Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]5)=[CH:22][CH:21]=4)[N:14]=3)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:34]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:26][N:27]5[CH2:28][CH2:29][N:30]([CH3:33])[CH2:31][CH2:32]5)=[CH:24][CH:25]=4)[N:14]=3)=[CH:11][N:10]([CH3:34])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CN1CCN(Cc2ccc(Nc3nccc(-c4c[nH]nc4-c4ccc(Cl)cc4)n3)cc2)CC1
Reactant: CO
Product: CN1CCN(Cc2ccc(Nc3nccc(-c4cn(C)nc4-c4ccc(Cl)cc4)n3)cc2)CC1

Procedure:
The title compound is prepared as described in Example 55 starting from {4-[3-(4chloro-phenyl)-1H-pyrazol-4-yl]-pyrimidin-2-yl}-[4-(4-methyl-piperazin-1-yl-methyl-phenyl]-amine (Example 32) and methanol.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[N+:18]([O-])([OH:20])=[O:19].[OH-].[Na+]>OS(O)(=O)=O>[CH3:1][NH:2][C:3]1[C:4]2[C:9]([N:10]=[C:11]3[C:16]=1[C:15](=[O:17])[CH2:14][CH2:13][CH2:12]3)=[CH:8][CH:7]=[C:6]([N+:18]([O-:20])=[O:19])[CH:5]=2
Reactant: CNc1c2c(nc3ccccc13)CCCC2=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CNc1c2c(nc3ccc([N+](=O)[O-])cc13)CCCC2=O
Yield: 47 %

Procedure:
In 100 ml of concentrated H2SO4 at 0° C. was added 4.83 g of 3,4-dihydro-9-(methylamino)acridin-1(2H)-one. While maintaining the reaction at 0° C., 1.92 ml (1 eq) of concentrated HNO3 (70 wt %) was added dropwise over 10 minutes. Since the reaction appeared complete after the addition based on thin layer chromatography, the reaction mixture was poured into ice and neutralized with 50% NaOH. At the basic point a precipitate formed. This was filtered and chromatographed on silica gel (EtOAc) and the product was recrystallized from diichloromethane/hexanes to yield 2.75 g (47%) of a solid, melting point 208° C.
Reaction SMILES: C([O:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[C:17](Cl)[N:16]=[C:15]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:27]=[CH:26][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[CH:17][N:16]=[C:15]2[CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=1
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCCCc1ncc(CO)n1Cc1ccc(O)cc1
Reaction time: 0.08 h
Yield: 110.9 %

Procedure:
A mixture of 1.00 g of 10% palladium/carbon and 1.00 g of 1-(4-benzyloxybenzyl)-2-butyl-4-chloro-5-hydroxymethylimidazole in 20 mL of methanol was stirred at 25° for five minutes. Hydrogen gas was bubbled into the solution, and the mixture was stirred under hydrogen gas (1 atm.) at 25° for 2 hours. The mixture was filtered, and the resulting solution concentrated in vacuo to furnish 0.75 g of 1-(4-hydroxybenzyl)-2-butyl-5-hydroxymethylimidazole; NMR (200 MHz, DMSO-d6): δ9.75 (bs, 1H); 7.55 (s, 1H); 6.91 (A2B2, 4H); 5.80 (bs, 1H); 5.35 (s, 2H); 4.45 (s, 2H); 2.89 (t, 2H); 1.44 (quint, 2H); 1.21 (sext., 2H); 0.80 (t, 3H).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[Cl:6][CH2:7][CH2:8][CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=O>CO.Cl.O>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:10](=[N:1][NH:2][C:3](=[S:4])[NH2:5])[CH2:9][CH2:8][CH2:7][Cl:6])=[CH:13][CH:14]=1
Reactant: NNC(N)=S
Reactant: O=C(CCCCl)c1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: CO
Product: NC(=S)NN=C(CCCCl)c1ccc(O)cc1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
Thiosemicarbazide (6.84 g, 75 mmol) was added under nitrogen to a solution of 4-chloro-4'-hydroxybutyrophenone (10.0 g, 50 mmol) in 175 mL of methanol plus 13.5 mL of 1 N HCl plus 12.5 mL of water and the reaction stirred room temperature for forty hours. The reaction was concentrated under reduced pressure to remove most of the methanol. The residue was partitioned between methylene chloride and water. The organic layer was separated, dried (MgSO4) and the solvent removed under reduced pressure to give 8.33 g of a white solid. Recrystallization of the solid from isopropyl alcohol gave 3.19 g (21%) of the title compound as a light yellow solid, mp 126-129° C.
Reaction SMILES: [CH3:1][C@@:2]1([C:18]([F:21])([F:20])[F:19])[CH2:17][N:5]2[C:6](=[O:16])[CH:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[N:9]=[C:4]2[NH:3]1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH2:23][N:3]2[C:4]3=[N:9][C:8]([N:10]4[CH2:11][CH2:12][O:13][CH2:14][CH2:15]4)=[CH:7][C:6](=[O:16])[N:5]3[CH2:17][C@@:2]2([CH3:1])[C:18]([F:21])([F:19])[F:20])=[CH:26][CH:27]=1
Reactant: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1
Reactant: Clc1ccc(CCBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: C[C@@]1(C(F)(F)F)Cn2c(nc(N3CCOCC3)cc2=O)N1CCc1ccc(Cl)cc1

