Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:32][O:33]CC1C=CC=CC=1)[O:11][C@H:12]2[N:16]1[CH:31]=[CH:30][C:20]([NH:21]C(=O)C2C=CC=CC=2)=[N:19][C:17]1=[O:18])C1C=CC=CC=1.C1CC=CCC=1>CO.[Pd]>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:32][OH:33])[O:11][C@H:12]2[N:16]1[CH:31]=[CH:30][C:20]([NH2:21])=[N:19][C:17]1=[O:18]
Reactant: O=C(Nc1ccn([C@@H]2O[C@@]3(COCc4ccccc4)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)n1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: C1=CCC=CC1
Product: Nc1ccn([C@@H]2O[C@@]3(CO)CO[C@@H]2[C@@H]3O)c(=O)n1

Procedure:
To a solution of nucleoside 57 (0.3 g, 0.55 mmol) in anhydrous methanol (22 cm3) were added 1,4-cyclohexadiene (5.0 cm3) and 10% palladium on carbon (0.314 g). The mixture was stirred under reflux for 18 h. Additional 10% palladium on carbon (0.380 g) and 1,4-cyclohexadiene (5.5 cm3) were added and the mixture was refluxed for 54 h. The reaction mixture was filtered through a pad of silica gel which was subsequently washed with methanol (1500 cm3). The combined filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography using dichloromethane/methanol (92.5:7.5, v/v) as eluent to give compound 57A as a white solid material (0.051 g, 36%). δH ((CD3)2SO) 7.73 (1H, d, J 7.7, 6-H), 7.12-7.20 (2H, br s, NH2), 5.74 (1H, d, J7.7, 5-H), 5.61 (1H, br s, 3′-OH), 5.39 (1H, s, 1′-H), 5.12 (1H, m, 5′-OH), 4.08 (1H, s, 2′-H), 3.80 (1H, d, J 7.7, 1″-Ha), 3.81 (1H, s, 3′-H), 3.74 (2H, m, 5′-Ha, 5′-Hb), 3.63 (1H, d, J7.7, 1″-Hb). δC ((CD3)2SO) 165.66 (C-4), 154.58 (C-2), 139.68 (C-6), 93.19 (C-5), 88.42, 86.73 (C-1′, C-4′), 78.87, 70.85, 68.32, 56.04 (C-2′, C-1″, C-3′, C-5′). FAB-MS m/z 256 [M+H]+.
Reaction SMILES: C(OC(C1C(=O)N(CCC(C)C)N2C=CC=C2C=1O)=O)C.NC1C=CC(NS(C)(=O)=O)=CC=1S(N)(=O)=O.[CH3:38][S:39]([NH:42][C:43]1[CH:48]=[CH:47][C:46]([NH:49][C:50]([C:52]2[C:57](=[O:58])[N:56]([CH2:59][CH2:60][CH:61]([CH3:63])[CH3:62])[N:55]3[CH:64]=[CH:65][CH:66]=[C:54]3[C:53]=2[OH:67])=O)=[C:45]([S:68](=[O:71])(=[O:70])[NH2:69])[CH:44]=1)(=[O:41])=[O:40].N12CCCN=C1CCCCC2>N1C=CC=CC=1>[OH:67][C:53]1[C:54]2[N:55]([CH:64]=[CH:65][CH:66]=2)[N:56]([CH2:59][CH2:60][CH:61]([CH3:63])[CH3:62])[C:57](=[O:58])[C:52]=1[C:50]1[NH:49][C:46]2[CH:47]=[CH:48][C:43]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[CH:44][C:45]=2[S:68](=[O:71])(=[O:70])[N:69]=1
Reactant: CC(C)CCn1c(=O)c(C(=O)Nc2ccc(NS(C)(=O)=O)cc2S(N)(=O)=O)c(O)c2cccn21
Agent: CCOC(=O)c1c(O)c2cccn2n(CCC(C)C)c1=O
Agent: CS(=O)(=O)Nc1ccc(N)c(S(N)(=O)=O)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)c(O)c2cccn21
Temperature: 120 °C
Reaction time: 3 h
Yield: 9.7 %

Procedure:
4-Hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (Example 1f, 0.098 g, 0.33 mmol) and 2-amino-5-methanesulfonylamino-benzenesulfonamide (Example 3d or Example 3d′, 0.089 g, 0.33 mmol) were mixed in pyridine (1.5 mL) and the mixture was stirred under a nitrogen atmosphere at 120° C. for 3 h. LC-MS analysis confirmed the disappearance of the starting material and the formation of the uncyclized intermediate 4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid (4-methanesulfonylamino-2-sulfamoyl-phenyl)-amide. 