Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([C:21](O)=[O:22])[CH:18]=[CH:17][C:15]=3[N:16]=2)=[O:10])=[C:4]([F:24])[CH:3]=1.[NH2:25][C:26]1[CH:35]=[CH:34][C:29]2[NH:30][C:31](=[O:33])[O:32][C:28]=2[CH:27]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[O:33]=[C:31]1[NH:30][C:29]2[CH:34]=[CH:35][C:26]([NH:25][C:21]([C:19]3[CH:18]=[CH:17][C:15]4[N:16]=[C:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=5[F:24])[S:13][C:14]=4[CH:20]=3)=[O:22])=[CH:27][C:28]=2[O:32]1
Reactant: O=C(Cc1ccc(Cl)cc1F)Nc1nc2ccc(C(=O)O)cc2s1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)cc1F)Nc1nc2ccc(C(=O)Nc3ccc4[nH]c(=O)oc4c3)cc2s1
Temperature: 25 °C
Yield: 20 %

Procedure:
Starting material 37 (60 mg, 0.2 mmol, 70% content) and 6-Amino-3H-benzooxazol-2-one (30, 25 mg, 0.2 mmol) were dissolved in 2 ml DMF. Then EDCI (38 mg, 0.2 mmol) and HOBt (31 mg, 0.2 mmol) were added. The reaction was stirred over night at ambient temperature, concentrated in vacuo and purified by prep HPLC (Method 1). By concentration of the pure fractions the desired product 38 (23 mg, 0.04 mmol, 24%) could be isolated.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][O:9][C:10]([N:12]2[CH2:19][CH2:18][CH2:17][C@H:13]2[C:14]([OH:16])=O)=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:34][C@H:35]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36]1>C(#N)C>[C:43]([O:42][C:40]([N:37]1[CH2:38][CH2:39][C@H:35]([NH:34][C:14](=[O:16])[C@@H:13]2[CH2:17][CH2:18][CH2:19][N:12]2[C:10]([O:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:21][CH:20]=2)=[O:11])[CH2:36]1)=[O:41])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)[C@@H]2CCCN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To a solution of 1-(4-nitrobenzyloxycarbonyl)-L-proline (3.67 g) in anhydrous acetonitrile (50 ml), N,N-carbonyldiimidazole (1.86 g) was added at room temperature. After stirring for one hour, a solution of (3S)-3-amino-1(tert-butoxycarbonyl)pyrrolidine (1.86 g) in anhydrous acetonitrile (20 ml) was added to the reaction mixture under ice cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was then concentrated by evaporation under reduced pressure. To the residue, ethyl acetate was added. The resulting mixture was washed with water and saturated saline, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue was purified by chromatography through a silica gel column (ethyl acetate:dichloromethane=1:1), whereby 3.31 g of (3S)-1-(tert-butoxycarbonyl)-3-[1-(4-nitrobenzyloxycarbonyl)-L-prolylamino]pyrrolidine were obtained as a colorless amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>[I-].[K+]>[CH2:35]([O:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[O:27][CH2:26][CH2:25][CH2:24][N:13]1[CH2:12][CH2:11][CH:10]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[OH:9])[CH2:15][CH2:14]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: ClCCCOc1ccccc1OCc1ccccc1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: [I-]
Agent: [K+]
Product: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(CCCOc2ccccc2OCc2ccccc2)CC1

Procedure:
Following the procedure of Example 2 and using potassium iodide catalyst, [α,α-bis(p-fluorophenyl)]-4-piperidinemethanol and 2-(3-chloropropoxy)-1-benzyloxybenzene are reacted to give 1-[3-(2-benzyloxyphenoxy)propyl]-α,α-bis(4-fluorophenyl)-4-piperidinemethanol which is reacted with hydrogen over palladium on carbon catalyst to give the title compound.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH2:9][O:8][C:7](=[O:10])[CH:6]=2)[CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19]([I:21])[CH:20]=1.CO>O1CCCC1>[Cl:22][C:18]1[N:17]=[CH:16][C:15]([CH2:14][N:4]([CH:1]2[CH2:3][CH2:2]2)[C:5]2[CH2:9][O:8][C:7](=[O:10])[CH:6]=2)=[CH:20][C:19]=1[I:21]
Reactant: Clc1ncc(CBr)cc1I
Reactant: O=C1C=C(NC2CC2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1C=C(N(Cc2cnc(Cl)c(I)c2)C2CC2)CO1
Temperature: 25 °C
Yield: 26.5 %