Procedure:
The product is prepared according to the procedure described in stage k of Example 1, using 100 mg of (2S)-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one (Example 1j) and 87 mg of 1-(2-bromoethyl)-4-chlorobenzene, replacing the sodium hydride with 214 mg of caesium carbonate. After purification by preparative HPLC/MS (method C), 65 mg of (2S)-1-[2-(4-chlorophenyl)ethyl]-2-methyl-7-(morpholin-4-yl)-2-(trifluoromethyl)-2,3-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C@@H:10]([OH:13])[CH2:11][OH:12])[N:5]=1)([O-])=O.[H][H]>[Pd].C(O)C>[NH2:1][C:4]1[CH:8]=[CH:7][N:6]([CH2:9][C@@H:10]([OH:13])[CH2:11][OH:12])[N:5]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccn(C[C@@H](O)CO)n1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccn(C[C@@H](O)CO)n1
Yield: 97.6 %

Procedure:
In a Parr shaker bottle was placed (R)-3-(3-nitro-pyrazol-1-yl)-propane-1,2-diol (3.17 g, 16.95 mmol), 10% palladium on activated carbon (200 mg) and ethanol (30 mL). The bottle was then placed on the Parr shaker at 50 psi of hydrogen pressure for 5 h. The reaction was then filtered through a pad of celite and washed with ethanol and concentrated in vacuo to afford (R)-3-(3-amino-pyrazol-1-yl)-propane-1,2-diol (2.60 g, 98%) as a yellow oil: LR-ES-MS m/z calculated for C6H11N3O2 [M]+ 157, observed [M+H]+ 158.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].C1(C(C)[CH:18]=[O:19])C=CC=CC=1>>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][CH:18]=[O:19])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(C=O)c1ccccc1
Product: N#Cc1ccc(CC=O)cc1

Procedure:
This compound was prepared from 4-cyanobenzaldehyde using a modification of a procedure previously used in the multi-step synthesis of 2-phenylpropanal {Allen, C. F. H.; van Allan, J., Org. Syn. Coll. Vol 3, 733-734 (1955)}.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][NH2:12].[C:18](OC(=O)C)(=[O:20])[CH3:19]>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][NH:12][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(CCCN)OC1CCCCO1
Solvent: c1ccncc1
Product: CCCCCC(CCCNC(C)=O)OC1CCCCO1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
To a stirred, ice cold solution of 4-(2-tetrahydropyranyloxy)nonylamine (7.29 g., 0.03 mole) in pyridine (40 ml.) is added acetic anhydride (3.06 g., 0.03 mole) at such a rate as to maintain the reaction temperature at 5°-10°C. The reaction is then allowed to stand at room temperature for 6 hours, poured into ice water (200 ml.) and extracted with ether (2 × 100 ml.). The ether is extracted with ice cold 5% hydrochloric acid (2 × 20 ml.), washed with brine (2 × 25 ml.), then dried over sodium sulfate. Evaporation in vacuo affords the subject compound as a pale yellow oil.
Reaction SMILES: [CH2:1]=[O:2].Cl.[Cl:4][C:5]1[CH:6]=[C:7]2[O:13][C:12](=[O:14])[NH:11][C:8]2=[N:9][CH:10]=1>O>[OH:2][CH2:1][N:11]1[C:8]2=[N:9][CH:10]=[C:5]([Cl:4])[CH:6]=[C:7]2[O:13][C:12]1=[O:14]
Reactant: O=c1[nH]c2ncc(Cl)cc2o1
Reactant: C=O
Agent: Cl
Solvent: O
Product: O=c1oc2cc(Cl)cnc2n1CO
Reaction time: 4 h
Yield: 85 %

