Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C@@H:15]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]([O:18]C(C)(C)C)=[O:17])[C:11]2=[O:27])[N:8]=1.[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31]>ClCCl>[F:28][C:29]([F:34])([F:33])[C:30]([OH:32])=[O:31].[CH3:1][O:2][CH2:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C@@H:15]([C:23]([CH3:25])([CH3:24])[CH3:26])[C:16]([OH:18])=[O:17])[C:11]2=[O:27])[N:8]=1
Reactant: COCc1nc(CN2CCN([C@H](C(=O)OC(C)(C)C)C(C)(C)C)C2=O)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCc1nc(CN2CCN([C@H](C(=O)O)C(C)(C)C)C2=O)cs1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution containing the product from Example 6G (1.28 g, 3.2 mmol) in dichloromethane (10 mL) was treated with trifluoracetic acid (5 mL), stirred at 25° C. for 4 hours and concentrated. The residue was chromatographed on silica gel eluting with 0-5% methanol in dichloromethane to give the title compound (1.2 g) as the trifluoroacetic acid salt.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19](O)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]([C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][C:33]2[CH:42]=[CH:41][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1)([CH3:24])[CH3:23]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:31]([CH2:32][C:33]1[CH:34]=[CH:35][C:36]([C:37]([O:39][CH3:40])=[O:38])=[CH:41][CH:42]=1)[C:28]1[CH:27]=[CH:26][C:25]([CH:22]([CH3:24])[CH3:23])=[CH:30][CH:29]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)cccc21
Reactant: COC(=O)c1ccc(CNc2ccc(C(C)C)cc2)cc1
Product: COC(=O)c1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)cc2)cc1
Yield: 57.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (2.3 g) and methyl 4-{[(4-isopropylphenyl)amino]methyl}benzoate (2.3 g) as starting materials, methyl 4-{[N-(5-benzyloxy-1,2,3,4-tetrahydronaphthalen-1-ylcarbonyl)-N-(4-isopropylphenyl)amino]methyl}benzoate (2.56 g) was obtained.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].Br[C:36]([CH3:43])([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:34])[N:8]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:36]([CH3:43])([CH3:42])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:29][CH:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]#[N:25])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)n(-c2ccc(O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2ccc(OC(C)(C)C(=O)OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 74 %

Procedure:
A solution of 4′-{[4-butyl-1-(4-hydroxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (2.3 g), ethyl 2-bromo-2-methylpropanoate (2.2 mL) and cesium carbonate (4.9 g) in dimethylacetamide (23 mL) was stirred at 100° C. for 2 days. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (2.1 g, 74%) as a pale-yellow liquid.
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:27]([NH2:29])=[O:28])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].[CH3:30][NH2:31]>CC#N>[CH3:30][NH:31][CH2:2][CH2:1][S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:27]([NH2:29])=[O:28])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4]
Reactant: CN
Reactant: C=CS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Solvent: CC#N
Product: CNCCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccccc4)cc23)CC1
Temperature: 80 °C
Yield: 54 %