Procedure:
200 mg (1.44 mmol) of 4-(cyclopropylamino)furan-2(5H)-one (VI-1) and 86 mg (2.17 mmol) of a 60% strength dispersion of sodium hydride in mineral oil in 100 ml of tetrahydrofuran are heated under reflux for 1 hour. After cooling to room temperature, 478 mg (1.44 mmol) of 3-bromomethyl-6-chloro-5-iodopyridine (VII-3) are added, and the mixture is heated under reflux for a further 6 hours. After cooling of the reaction mixture to room temperature and addition of methanol, the mixture is concentrated under reduced pressure. The residue is taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by column chromatography on silica gel (silica gel 60-Merck, particle size: 0.04 to 0.063 mm) using the mobile phase mixture ethyl acetate:cyclohexane (3:1) gives 149 mg (26% of theory) of 4-[[(6-chloro-5-iodopyridin-3-yl)methyl](cyclopropyl)amino]furan-2(5H)-one.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([Cl:16])=[CH:10][N:9]=1>O>[Cl:16][C:11]1[CH:12]=[C:13]([O:14][CH3:15])[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=1
Reactant: COc1cc(Cl)cnc1Br
Reactant: C1CNCCN1
Solvent: O
Product: COc1cc(Cl)cnc1N1CCNCC1
Yield: 32.7 %

Procedure:
Anhydrous piperazine (13.41 g) and 2-bromo-5-chloro-3-methoxypridine (3.50 g) were heated in an autoclave at 100° C. for 20 h. The mixture was dissolved in water (10 mL) and extracted with CH2Cl2 (3×100 mL). The combined organic extracts were washed with a saturated NaCl soution, dried with K2CO3, filtered and concentrated under reduced pressure. Silica gel chromatography (CH2Cl2 /MeOH; 90:10) of the residue yielded product (1.17 g, 33%).
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](O)=[O:11].[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[C:1]1([CH3:19])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:40])[CH2:38][CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1)=[O:11]
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: Cc1cc(C)c(C(C(=O)O)c2ccccc2)c(C)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3c(C)cc(C)cc3C)CC2)c1

Procedure:
Example 14 was prepared from mesityl(phenyl) acetic acid and N-{3-[1-(3-aminopropyl) 4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 9: ESMS m/e: 526.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:14]([F:23])=[CH:15][C:16]([O:21][CH3:22])=[C:17]([CH:20]=1)[CH:18]=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:17]3[CH:20]=[C:13]([Cl:12])[C:14]([F:23])=[CH:15][C:16]=3[O:21][CH3:22])/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: COc1cc(F)c(Cl)cc1C=O
Solvent: C1CCNC1
Solvent: CO
Product: COc1cc(F)c(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21
Temperature: 70 °C

Procedure:
To the mixture of 6-chloro-1,3-dihydro-indol-2-one (3.4 g, 20.3 mmol) and 5-chloro-4-fluoro-2-methoxy-benzaldehyde (3.2 g, 17 mmol) in methanol (50 mL) was added pyrrolidine (1.2 g, 17 mmol) dropwise. Then the mixture was heated at 70° C. for 1 h. After cooled to room temperature, the mixture was filtered to give the crude product which was used for the next step reaction without further purification.
Reaction SMILES: [F:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][C:18]=1[CH3:25]>>[F:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[C:18]([CH3:25])[CH:19]=1)=[O:5]
Reactant: CON(C)C(=O)c1cccc(F)c1F
Reactant: COc1ccc([Mg]Br)cc1C
Product: COc1ccc(C(=O)c2cccc(F)c2F)cc1C

