Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[C:8](=[O:17])[N:9]([CH3:16])[C:10](=[O:15])[N:11]([CH3:14])[C:12]=2[CH3:13])[CH:2]=1.[Br:19]Br>C(Cl)Cl.CC(C)=O>[Br:19][CH2:13][C:12]1[N:11]([CH3:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8](=[O:17])[C:7]=1[C:3]1[CH:2]=[C:1]([CH3:18])[CH:6]=[CH:5][CH:4]=1
Reactant: Cc1cccc(-c2c(C)n(C)c(=O)n(C)c2=O)c1
Reactant: BrBr
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cccc(-c2c(CBr)n(C)c(=O)n(C)c2=O)c1
Reaction time: 0.17 h
Yield: 101.2 %

Procedure:
In a 25 mL 2-neck round bottom flask equipped with a condenser, addition funnel and air lock, compound 3d (1.00 g, 3.67 mmol) was dissolved in CH2Cl2 (6 mL) and held at reflux. Bromine (200 μL, 0.624 g, 3.9 mmol) was mixed with CH2Cl2 (9 mL) in the addition funnel and added dropwise to the solution of 3d at such a rate that the color was discharged between drops. The last few drops caused the reaction to stay brown. The reaction continued for 10 min before the color was discharged by the addition of a few drops of acetone. TLC showed the reaction was quantitative. The reaction was dried in vacuo and the remaining solid crystallized from 2-propanol to yield 4d (1.20 g, 93%); m.p. 136.1-137° C. 1H NMR (600 MHz, CD2Cl2) δ 7.67 (s, 1H), 7.63 (d, J=7.8, 1H), 7.45 (d, J=7.5, 1H), 7.37 (t, J=7.6, 1H), 4.22 (s, 2H), 3.60 (d, J=6.6, 3H), 3.30 (d, J=7.7, 3H), 2.41 (s, 3H). 13C NMR (151 MHz, CD2Cl2) δ 193.00, 160.95, 152.09, 149.09, 139.30, 137.77, 135.37, 130.22, 129.04, 127.11, 115.04, 31.98, 28.62, 23.75, 21.55. MS (ES+) (m/z): [M+1]+ calculated for C15H16BrN2O3, 351.03. found 350.99.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([C:16]([N:18]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)=O)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CO>C(Cl)(Cl)Cl>[CH:11]1[C:12]2[C:13]3([CH2:16][N:18]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(N1CCC(O)CC1)C12CC(c3ccccc31)c1ccccc12
Solvent: CO
Solvent: ClC(Cl)Cl
Product: OC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 88 %

Procedure:
Using a procedure similar to that described in Example 82b except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylcarbonyl)piperidin-4-ol (described in Example 83b), the title compound was formed in 88% yield as a white solid TLC analysis (Rf 0.59, 10% methanol in chloroform). MS (CI, CH4) m/z 306 (M+1,100), 334 (M+29,14), 288 (62), 114(8)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH2:37]([C:39]1[C:40]([N:49]2[CH2:54][CH2:53][CH:52]([N:55]3[CH2:60][CH2:59][N:58]([S:61]([CH3:64])(=[O:63])=[O:62])[CH2:57][CH2:56]3)[CH2:51][CH2:50]2)=[CH:41][C:42]([O:46][CH2:47][CH3:48])=[C:43]([CH:45]=1)[NH2:44])[CH3:38].Cl>C(O)C(F)(F)F>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:44][C:43]3[CH:45]=[C:39]([CH2:37][CH3:38])[C:40]([N:49]4[CH2:50][CH2:51][CH:52]([N:55]5[CH2:56][CH2:57][N:58]([S:61]([CH3:64])(=[O:63])=[O:62])[CH2:59][CH2:60]5)[CH2:53][CH2:54]4)=[CH:41][C:42]=3[O:46][CH2:47][CH3:48])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH2:35][CH3:36]
Reactant: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(CC)cc1N
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cl
Solvent: OCC(F)(F)F
Product: CCOc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)c(CC)cc1Nc1nccc(-c2c(-c3ccc(OCC)c(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 170 °C
Yield: 64.3 %