Procedure:
To a solution of 3-[1-(ethenylsulfonyl)-4-piperidinyl]-5-phenyl-1H-indole-7-carboxamide (26 mg, 0.063 mmol) in CH3CN (1.0 mL), were added methylamine (19.5 mg, 0.63 mmol). The reaction solution was heated to 80° C. overnight. After which time the reaction mixture was purified by reverse phase HPLC (water/CH3CN, 0.1% TFA 10-90%) to give the title compound (15 mg, 54%).
Reaction SMILES: [CH:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH:13]=[O:14])=[CH:10][CH:9]=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=2)([CH3:3])[CH3:2].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:18]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=2)[C:12]([CH:13]=[O:14])=[C:4]1[CH:1]([CH3:3])[CH3:2])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)c1[nH]c2cc([N+](=O)[O-])ccc2c1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)c1c(C=O)c2ccc([N+](=O)[O-])cc2n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-isopropyl-6-nitro-1H-indole-3-carbaldehyde (Compound 121, 244 mg, 1.05 mmol) in DMF (10 ml) was added benzyl bromide (0.62 ml, 5.26 mmol) and K2CO3 (726 mg, 5.26 mmol). The reaction was stirred at room temperature for 16 h, diluted with EtOAc, washed with H2O and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→50% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][C:12]1[CH:13]=[N:14][N:15]([CH2:17][C:18]2[C:19]([CH3:24])=[N:20][O:21][C:22]=2[CH3:23])[CH:16]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](=[O:30])=[N:26][C:27](Cl)=[O:28]>C1COCC1>[CH2:1]([N:8]1[C:27](=[O:28])[NH:26][C:25](=[O:30])[N:11]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]3[C:19]([CH3:24])=[N:20][O:21][C:22]=3[CH3:23])[CH:16]=2)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NC(=O)Cl
Reactant: Cc1noc(C)c1Cn1cc(NC(=O)NCc2ccccc2)cn1
Solvent: C1CCOC1
Product: Cc1noc(C)c1Cn1cc(-n2c(=O)[nH]c(=O)n(Cc3ccccc3)c2=O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)urea (example 95b) (100 mg, 0.31 mmol) in THF (2 mL) was cooled to 0° C. and n-chlorocarbonyl isocyanate (97 mg, 0.92 mmol) was slowly added. After addition, the reaction was allowed to warm up to room temperature and stirred for 1 hour. The reaction was concentrated and the residue was purified by silica column chromotography (100% to 90% dichloromethane in methanol: 30 minute gradient) to afford 1-benzyl-3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1,3,5-triazinane-2,4,6-trione (112 mg, 93%) as a white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.12 (s, 3H), 2.38 (s, 3H), 4.87 (s, 2H), 5.16 (s, 2H), 7.23-7.34 (m, 5H), 7.45 (s, 1H), 7.90 (s, 1H), 11.93 (s, 1H). LC/MS; [M+H] calculated for C19H18N6O4; expected 395.14; found 395.15. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 1.14 μM.
Reaction SMILES: CC([CH:5]([N:25]([C:29]([C:31]1[N:35](COCC[Si](C)(C)C)[CH:34]=[N:33][C:32]=1[Cl:44])=[O:30])C(=O)[O-])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[C:16]([C:22]#[N:23])[CH:15]=2)[C:7]=1[F:24])(C)C.[B-](F)(F)(F)F.[CH3:50]C[O+](CC)CC.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:44][C:32]1[N:33]([CH3:50])[CH:34]=[N:35][C:31]=1[C:29]([NH:25][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([O:13][C:14]2[CH:19]=[C:18]([CH2:20][OH:21])[CH:17]=[C:16]([C:22]#[N:23])[CH:15]=2)[C:7]=1[F:24])=[O:30]
Reactant: CC[O+](CC)CC
Reactant: CC(C)(C)C(c1ccc(Cl)c(Oc2cc(C#N)cc(CO)c2)c1F)N(C(=O)[O-])C(=O)c1c(Cl)ncn1COCC[Si](C)(C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(CO)c3)c2F)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.4 %

Procedure:
To a solution of 1,1-dimethylethyl[(4-chloro-3-{[3-cyano-5-(hydroxymethyl)phenyl]oxy}-2-fluorophenyl)methyl]{[4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazol-5-yl]carbonyl}carbamate (66 mg, 0.099 mmol) in DCM (5 ml) was added Meerwein's reagent (16.13 mg, 0.109 mmol) and the reaction mixture was stirred for 4 hours at RT. TFA (2.0 ml, 26.0 mmol) was added and the reaction mixture was stirred at RT for another 2 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give the title compound (34 mg, 76% yield). 1H NMR (DMSO-d6) δ ppm 8.66 (t, 1H) 7.87 (s, 1H) 7.44-7.57 (m, 2H) 7.25-7.39 (m, 2H) 7.19 (s, 1H) 4.51 (s, 2H) 4.45 (d, 2 H) 2.50 (s, 3H). LC-MS (ES+) m/z 449.11 [M+H].
Reaction SMILES: C([N:4]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]2[CH:17]=[C:18]([O:27]C(=O)C)[C:19]([O:23]C(=O)C)=[C:20]([S:21][CH3:22])[C:7]=2[CH2:6][CH2:5]1)(=O)C.C(OC(=O)C)(=[O:33])C.I([O-])(=O)(=O)=O.[Na+]>N1C=CC=CC=1.CO>[OH:23][C:19]1[C:18]([OH:27])=[CH:17][C:8]2[CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][NH:4][CH2:5][CH2:6][C:7]=2[C:20]=1[S:21]([CH3:22])=[O:33]
Reactant: CC(=O)OC(C)=O
Reactant: CSc1c2c(cc(OC(C)=O)c1OC(C)=O)C(c1ccccc1)CN(C(C)=O)CC2
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: c1ccncc1
Product: CS(=O)c1c(O)c(O)cc2c1CCNCC2c1ccccc1