Procedure:
Prepared according to Method A step B from 2,3-difluoro-N-methoxy-N-methyl-benzamide (2.5 g, 12.4 mmol) and 4-methoxy-3-methyl-phenylmagnesium bromide (26 mL, 0.5 M in THF) to give 0.97 g of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11](B(O)O)=[CH:10][C:9]=2[F:17])=[CH:4][N:3]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[S:29]([NH:32][CH2:33][CH3:34])(=[O:31])=[O:30]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][C:20]=3[S:29]([NH:32][CH2:33][CH3:34])(=[O:31])=[O:30])=[CH:10][C:9]=2[F:17])=[CH:4][N:3]=1
Reactant: CCNS(=O)(=O)c1cc(C(F)(F)F)ccc1Br
Reactant: Nc1ncc(-c2ncc(B(O)O)cc2F)cn1
Product: CCNS(=O)(=O)c1cc(C(F)(F)F)ccc1-c1cnc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using (6-(2-aminopyrimidin-5-yl)-5-fluoropyridin-3-yl)boronic acid and 2-bromo-N-ethyl-5-(trifluoromethyl)benzenesulfonamide. MS (ESI): mass calcd. for C18H15F4N5O2S, 441.09; m/z found, 442.0 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.94 (d, J=1.1, 2H), 8.51-8.46 (m, 1H), 8.37-8.31 (m, 1H), 8.03 (dd, J=8.1, 1.9, 1H), 7.81 (dd, J=11.9, 1.8, 1H), 7.68 (d, J=7.9, 1H), 2.86 (q, J=7.3, 2H), 1.02 (t, J=7.2, 3H).
Reaction SMILES: C(O[C:4](=[O:6])C)=O.ClCCl.[CH3:10][C:11]1[N:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:26])[CH:21]=3)[CH:18]=[CH:19][C:14]2=[N:13][N:12]=1>ClCCl.CO>[CH3:10][C:11]1[N:15]2[N:16]=[C:17]([C:20]3[CH:21]=[C:22]([NH:26][CH:4]=[O:6])[CH:23]=[CH:24][CH:25]=3)[CH:18]=[CH:19][C:14]2=[N:13][N:12]=1
Reactant: CC(=O)OC=O
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Solvent: ClCCl
Solvent: CO
Product: Cc1nnc2ccc(-c3cccc(NC=O)c3)nn12
Reaction time: 12 h

Procedure:
To 5.53 ml of acetic-formic anhydride was added 250 ml dichloromethane followed by 10 g of 3-methyl-6-[3-(amino)-phenyl]-1,2,4-triazolo[4,3-b]pyridazine. The solution was stirred for 12 hours, then diluted with 1 liter of dichloromethane-methanol (9:1). This solution was washed with saturated aqueous sodium bicarbonate, dried, and concentrated in vacuo. The residue was recrystalized from dichloromethane-methanol to give 6.7 g of an off-white powder, mp 265°-268° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.CCN(C(C)C)C(C)C.[CH3:21][C:22]1[N:27]=[CH:26][C:25]([CH2:28][NH2:29])=[CH:24][CH:23]=1>CCCCO>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:29][CH2:28][C:25]2[CH:26]=[N:27][C:22]([CH3:21])=[CH:23][CH:24]=2)[N:10]=1
Reactant: Fc1nc(Cl)c2[nH]cnc2n1
Reactant: Cc1ccc(CN)cn1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(CNc2nc(F)nc3[nH]cnc23)cn1
Reaction time: 1 h