Procedure:
A mixture of 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.10 g, 0.198 mmol), 5-ethyl-2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (Example 204, Step E) (0.081 g, 0.198 mmol) and HCl (4N,1,4-Dioxane, 0.099 mL, 0.395 mmol) in Trifluoroethanol (8 mL) was heated at 170° C. for 40 min in the microwave. The reaction was quenched with 7N NH3 in MeOH and then concentrated to dryness. The residue was then dissolved in DCM and concentrated onto silica gel. Purification by flash column chromatography followed by recrystallization from DCM and EtOH afforded the title compound N-(2,6-difluorophenyl)-5-(3-{2-[(5-ethyl-2-(ethyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}phenyl)amino]-4-pyrimidinyl}imidazo[1,2-a]pyridin-2-yl)-2-(ethyloxy)benzamide (0.112 g, 61%) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.75 (s, 1H), 9.26-9.40 (m, 1H), 8.40 (s, 1H), 8.27 (d, J=5.22 Hz, 1H), 8.07 (d, J=2.02 Hz, 1H), 7.77 (dd, J=8.57, 2.25 Hz, 1H), 7.71 (d, J=8.98 Hz, 1H), 7.59 (s, 1H), 7.33-7.51 (m, 2H), 7.27 (d, J=8.61 Hz, 1H), 7.15-7.24 (m, 2H), 6.88-6.98 (m, 1H), 6.81 (s, 1H), 6.60 (d, J=5.22 Hz, 1H), 4.21-4.34 (m, 2H), 4.07 (q, J=6.93 Hz, 2H), 3.07-3.17 (m, 4H), 2.97-3.06 (m, 2H), 2.87 (s, 3H), 2.59-2.77 (m, 6H), 2.55 (q, J=7.45 Hz, 2H), 2.37-2.46 (m, 1H), 1.79-1.90 (m, 2H), 1.53-1.68 (m, 2H), 1.44 (t, J=6.92 Hz, 3H), 1.26 (t, J=6.97 Hz, 3H), 1.10 (t, J=7.51 Hz, 3H). MS (M-2H, ES−) 878.
Reaction SMILES: CS[C:3]1[N:4]=[N:5][CH:6]=[CH:7][N:8]=1.[CH3:9][N:10]([CH2:12][CH2:13][NH2:14])[CH3:11]>C(O)(C)C>[CH3:9][N:10]([CH3:11])[CH2:12][CH2:13][NH:14][C:3]1[N:4]=[N:5][CH:6]=[CH:7][N:8]=1
Reactant: CN(C)CCN
Reactant: CSc1nccnn1
Solvent: CC(C)O
Product: CN(C)CCNc1nccnn1

Procedure:
3-Methylthio-1,2,4-triazine (19.1 g., 0.15 mole) and unsym-dimethylethylene diamine (35.2 g., 0.40 mole) are dissolved in 100 ml of isopropyl alcohol and the mixture is heated under reflux in a nitrogen atmosphere for five days. The solvent is removed under reduced pressure and the residue is distilled at 0.5 mm of Hg. 3-(2-Dimethylaminoethylamino)-1,2,4-triazine is collected at 168°-169° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25]/[CH:26]=[C:27](\[CH3:34])/[CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.O>ClCCl>[CH:2]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:4]=1[CH2:25]/[CH:26]=[C:27](\[CH3:34])/[CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:1]
Reactant: COC(=O)CC/C(C)=C/Cc1c(CO)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC/C(C)=C/Cc1c(C=O)c(C)c2c(c1OS(=O)(=O)c1ccc(C)cc1)C(=O)OC2

Procedure:
Methyl (E) 6-(1,3-dihydro-6-hydroxymethyl-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate (0.2 g) is dissolved in dichloromethane (10 ml) and pyridinium chlorochromate (0.15 g) is added. After one hour water (25 ml) is added. The organic solution is dried and evaporated and the residue is chromatographed on silica gel, eluting with hexane:ethyl acetate, to afford methyl (E) 6-(1,3-dihydro-6-formyl-7-methyl-3-oxo-4-p-toluenesulfonyloxyisobenzofuran-5-yl)-4-methyl-4-hexenoate.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].C(=O)([O-])O.[Na+].[Br:19]Br>CO>[Br:19][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([F:12])([F:13])[F:1]
Reactant: O=C(Nc1ccccc1)C(F)(F)F
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccccc1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of the N-trifluoroacetylaniline (2.00 mmol) and a sodium hydrogen carbonate (0.21 g, 2.50 mmol, 1.25 eq) in methanol (10 mL) at 0° C. is added dropwise bromine (0.113 mL, 2.19 mmol, 1.1 eq). The resulting reaction mixture is then stirred at 25° C. for 30 minutes. The reaction mixture is then evaporated under reduced pressure, and the residue is placed in water made acidic to pH 3 with HCl (10 mL). This aqueous mixture is extracted with ethyl acetate (3×15 mL). The extracts is combined, dried (MgSO4), and evaporated under reduced pressure. The residue is column chromatographed using silica gel (approximately 50 g) and elution with an appropriate solvent system to afford the corresponding 2-bromo-N-trifluoroacetylaniline.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:12]([O-])=O)[CH:11]=1)[NH:8][C:7](=[O:15])[CH:6]([NH:16][C:17](=[O:19])[CH3:18])[CH2:5]2.C([O-])=O.[NH4+].O>C(O)C.[Pd]>[NH2:12][C:10]1[CH:11]=[CH:2][CH:3]=[C:4]2[C:9]=1[NH:8][C:7](=[O:15])[CH:6]([NH:16][C:17](=[O:19])[CH3:18])[CH2:5]2
Reactant: CC(=O)NC1Cc2cc(Br)cc([N+](=O)[O-])c2NC1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(=O)NC1Cc2cccc(N)c2NC1=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 84.8 %