1,8-Diazabicyclo[5,4,0]undec-7-ene (DBU) (150 μL, 1.0 mmol) was added and the mixture was stirred under nitrogen atmosphere at 120° C. for 16 h. LC-MS analysis indicated completion of the reaction and the mixture was concentrated in vacuo. The crude material was dissolved in dimethylsulfoxide and purified by preparative HPLC (Column ODS-A 100 Å, 5μ. 150×21.2 mm. Flow 22 mL/min, 30-100% acetonitrile/water with 0.01% trifluoroacetic acid) and lyophilized from water and 1,4-dioxane to afford the desired product, N-{3-[4-hydroxy-1-(3-methyl-butyl)-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-methanesulfonamide (0.016 g, 0.032 mmol, 9.7% yield) as a light brown powder. 1H NMR (DMSO-d6) δ 0.96 (6H, d, J=6.3 Hz), 1.55-1.60 (2H, m), 1.67-1.77 (1H, m), 3.07 (1H, s), 4.40 (2H, t, J=7.8 Hz), 6.70 (1H, s), 7.02 (1H, s), 7.52-7.67 (3H, m), 7.90 (1H, s), 10.20 (1H, s); LC-MS (ESI) calcd for C20H23N5O6S2 493.1 found 494.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.BrN1C(=O)CCC1=O.C(#N)N(C)C>C(OC)(=O)CC.[Hg]>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:9][CH:10]=1)[C:6](=[O:8])[O:7][CH2:11]2
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: O=C1CCC(=O)N1Br
Agent: [Hg]
Solvent: CCC(=O)OC
Solvent: CN(C)C#N
Product: O=C1OCc2cc(Br)ccc21
Reaction time: 1 h

Procedure:
A solution of 0.43 g (2.0 mmol) of 4-bromo-2-methyl-benzoic acid, 0.34 g (1.9 mmol) of N-bromosuccinimide and 20 mg of azaisobutyronitrile in 7 ml of methyl propionate is heated to boiling for 1 hour under a nitrogen atmosphere and irradiated with a mercury vapour lamp. The reaction mixture is concentrated, taken up in methylene chloride, washed with H2O, dried with Na2SO4 and purified by flash chromatography (silica gel; ethyl acetate/petroleum ether=5:95 to 15:85).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[N:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]2[C:5]=1[NH:11][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:48]([CH3:50])([CH3:49])[CH:47]2[OH:51])=[O:20]
Reactant: COC(=O)c1cc(Cl)ccc1N=Cc1cccc(Br)c1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(Br)c1)C(C)(C)C2O
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred mixture solution of 2-[(3-bromo-benzylidene)-amino]-5-chloro-benzoic acid methyl ester (39.8 g, 113.2 mmol) and ytterbium(III) triflate hydrate (10.5 g, 16.9 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (10.4 mL, 113.2 mmol) and water (2.1 mL, 113.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-6-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (48 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrClNO3 (M+H)+: 425.73, observed: 405.9 & 407.9.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:12]2[O:13][C:14]3[C:23]([CH3:24])=[CH:22][C:21]([C:25]([OH:27])=[O:26])=[CH:20][C:15]=3[S:16](=[O:19])(=[O:18])[CH2:17][C:11]=2[CH:10]=[C:9]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:8]=1.Cl.[CH:35](O)([CH3:37])[CH3:36]>>[ClH:6].[CH:35]([O:26][C:25]([C:21]1[CH:22]=[C:23]([CH3:24])[C:14]2[O:13][C:12]3[C:7]([Cl:6])=[CH:8][C:9]([N:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)=[CH:10][C:11]=3[CH2:17][S:16](=[O:18])(=[O:19])[C:15]=2[CH:20]=1)=[O:27])([CH3:37])[CH3:36]
Reactant: CC(C)O
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N3CCNCC3)cc1CS2(=O)=O
Agent: Cl
Agent: O=S(=O)(O)O
