Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][CH:9]([CH3:13])[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([CH:14]=[O:15])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:23][CH3:24]>CN(C=O)C>[CH2:23]([O:1][C:2]1[C:7]2[O:8][CH:9]([CH3:13])[C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[C:4]([CH:14]=[O:15])[CH:3]=1)[CH3:24]
Reactant: CC1Oc2c(O)cc(C=O)cc2NC1=O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)cc2c1OC(C)C(=O)N2
Temperature: 23 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
To a 20 mL screw cap vial was added 8-hydroxy-2-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carbaldehyde 398A (0.619 g, 2.99 mmol) and cesium carbonate (0.973 g, 2.99 mmol). The mixture was suspended in DMF (5.98 mL) and then cooled in an ice bath. Iodoethane (0.241 mL, 2.99 mmol) was added in 2 portions over 5 minutes. The reaction mixture was stirred for 2 hr, slowly warmed to 23° C., and the stirred for 18 hr. The crude material was purified by prep HPLC-MS (30-50% MeCN in water, basic mode) and the fractions were collected and concentrated in vacuo. The resulting solid was isolated by filtration, washed with water and dried in vacuo to give a tan solid (0.404 g, 57% yield): 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (t, J=6.95 Hz, 3H) 1.46 (d, J=6.82 Hz, 3H) 4.14 (qd, J=6.99, 1.77 Hz, 2H) 4.72-4.88 (m, 1H) 7.07 (d, J=1.77 Hz, 1H) 7.24 (d, J=1.77 Hz, 1H) 9.82 (s, 1H) 10.92 (s, 1H). ESI-MS: m/z 236.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH2:29]C)[CH:23]=O)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1)[CH3:18]
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Reactant: CCOc1ccc(C=O)cc1OCC
Product: CCOc1cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)ccc1OC
Yield: 26 %

Procedure:
The title compound (10 mg, 26%) was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 3-ethoxy-4-ethoxy-benzaldehyde. MS: 384.5 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH2:7][C:6](Br)([CH:17]([CH3:19])[CH3:18])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22].C1CN2C(=NCCC2)C1.Cl>CS(C)=O>[CH3:1][C:2]1[C:10]2[O:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[C:8]2[CH:7]=[C:6]([CH:17]([CH3:18])[CH3:19])[C:5](=[O:21])[C:4]=2[C:3]=1[CH3:22]
Reactant: Cc1c2c(c3cc(C(=O)O)oc3c1C)CC(Br)(C(C)C)C2=O
Agent: C1CN=C2CCCN2C1
Agent: Cl
Solvent: CS(C)=O
Product: Cc1c2c(c3cc(C(=O)O)oc3c1C)C=C(C(C)C)C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4,5-dimethyl-6-oxo-7,8-dihydro-7-bromo-7-isopropyl-6H-indeno[5,4-b]furan-2-carboxylic acid (0.01 mole) in dimethylsulfoxide (50 ml.) is treated with 1,5-diazabicyclo[4.3.0] -5-nonene (0.20 mole) and stirred in an inert (nitrogen) atmosphere at 25°C. for 1 hour; poured into 1.0 N hydrochloric acid to afford 4,5-dimethyl-6-oxo-7-isopropyl-6H-indeno-[5,4-b]furan-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:3]=12.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][CH2:14][CH:15]([OH:16])[C:3]=12
Reactant: Nc1c2c(nc3cnccc13)CCCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1c2c(nc3cnccc13)CCCC2O
Reaction time: 1 h