Procedure:
N-(6-Bromo-8-nitro-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide (15 g) was suspended in ethanol (150 mL), and ammonium formate (28.8 g) and 10% Pd—C (water content: 53%) (1.5 g) were added thereto. The mixture was heated at 80° C. while being stirred for 30 minutes, and water (150 mL) and ethanol (150 mL) were added thereto, followed by filtration while being heated. The filtrate was concentrated under reduced pressure, and the formed precipitates were recovered through filtration. The thus-obtained solid was washed with ethanol and diisopropyl ether, followed by drying, whereby the title compound (8.5 g) was yielded.
Reaction SMILES: N1C=CC=CC=1.[C:7]1([CH2:13][C:14]#[C:15][CH2:16]O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P(Br)(Br)[Br:19]>C1(C)C=CC=CC=1>[Br:19][CH2:16][C:15]#[C:14][CH2:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrP(Br)Br
Reactant: OCC#CCc1ccccc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: BrCC#CCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
14.5 ml of pyridine were added to a mixture of 140.4 g (0.96 mol) of 4-phenyl-2-butyn-1-ol (prepared according to G. Dupont, Bull. Soc. Chim. Fr., 1954, page 816) and 600 ml of dry toluene, after which 119.1 g (0.44 mol) of phosphorus tribromide were added dropwise in the course of 2 hours, the temperature not being allowed to exceed 50° C. The mixture was stirred overnight at room temperature and then poured onto 1,000 ml of ice water, the organic phase was separated off and the aqueous phase was extracted several times with methyl tert-butyl ether. The combined organic phases were then washed neutral and dried. The crude product obtained after the solvent had been stripped off under reduced pressure was subjected to fractional distillation. Yield: 126 g of product having a purity of 93% according to gas chromatography; bp.: 83°-85° C. at 0.3 mbar.
Reaction SMILES: [CH:1]1([C:4](=O)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.O.[NH2:10][NH2:11]>C(O)C>[CH:1]1([C:4]2[CH:5]=[C:6]([NH2:7])[NH:11][N:10]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: N#CCC(=O)C1CC1
Solvent: O
Solvent: CCO
Product: Nc1cc(C2CC2)n[nH]1
Yield: 80 %

Procedure:
5 g (0.046 mol) of 3-cyclopropyl-3-oxo-propanenitrile were dissolved in 200 ml of ethanol and 2.26 ml (0.046 mol) of hydrazine hydrate were added. The solution was maintained at reflux for 5 hours and then the solvent evaporated under vacuum. The residue was re-dissolved with methylene chloride and washed several times with brine. The organic layer was dried over anhydrous sodium sulfate and the solvent evaporated to give 4.53 g (80% yield) of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[C:5]([Cl:22])=[CH:4][N:3]=1.[CH2:23]([N:25]1[CH2:31][CH2:30][C:29]2[CH:32]=[C:33]([NH2:36])[CH:34]=[CH:35][C:28]=2[CH2:27][CH2:26]1)[CH3:24].Cl.C(=O)([O-])[O-]>COCCO.O1CCOCC1>[Cl:22][C:5]1[C:6]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[N:7][C:2]([NH:36][C:33]2[CH:34]=[CH:35][C:28]3[CH2:27][CH2:26][N:25]([CH2:23][CH3:24])[CH2:31][CH2:30][C:29]=3[CH:32]=2)=[N:3][CH:4]=1
Reactant: O=C(N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl)C(F)(F)F
Reactant: CCN1CCc2ccc(N)cc2CC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: COCCO
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NC(=O)C(F)(F)F)n3)cc2CC1
Temperature: 120 °C
Reaction time: 7 h
Yield: 45 %

