH:28][C:29]1[CH:30]=[N:31][C:32]([C:36]2[CH2:37][CH2:38][NH:39][CH2:40][CH:41]=2)=[C:33]([CH3:35])[CH:34]=1)=[O:27].O>N1C=CC=CC=1>[C:1]([N:39]1[CH2:40][CH:41]=[C:36]([C:32]2[N:31]=[CH:30][C:29]([NH:28][C:26]([C:12]3[CH:13]=[N:14][N:15]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=4)[C:11]=3[CH3:10])=[O:27])=[CH:34][C:33]=2[CH3:35])[CH2:37][CH2:38]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1cc(NC(=O)c2cnn(-c3ccc(C(F)(F)F)cn3)c2C)cnc1C1=CCN(C(=O)c2ccccc2)CC1
Temperature: 40 °C
Reaction time: 6 h

Procedure:
Benzoyl chloride (75 μl) was added to a solution of 5-methyl-N-[5-methyl-6-(1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (221 mg) in pyridine (2.5 ml), and stirred at 40° C. for six hours. Water was added to the reaction solution, the precipitated solid was washed with ethanol and water to give the titled compound (218 mg) as a white solid.
Reaction SMILES: C1COCC1.Cl[C:7]1[NH:11][C:10]2[CH:12]=[C:13]([NH:27][C:28]([C:30]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=3[Cl:37])=[O:29])[CH:14]=[C:15]([C:16]([NH:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[CH3:26])=[O:17])[C:9]=2[N:8]=1.[NH2:38][CH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42]>C(OCC)(=O)C>[Cl:25][C:21]1[C:20]([CH3:26])=[C:19]([NH:18][C:16]([C:15]2[C:9]3[N:8]=[C:7]([NH:38][CH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][OH:42])[NH:11][C:10]=3[CH:12]=[C:13]([NH:27][C:28]([C:30]3[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]=3[Cl:37])=[O:29])[CH:14]=2)=[O:17])[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2cc(Cl)ccc2Cl)cc2[nH]c(Cl)nc12
Reactant: CC(C)(CN)CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cccc1NC(=O)c1cc(NC(=O)c2cc(Cl)ccc2Cl)cc2[nH]c(NCC(C)(C)CO)nc12
Yield: 88.4 %

Procedure:
THF (1 mL) was added to 2-chloro-N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide (50 mg) and 3-amino-2,2-dimethyl-1-propanol (400 mg). The mixture was stirred at 150° C. in a sealed pressure-proof stainless steel container for 8 hours. The reaction mixture was diluted with ethyl acetate, washed with brine and concentrated under reduced pressure. The residue was purified on column chromatography to obtain N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide (50 mg) as pale yellow powder. This was dissolved in MeOH (1 mL), and 2N Hydrogen chloride/EtOH solution (1 Eq) was added, and it was stirred and concentrated. The residue was triturated in diethyl ether, and the precipitate was collected by filtration and dried to obtain the titled compound (40 mg) as white powder.
Reaction SMILES: C[C:2]1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1C=CC=CC=1.[Br:17][CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])C(Cl)=O>ClCCCl>[Br:17][CH:18]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:4](=[O:5])[CH2:6][C:7]([O:9][CH3:2])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CCCCCCCCCCCCCCC(Br)C(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCC(Br)C(=O)CC(=O)OC