Procedure:
8 parts of 38% formaldehyde solution and 25 parts of 2N hydrochloric acid are added to a solution of 8.5 parts of 6-chlorooxazolo-[4,5-b]-pyridin-2-(3H)-one in 60 parts of water, and the whole is stirred for 4 hours at 50° to 60° C. After cooling with ice, filtration is performed and the residue is washed with ice water. There are obtained 8.5 parts of 3-hydroxymethyl-6-chloro-oxazolo[ 4,5-b]pyridin-2-(3H)-one (85% of theory), m.p. 137°-139° C.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[CH3:12][S:13]([C:16]1[CH:30]=[CH:29][C:19]2[N:20]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:21]=[N:22][C:18]=2[CH:17]=1)(=[O:15])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:12][S:13]([C:16]1[CH:30]=[CH:29][C:19]2[N:20]([CH:23]3[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][C:4]([C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=4)=[O:5])[CH2:27][CH2:28]3)[CH:21]=[N:22][C:18]=2[CH:17]=1)(=[O:15])=[O:14]
Reactant: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCNCC1
Reactant: O=C(CCCl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc2c(c1)ncn2C1CCN(CCC(=O)c2ccccc2)CC1
Reaction time: 48 h

Procedure:
3-Chloropropiophenone (860 mg) was added to a mixture of 5-(methylsulfonyl)-1-piperidin-4-yl-1H-benzimidazole (1.395 g) and potassium carbonate (1.38 g) in DMF (30 ml) and stirred for 2 days. The reaction mixture was evaporated to dryness and the residue was dissolved in dichloromethane (20 ml), washed with water (15 ml) and brine (15 ml), dried and evaporated to dryness to give the title compound, yield 2.07 g, M+H 412, NMR (CDCl3) 2.2 (m, 4H) 2.3-2.4 (m, 2H) 2.9 (m, 2H) 3.1 (s, 3H) 3.2-3.3 (m, 4H) 4.3 (m, 1H) 7.5 (m, 2H) 7.6 (m, 2H) 7.9 (m, 2H) 8.0 (m, 1H) 8.2 (s, 1H) 8.4 (s, 1H).
Reaction SMILES: [CH3:1][P:2](=[O:7])([CH:5]=[CH2:6])[CH:3]=[CH2:4].[C:8]([N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>C1COCC1.O>[CH3:1][P:2]1(=[O:7])[CH2:5][CH2:6][N:21]([CH:18]2[CH2:17][CH2:16][N:15]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:20][CH2:19]2)[CH2:4][CH2:3]1
Reactant: C=CP(C)(=O)C=C
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(N2CCP(C)(=O)CC2)CC1
Yield: 46.5 %

Procedure:
A solution of methyl divinyl phosphine oxide (140 mg, 1.21 mmol) and 1-Boc-4-aminopiperidine (265 mg, 1.33 mmol) in 1:1 THF/water (3 mL) was heated at reflux for 16 h. The reaction mixture was concentrated in vacuo and the residue was purified by silica gel chromatography (0-10% 7N ammonia in methanol:dichloromethane) to afford the desired compound as a white solid (178 mg, 38% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([B:10]2[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]2)=[CH:5][N:4]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:9][C:8]2[C:3]([O:2][CH3:1])=[N:4][CH:5]=[C:6]([B:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]3)[CH:7]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1N
Product: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1NS(=O)(=O)c1ccc(F)cc1
Yield: 38 %