Procedure:
N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-2,2,2-trifluoro-acetamide (204 mg, 0.571 mmol) was added into a Vial, followed by a solution of 3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (106 mg, 0.557 mmol) in 2-Methoxyethanol (7 mL). 4 M of Hydrogen chloride in 1,4-Dioxane (0.2 mL) was added and the reaction was heated at 120° C. After 7 h, the reaction was cooled to room temperature, Macroporous carbonate resin (3.16 mmol/g loading; 530 mg, 1.68 mmol) was added and stirred 30 min. The polymer was filtered off, and the solvent removed in vacuo. The residue was dissolved in DCM, then chromatographed (2×12 g SiO2, ISCO, 0-10% MeOH:DCM) to afford N-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-2,2,2-trifluoro-acetamide (128 mg, 45%) as a beige solid. m.p.=165° C.; LCMS (m/e) 511 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.98 (s, 1H), 7.94 (s, 1H), 7.32 (m, 2H), 7.08 (d, 1H, J=8.1 Hz), 6.93 (s, 1H), 5.27 (d, 1H, J=7.4 Hz), 3.99 (m, 1H), 3.87 (m, 1H), 3.68 (m, 3H), 3.11 (m, 2H), 2.7-2.9 (m, 4H), 2.30 (d, 1H, J=11.4 Hz), 2.16 (d, 1H, J=11.7 Hz), 1.8-1.9 (m, 2H), 1.2-1.6 (m, 8H).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[N+:20]([O-])([OH:22])=[O:21].O>C(O)(=O)C>[Br:1][C:2]1[CH:19]=[CH:18][C:5]([N:6]([CH3:17])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(C)c2ccc(Br)cc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(C)c2ccc(Br)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 62.7 %

Procedure:
4′-Bromo-N-methyl-p-toluenesulfonanilide (0.90 g (2.65 mmol)) was dissolved in 5.0 ml of acetic acid. To this, 97% fuming nitric acid (0.64 ml (15.0 mmol)) was added dropwise, and the mixture was heated at 100° C. for 1.5 hours with stirring, followed by cooling to room temperature. Then, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:3) as eluent, to give 0.64 g (63%) of the title compound as pale yellow crystals.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[CH:9][C:10]3[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:13]([CH2:21][CH3:22])[C:11]=3[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:29]([NH:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)(=[O:31])[CH3:30]>CN(C)C=O.O>[C:29]([NH:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[N:8]=[CH:9][C:10]4[C:16](=[O:17])[C:15]([C:18]([OH:20])=[O:19])=[CH:14][N:13]([CH2:21][CH3:22])[C:11]=4[N:12]=3)[CH2:6][CH2:5]2)=[CH:35][CH:34]=1)(=[O:31])[CH3:30]
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Reactant: CC(=O)Nc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(Cc4ccc(NC(C)=O)cc4)CC3)nc21
Yield: 80.7 %

Procedure:
To a suspension of 35.3 g of 2-(1-piperazinyl)-8-ethyl-5,8-dihydro-5-oxopyrido[2,3-d]pyrimidine-6-carboxylic acid in 500 ml of dimethylformamide was added a solution of 39.0 g of potassium carbonate in 50 ml of water and then 39.5 g of p-acetamidobenzyl bromide. The mixture was heated at 80°-90° C. for 1.5 hours with stirring. After removal of a small amount of the insoluble material by filtration, the filtrate was concentrated to dryness under reduced pressure and the residue was dissolved in 100 ml of water. The solution was adjusted to pH 7.0 with acetic acid. The precipitate was collected by filtration and recrystallized from a mixture of dimethylformamide and ethanol to give the product (42.3 g), m.p. 216.5°-219° C.
Reaction SMILES: [ClH:1].C(O[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1)=[NH:6])C.[NH3:34].C(O)C>>[ClH:1].[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[CH2:17][CH2:18][O:19][C:20]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)=[CH:23][C:21]=3[CH:22]=2)=[O:15])=[CH:9][CH:8]=1)(=[NH:34])[NH2:6]
Reactant: CCOC(=N)c1ccc(NC(=O)C2=Cc3cc(-c4ccc(C)cc4)ccc3OCC2)cc1
Reactant: N
Agent: Cl
Solvent: CCO
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(=N)N)cc2)CCO3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-[4-(ethoxycarbonimidoyl)phenyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide hydrochloride (364 mg) was added a solution of 14% ammonia/ethanol (5 ml). The resulting mixture was stirred at room temperature overnight and then at 50° C. for 3 hours. The reaction mixture was concentrated, the residue was suspended in ethyl acetate and 4 N hydrochloric acid/ethyl acetate was added. The precipitate was collected by filtration, was washed with ethyl acetate and further was recrystallized from acetonitrile/methanol/ethyl acetate to obtain N-(4-amidinophenyl)-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide hydrochloride (compound 42) (127 mg) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[CH:15]1([CH2:20][CH2:21][OH:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:20][CH2:21][O:22][C:2]2[CH:3]=[C:4]3[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]3[C:6](=[O:8])[N:7]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: OCCC1CCCC1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCCC3CCCC3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and 2-cyclopentylethanol.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:25][C:26](=[O:38])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:38]=[C:26]1[CH2:27][C:28]([C:30]2[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=2)[C:36]#[N:37])=[N:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[CH:10][C:9]=2[NH:25]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1NC(=O)CC(=O)c1cccc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cccc(C2=Nc3ccc(-c4ccc(OC(F)(F)F)cc4)cc3NC(=O)C2)c1