Procedure:
To a cooled solution of 5-amino-6,7,8,9-tetrahydrobenzo[b][1,7]naphthyridin-6-one (3.05 g) was added 14.5 ml of 1M lithium aluminum hydride in tetrahydrofuran. This was stirred for 1 hour.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:18][C@@H:17]3[CH2:19][CH2:20][C@@H:14]([CH2:15][N:16]3C3C=CC(OC)=CC=3)[CH2:13]1)[N:6]=[CH:5]2.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[N:50]1[N:51]([C:55]2[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][C:56]=2[C:57](O)=[O:58])[N:52]=[CH:53][CH:54]=1.C([O-])(O)=O.[Na+]>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:18][C@@H:17]3[CH2:19][CH2:20][C@@H:14]([CH2:15][N:16]3[C:57](=[O:58])[C:56]3[CH:60]=[C:61]([CH3:64])[CH:62]=[CH:63][C:55]=3[N:51]3[N:52]=[CH:53][CH:54]=[N:50]3)[CH2:13]1)[N:6]=[CH:5]2
Reactant: Cc1ccc(-n2nccn2)c(C(=O)O)c1
Reactant: COc1ccc(N2C[C@@H]3CC[C@H]2CN(c2ncc4cc(F)ccc4n2)C3)cc1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O
Product: Cc1ccc(-n2nccn2)c(C(=O)N2C[C@@H]3CC[C@H]2CN(c2ncc4cc(F)ccc4n2)C3)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a solution of 6-fluoro-2-[(1S,5S)-6-(4-methoxyphenyl)-3,6-diazabicyclo[3.2.2]non-3-yl]quinazoline (E-5, 0.020 g, 0.053 mmol, 1.0 equiv) in acetonitrile/water (0.3 mL total; 2:1) at 0° C. was added ceric ammonium nitrate (0.043 g, 0.079 mmol, 1.5 equiv) and the reaction was stirred 1 h. At 1 h, added more ceric ammonium nitrate (0.0 43 g, 0.079 mmol, 1.5 equiv) and the reaction was complete after 2 h. The reaction mixture was quenched with 10% aqueous sodium thiosulfate and concentrated directly. The resulting residue was azeotroped with methanol (2×10 mL) and toluene (2×20 mL). The oily residue was dissolved in DMF (0.3 mL) and to this solution was added EDC (0.030 g, 0.16 mmol, 3.0 equiv), HOBt (0.024 g, 0.16 mmol, 3.0 equiv), triethylamine (0.037 mL, 0.26 mmol, 5.0 equiv), and 2-(2H-1,2,3-triazol-2-yl)-5-methylbenzoic acid (0.032 g, 0.16 mmol, 3.0 equiv). The reaction mixture was heated to 70° C. for 1 h and cooled to ambient temperature. The reaction was partitioned between ethyl acetate (20 mL) and saturated NaHCO3 (20 mL) and the organic phase was washed with water (4×10 mL). The combined organic phase was dried over MgSO4, concentrated and purified by column chromatography on silica gel (0 to 100% ethyl acetate in hexanes). The resulting product was further purified by reverse phase column chromatography (15 to 85% acetonitrile in water, 0.1% TFA buffer) to afford, after free-basing with saturated NaHCO3, E-6 as a yellow foam. HRMS [M+H] C25H24FN7O calc'd 458.2104, found 458.2115.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH3:30]>C(O)C.O.CCOC(C)=O>[NH2:30][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: N
Reactant: O=C(Nc1ccc(Oc2cc(Cl)ncn2)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ncn1