Procedure:
A solution of 8.6 g (20 mm) of 3-acetyl-7,8-diacetoxy-1-phenyl-6-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine (prepared by reacting the dihydroxy parent with an excess of acetic anhydride in pyridine at room temperature) in 40 ml of methanol at -5° is treated with 40 ml of 0.52 M sodium periodate (20.8 mm) dropwise over 15 minutes at 0°. The mixture is cooled overnight, then filtered to give a solid which is washed with methylene chloride. The organic extracts are combined, dried and evaporated in vacuo. The residue is heated at reflux in ethanolic hydrochloric acid overnight. The volatiles are removed and the residue taken up in water. Neutralization with ammonia and extraction with ethyl acetate gives the desired 7,8-dihydroxy-6-methylsulfinyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine. The hydrochloride salt is formed by treatment with ethereal hydrogen chloride.
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[Cl:5][C:6]1[CH:7]=[C:8]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:10][C:11]=1Cl>>[N+:13]([C:8]1[CH:9]=[CH:10][C:11]([NH:3][CH2:2][CH2:1][NH2:4])=[C:6]([Cl:5])[CH:7]=1)([O-:15])=[O:14]
Reactant: NCCN
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Product: NCCNc1ccc([N+](=O)[O-])cc1Cl

Procedure:
Ethylene diamine is reacted with 3,4-dichloronitrobenzene to form 4-nitro-2-chloro-N-(β-aminoethyl) aniline, which is reacted in an acetic solution with potassium isocyanate to form 4-nitro-2-chloro-N-(β-ureidoethyl) aniline. This latter compound is reduced with hydrazine in the presence of Raney's nickel, yielding 4-amino-2-chloro-N-(β-ureidoethyl) aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][CH2:12]OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH2:10][O:11][CH3:12])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Cl)c1
Reactant: COCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: COCOCc1ccnc(Cl)c1
Yield: 71 %

Procedure:
4.30 g of 2-chloro-4-pyridinemethanol, 20 ml of dimethoxymethane and 0.57 g of p-toluenesulfonic acid monohydrate were suspended in 200 ml of benzene. The suspension was passed through a Soxhlet extractor containing 25 g of 2 Å molecular sieves, and refluxed for 20 hours. After cooling, the reaction solution was washed with a saturated solution of sodium hydrogen carbonate and water, dried, and concentrated under reduced pressure. The residue was distilled to give 4.0 g (yield 71%) of 2-chloro-4-(methoxymethoxymethyl)-pyridine.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:20]([O:23][C@@H:24]([CH3:28])[C:25](Cl)=[O:26])(=[O:22])[CH3:21]>CO>[C:20]([O:23][C@@H:24]([CH3:28])[C:25]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:26])(=[O:22])[CH3:21]
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12
Solvent: CO
Product: CC(=O)O[C@@H](C)C(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-2-benzoyl-6-chloroindole (Example 1) and (S)-(−)-2-acetoxypropionyl chloride. m.p.: 80-85° C. 1H-NMR (CDCl3) δ: 10.81 (1H, br s), 8.37 (1H, d, J=8.8 Hz), 8.31 (1H, br s), 7.82-7.77 (2H, m), 7.70-7.53 (3H, m), 7.29 (1H, d, J=1.5 Hz), 7.12 (1H, dd, J=1.5, 8.8 Hz), 5.44 (1H, q, J=7.0 Hz), 2.33 (3H, s), 1.61 (3H, d, J=7.0 Hz) [α]D23 −42.30 (MeOH, c=0.87)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](Cl)=[O:10])=[CH:4][CH:3]=1.[C:12]1([NH:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:18]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CCNc1ccccc1
Product: CCOC(=O)CCN(C(=O)Cc1ccc(Cl)cc1)c1ccccc1

Procedure:
By a procedure similar to that of example 1.115.1, starting from 4-chlorophenylacetyl chloride and ethyl N-phenyl-3-aminopropionate, ethyl 3-[2-(4-chlorophenyl)-N-phenylacetamido]propanoate was obtained as light tan oil.
Reaction SMILES: [Cl:1][C:2](=[CH2:10])[C:3]([CH3:9])([CH3:8])[C:4]([O:6]C)=[O:5].[OH-].[Na+]>O>[Cl:1][C:2](=[CH2:10])[C:3]([CH3:9])([CH3:8])[C:4]([OH:6])=[O:5]
Reactant: C=C(Cl)C(C)(C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(Cl)C(C)(C)C(=O)O
Temperature: 25 °C
Yield: 70.7 %