Product: Cc1cc(C(=O)OC(C)C)cc2c1Oc1c(Cl)cc(N3CCNCC3)cc1CS2(=O)=O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Concentrated sulphuric acid (1 mL) was added dropwise to a stirred solution of compound of Example 18 (0.5 g, 1.18 mmol) in dry isopropanol (50 mL) at 90° C. The reaction mixture was stirred at 90° C. for 2 h. Solvent was removed and the residue was taken in chloroform (100 mL) and this was neutralized using sodium carbonate solution (10%). Chloroform layer was washed with water, brine and dried over sodium sulphate. Solvent was removed and the product obtained was converted to hydrochloride salt by using isopropanol/ethereal-HCl to obtain the title compound. Yield: 0.4 g (67.79%); mp: 262-64° C.; 1H NMR (DMSO-d6, 300 MHz): δ 1.29 (d, 6H, 2CH3), 2.63 (s, 3H, CH3), 3.18 (bs, 4H, 2CH2), 3.44 (bs, 4H, 2CH2), 5.11(s, 1H, CH), 5.17 (s, 2H, CH2), 7.19 (s, 2H, Ar), 8.07 (s, 1H, Ar), 8.11 (s, 1H, Ar), 9.45 (bs, 2H, NH, HCl); MS: m/e (ES+) 465 (M+1, free base).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH2:9])=[N:6][C:7]=1[Cl:8].[Na].[C:14](Cl)(=[O:16])[CH3:15]>>[Cl:1][C:2]1[N:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]([NH:9][C:14](=[O:16])[CH3:15])=[N:6][C:7]=1[Cl:8]
Reactant: CC(=O)Cl
Reactant: Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Agent: [Na]
Product: CC(=O)Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]

Procedure:
To 1.0 g of 5,6-dichloro-3-nitropyrazinamine in 15 ml acetyl chloride under nitrogen atmosphere at room temperature is added 0.84 g anhydrous sodium bicarabonate. The reaction mixture is then stirred and heated at reflux for 4 days. Excess acetyl chloride is then removed in vacuo and the residue is chromatographed on silica gel. The desired product is eluted from the column with chloroform.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([B:19]2[O:27][C:24]([CH3:26])([CH3:25])[C:21]([CH3:23])([CH3:22])[O:20]2)=[CH:15][CH:14]=1.[OH-].[Na+]>CO>[CH3:25][C:24]1([CH3:26])[C:21]([CH3:22])([CH3:23])[O:20][B:19]([C:16]2[CH:15]=[CH:14][C:13]([CH2:12][O:1][NH:2][C:3](=[O:10])[C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:18][CH:17]=2)[O:27]1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Reactant: O=C(NO)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)OB(c2ccc(CONC(=O)c3ccccc3)cc2)OC1(C)C
Temperature: 25 °C
Yield: 6 %

Procedure:
N-hydroxybenzamide (0.17 g, 1.2 mmol) was dissolved in 8 mL of MeOH followed by the addition of 4-bromomethylphenyl boronic acid pinacol ester (0.40 g, 1.30 mmol). A 40% aqueous solution of NaOH (2 mL) was then added dropwise and the reaction was left to stir at reflux overnight. After cooling to room temperature and concentrated, concentrated HCl was added until a pH of 1 was observed. The resulting solution was then extracted with EtOAc and washed with brine. The organic layer was collected and dried over MgSO4 then purified via silica gel chromatography affording B16 in 6% yield (0.03 g, 0.07 mmol). 1HNMR (400 MHz, CDCl3) δ=8.61 (br, 1H, NH), 7.83 (d, J=8 Hz, 2H), 7.64 (d, J=7.6 Hz, 2H), 7.51-7.37 (m, 5H), 5.04 (s, 2H), 1.35 (s, 12H). 13C NMR (100 MHz, CDCl3) δ=166.67, 138.45, 135.32, 132.35, 132.10, 128.95, 128.72, 127.25, 84.18, 78.45, 25.10. ESI-MS(+): m/z 354.10 [M+H]+, 376.10 [M+Na]+.