Procedure:
In a sealed tube under N2-atmosphere, N-(4-(4-chloropyrimidin-6-yl-oxy)-phenyl)-N′-(4-chloro-3-trifluoromethyl-phenyl)-urea (443 mg, 1.00 mmol) and 25% aqueous NH3 (2 ml) in ethanol (2 ml) is stirred for 22 h at 80° C. Then the reaction mixture is diluted with water and AcOEt, the aqueous layer separated off and extracted 3 times with AcOEt. The organic phases are washed with 3 portions of water and brine, dried (Na2SO4) and concentrated. Column chromatography (SiO2; CH2Cl2/MeOH 9:1) yields the title compound: m.p.: 197-198° C.; 1H-NMR (DMSO6): 9.20 (s, HN), 8.93 (s, HN), 8.12 (m, 1H), 8.08 (s, 1H), 7.63 (m, 2H), 7.51 (d, 2H), 7.08 (d, 2H), 6.82 (s, H2N), 5.67 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[C:10]([C:12]3[C@H:13]([CH3:26])[C@@H:14]4[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:15]4[C:16]=3[C:17]([O-:19])=[O:18])[S:9][C:8]=12)(=[O:3])[CH3:2].[Na+].[CH2:28]([O:30][C:31]([O:33][CH:34](I)[CH3:35])=[O:32])[CH3:29].C(OCC)(=O)C>CN(C=O)C>[C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[C:10]([C:12]3[C@H:13]([CH3:26])[C@@H:14]4[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:15]4[C:16]=3[C:17]([O:19][CH:28]([O:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:29])=[O:18])[S:9][C:8]=12)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Reactant: CCOC(=O)OC(C)I
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)OC(C)OC(=O)C1=C(c2cn3cnc(C(C)=O)c3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: -10 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
Sodium(1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (71.9 mg) was dissolved in 2.0 ml of DMF. 1-(Ethoxycarbonyloxy)ethyl iodide (66.3 mg) was added to the solution in an argon atmosphere at −20° C. The mixture was stirred for 2 hr while raising the temperature to −10° C. Ethyl acetate (20 ml) was added to the reaction solution. The mixture was extracted twice, followed by washing twice with 10 ml of semisaturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under the reduced pressure to a volume of 2 ml. The residue was purified by column chromatography on silica gel (chloroform:methanol=15:1) and Sephadex LH-20 (dichloromethane:methanol=1:1) in that order to give 57.4 mg of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[NH:17][C:16](=[O:24])[N:15]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:14]2=[O:30])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[NH:17][C:16](=[O:24])[N:15]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:14]2=[O:30]
Reactant: CC(C)(C)OC(=O)NCCNc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCCN)cc2c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 114.2 %

Procedure:
To an ice-cooled solution of [2-(3-Methanesulfonylamino-7-nitro-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-6-ylamino)-ethyl]-carbamic acid tert-butyl ester (10 mg, 0.022 mmol) in dichloro-methane (0.5 ml) is added trifluoroacetic acid (0.25 ml). The reaction mixture is stirred at 0° C. for 3 h. The mixture is filtered and the resulting red solid dried under vacuum to afford 9 mg (87%) of a red powder. Rt=2.13 min.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[NH2:10][CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:11][N:10]=1
Reactant: O=C(Cl)c1sccc1Cl
Reactant: COc1ccc(C(=O)CN)cc1
Product: COc1ccc(-c2cnc(-c3sccc3Cl)o2)cc1

Procedure:
3-Choloro-thiophene-2-carboxylic acid-[2-(4-methoxy-phenyl)-2-oxo-ethyl]-amide: The title compound was prepared from 3-chloro-thiophene-2-carbonyl chloride and 2-amino-4′-methoxyacetophenone by a procedure similar to Example 93a as an orange solid. 1H NMR (DMSO-d6): 8.30 (s, NH), 8.02 (d, J=9.0 Hz, 1H), 7.89 (d, J=6.6 Hz, 2H), 7.20 (d, J=6.0 Hz, 2H), 7.10 (d, J=8.7 Hz, 1H), 4.80 (d, J=5.4 Hz, 2H), 3.86 (s, 3H).
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:22](#[N:25])[CH:23]=[CH2:24].C1(C=CC(O)=CC=1)O.C([O-])(O)=O.[Na+]>O1CCOCC1.C(N(CC)CC)C>[CH2:2]([N:9]1[C@@H:14]2[CH:23]([C:22]#[N:25])[CH2:24][C@@:10]1([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](=[O:15])[CH:12]=[CH:13]2)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Oc1ccc[n+](Cc2ccccc2)c1-c1ccccc1
Reactant: C=CC#N
Agent: O=C([O-])O
Agent: Oc1ccc(O)cc1
Agent: [Br-]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#CC1C[C@@]2(c3ccccc3)C(=O)C=C[C@@H]1N2Cc1ccccc1
Temperature: 80 °C

Procedure:
A mixture of N-benzyl-3-hydroxy-2-phenylpyridinium bromide (150 g, 0.44 mol), acrylonitrile (300 ml), triethylamine (95 ml), hydroquinone (125 mg) and 1,4-dioxane (650 ml) was heated at reflux (80° C.) for 68 hours and cooled to room temperature. The reaction mixture was poured onto saturated aqueous NaHCO3 (1 l) and extracted into an 1:1 mixture of iso-hexane:diethyl ether (3×500 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give a mixture of regio and stereoisomers in the ratio
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:10]=2)=[CH:5][CH:4]=1>[Pd].CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH:11]([NH:15][CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2=CC(NCCCc3ccccc3)CCC2)cc1
Agent: [Pd]
Solvent: CO
Product: COc1ccc(C2CCCC(NCCCc3ccccc3)C2)cc1
Reaction time: 3 h