Procedure:
To a stirred solution of 6-chloro-2-fluoropurine (0.4 g, 2.3 mmol) in n-BuOH (50 ml) under an argon atmosphere at 0° C., was added DIEA (2.5 ml, 14.7 mmol) followed by (6-methylpyridin-3-yl)methanamine (0.36 g, 2.95 mmol). The reaction mixture was stirred at this temperature for 1 h and then allowed to return to room temperature and stirred for 4 h, it was still seen incomplete, hence heated the reaction to 100° C. and left at that temperature for 8 h. The solvent was evaporated in vacuo and the residue was purified by gradient column chromatography on silica gel, eluted with CHCl3:MeOH (100:0→90:10), to afford the product as a white solid; Yield: 0.38 g (65%) δH CDCl3, 250 MHz) 2.44 (3 H, s, CH3), 3.66-3.57 (2 H, m, NHCH2), 4.63 (1H, s, br, NH), 7.25 (1 H, d, J 7.5, ArH), 7.71 (1 H, dd, J 2.5, 7.5, ArH), 8.14 (1 H, s, ArH), 8.49 (1 H, s, ArH), 9.07 (1 H, s, br, NH); δC (CDCl3, 250 MHz) 159.12 (C), 158.62 (C), 157.61 (C), 155.56 (C), 147.44 (CH), 146.99 (CH), 136.32 (C), 123.05 (2×CH), 119.42 (C), 41.64 (CH2), 18.47 (CH3); m/z 259.2 (M+H)
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:19].[O:20]=[C:21]([NH:27][C:28]1[CH:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=1)[CH2:22][CH2:23][C:24]([OH:26])=[O:25]>>[OH:19][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:7]=2)[C:2]=1[C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:21](=[O:20])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2ccc(NC(=O)CCC(=O)O)cc2)OC1(C)C
Reactant: Oc1cccc(-c2ccc3c(Br)c(O)ccc3c2)c1
Product: O=C(O)CCC(=O)Nc1ccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)cc1
Reaction time: 0.17 h
Yield: 12 %

Procedure:
The compound is prepared by the reaction of 1-bromo-6-(3-hydroxyphenyl)-naphthalene-2-ol (100 mg, 0.32 mmol, 1 eq) with 4-oxo-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylamino)butanoic acid (101.3 mg, 0.32 mmol, 1 eq) according to method A in 10 min. Purification by column chromatography with dichloromethane/methanol 90/10 yields the desired compound in a yield of 12%, 16 mg.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH3:23])[C:9]3[N:13]=[C:12]([C:14]4[C:15](=[O:21])[NH:16][CH:17]=[CH:18][C:19]=4I)[NH:11][C:10]=3[CH:22]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[C:24]1([C@@H:30]([CH2:32][OH:33])[NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN1CCOCC1>CN(C=O)C>[OH:33][CH2:32][C@@H:30]([NH:31][C:19]1[CH:18]=[CH:17][NH:16][C:15](=[O:21])[C:14]=1[C:12]1[NH:11][C:10]2[CH:22]=[C:6]([N:1]3[CH:5]=[CH:4][N:3]=[CH:2]3)[CH:7]=[C:8]([CH3:23])[C:9]=2[N:13]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(I)cc[nH]c3=O)nc12
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(-n2ccnc2)cc2[nH]c(-c3c(N[C@H](CO)c4ccccc4)cc[nH]c3=O)nc12
Temperature: 80 °C
Yield: 52.1 %

Procedure:
To a solution of 3-(6-imidazol-1-yl-4-methyl-1H-benzimidazol-2-yl)-4-iodo-1H-pyridin-2-one (30 mg, 0.072 mmol) in DMF (1 mL) were added (S)-(−)-2-phenylglycinol (26 mg, 0.18 mmol) and N-methylmorpholine (0.1 mL). The reaction mixture was heated to 80° C. for 6 h and cooled to room temperature. The solvent was removed under vacuum and the residue was purified by prep. HPLC to yield the title compound (16 mg, 52%). 1H NMR (300 MHz, CD3OD) δ 8.07 (1H, narrow t, J=1.7 Hz), 7.76 (2H, s), 7.27–7.48 (7H, m), 7.21 (1H, d, J=7.5 Hz), 6.11 (1H, d, J=7.5 Hz), 4.92 (1H, m), 4.03 (1H, dd, J=4.5, 11.2 Hz), 3.95 (1H, dd, J=6.2, 11.2 Hz), 2.75 (3H, s). LCMS (M+H)+ m/z 427 (t=1.44 min.)
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=O)C.[CH3:14][NH:15][CH3:16].[OH-].[Na+].Cl>C1COCC1.O>[OH:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([N:15]([CH3:16])[CH3:14])=[O:8]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.5 %

