Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:12][N:13]([CH3:27])[CH:14]1[CH2:19][CH2:18][C:17]([C:20]2[N:25]=[C:24]([NH2:26])[CH:23]=[CH:22][CH:21]=2)=[CH:16][CH2:15]1>>[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:26][C:24]1[CH:23]=[CH:22][CH:21]=[C:20]([C:17]2[CH2:18][CH2:19][CH:14]([N:13]([CH3:27])[CH3:12])[CH2:15][CH:16]=2)[N:25]=1)=[O:5]
Reactant: CN(C)C1CC=C(c2cccc(N)n2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Product: CN(C)C1CC=C(c2cccc(NC(=O)c3ccc(F)cc3Cl)n2)CC1
Product: Cl
Yield: 78 %

Procedure:
Using a method similar to example 1, using 2-chloro-4-fluoro-benzoyl chloride (116 mg, 0.60 mmol) and 6-(4-dimethylamino-cyclohex-1-enyl)-pyridin-2-ylamine, isomer 1 (preparation 10, 100 mg, 0.46 mmol) provides of the title compound as a colorless oil (135 mg, 78%): MS (ES): m/z=374.1 (M+H)+; 1HNMR (CDCl3): δ 8.80 (s, br, 1H), 8.19 (d, 1H), 7.69 (m, 2H), 7.18 (m, 2H), 7.05 (m, 1H), 6.64 (m, 1H), 2.70 (m, 1H), 2.46 (m, 3H), 2.36 (s, 6H), 2.16 (m, 2H), 1.54 (m, 1H). Di-hydrochloride salt: Anal. cal'd for C20H21ClFN3O.2HCl: C, 53.77; H, 5.19; N, 9.41. Found: C, 54.13; H, 5.34; N, 9.41.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[I:12](O)(=O)(=O)=O.S(=O)(=O)(O)O.II>O.C(O)(=O)C>[I:12][C:7]1[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][C:1]([OH:11])=[O:10])=[CH:9][CH:8]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])O
Agent: II
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CCc1ccc(I)cc1
Temperature: 105 °C
Yield: 460.8 %

Procedure:
Hydrocinnamic acid is iodinated to form 4-iodohydrocinnamic acid. The process is performed by mixing 201.2 g hydrocinnamic acid, 1 L acetic acid, 152 mL water, 52.8 g periodic acid, 76 mL sulfuric acid, and 144 g iodine. The mixture is heated at 105° C. for 6.5 hours. Next, 200 mL water is added, and the mixture is cooled to room temperature overnight. The solid product in the resultant mixture is filtered and washed with water, yielding 350 g unpurified 4-iodohydrocinnamic acid. Further purification is not necessary and is not conducted, and the product is used as is in the second step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.[C:15]([O:24][CH3:25])(=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH2:18].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([NH:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[C:15]([O:24][CH3:25])=[O:23])=[O:14])=[CH:2]1
Reactant: COC(=O)c1ccccc1N
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1NC(=O)CCc1c[nH]c2ccccc12
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
To a solution of 3-(3-indolyl)propionic acid (6.0 g, 32 mmol) in 100 ml THF at room temperature was added 1,1-carbonyldiimidazole (5.14 g, 32 mmol). The reaction mixture was stirred under a dry atmosphere for 30 minutes, after which methyl anthranilate (4.79 g, 32 mmol) was added, and the reaction mixture was stirred at reflux for 30 minutes. No reaction was detected by thin layer chromatography (TLC). Pyridinium p-toluenesulfonate (PPTS) [6.36 g, 25 mmol] was added, and the mixture was stirred at reflux for two days. The reaction mixture was allowed to cool, and the solvent was removed in vacuo. The resulting product was taken up in ethyl acetate and washed (lN HCl, H2O, saturated NaHCO3, and brine) and dried over anhydrous magnesium sulfate. Concentration in vacuo provided a light yellow solid which, when triturated with ethyl acetate/hexane, gave, upon filtration, 7.19 g (70% yield) of 3-(3-indolyl)-N-(2-methoxycarbonylphenyl)propionamide as an off white granular solid.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.CO>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:23]4[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=[C:21]([C:20]([F:19])([F:35])[F:34])[CH:22]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc(C(F)(F)F)cc(C(F)(F)F)c4)cc3CC[C@@H]12
Yield: 67.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 3,5-bis(trifluoromethyl)phenylboronic acid (213 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL of methanol, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 194 mg (68%) of the title compound as a white solid. mp 110°-112°. FDMS: m/e=441 α[D]589 =+80.70 (c=1.05, methanol).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1)=[CH2:2].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>CCCCCC>[CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(CCl)cc1
Reactant: C1CCNC1
Solvent: CCCCCC
Product: C=Cc1ccc(CN2CCCC2)cc1
Temperature: 0 °C