Procedure:
1.8 mol of Meldrum's acid were mixed with 3.96 mol of pyridine in a round-bottomed flask containing 1,2-dichloroethane, placed at 0° C. under argon and with stirring. 1.98 mol of 2-bromohexadecanoyl chloride were then introduced slowly and the mixture was left stirring for 2 hours at 0° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][C@H:14]([C:19]([OH:21])=O)[CH2:15][C:16](=[O:18])[NH2:17])=[O:12].C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.[OH:54][C@H:55]([C@@H:73]([NH2:81])[CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH2:56][N:57]([CH2:66][CH:67]1[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]1)[NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60]>C1COCC1>[OH:54][C@H:55]([C@@H:73]([NH:81][C:19](=[O:21])[C@H:14]([CH2:15][C:16](=[O:18])[NH2:17])[NH:13][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1)=[O:12])[CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][CH:76]=1)[CH2:56][N:57]([CH2:66][CH:67]1[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72]1)[NH:58][C:59]([O:61][C:62]([CH3:65])([CH3:63])[CH3:64])=[O:60]
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Reactant: CC(C)(C)OC(=O)NN(CC1CCCCC1)C[C@H](O)[C@@H](N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NN(CC1CCCCC1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
At 5° C., 940 mg (3.27 mmol) of quinoline-2-carbonyl-(L)-asparagine (in the form of the hydrochloride salt) are dissolved in 35 ml of THF, and 736 mg (3.57 mmol) of DCC are added. After 10 min, 482 mg (3.57 mmol) of HOBT, 0.82 ml (7.44 mmol) of NMM and 1.165 g (2.98 mmol) of 1-[2(S)-hydroxy-3(S)-amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[tert-butoxycarbonyl]-hydrazine are added and the mixture is stirred at RT for 18 h. The reaction mixture is filtered and the filtrate is concentrated by evaporation. The residue is partitioned between 3 portions of ethyl acetate, saturated NaHCO3 solution, water and brine, and the organic phases, which have been dried with Na2SO4, are concentrated by evaporation and subjected to column chromatography (SiO2, ethyl acetate) to yield the title compound: TLC Rf (O)=0.16; tRet (V)=16.5 min; FAB-MS (M+H)+ =661.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([O:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH2:20][CH2:21][O:22][CH3:23])=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10]=[CH:9][CH:8]=2)=[CH:4][C:3]=1[F:26].[F:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]=[C:35]=[O:36]>C1(C)C=CC=CC=1>[C:17]([C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:19][CH2:20][CH2:21][O:22][CH3:23])[N:10]=[CH:9][CH:8]=[C:7]2[O:6][C:5]1[CH:24]=[CH:25][C:2]([NH:1][C:35]([NH:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[F:27])=[O:36])=[C:3]([F:26])[CH:4]=1)#[N:18]
Reactant: O=C=Nc1ccccc1F
Reactant: COCCOc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1C#N
Solvent: Cc1ccccc1
Product: COCCOc1cc2nccc(Oc3ccc(NC(=O)Nc4ccccc4F)c(F)c3)c2cc1C#N
Yield: 72 %

Procedure:
4-(4-Amino-3-fluorophenoxy)-6-cyano-7-(2-methoxyethoxy)quinoline (100 mg) was added to 4.5 ml of toluene, and the mixture was heated to reflux. After then adding 2-fluorophenyl isocyanate (0.05 ml), the mixture was further heated to reflux for 1 hour. After cooling, the precipitated solid was filtered out and washed with ethyl acetate/toluene==1/1 to obtain 100 mg of the title compound as light brown crystals (72% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.II.Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:14][CH3:15])[CH2:9][CH2:10][N:11]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: COC1(c2ccc(Cl)cc2)CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: II
Solvent: CC(C)O
Solvent: Cc1cccc(C)n1
Product: COC1(c2ccc(Cl)cc2)CCN(CCC=C2c3cc(C(C)(C)O)ccc3OCc3ncccc32)CC1
Temperature: 80 °C
Reaction time: 20 h
Yield: 84.3 %

Procedure:
4-(4-Chloro-phenyl)-4-methoxy-piperidine (0.072 g, 0.319 mmol) was dissolved in isopropanol (5 mL) and 2,6-lutidine (0.034 g, 37 uL, 0.319 mmol) was added. Catalytic iodine was also added. The resulting suspension was warmed to 80° C. Solid 2-[5-(3-Bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.060 g, 0.160 mmol) was added in approximately equal portions over 2 h. Stirring was continued an additional 20 h at 80° C. The mixture was concentrated and the resulting residue purified by silica gel chromatography (ethyl acetate to 87/10/3 ethyl acetate/methanol/triethylamine gradient) to afford the title compound (70 mg, 42%).