Procedure:
Prepared from {3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4′-trifluoromethoxy-biphenyl-4-yl}-carbamic acid tert.-butyl ester (Example K24) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow powder (23 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-])=O)[CH:20]=2)[N:15]([CH3:25])[CH:14]=1)[C:6]([O-:8])=[O:7].N[C:27]1C=C2C(=CC=1)NC=C2CC1C=CC(C(OC)=O)=CC=1OC>O1CCCC1.[Pd]>[NH2:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:25])[CH:14]=[C:13]2[CH2:12][C:11]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:27])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc(N)cc23)c(OC)c1
Reactant: COc1cc(C(=O)[O-])ccc1Cc1cn(C)c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cc2cn(C)c3ccc(N)cc23)c(OC)c1
Yield: 98 %

Procedure:
A solution of (E) (0.56 g.) in tetrahydrofuran (30 ml.) was hydrogenated in the presence of palladium-on-carbon (10% w/w: 0.1 g.), as described for the amino ester (A) in Example 1, to give methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (D) (0.50 g., 98%) as pale yellow foam: NMR: 3.6(s, H, NCH3), 3.8(s,3H, CO.OCH3), 3.9(br s,5H, OCH3 and CH2.Ar), 4.45(br,2H, NH2), 6.54(m,2H), 6.86(s,1H), 7.04(m,2H), 7.40(m,2H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[N:14][S:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:34]([O:38][CH3:39])(=[O:37])[CH:35]=[CH2:36]>CN(C=O)C>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:2](/[CH:36]=[CH:35]/[C:34]([O:38][CH3:39])=[O:37])=[C:3]([CH:4]=[O:5])[CH:6]=3)=[C:16]([C:17]([F:20])([F:19])[F:18])[S:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: C=CC(=O)OC
Reactant: O=Cc1cc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)cc1C=O
Temperature: 105 °C
Yield: 41.2 %

Procedure:
2-Bromo-5-((3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methoxy)benzaldehyde (300 mg, 0.63 mmol), dichlorobis(tri-o-tolyphosphine) palladium (35 mg, 0.045 mmol), potassium carbonate (174 mg, 1.26 mmol) in DMF (2 mL) was purged under reduced pressure and backfilled with argon gas. Methyl acrylate (0.114 mL, 1.26 mmol) was added and heated at 105° C. for 3 hrs. The reaction mixture was filtered through a pad of diatomaceous earth. The filtrate was washed with ethyl acetate. The organic layers were washed with water and brine, dried, filtered, and the filtrate was then concentrated. The resultant residue was purified by column chromatography on a 50 g silica gel column, eluting with 0-20% ethyl acetate/heptanes, to give compound 267b as a yellow solid (125 mg, 41% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[NH2:16][CH2:17][CH:18]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29])[C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20]>>[CH2:31]([O:30][C:28]([NH:27][CH:18]([C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:17][NH:16][C:13]([CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[CH2:8][CH2:9]1)=[O:14])=[O:29])[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: NCC(NC(=O)OCc1ccccc1)C(=O)N1CCCCC1
Product: O=C(NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1)OCc1ccccc1
Yield: 44 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 1-[-3-amino-2-(benzyloxycarbonylamino)propionyl]piperidine to give N-[2-(benzyloxycarbonylamino)-2-(piperidinocarbonyl)ethyl]-1-(4-pyridyl)piperidine-4-carboxamide in 44% yield;