Procedure:
A mixture of (RS)-[3-(4-methoxy-phenyl)-cyclohex-2-enyl]-(3-phenyl-propyl)-amine (1.54 g, 4.79 mmol), 10% Pd/C (0.3 g) and MeOH (30 ml) was hydrogenated for 3 h. Removal of the catalyst, evaporation of the solvent and separation of the isomers by flash-chromatography over SiO2 (Biotage 40, 90 g) eluting with AcOEt gave (1RS,3SR)-[3-(4-methoxy-phenyl)-cyclohexyl]-(3-phenyl-propyl)-amine (0.64 g, 41%, light yellow oil, MS: m/e=324.4 (M+H+)) and (1RS,3RS)-[3-(4-methoxy-phenyl)-cyclohexyl]-(3-phenyl-propyl)-amine (0.34 g, 22%, light yellow oil, MS: m/e=324.4 (M+H+)).
Reaction SMILES: C([Li])CCC.[Cl-].[Cl:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[C:28]([C:31]1[CH:32]=[CH:33][C:34]2[O:40][CH2:39][C:38](=O)[CH:37]=[CH:36][C:35]=2[CH:42]=1)(=[O:30])[CH3:29]>O1CCCC1.CCCCC>[Cl:7][CH:8]=[C:38]1[CH:37]=[CH:36][C:35]2[CH:42]=[C:31]([C:28](=[O:30])[CH3:29])[CH:32]=[CH:33][C:34]=2[O:40][CH2:39]1
Reactant: CC(=O)c1ccc2c(c1)C=CC(=O)CO2
Reactant: ClC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(=O)c1ccc2c(c1)C=CC(=CCl)CO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
1.1 equivalents of n-butyllithium are added to 309 mg (0.89 mmol) of chloromethyltriphenylphosphonium chloride in 5 ml of tetrahydrofuran cooled to 0° C. After stirring for one hour, 150 mg (0.74 mmol) of 7-acetyl-1-benzoxepin-3(2H)-one, prepared according to example 79, are added at ambient temperature. The medium is stirred for a further 1 hour. After the usual treatments and evaporating the solvent under reduced pressure, the crude reaction product is taken up in pentane in order to precipitate triphenylphosphine oxide. Evaporation of the solvents provides 95.5 mg (55%) of 1-[3-(chloromethylene)-2,3-dihydro-1-benzoxepin-7-yl]ethanone in the form of a mixture of two Z/E isomers in a 90/10 ratio; 1H NMR (C6D6): 7.85 (d, 1H, J=2.2 Hz), 7.76 (dd, 2.2 Hz and 8.4 Hz), 7.04 (d, 8.4 Hz), 6.85 (d, J-=11.8 Hz, 1H), 6.57 (d, J=11.8 Hz, 1H), 6.16 (s, 1H), 4.57 (4.87) (s, 2H), 2.56 (s, 3H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][O:12][CH:11]=2)[CH:7]=[CH:6][C:5]=1[CH3:15])[CH3:2].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][O:26][CH2:27][C:28]([OH:30])=O)=[C:19]([C:32]([O:34]C)=[O:33])[CH:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:31])[CH2:25][O:26][CH2:27][C:28]([N:3]([CH2:1][CH3:2])[C:4]2[CH:9]=[C:8]([C:10]3[CH:14]=[CH:13][O:12][CH:11]=3)[CH:7]=[CH:6][C:5]=2[CH3:15])=[O:30])=[C:19]([CH:18]=1)[C:32]([OH:34])=[O:33]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: CCNc1cc(-c2ccoc2)ccc1C
Product: CCN(C(=O)COCC(=O)Nc1ccc(Cl)cc1C(=O)O)c1cc(-c2ccoc2)ccc1C