Procedure:
A 1 L (liter) round bottom flask was charged with hexane (400 mL) and 4-vinylbenzyl chloride (104.4 g, 0.68 moles). The reaction flask was placed into an ice/water bath and stirred with a magnetic stir bar. Two equivalents of pyrrolidine (130 g, 1.37 moles) were added over the course of 1 hour. After completed addition the ice/water bath was removed and the reaction was stirred at room temperature overnight. Solids were removed via vacuum filtration and volatiles were removed under vacuum to render the product in quantitative yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.Cl[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])[CH:6]=[CH:5]2
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: OCCCCCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: OCCCCCCOc1ccc2cc(Br)ccc2c1
Temperature: 65 °C

Procedure:
A mixture of 5 g of 6-bromo-2-naphthol, 50 ml of dimethyl sulphoxide, 3.3 ml of 6-chlorohexanol, 7.1 g of potassium iodide and 7.1 g of potassium carbonate (ground and activated at 80° C. in a high vacuum) was heated to 65° C. for 16 hrs. Then, the mixture was cooled, partitioned between ethyl acetate and water, and the organic phase was washed several times with water, dried over magnesium sulphate, filtered and evaporated. Chromatography of the residue on 200 g of silica gel with toluene/ethyl acetate (3:1) and subsequent crystallization form toluene/hexane (8:1) gave 5.2 g of 6-bromo-2-(6-hydroxyhexyloxy)naphthalene as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[CH2:25][CH2:24][N:10]3[C:11](=[O:23])[N:12]([CH:17]4[CH2:22]CSC[CH2:18]4)[C:13](=[O:16])[C:14]([OH:15])=[C:9]3[C:8]2=[O:26])=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:34].[CH3:40][S:41]([CH3:43])=[O:42]>ClCCl>[O:42]=[S:41]1(=[O:34])[CH2:43][CH2:22][CH:17]([N:12]2[C:13](=[O:16])[C:14]([OH:15])=[C:9]3[C:8](=[O:26])[N:7]([CH2:6][C:5]4[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=4)[CH2:25][CH2:24][N:10]3[C:11]2=[O:23])[CH2:18][CH2:40]1
Reactant: CS(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1c2c(O)c(=O)n(C3CCSCC3)c(=O)n2CCN1Cc1ccc(F)cc1
Solvent: ClCCl
Product: O=C1c2c(O)c(=O)n(C3CCS(=O)(=O)CC3)c(=O)n2CCN1Cc1ccc(F)cc1
Reaction time: 1 h

Procedure:
To a solution of 2-(4-fluorobenzyl)-9-hydroxy-7-tetrahydro-2H-thiopyran-4-yl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,6,8(7H)-trione (30 mg, 0.074 mmol, Example 36). in dichloromethane (2 mL) was added 3-Chloroperoxybenzoic acid (38 mg, 0.165 mmol). The reaction was stirred at room temperature and after one hour DMSO was added (0.2 mL). After stirring for one hour, the dichloromethane was evaporated under a stream of nitrogen and the reaction was diluted with water and aq. NaHCO3. The precipitated product was collected by filtration and rinsed with water and diethyl ether. Drying under high vacuum provided the title compound. 1H NMR (400 MHz, CDCl3) δ 11.8 (s, 1H), 7.3 (m, 2H), 7.07 (t, J=8.6 Hz, 2H), 5.07 (tt, J=12.0, 3.2 Hz, 1H), 4.69 (s, 2H), 4.00 (t, J=5.6 Hz, 2H), 3.53 (t, J=5.6 Hz, 2H), 3.35 (m, 2H), 3.16 (m, 4H), 1.95 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[CH3:20][CH2:21][CH:22]([Mg]Br)[CH2:23][CH3:24].CCOCC.[NH4+].[Cl-]>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([OH:14])[CH:22]([CH2:23][CH3:24])[CH2:21][CH3:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(CC)[Mg]Br
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(CC)[C@@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C