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].C[C:21]([N:23](C)C)=O>CCOC(C)=O.[Fe-4](C#N)(C#N)(C#N)(C#N)(C#N)C#N.[K+].[K+].[K+].[K+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH:5]=[CH:4][CH:3]=[C:2]2[C:21]#[N:23]
Reactant: COc1cccc2c(I)cccc12
Reactant: CC(=O)N(C)C
Agent: N#C[Fe-4](C#N)(C#N)(C#N)(C#N)C#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: COc1cccc2c(C#N)cccc12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 1-iodo-5-methoxynapthalene (J. A. O'Meara et al., J. Med. Chem., 2005, 48, 5580-5588 1.104 g, 3.89 mmol) in dimethylacetamide (6 mL) at rt under nitrogen, was added potassium ferrocyanide (494 mg, 1.17 mmol), Na2CO3 (412 mg, 3.89 mmol) and palladium acetate (43 mg, 0.19 mmol). The reaction mixture was stirred at 120° C. for 3 h, cooled, diluted with EtOAc (100 mL) and filtered through Celite. The organic phase was washed with water (30 mL), NaHCO3 (30 mL), brine (30 mL) and dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (isohexane:EtOAc, 90:10 to 85:15) to give the title compound: RT=3.64 min; m/z (ES+)=184.0 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].[Na+].[Cl-].P([O-])([O-])([O-])=[O:12].[K+].[K+].[K+]>>[C:1]([NH2:2])(=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: N#Cc1cccnc1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Product: NC(=O)c1cccnc1
Temperature: 30 °C
Reaction time: 0.17 h

Procedure:
A reaction mixture comprising 3-cyanopyridine 20 (0.1-1.0 M; 1.0-1.8 ml), aqueous NaCl solution (0.85% (w/v); 0.7 to 0.1 ml), potassium phosphate buffer (0.1 M; pH 7.0; 0.3 ml) and cell suspension (0.01 ml) was incubated with shaking at 30° C. for 10 min. The total volume of the reaction mixture was between 2.0 to 2.2 ml, depending on the 3-cyanopyridine concentration. The reaction was stopped by adding HC1(2 M; 0.1 ml). After centrifugation of the reaction mixture (12 000 rpm; 5 min), the amount of nicotinamide produced was determined by means of HPLC according to Example 1. The KM value determined was 160 mM (FIG. 10).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([CH2:12][CH2:13][CH2:14]OS(C)(=O)=O)[C:8]1=[O:28].I.[CH2:37]([O:39][C:40]([CH2:42][N:43]1[C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=2[N:45]=[C:44]1[NH:52][CH:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1)=[O:41])[CH3:38].C(N(CC)CC)C>C(#N)C.ClCCl>[CH3:35][O:34][C:30]1[CH:29]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:31]=1[O:32][CH3:33])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][CH2:14][N:56]2[CH2:57][CH2:58][CH:53]([NH:52][C:44]3[N:43]([CH2:42][C:40]([O:39][CH2:37][CH3:38])=[O:41])[C:47]4[CH:48]=[CH:49][CH:50]=[CH:51][C:46]=4[N:45]=3)[CH2:54][CH2:55]2)([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:8]1=[O:28]
Reactant: COc1cc(CN2CCC(CCCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Reactant: CCOC(=O)Cn1c(NC2CCNCC2)nc2ccccc21
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)Cn1c(NC2CCN(CCCC3(Cc4ccc(F)cc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21