Procedure:
2-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (200 mg, 0.8 mmol) was treated with 4-fluorobenzenesulfonyl chloride (311 mg, 1.6 mmol) according to the method described In Preparation 15b to give 124 mg (37.5% yield) of the title compound as an oil. Purity 88%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([F:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Cl:22].C1C(=O)N([Br:31])C(=O)C1.Br>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([F:13])=[C:6]([F:14])[C:5]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:31])=[CH:18][C:17]=1[Cl:22]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccccc1Cl
Agent: Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(C)=O)c(F)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 19 h
Yield: 87 %

Procedure:
A mixture of 5-acetyl-2-(2-chlorophenylamino)-3,4-difluorobenzoic acid methyl ester (251 mg, 0.739 mmol), NBS (139 mg, 0.781 mmol), and catalytic amount of HBr (48%) in DMF (3 mL) was stirred for 19 hours at room temperature. The reaction mixture was diluted with EtOAc, and washed with water (5×). The organic layer was dried over MgSO4, filtered, and concentrated to give the desired product (269 mg, 87%) that was used directly without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:17][C:4]1[C:5]2[C:6](=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:8][N:9]=2)[CH:16]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(CBr)c2noc(-c3ccccc3)c2c1

Procedure:
A mixture of 16.2 g (0.067 mole) of 5-chloro-7-methyl-3-phenyl-2,1-benzisoxazole, 11.9 g (0.067 mole) of N-bromosuccinimide, 275 ml of carbon tetrachloride and 0.1 g of dibenzoylperoxide was heated at reflux under illumination of a flood lamp for 2 hr. The mixture was filtered and the filtrate was washed once with a saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated to give a yellow solid as residue. An NMR analysis of the residue showed it was a mixture containing 8% of starting methyl compound, 83% of monobromo compound and 9% of dibromo compound. An analytical sample, m.p. 142°-144° C., was obtained by recrystallizing twice from ethyl acetate.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[Cl:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:56][N:57]1[CH2:62][CH2:61][CH:60]([NH2:63])[CH2:59][CH2:58]1>>[Cl:31][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:22]=1[NH:21][C:19]1[N:18]=[CH:17][C:8]2[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[C:7]=2[N:20]=1)[C:26]([NH:63][CH:60]1[CH2:61][CH2:62][N:57]([CH3:56])[CH2:58][CH2:59]1)=[O:28]
Reactant: CN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3Cl)ncc21
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CN1CCC(NC(=O)c2ccc(Nc3ncc4c(n3)N(C3CCCC3)CC(F)(F)C(=O)N4C)c(Cl)c2)CC1