Procedure:
(S)-3-Formylpyrrolidine-1-carboxylic acid t-butyl ester (0.8 g, 3.8 mmol;) and THF (8 mL, 90 mmol) were combined under nitrogen, and the resulting solution was cooled to −78° C. 2M 3-Pentylmagnesium bromide in ether (4.70 mL, 9.4 mmol) was then added dropwise over 1 hour. The mixture was allowed to warm to room temperature slowly overnight. Then aqueous saturated NH4Cl (5 mL) was added dropwise to quench the reaction. The resulting mixture was extracted with EtOAc (2×25 mL), and the combined organic layers were washed with saturated aqueous NaHCO3 (25 mL) and saturated aqueous NaCl (25 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (5-25% EtOAc in Hexanes) to yield the following as clear oils:
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:25])[NH:7][CH:8]([CH3:24])[C:9](=[O:23])[NH:10][CH:11]1[CH2:15][CH2:14][N:13](CC2C=CC=CC=2)[CH2:12]1)([CH3:4])[CH3:3].[H][H]>CO.[Pd]>[CH3:4][C:2]([O:5][C:6](=[O:25])[NH:7][CH:8]([CH3:24])[C:9](=[O:23])[NH:10][CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)([CH3:1])[CH3:3]
Reactant: [H][H]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)NC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(NC(=O)OC(C)(C)C)C(=O)NC1CCNC1
Yield: 97.2 %

Procedure:
A solution of 6.9 g (20 mmol) of [1-methyl-2-oxo-2-[(1-(phenylmethyl)-3-pyrrolidinyl)amino]ethyl]-carbamic acid 1,1-dimethylethyl ester in 100 ml of methanol was treated with 1.0 g of 20% palladium on carbon and shaken in a hydrogen atmosphere at pressures of 33.6 to 52.7 psi and temperatures of 23.5°-27.0 for 18 hours. The catalyst was removed by filtration and the solvent evaporated to give 5.0 g of the title compound as a viscous liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Yield: 93.6 %

Procedure:
To a solution of 1-t-butoxycarbonyl-4-hydroxypiperidine (50.1 g) in N,N-dimethylacetamide (550 ml) was added sodium hydride (10.5 g) with stirring under ice-cooling, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, to the reaction mixture was added dropwise a solution of 4-fluoronitrobenzene (42.2 g) in N,N-dimethylacetamide (100 ml) with stirring at the same temperature, and the resulting mixture was furthermore stirred at room temperature overnight. After stirring, to the reaction mixture was added water and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (13:7) as the eluent to afford the title compound (75.1 g, yield: 93%) as a pale yellow solid.
Reaction SMILES: C(O)(=O)C.Cl.[Cl:6][C:7]1[CH:16]=[C:11]([C:12]([NH:14][OH:15])=[O:13])[C:10]([OH:17])=[CH:9][CH:8]=1.C(O[CH:21](OCC)[CH2:22][CH2:23][CH2:24][Cl:25])C>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[O:17][CH:21]([CH2:22][CH2:23][CH2:24][Cl:25])[N:14]([OH:15])[C:12](=[O:13])[C:11]=2[CH:16]=1
Reactant: CCOC(CCCCl)OCC
Reactant: O=C(NO)c1cc(Cl)ccc1O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2cc(Cl)ccc2OC(CCCCl)N1O
Reaction time: 8 h