Procedure:
A mixture of methyl 3-chloro-2,2-dimethylbut-3-enoate (33 g, 0.2 mol) and NaOH (9.6 g, 0.24 mol) in water (200 mL) was heated at reflux for 5 h. The mixture was cooled to ambient temperature and extracted with ether. The organic layer was discarded. The aqueous layer was acidified with cold 20% HCl solution and extracted ether (200 mL×3). The combined organic layers were dried and evaporated under reduced pressure to give 3-chloro-2,2-dimethyl-but-3-enoic acid (21 g, 70%), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 7.90 (brs, 1H), 5.37 (dd, J=2.4, 6.8 Hz, 2H), 1.47 (s, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15]C)=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][CH3:23])=[N:10][C:11]=2[NH2:17].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[NH2:17][C:11]1[N:10]=[C:9]([O:18][C@@H:19]([CH3:24])[CH2:20][CH2:21][CH2:22][CH3:23])[N:8]=[C:7]2[C:12]=1[NH:13][C:14](=[O:15])[N:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Reactant: C1CCNCC1
Product: CCCC[C@H](C)Oc1nc(N)c2[nH]c(=O)n(CCCCN3CCCCC3)c2n1

Procedure:
Prepared similarly to Example 29 from 9-(4-chlorobutyl)-8-(methyloxy)-2-{[(1S)-1-methylpentyl]oxy}-9H-purin-6-amine and piperidine.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1)=[O:17].[F:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[C:34]([CH3:39])[CH:33]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:36][C:35]3[CH:37]=[CH:38][C:32]([F:31])=[CH:33][C:34]=3[CH3:39])=[C:3]([C:16]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: Cc1cc(F)ccc1N
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Product: CCOC(=O)c1cnn2c(Nc3ccc(F)cc3C)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 95.4 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine (0.10 g, 0.23 mmol) obtained in Example 81, step 2 and 4-fluoro-2-methylaniline (0.044 g, 0.35 mmol), the title compound (0.114 g, 96%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[C:25](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:25])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)n[nH]1
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(OCc2c(-c3ccc(F)cn3)noc2C)nn1C
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To a solution of 5-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (700 mg, 2.1 mmol) in DMF (10 mL) at room temperature was added cesium carbonate (686 mg, 2.1 mmol) and methyliodide (299 mg, 0.13 mL, 2.1 mmol) and the resulting mixture stirred for 30 min. The resulting mixture was then evaporated and extracted with ethyl acetate and water. The organic extract was then washed with water, brine, dried over sodium sulfate and evaporated. Purification by chromatography (silica, heptane:ethyl acetate=4:1 to 2:3) afforded the title compound (354 mg, 49%) which was obtained as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)=[CH:3][N:2]=1.[CH:17]1([NH:22][CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18]1>O1CCCC1>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([N:22]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH3:23])=[O:16])=[CH:3][N:2]=1
Reactant: CNC1CCCC1
Reactant: O=C(Nc1ccnnc1)Oc1ccccc1
Solvent: C1CCOC1
Product: CN(C(=O)Nc1ccnnc1)C1CCCC1