Procedure:
Using the same method as in Example 15-(i), N-ethyl-5-(furan-3-yl)-2-methylaniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-(ethyl[5-(furan-3-yl)-2-methylphenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 73%).
Reaction SMILES: Cl.[S:2]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1CC#N)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:20]([OH:23])(=[O:22])[CH3:21]>>[S:2]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:21][C:20]([OH:23])=[O:22])([C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=1)(=[O:3])=[O:4]
Reactant: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CC#N)cc1
Reactant: CC(=O)O
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N2CCC[C@H]2CC(=O)O)cc1
Temperature: 0 °C
Yield: 48.2 %

Procedure:
Concentrated hydrochloric acid (20 ml) was added to a solution of (2S)-2-(1-tosylpyrrolidin-2-yl) acetonitrile (4.35 g) prepared in Reference Example 50 in acetic acid (4 ml) and then the reaction solution was heated under reflux for 3 hours. After cooling the reaction solution, it was poured into ice water and then extracted with ether. The resulting organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was subjected to silica gel column chromatography and then eluted with chloroform/methanol (99/1) to give 6.93 g (yield 48.2%) of the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.C1(S([N:20]2[C:24]3=[N:25][CH:26]=[CH:27][CH:28]=[C:23]3[C:22]([C:29]3[CH:34]=[CH:33][N:32]=[C:31](Cl)[N:30]=3)=[CH:21]2)(=O)=O)C=CC=CC=1>>[CH3:1][N:2]([CH3:10])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:31]2[N:30]=[C:29]([C:22]3[C:23]4[C:24](=[N:25][CH:26]=[CH:27][CH:28]=4)[NH:20][CH:21]=3)[CH:34]=[CH:33][N:32]=2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(N)cc1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: CN(C)c1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 58.4 %

Procedure:
Using the procedure of example 1, N,N-dimethyl-p-phenylenediamine (221 mg) was reacted with compound 1f (100 mg) to provide compound 38 (52 mg, 29%). 1H NMR (400 MHz, CD3OD) δ 8.85 (d, J=8.0 Hz, 1H), 8.25 (d, J=8.0 Hz, 1H), 8.20 (s, 1H), 8.18 (d, J=4.8 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 7.43 (m, 1H), 7.18 (dd, J=8;0 Hz, 5.6 Hz, 1H), 7.12 (d, J=5.6 Hz, 1H), 6.88 (d, J=8.0 Hz, 1H), 6.85 (d, J=8.0 Hz, 1H), 2.90 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[Br:10].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:4][C:3]=1[Br:10]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: C1COCCN1
Product: Fc1ccc(CN2CCOCC2)cc1Br

Procedure:
In the same manner as Step B in Example 1-D-26, using 4-fluoro-3-bromo-benzaldehyde (270 mg) and morpholine (0.23 ml), reductive amination was carried out, to obtain a crude product of 2-fluoro-5-morpholin-4-ylmethyl-bromobenzene as a colorless oil (344 mg). In the same manner as Example 1-D-08, bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (92 mg) and using a crude product (66 mg) of 2-fluoro-5-morpholin-4-ylmethyl-bromobenzene obtained in the above step instead of 4-bromobenzoic acid methyl ester, a crude product of 5-[7-(2-fluoro-5-morpholin-4-ylmethyl-phenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine was obtained. Using a crude product (90 mg) of 5-[7-(2-fluoro-5-morpholin-4-ylmethyl-phenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl-bis-(4-methoxy-benzyl)-amine, according to the above Deprotection method 2, 5-[7-(2-fluoro-5-morpholin-4-ylmethyl-phenyl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-ylamine was obtained as a colorless powder (5.4 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:6].[CH2:11](I)[CH3:12].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:11]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH:5]=[O:6])[CH3:12]
Reactant: CCI
Reactant: Cc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1cc(C=O)ccc1C