Procedure:
A mixture of acetylsalicyloyl chloride (3.4 g, 17 mmol) in 120 mL of THF was added dropwise to 30 mL of 40% aqueous dimethylamine (66 mmol). The mixture was stirred at room temperature for 3 hours and then sodium hydroxide (4 g, 0.1 mmol) was added. The mixture was stirred at room temperature for approximately 60 hours and then poured into 20 mL of water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated. The residue was purified on silica gel by flash chromatography eluting with 6% methanol/methylene chloride to give 2-hydroxy-N,N-dimethylbenzamide (2.4 g, 14.53 mmol), m.p. 145°-152° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:5][C:6]3[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12](O)=[O:13])[C:8](=[O:22])[C:7]=3[O:23][C:24]=2[CH:25]=[CH:26][CH:27]=1.C(Cl)(=O)C(Cl)=O.[NH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>C(Cl)Cl.O>[CH:16]1([CH2:15][C@H:11]([N:9]2[CH2:10][C:6]3[CH2:5][C:4]4[C:3]([O:2][CH3:1])=[CH:27][CH:26]=[CH:25][C:24]=4[O:23][C:7]=3[C:8]2=[O:22])[C:12]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=2)=[O:13])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Reactant: Nc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Product: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2ccccn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.7 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 0.64 mmol), in methylene chloride (10 mL) was treated with oxalyl chloride (0.07 mL, 0.64 mmol) at 0° C. The mixture was warmed to 25° C. and stirred for additional 2 hours. Then, the reaction mixture was cooled to 0° C., and N,N′-diisopropylethyl amine (0.34 mL, 1.92 mmol) and commercially available 2-amino-pyridine (68 mg, 0.64 mmol), were added. The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradiant elution, afforded (S)-3-cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-N-pyridin-2-yl-propionamide (42 mg, 17.4%), as a white solid. 1H NMR (DMSO-d6) δ: 10.85 (s, 1H), 8.33 (d, J=3.9 Hz, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.77 (t, J=7.3 Hz, 1H), 7.22 (t, J=8.3 Hz, 1H), 7.12 (t, J=5.9 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 5.08 (br. s., 1H), 4.39 (d, J=18.6 Hz, 1H), 4.03 (d, J=19.1 Hz, 1H), 3.82 (s, 3H), 3.55 (s, 2H), 1.49-1.88 (m, 7H), 0.85-1.32 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12](OC)=[O:13])[CH:5]=[N:6][C:7]=1[C:8]([F:11])([F:10])[F:9].CC(C[AlH]CC(C)C)C>C(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[N:6][C:7]=1[C:8]([F:9])([F:10])[F:11]
Reactant: COC(=O)c1cnc(C(F)(F)F)c(Br)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: CO
Product: OCc1cnc(C(F)(F)F)c(Br)c1
Temperature: 0 °C
Yield: 54 %