Procedure:
A stirred solution of 2.0 grams of phenyl N-(4-pyridazinyl)carbamate (prepared as in Example 2, Step A) and 0.9 gram of N-cyclopentyl-N-methyl amine in tetrahydrofuran is heated under reflux for 18 hours. The reaction mixture is filtered and the filtrate concentrated under reduced pressure to a residue. The residue is purified by column chromatography on silica gel to yield N-(4-pyridazinyl)-N'-cyclopentyl-N'-methylurea.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:8]=2[C:9]2[C:10]([CH2:23][O:24][CH3:25])=[C:11]([C:20](O)=[O:21])[N:12]=[CH:13][C:14]=2[NH:15]3)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:40]([NH2:43])([CH3:42])[CH3:41].O>CN(C)C=O>[CH:40]([NH:43][C:20]([C:11]1[N:12]=[CH:13][C:14]2[NH:15][C:16]3[C:8]([C:9]=2[C:10]=1[CH2:23][O:24][CH3:25])=[C:7]([O:6][C:5]1[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH:19]=[CH:18][CH:17]=3)=[O:21])([CH3:42])[CH3:41]
Reactant: CC(C)N
Reactant: COCc1c(C(=O)O)ncc2[nH]c3cccc(Oc4ccc(Cl)cc4)c3c12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: COCc1c(C(=O)NC(C)C)ncc2[nH]c3cccc(Oc4ccc(Cl)cc4)c3c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
382 mg of 5-(4-chlorophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acid in 10 ml of dimethylformamide is mixed with 380 mg of carbonyldiimidazole. After 2 hours stirring at room temperature, 1 ml of isopropylamine is added and stirred overnight. After mixing with water, it is extracted with ethyl acetate. The ethyl acetate phase is dried, filtered and concentrated. The residue is chromatographed over silica gel with methylene chloride: acetone=1:1 as eluant. 90 mg of 5-(4-chlorophenoxy)-4-methoxymethyl-beta-carboline-3-carboxylic acid isopropylamide with a melting point of 255° C. is obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH:15]2[CH2:17][CH2:16]2)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:15]1([NH:14][C:4]2[N:3]=[C:2]([N:28]3[CH2:27][CH2:26][N:25]([C:22]4[CH:21]=[CH:20][C:19]([F:18])=[CH:24][CH:23]=4)[CH2:30][CH2:29]3)[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=2)[CH2:17][CH2:16]1
Reactant: N#Cc1c(Cl)nc(NC2CC2)nc1NCCO
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NC2CC2)nc1N1CCN(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 47b, 4-chloro-2-cyclopropylamino-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 47a) was treated with the 1-(4-fluorophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield the 2-cyclopropylamino-4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=398.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH3:8][N:9]([CH3:17])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1.CCOCC>C(Cl)Cl>[C:5]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]([CH3:17])[CH3:8])=[CH:11][CH:12]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: CN(C)c1ccc(N)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To a solution of acetic anhydride (11.5 mL, 12.45 g, 0.122 mol) in anhydrous CH2Cl2 (100 mL) was added N,N-dimethyl-1,4-phenylenediamine (11.37 g; 83.5 mmol) portion-wise over 30 min at 0° C. The mixture was allowed to gradually warm to room temperature and stirred for 24 hours. The solvent was removed under high vacuum to obtain a black residue which was stirred with Et2O (20 mL) at room temperature. The suspension was filtered and the solid washed with Et2O (3×20 mL). The solid residue was dried under high vacuum to obtain the intermediate N-acetyl-N′,N′-dimethyl-1,4-phenylenediamine as a black solid (12.8 g, 86%) which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.O[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=1>>[N:12]1[CH:13]=[CH:14][C:9]([N:6]2[CH2:5][CH2:4][CH:3]([CH2:2][O:1][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH:18][CH:17]=3)[CH2:8][CH2:7]2)=[CH:10][CH:11]=1
Reactant: OCC1CCN(c2ccncc2)CC1
Reactant: COC(=O)CCc1ccc(O)cc1
Product: COC(=O)CCc1ccc(OCC2CCN(c3ccncc3)CC2)cc1
Yield: 14 %

Procedure:
Following the method of Example 96, but starting from 4-(4-hydroxymethylpiperidin-1-yl)pyridine and methyl 3-(4-hydroxyphenyl)propionate, the title compound was prepared in 14% yield: m.p. 96.5°-98.5° C.; NMR (d6DMSO) δ 8.13(2H, d), 7.11(2H, d), 6.83(4H, m), 3.97(2H, dm), 3.81(2H, d), 3.56(3H, s), 2.87(2H, dr), 2.77(2H, t), 2.57(2H, t), 2.01(1H, m), 1.84(2H, m), 1.30(2H, m); m/e 355 (M+H)+ ; calculated for C21H26 N2O3.0.75H2O: C, 68.5; H, 7.2; N, 7.8. found: C, 68.5; H, 7.5; N, 7.6%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH2:18][CH3:19])=[O:11])=[CH:6][CH:5]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(CCCl)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(CCCl)cc1

Procedure:
To a suspension of 4-(2-chloroethyl)benzenecarboxylic acid (52.5 mmol; 9.7 g) in anhydrous ethanol (57 ml) was added concentrated sulfuric acid (3.0 ml). The mixture was stirred at reflux for 2 hours 30 minutes. After cooling, the ethanol was removed under reduced pressure and the crude product obtained was dissolved in chloroform (200 ml). The organic phase was washed first with 1N NaOH (100 ml) and then with saturated NaCl solution (3×100 ml). After drying over anhydrous sodium sulfate and removing the solvent under reduced pressure, 12.0 g (100%) of pure product were thus obtained as a pale yellow oil.