Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O-:9])=O.[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[CH:13][CH:12]=1
Reactant: O=C([O-])c1ccccn1
Reactant: NCc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1ccc(CNC(=O)c2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.2 %

Procedure:
Pyridine-2-carboxylate (Aldrich; 0.35 g, 2.84 mmol), 4-aminobenzylamine (Aldrich; 0.51 g, 4.26 mmol) and HATU (1.65 g, 4.26 mmol) were dissolved in DMF (7.5 ml). N,N-Diisopropylethylamine (1.5 ml, 8.53 mmol) was added and the mixture stirred at room temperature for 2 h. The mixture was absorbed on to an SCX column, washed with methanol and eluted with ammonia in methanol. Product containing fractions were concentrated and the residue purified by normal phase chromatography (2% MeOH/DCM) to give a yellow solid (440 mg). which was suspended in DCM/Et2O and filtered to give the title compound as a pale yellow solid (235 mg, 36%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[CH:8]=[C:7](OS(C(F)(F)F)(=O)=O)[CH:6]=[CH:5][C:4]=2[C:3]1=[O:22].C(N(CC)CC)C.[CH3:30][Si:31]([C:34]#[CH:35])([CH3:33])[CH3:32].C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][CH:2]1[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:35]#[C:34][Si:31]([CH3:33])([CH3:32])[CH3:30])[CH:8]=2)[C:3]1=[O:22]
Reactant: C#C[Si](C)(C)C
Reactant: CC1CC(C)(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC1CC(C)(C)c2cc(C#C[Si](C)(C)C)ccc2C1=O
Yield: 104.6 %

Procedure:
Following General Procedure D and using trifluoro-methanesulfonic acid 6,8,8-trimethyl-5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yl ester (Intermediate 196, 1.45 g, 4.3 mmol), triethyl amine (5 mL), copper(I)iodide (0.21 g, 0.26 mmol), trimethylsilyl acetylene (3 mL, 21 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.75 g, 1.07 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5% ethyl acetate in hexane as the eluent, the title compound (1.28 g, ˜100%) was obtained.
Reaction SMILES: I[C:2]1[C:7]([C:8]([NH:10][NH:11][CH:12]2[CH2:17][CH2:16][CH2:15][O:14][CH2:13]2)=[O:9])=[C:6]([O:18][CH3:19])[N:5]=[CH:4][CH:3]=1.N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:19][O:18][C:6]1[C:7]2[C:8](=[O:9])[NH:10][N:11]([CH:12]3[CH2:17][CH2:16][CH2:15][O:14][CH2:13]3)[C:2]=2[CH:3]=[CH:4][N:5]=1
Reactant: COc1nccc(I)c1C(=O)NNC1CCCOC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1nccc2c1c(=O)[nH]n2C1CCCOC1
Yield: 31.3 %

Procedure:
A solution of 4-iodo-2-methoxy-N′-(tetrahydro-2H-pyran-3-yl)nicotinohydrazide (484 mg), L-proline (29.5 mg), potassium carbonate (355 mg) and copper(I) iodide (24.4 mg) in DMSO (25 mL) was stirred under nitrogen atmosphere at room temperature for 3 hr. The reaction mixture was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (100 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[O:8].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])=[CH:12][C:11]=1O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>C(O)C>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[O:8][C:11]2[CH:12]=[C:13]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:15][C:10]=2[N:9]=1
Reactant: Cn1cccc1C=O
Reactant: COC(=O)Cc1ccc(N)c(O)c1
Solvent: CCO
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: COC(=O)Cc1ccc2nc(-c3cccn3C)oc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
In ethanol (10 ml), 1-methylpyrrole-2-carbaldehyde (0.33 ml, 3.09 mmol) and methyl 4-amino-3-hydroxyphenylacetate (559 mg, 3.09 mmol) were stirred for 4 hours at room temperature. Iodobenzene diacetate (1.19 g, 3.70 mmol) was added to the reaction mixture. After stirring at room temperature for 30 minutes, the reaction mixture was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (3:1, v/v) eluate fractions, methyl (2-(1-methyl-2-pyrrolyl)-6-benzoxazolyl)acetate (228 mg, 27%) was obtained as a yellow solid.
Reaction SMILES: [BH4-].[Na+].Br[CH:4]1[CH:9]2[CH:10]([OH:15])[CH:11]([OH:14])[CH:12]([OH:13])[C:5]1([CH2:17][OH:18])[O:6][C:7](=[O:16])[NH:8]2.C(O)(=O)C>O>[OH:15][CH:10]1[CH:11]([OH:14])[CH:12]([OH:13])[C:5]2([CH2:17][OH:18])[CH2:4][CH:9]1[NH:8][C:7](=[O:16])[O:6]2
Reactant: O=C1NC2C(O)C(O)C(O)C(CO)(O1)C2Br
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC2CC(CO)(O1)C(O)C(O)C2O
Yield: 87 %