Procedure:
To a solution of methyl 5-bromo-6-(trifluoromethyl)-3-pyridinecarboxylate (for a synthesis see Preparation 12(b)) (698 mg, 2.457 mmol) in DCM (20 ml) stirred under N2 at 0° C. was added DIBAL-H (1.5 M solution in toluene, 4.91 ml, 7.37 mmol) dropwise. The reaction mixture was stirred at 0° C. for 3 h and at room temperature overnight. The reaction mixture was diluted with MeOH and concentrated under reduced pressure. The residue was treated with a 1N HCl solution and extracted twice with EtOAc. The combined organic phases were dried over anhydrous Na2SO4 and concentrated under reduced. The crude material was purified by Flashmaster chromatography on a 10 g silica gel cartridge using hexane/EtOAc 95:5 as eluent to afford [5-bromo-6-(trifluoromethyl)-3-pyridinyl]methanol (297 mg, 54%) no pure enough to be used in the next step. The title compound was re-purified by preparative HPLC (column XTerra 30×150 mm, gradient elution: 30 to 80% CH3CN/H2O, uv detection 254 nm) to give the title compound (157 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[N:20]([C:21]5[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=5[CH3:28])[NH2:24])[CH:19]=[CH:18][N:16]4[N:17]=3)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:31]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([S:42]([F:47])([F:46])([F:45])([F:44])[F:43])[CH:41]=1)[C:36](O)=[O:37])#[N:32]>>[C:31]([C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([S:42]([F:46])([F:47])([F:43])([F:44])[F:45])[CH:41]=1)[C:36]([NH:24][C:23]1[CH:25]=[CH:26][C:27]([CH3:28])=[C:21]([N:20]2[C:15]3[N:16]([N:17]=[C:13]([C:11]4[CH:10]=[N:9][N:8]([CH2:7][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:30][CH:29]=5)[CH:12]=4)[CH:14]=3)[CH:18]=[CH:19]2)[CH:22]=1)=[O:37])#[N:32]
Reactant: COc1ccc(Cn2cc(-c3cc4n(-c5cc(N)ccc5C)ccn4n3)cn2)cc1
Reactant: N#Cc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Product: COc1ccc(Cn2cc(-c3cc4n(-c5cc(NC(=O)c6cc(C#N)cc(S(F)(F)(F)(F)F)c6)ccc5C)ccn4n3)cn2)cc1

Procedure:
80 mg (0.16 mmol) of the compound of Example 60A and 66 mg (0.24 mmol) of the compound of Example 23A were reacted with one another analogously to Example 48A. In deviation from the work-up described therein, here, the mixture was separated directly into its components by preparative HPLC (Method 21). The product-containing fractions were concentrated under reduced pressure and the residue was dried under high vacuum. This gave 84 mg (64% of theory, 80% pure) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:24]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:24]([O:25][CH:26]([CH3:28])[CH3:27])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: CC(C)Oc1cc2c(cc1Cl)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1cc2c(cc1Cl)[nH]c(=O)n2C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
A solution of 1,1-dimethylethyl 4-{5-chloro-6-[(1-methylethyl)oxy]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}-1-piperidinecarboxylate (D86, 140 mg, 0.34 mmol) in dichloromethane (3 ml) was treated with trifluoroacetic acid (3 ml) and stirred at room temperature under argon for 1 hr. The mixture was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate (×3). The combined extract was dried (MgSO4) and concentrated under vacuum to leave the title compound as a red oil (94 mg, 83%). M++H=310.0.
Reaction SMILES: [CH:1]1([C:6]2[NH:7][C:8]3[CH2:9][C:10]([CH3:36])([CH3:35])[CH2:11][C:12](=[O:34])[C:13]=3[CH:14]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:15]=2[C:16](=[O:27])[C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>ClCCl>[CH:1]1([C:6]2[C:15]([C:16](=[O:27])[C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:26])[F:24])=[CH:21][CH:22]=3)=[C:14]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[C:13]3[C:12](=[O:34])[CH2:11][C:10]([CH3:36])([CH3:35])[CH2:9][C:8]=3[N:7]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)CC(=O)C2=C(C1)NC(C1CCCC1)=C(C(=O)c1ccc(C(F)(F)F)cc1)C2C1CCCCC1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: CC1(C)CC(=O)c2c(nc(C3CCCC3)c(C(=O)c3ccc(C(F)(F)F)cc3)c2C2CCCCC2)C1
Temperature: 25 °C

Procedure:
3.13 g (6.3 mmol) of the compound from Example 1A are dissolved in 64 ml of dichloromethane, and 1.42 g (6.3 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) are added a little at a time at 0° C. With stirring, the mixture is warmed to room temperature over a period of 3 h. The mixture is concentrated on a rotary evaporator and the residue is purified by chromatography (silica gel, mobile phase: cyclohexane/ethyl acetate 5:1).