Procedure:
6-Chloro-2-(3-chloropropyl)-2,3-dihydro-3-hydroxy-4H-1,3-benzoxazin-4-one was prepared by adding 250 ml. of glacial acetic acid saturated with hydrogen chloride gas to 37 g. of 5-chlorosalicylhydroxamic acid. 4-Chlorobutyraldehyde diethyl acetal (34 g.) and 50 ml. of glacial acetic acid saturated with hydrogen chloride gas were then added simultaneously with stirring at a rate to maintain a temperature of 25° to 40° C. The resulting mixture was stirred and heated at 55° to 60° C. for 2 hours and then allowed to stand at room temperature overnight. Mixture was poured into a mixture of ice and water, and when oil solidified it was removed by filtrating, washed with water, and air-dried. The crude product weighed 31.5 g. and melted at 70°-75° C. A sample recrystallized from ligroin at 80°-81° C.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([CH2:11][C:12]#[N:13])[CH:5]=1)#[N:2].Cl.N[C:16]1[C:21]([F:22])=[C:20]([F:23])[CH:19]=[C:18]([F:24])[C:17]=1[SH:25]>>[F:22][C:21]1[C:16]2[N:2]=[C:1]([CH2:3][C:4]3[CH:5]=[C:6]([CH2:11][C:12]#[N:13])[CH:7]=[C:8]([Cl:10])[CH:9]=3)[S:25][C:17]=2[C:18]([F:24])=[CH:19][C:20]=1[F:23]
Reactant: N#CCc1cc(Cl)cc(CC#N)c1
Reactant: Nc1c(F)c(F)cc(F)c1S
Agent: Cl
Product: N#CCc1cc(Cl)cc(Cc2nc3c(F)c(F)cc(F)c3s2)c1
Yield: 27.8 %

Procedure:
The procedure of Example 22-i) was repeated using 1,3-biscyanomethyl-5-chlorobenzene (650 mg, 3.4 mmol) and 2-amino-3,4,6-trifluorothiophenol hydrochloride (735 mg, 3.4 mmol) and the resultant product was crystallized from isopropyl ether to give 3-[(4,5,7-trifluorobenzothiazol-2yl)methyl]-5-chlorophenylacetonitrile (333 mg, 28%) as a colorless powder.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:12])[CH:9]=[CH:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C(C(=O)CC=C)=CC=CN=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>C(O)C>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][N:32]2[C:2]3[C:7](=[CH:6][CH:5]=[CH:4][N:3]=3)[C:8](=[O:12])[CH2:9][CH:10]2[CH3:11])=[CH:29][CH:28]=1
Reactant: COc1ccc(CN)cc1
Reactant: CC=CC(=O)c1cccnc1Cl
Agent: C=CCC(=O)c1cccnc1Cl
Solvent: CCO
Product: COc1ccc(CN2c3ncccc3C(=O)CC2C)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
[Step 3] 2.2 g of the mixture of 1-(2-chloropyridin-3-yl)but-2-en-1-one and 1-(2-chloropyridin-3-yl)but-3-en-1-one and 4-methoxybenzylamine were dissolved in 30 mL of ethanol and stirred overnight at 70° C. Following completion of the reaction, the solution was concentrated under reduced pressure and water was added to the resulting residue followed by extracting three times with chloroform. After washing with saturated brine and dehydrating with anhydrous sodium sulfate, the solution was concentrated under reduced pressure and the resulting residue was purified using silica gel chromatography (ethyl acetate:hexane=1:3) to obtain 2.7 g of 1-(4-methoxybenzyl)-4-oxo-2-methyl-2,3-dihydro-1H-[1,8]-naphthyridine in the form of a yellow oil (80%).
Reaction SMILES: [NH2:1][C:2]1[C:18]([O:19][CH3:20])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:31][C:30]=2[O:41][CH3:42])[C:25]([F:43])=[CH:24][N:23]=1>>[F:43][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[CH:31][C:30]=2[O:41][CH3:42])=[N:27][C:22]([NH:1][C:2]2[C:18]([O:19][CH3:20])=[CH:17][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C:12]([N:14]([CH3:16])[CH3:15])=[O:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:23][CH:24]=1
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1F
Reactant: COc1cc2c(cc1N)CCN(CC(=O)N(C)C)CC2
Product: COc1cc2c(cc1Nc1ncc(F)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCN(CC(=O)N(C)C)CC2