Reaction time: 12 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(3-methanesulfonyloxypropyl)-2-oxopyrrolidine (0.35 g, 0.68 mmol), (1-(ethoxycarbonylmethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt (0.38 g, 0.68 mmol), and triethylamine (0.276 g, 2.72 mmol) in acetonitrile (15 mL). Heat to reflux. After 12 hours, cool the reaction mixture, dilute with dichloromethane, and extract with brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with 5% methanol/0.5% concentrate aqueous ammonium hydroxide/dichloromethane to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]4[N:21]=[CH:22][CH:23]=[CH:24][C:12]=4[N:11]3[C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([C:32]3([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)[CH:5]=[CH:6][CH:7]=1.[ClH:44].O1CCOCC1>C(Cl)Cl>[ClH:44].[ClH:44].[ClH:44].[ClH:44].[NH2:36][C:32]1([C:29]2[CH:28]=[CH:27][C:26]([C:25]3[N:11]4[C:12]5[CH:24]=[CH:23][CH:22]=[N:21][C:13]=5[NH:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[C:10]4=[N:9][C:8]=3[C:4]3[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=3)[NH2:1])=[CH:31][CH:30]=2)[CH2:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4cccc(N)c4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1cccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 83.8 %

Procedure:
tert-Butyl (1-{4-[2-(3-aminophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (40.0 mg, 0.0701 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 15.5 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (36.2 mg, 83.8%) as pale red solid. 1H-NMR (DMSO-d6) 400 MHz δ: 8.78 (br s, 2H), 8.63 (s, 1H), 8.11 (dd, J=4.8, 1.6 Hz, 1H), 7.96-7.92 (m, 1H), 7.60-7.48 (m, 3H), 7.42-7.09 (m, 8H), 6.93 (dd, J=8.2, 1.4 Hz, 1H), 6.75 (dd, J=7.8, 4.6 Hz, 1H), 2.65-2.48 (m, 4H), 2.27-2.13 (m, 1H), 1.90-1.76 (m, 1H); LCMS: 471 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][NH:15][C:16](=O)[CH3:17])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1.C([O-])(O)=O.[Na+].C(Cl)Cl>COCCOC>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][NH:15][C:16](=[S:28])[CH3:17])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(=O)NCc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(=S)NCc1cn(-c2ccc(Cl)c(Cl)c2)cn1

Procedure:
To a suspension of N-[1-(3,4-dichloro-phenyl)-1H-imidazol-4-ylmethyl]-acetamide (1.1 g, 3.7 mmol) in 1,2 dimethoxyethane (11 ml) was added Lawesson's reagent (0.82 g, 2.0 mmol) and the mixture refluxed for 90 min. After addition of saturated NaHCO3 solution (50 ml) and extraction with CH2Cl2 (3×100 ml) the combined organic phases were dried (Na2SO4), concentrated and the obtained crude product was chromatographed [silica, elution with gradient CH2Cl2 to 100% (CH2Cl2/MeOH=9:1)]. The title compound was obtained as a brown crystalline material (0.75 g, 68%). Mp. 166-170° C. (MeOH/CH2Cl2), MS: m/e=299 (M+).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[CH:10]=[C:11]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[CH:21][CH:22]=3)[N:17]([C:32]3[N:37]=[CH:36][N:35]=[C:34]([NH:38][CH3:39])[CH:33]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:20]2[CH:19]=[C:18]3[C:23]([C:15]([C:11]4[CH:10]=[C:9]([NH:8][C:1](=[O:3])[CH3:2])[CH:14]=[CH:13][CH:12]=4)=[CH:16][N:17]3[C:32]3[CH:33]=[C:34]([NH:38][CH3:39])[N:35]=[CH:36][N:37]=3)=[CH:22][CH:21]=2)=[CH:29][CH:28]=1
Reactant: CC(=O)OC(C)=O
Reactant: CNc1cc(-n2cc(-c3cccc(N)c3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNc1cc(-n2cc(-c3cccc(NC(C)=O)c3)c3ccc(-c4ccc(OC)cc4)cc32)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