Procedure:
The title compound was prepared by reaction of commercially available 3-hydroxy-4-methyl-benzaldehyde with ethyl iodide in DMF using K2CO3 as base in analogy to the procedure described in M. J. Ashton, D. C. Cook, G. Fenton, J.-A. Karlsson, M. N. Palfreyman, D. Raeburn, A. J. Ratcliffe, J. E. Souness, S. Thurairatnam and N. Vicker J. Med. Chem. 1994, 37, 1696-1703.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[NH:13]C(=O)OC(C)(C)C.CN(C)[C@@H]1CCN(CC2C=CC(C(O)=O)=CC=2)C1.[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][O:46][C:47]([NH:49][C:50]2[CH:58]=[CH:57][C:53]([C:54](O)=[O:55])=[CH:52][CH:51]=2)=[O:48])[CH:40]=1>>[NH2:13][C:3]1[CH:4]=[CH:5][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:7][C:2]=1[NH:1][C:54]([C:53]1[CH:52]=[CH:51][C:50]([NH:49][C:47](=[O:48])[O:46][CH2:45][C:41]2[CH:40]=[N:39][CH:44]=[CH:43][CH:42]=2)=[CH:58][CH:57]=1)=[O:55]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Reactant: O=C(Nc1ccc(C(=O)O)cc1)OCc1cccnc1
Agent: CN(C)[C@@H]1CCN(Cc2ccc(C(=O)O)cc2)C1
Product: Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(NC(=O)OCc2cccnc2)cc1
Yield: 31 %

Procedure:
Following the same procedure as described in Example 1, steps 6 and 7 (scheme 1), using compound 4 but substituting compounds 7 & 8 for compounds 281 & 282, the title compound 283 was obtained (step 2: 31% yield, step 3: 23% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14]Br)[CH2:10][CH2:9]2)=[CH:5][CH:4]=1.[I-:18].[Na+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][CH:8]2[CH2:13][CH2:12][CH:11]([CH2:14][I:18])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CC2CCC(CBr)CC2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(CC2CCC(CI)CC2)cc1

Procedure:
A mixture of 17.5 g. (0.065 m) of 4-(4-methoxybenzyl)-cyclohexylmethyl bromide, 11 g. (0.073 m) of sodium iodide and 100 ml. of acetone was heated under reflux for two hours. The solvent was removed, the residue partitioned between water and ether, and the ether layer dried and concentrated to give 19.8 g. of oil, used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]([CH2:11][CH2:12][CH2:13][C:14]([CH3:16])=[CH2:15])=[CH:3][CH:4]=[CH:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9].P(=O)(O)(O)O.O>C1C=CC=CC=1>[CH3:15][C:14]1([CH3:16])[CH2:13][CH2:12][CH2:11][CH:2]([CH3:1])[CH:3]1[CH2:4][CH2:5][CH:6]([OH:10])[CH2:7][CH2:8][CH3:9]
Reactant: C=C(C)CCCC(C)=CC=CC(=O)CCC
Agent: O=P(O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: CCCC(O)CCC1C(C)CCCC1(C)C
Temperature: 20 °C
Reaction time: 2 h

Procedure:
1.66 kilograms of 8,12-dimethyltrideca-5,7,12-tri-en-4-on dissolved in 3 kilograms benzene are dropped while stirring at 10°-15° C. into 1.66 kilograms phosphoric acid and the reaction mixture is stirred for 2 hours at 20° C. and thereafter for 3 hours at 30° C. Thereupon water is added, the aqueous phase is extracted twice with benzene, the benzene extract is neutrally washed with sodium carbonate solution, and the benzene is then removed by distillation. The reaction product is purified by distillation. The yield is 1.3 kilograms 1-(2',6',6'-trimethylcyclohex-2'-enyl)-hex-1-en-3-on.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH2:17][NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])[OH:16])=[N:13][CH:14]=1)C1C=CC=CC=1>[Pd].C(O)C>[C:19]([NH:18][CH2:17][CH:15]([C:12]1[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][N:13]=1)[OH:16])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)NCC(O)c1ccc(OCc2ccccc2)cn1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)NCC(O)c1ccc(O)cn1

Procedure:
A solution of 600 mg. (2 mmol) of 5-benzyloxy-α-(N-t-butylaminomethyl)-2-pyridinemethanol (liberated from the hydrochloride salt) in 100 ml. of ethanol is hydrogenated over 600 mg. of 10% palladium-on-carbon at 50 psi for 10 minutes. The catalyst is filtered and ethanol evaporated to dryness. The residue is recrystallized from ethanol to give α-(t-butylaminomethyl)-5-hydroxy-2-pyridinemethanol, m.p. 163°-165°C.