Procedure:
The title compound was prepared from 2-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-N,N-dimethyl-acetamide and (2-Chloro-5-fluoro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine in an analogous manner to Example 61e. Product isolated as a pale yellow solid (0.037 g, 39%). MP: 80-107° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.30 (d, 1H, J=8.6 Hz), 8.13 (s, 1H), 7.93-7.90 (m, 1H), 7.39 (s, 1H), 7.22-7.18 (m, 1H), 6.63 (s, 1H), 6.56-6.49 (m, 2H), 3.93-3.88 (m, 7H), 3.86 (s, 3H), 3.27 (s, 2H), 3.17-3.12 (m, 7H), 2.98 (s, 3H), 2.91-2.85 (m, 4H), 2.74-2.65 (m, 4H). MS: 580.32 (MH)+.
Reaction SMILES: [OH:1][CH:2]([CH2:26]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:24](=[O:25])[C:23]2[N:21]([CH3:22])[CH:20]=[N:19][C:18]=2[N:16]([CH3:17])[C:14]1=[O:15].[BrH:28].O.[Na].[C:31]([OH:34])(=O)[CH3:32]>>[C:31]([O:1][CH:2]([CH2:26][Br:28])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:24](=[O:25])[C:23]2[N:21]([CH3:22])[CH:20]=[N:19][C:18]=2[N:16]([CH3:17])[C:14]1=[O:15])(=[O:34])[CH3:32]
Reactant: CC(=O)O
Reactant: Cn1cnc2c1c(=O)n(CCCCCCCCCCC(O)CO)c(=O)n2C
Reactant: Br
Agent: [Na]
Solvent: O
Product: CC(=O)OC(CBr)CCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
1-(1 1,12-Dihydroxydodecyl)-theobromine, prepared above (2.50 g, 6.58 mmol), was stirred with hydrogen bromide (6.39 ml of a 30% solution in acetic acid, 19.73 mmol) for 2 hours. The mixture was then added over 10 minutes to water (25 ml), ice (30 g) and sodium hydrideCO3 (15 g). The resulting mixture was then stirred for 30 minutes. The mixture was extracted with dichloromethane (3×50 ml), and the organic phases combined and dried with magnesium sulfate. The solvent was evaporated to afford a residue (3.18 g, 99%) of 1-(11-acetoxy-12-bromododecyl)-3,7-dimethylxanthine. Without further purification, this crude product was taken up in methanol (10 ml) and treated with a solution of sodium methoxide (prepared from sodium, 0.160 g, 6.90 mmol, and 20 ml methanol). After 60 minutes, the reaction was added to water (30 ml) and extracted with dichloromethane (3×50 ml). The organic portions were combined, dried and evaporated t produce 2.20 g of a white solid, 1-(1 1,12-oxidododecyl)-3,7-dimethylxanthine (93% yield)
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[C:15](O)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[ClH:45]>CN(C)C=O>[C:15]([NH:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[ClH:45]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NC1CCNCC1)c1ccccc1

Procedure:
A mixture comprising 4-amino-1-(tert-butoxycarbonyl)piperidine (700 mg), benzoic acid (512 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (804 mg), 1-hydroxybenzotriazole (567 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 16 hours to undergo reaction, and the resulting compound was acid-treated with hydrochloric acid to obtain 4-(benzoylamino)piperidine•hydrochloride.
Reaction SMILES: C(O[C:4]([C:6]1[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=1[CH:14]([NH:23][C:24]1[CH:29]=[C:28]([Cl:30])[C:27](=[O:31])[N:26]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[CH:25]=1)[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)=[O:5])C.[Cl-].C[Al+]C>>[Cl:30][C:28]1[C:27](=[O:31])[N:26]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[CH:25]=[C:24]([N:23]2[C:4](=[O:5])[C:6]3[CH:10]=[CH:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:7]=3[CH:14]2[C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[CH:29]=1
Reactant: CCOC(=O)c1ccn(C(C)C)c1C(Nc1cc(Cl)c(=O)n(Cc2ccc(OC)cc2)c1)c1ccc(C#N)cc1
Agent: C[Al+]C
Agent: [Cl-]
Product: COc1ccc(Cn2cc(N3C(=O)c4ccn(C(C)C)c4C3c3ccc(C#N)cc3)cc(Cl)c2=O)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for Step F1, but 2-[[5-chloro-1-(4-methoxy-benzyl)-6-oxo-1,6-dihydro-pyridin-3-ylamino]-(4-cyano-phenyl)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester (Step AF2) was used instead of 2-[(4-chloro-phenyl)-(4-hydroxy-cyclohexylamino)-methyl]-1-isopropyl-1H-pyrrole-3-carboxylic acid ethyl ester, and dimethylaluminium chloride [1184-58-3] (1M/hexanes) was used instead of trimethylaluminium. The title compound was obtained as a white solid. ESI-MS: tR=1.00 min, [M+H]+ 513/515 (LC-MS 1).