Acetic anhydride (20.3 μL, 0.214 mmol) was added to a mixture solution of 6-(3-(3-aminophenyl)-6-(4-methoxyphenyl)-1H-indol-1-yl)-N-methylpyrimidin-4-amine (30 mg, 0.071 mmol) and pyridine (28.7 μL, 0.355 mmol) in methylene chloride (2 mL) at room temperature. After stirring for 1 hour at room temperature, the reaction solution was added to saturated sodium bicarbonate aqueous solution and then extracted with ethyl acetate. The collected organic layer was washed with brine and concentrated under reduced pressure by drying with anhydrous magnesium sulfate. The residue was purified by chromatography (preparative HPLC). The target compound (15 mg) was obtained as white solid.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][NH:7][CH2:8][C:9]1[C:10]([N:20]([CH2:23][CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH2:21][CH3:22])=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19].[Br:37][C:38]1[CH:39]=[N:40][C:41](Cl)=[N:42][CH:43]=1.[F-].[K+].O>CN(C)C=O.CCOC(C)=O>[F:36][C:2]([F:35])([F:1])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[CH2:6][N:7]([CH2:8][C:9]1[C:10]([N:20]([CH2:23][CH:24]2[CH2:27][CH2:26][CH2:25]2)[CH2:21][CH3:22])=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:19])[C:41]1[N:42]=[CH:43][C:38]([Br:37])=[CH:39][N:40]=1
Reactant: CCN(CC1CCC1)c1nc2c(C)cccc2cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Clc1ncc(Br)cn1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN(CC1CCC1)c1nc2c(C)cccc2cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
A mixture of {3-[(3,5-bis-trifluoromethyl-benzylamino)-methyl]-8-methyl-quinolin-2-yl}-cyclobutylmethyl-ethyl-amine (0.23 g, 0.46 mmol), 5-bromo-2-chloropyrimidine (0.09 g, 0.46 mmol), and potassium fluoride (0.11 g, 1.8 mmol) in dimethyl formamide (10 ml) was heated at 80° C. overnight. After cooling the reaction to ambient temperature water (10 mL) and EtOAc (20 mL) were added and stirred for 0.5 h. Thereafter, the organic layer was separated, washed with brine, dried over sodium sulfate, filtered and solvent evaporated in vacuo. The crude was purified by chromatography using silica gel to afford the title compound as a colorless liquid (0.14 g, 47%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.Cl.Cl.[NH2:13][CH:14]([CH2:23][CH3:24])[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:16].C(=O)([O-])O.[Na+]>O1CCCC1.C(N(CC)CC)C>[CH:1]([NH:13][CH:14]([CH2:23][CH3:24])[C:15]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)=[O:16])=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: CCC(N)C(=O)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(NC=O)C(=O)c1cccnc1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To acetic anhydride (2.39 ml) was added dropwise formic acid (0.97 ml) under ice-cooling, and the mixture was stirred at 50° C. for 30 minutes. The mixture was ice-cooled again, and diluted with tetrahydrofuran (9 ml). To the mixture were added 2-amino-1-(3-pyridyl)-1-butanone dihydrochloride (600 mg) and triethylamine (1.41 ml), and the mixture was stirred under ice-cooling for 1.5 hours. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was triturated with ethyl acetate-diethyl ether to obtain 2-formylamino-1-(3-pyridyl)-1-butanone (440 mg) as colorless powder.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=1/[CH:28]=[CH:29]/[C:30](O)=[O:31]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:30](=[O:31])/[CH:29]=[CH:28]/[C:21]3[C:22]([F:27])=[CH:23][CH:24]=[C:25]([F:26])[C:20]=3[Cl:19])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1c(F)ccc(F)c1Cl
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3c(F)ccc(F)c3Cl)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(2-chloro-3,6-difluoro-phenyl)-acrylic acid.