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-chlorobenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylpiperidin-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.77 (m, 15H) 2.23 (s, 3H) 2.84 (m, 2H) 3.96-4.07 (t, J=12 Hz, 2H) 4.66 (m, 1H) 7.80 (dd, J=8.5, 1.9 Hz, 1H) 8.00 (d, J=1.8 Hz, 1H) 8.08 (d, J=8.6 Hz, 1H) 8.19-8.33 (m, 2H) 8.58 (s, 1H). [M+H] calc'd for C26H32ClF2N7O2, 548. found 548.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[NH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:39]=1[NH:38][CH:37]=[CH:36]2>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:30][C:31]3[CH:32]=[CH:33][CH:34]=[C:35]4[C:39]=3[NH:38][CH:37]=[CH:36]4)=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Nc1cccc2cc[nH]c12
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3cccc4cc[nH]c34)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 99.9 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine (0.25 g, 0.61 mmol) obtained in Example 19, step 4 and 7-aminoindole (0.128 g, 0.97 mmol), the title compound (0.310 g, 99%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:12][CH2:13][CH2:14][CH2:15][N:16]=[C:17]=[O:18].[N-]=C=O>Cl>[Cl:11][C:10]1[C:2]([NH:1][C:17]([NH:16][CH2:15][CH2:14][CH2:13][Cl:12])=[O:18])=[C:3]([CH:7]=[CH:8][CH:9]=1)[C:4]([OH:6])=[O:5]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: O=C=NCCCCl
Agent: Cl
Agent: [N-]=C=O
Product: O=C(NCCCCl)Nc1c(Cl)cccc1C(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A 250 mL round bottom flask is charged with 2-amino-3-chlorobenzoic acid (5.00 g, 29.1 mmol) and 100 mL of 5% aqueous KHCO3. The slurry is cooled to 0° C., and 3-chloropropylisocyanate (6.0 mL, 58 mmol) is added. The mixture is then allowed to warm to room temperature over 16 hours. HPLC analysis shows some starting material remaining, so the solution is recooled to 0° C. and an additional portion of the isocyanate (3.0 mL, 29 mmol) is added. After 2 h, the solution is acidified with 1 N HCl (ca. 40 mL), and the resulting yellow solid is filtered, rinsing with 1 N HCl. The resulting solid (35.5 g) is recrystallized from 80 mL of hot ethanol, to provide the product as a white solid: 4.22 g, 14.5 mmol, 50% yield. M.p. 124.4-124.8° C. 1H NMR (CD3OD): 7.84 (d, J=8,1H), 7.64 (d, J=8,1H), 7.24 (t, J=8,1H), 3.68 (t, J=7, 2H), 3.37 (t, J=6, 2H), 2.01 (m, 2H). MS (CI): 289 (M-H, 100), 196 (M-ClCH2CH2CH2NH, 25).
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]2[CH2:11][CH:10]([OH:12])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.O>C1COCC1>[C:13]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:11][CH:10]([O:12][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=3)[CH2:9]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 23 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
0.5 g (2 mmole) of 1-(diphenylmethyl)-3-hydroxyazetidine is added to a suspension of 0.06 g (2.3 mmole) of NaH in 20 ml of dry THF, under an argon atmosphere. After agitation for one hour at 23° C., a solution of 0.29 g (2.1 mmole) of 4-fluoronitrobenzene in 5 ml of dry THF is added dropwise to the reaction mixture. Agitation is maintained for another 2 hours at 23° C. and the mixture is finally poured into 25 ml of water. The product is extracted twice with 25 ml of ethyl acetate, the organic phase is then washed twice with 25 ml of brine, dried over magnesium sulphate, filtered and concentrated under vacuum. The product is purified on a silica column (eluent: 12% ethyl acetate in heptane). The pure fractions are evaporated in order to produce a colourless oil with a yield of 40%.
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1([CH3:13])[CH3:12].[CH3:14][O:15][C:16](=[O:19])[CH2:17]Br>C(OCC)C>[CH3:14][O:15][C:16](=[O:19])[CH2:17][NH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][C:3]1([CH3:13])[CH3:12]
Reactant: COC(=O)CBr
Reactant: CC1(C)CCc2ccccc2C1N
Solvent: CCOCC
Product: COC(=O)CNC1c2ccccc2CCC1(C)C
Temperature: 25 °C
Reaction time: 70 h

Procedure:
65.2 g of 1-amino-2,2-dimethyl-1,2,3,4-tetrahydronaphthalene are solved in 250 ml of diethyl ether. To this solution is dropwise added a solution of 28.5 g of bromoacetic acid methyl ester in 150 ml of diethyl ether. The mixture is stirred at room temperature for 70 hours. The precipitate is separated and the solution is concentrated to dryness, yielding N-(2,2-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl) glycine methyl ester quantitatively.
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[F:10][C:11]1[CH:16]=[C:15]([C:17]2[O:21][N:20]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28]O)=[CH:24][CH:23]=3)[N:18]=2)[CH:14]=[CH:13][C:12]=1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>ClCCl>[Cl:3][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:19]2[N:18]=[C:17]([C:15]3[CH:14]=[CH:13][C:12]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[C:11]([F:10])[CH:16]=3)[O:21][N:20]=2)=[CH:23][CH:24]=1
Reactant: OCc1ccc(-c2noc(-c3ccc(-c4ccccc4)c(F)c3)n2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Fc1cc(-c2nc(-c3ccc(CCl)cc3)no2)ccc1-c1ccccc1
Temperature: 80 °C

Procedure:
Thionyl chloride (20 mL, 0.274 mol) and N,N-dimethylformamide (2 mL) are added to a stirred solution of 4-[5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole-3-yl]phenylmethanol (32 g, 0.092 mol) in dichloromethane (150 mL) at 0° C. The reaction mixture is heated at 80° C. for 1 hour and then concentrated under reduced pressure. The residue is neutralized with a saturated aqueous sodium bicarbonate solution (150 mL) to furnish a solid which is filtered and washed with n-hexane (150 mL) to give 3-(4-chloromethylphenyl)-5-(2-fluorobiphenyl-4-yl)-1,2,4-oxadiazole.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)=[CH:4][C:3]=1[CH:15]=[CH2:16].Cl.[CH3:18]O>CCOCC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[CH3:18])=[CH:4][C:3]=1[CH:15]=[CH2:16]
Reactant: C=Cc1cc(OC[C@H]2CCCN2)cnc1Cl
Reactant: CO
Agent: Cl
Solvent: CCOCC
Product: C=Cc1cc(OC[C@H]2CCCN2C)cnc1Cl

Procedure:
To a solution of 6-chloro-5-ethenyl-3-(2-(R)-pyrrolidinylmethoxy)pyridine in Et2O was added hydrogen chloride (1.0 M in Et2O) carefully to afford the tittle compound: mp 173-175° C.; 1H NMR (D2O) δ 2.04-2.18 (m, 2H), 2.23 (m, 1H), 2.40 (m, 1H), 3.04 (s, 3H), 3.29 (m, 1H), 3.73 (m, 1H), 3.95 (m, 1H), 4.37 (dd, 1H, J=6.0, 11.0 Hz), 4.53 (dd, 1H, J=3.0, 11.0 Hz), 5.61 (d, 1H, J=11.0 Hz), 5.94 (d, 1H, J=17.5 Hz), 7.02 (dd, 1H, J=11.0, 17.5 Hz), 7.73 (d, 1H, J=3.0 Hz), 8.04 (d, 1H, J=3.0 Hz); MS (CI/NH3) m/z 253 (M+H)+. Anal. Calcd for C13H17ClN2O.1.1 HCl: C, 53.32; H, 6.23; N, 9.57. Found: C, 53.51; H, 6.48; N, 9.20. [α]25D +7.4 (c 0.66, MeOH).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].F[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>CC(N(C)C)=O>[CH3:1][C:2]1[N:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1nc2ccccc2n1-c1ccccn1
Temperature: 100 °C
Reaction time: 0.83 h
Yield: 71.3 %

Procedure:
To a stirred solution of 2-methyl-1H-benzimidazole (6.61 g, 50 mmol) in dimethylacetamide (40 ml) at room temperature under a nitrogen atmosphere was added sodium hydride (2.40 g, 60 mmol) in portions during 15 min. At the point where the reaction mixture was too viscous to stir, the reaction was diluted with 100 ml of dimethylacetamide. After 50 min., a solution of 2-fluoropyridine (5.83 g, 60 mmol) in dimethylacetamide (30 ml) was added during 15 min. The resulting mixture was heated at 100° C. for 2 h and then to reflux for about 4 h. Volatiles were removed by evaporation under reduced pressure. The residue was dissolved into ethyl acetate (200 ml) and washed consecutively with water (3×100 ml) and brine (100 ml). The organic layer was dried (magnesium sulfate) and concentrated to dryness. Purification by column chromatography (silica gel, 300 g; n-hexane/ethyl acetate (17/3)) yielded 7.46 g (71%) of the titled compound as a light yellow liquid. 1H-NMR (CDCl3) δ: 8.72-8.67 (1H, m), 7.95 (1H, ddd, J=7.7, 7.7, 1.8 Hz), 7.78-7.74 (1H, m), 7.49-7.36 (3H, m), 7.32-7.20 (2H, m), 2.69 (3H, s).