Procedure:
Sodium borohydride (55 g) is added by portions to a solution of 9-bromo-6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane (100 g) in water (1.3 l) at 25°-30° C. with stirring. After stirring for 2 hours at the same temperature, the reaction mixture is adjusted to pH 6-7 with acetic acid and concentrated to about 800 ml under reduced pressure. The concentrate is chromatographed on a column of activated carbon (4.8 l), and the column is washed with water (5 l) and eluted with 50% aqueous methanol. The eluate is concentrated under reduced pressure. Methanol (350 ml) is added to the residue and refluxed for 10-20 minutes to remove a methanol soluble by-product. The mixture is allowed to stand in a refrigerator overnight, and the resulting crystals are collected by filtration, followed by washing with cold methanol and drying in a desiccator under reduced pressure to give 6,7,8-trihydroxy-1-hydroxymethyl-3-oxo-2-oxa-4-azabicyclo[3.3.1]nonane (64 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[CH2:16]=O>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([O:14][CH3:15])[CH2:13][CH2:12][N:11]([CH3:16])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COC1(c2cc(F)cc(F)c2)CCNC1
Reactant: C=O
Solvent: O=CO
Product: COC1(c2cc(F)cc(F)c2)CCN(C)C1

Procedure:
Preparation according to Example 16. (−)-3-(3,5-difluorophenyl)-3-methoxypyrrolidine (0.02 g, 0.094 mmol), formic acid (1 ml) and formaldehyde (40% solution in water, 1 ml) was heated at 85° C. for 5 h, workup according to preparation 16. MS m/z (relative intensity, 70 eV) 227 (M+, 5), 212 (32), 197 (28), 141 (45), 57 (bp).
Reaction SMILES: [NH3:1].[N:2]([CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[C:3]=[O:4]>CO>[CH2:5]([NH:2][C:3]([NH2:1])=[O:4])[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: N
Reactant: CCCCCN=C=O
Solvent: CO
Product: CCCCCNC(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 7.0 M solution of ammonia in methanol (32 mL) was dropwise added 1-isocyanatopentane (5.0 g, 0.044 mol). After the addition, the mixture was stirred at room temperature for 1 h and concentrated under reduced pressure to give a white solid, which was directly used for next step without further purification. LCMS calculated for C6H15N2O (M+H): 131.1. found 131.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])[C:6]=1[C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1.[H-].[Na+].Cl[C:28]1[N:33]=[CH:32][C:31]([Br:34])=[CH:30][N:29]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[Br:34][C:31]1[CH:30]=[N:29][C:28]([O:1][CH2:2][CH2:3][O:4][C:5]2[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:13])=[O:14])[C:6]=2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[N:33][CH:32]=1
Reactant: CCCS(=O)(=O)Nc1ncnc(OCCO)c1-c1ccc(C)cc1
Reactant: Clc1ncc(Br)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ncnc(OCCOc2ncc(Br)cn2)c1-c1ccc(C)cc1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 39.1 %

Procedure:
n-Propanesulfonic acid [6-(2-hydroxy-ethoxy)-5-p-tolyl-pyrimidin-4-yl]-amide (115 mg) was dissolved in THF (15 ml). Sodium hydride (60 mg) was added followed by stirring for 15 min at 50° C. Then 2-chloro-5-bromo-pyrimidine (135 mg) was added and stirring was continued for 8 h at 75° C. The reaction mixture was poured onto ice water, acidified with solid citric acid and extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered and the solvent was evaporated. The crude material was purified by plate chromatography with diethyl ether to give n-propanesulfonic acid {6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-5-p-tolyl-pyrimidin-4-yl}-amide (65 mg) as a white powder. LC-MS: tR: 4.91, [M+H]+: 510.13.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O.Cl>C1COCC1.O>[C:22]([O:21][C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([OH:12])=[O:11])([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)[C@H](CCCCCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 1.5 h

Procedure:
I2 was dissolved in a mixture of THF and H2O (4:1, 0.35M solution) at RT and LiOH.H2O (1.1 eq.) was added and the mixture was then stirred for 1.5 hr. 1M HCl was added until pH 4-5, then the THF was removed under reduced pressure. The aqueous phase was extracted with EtOAc (3×); the collected organic phases were washed with brine and then dried (Na2SO4). After removal of the solvent the title compound was obtained as a colorless oil which solidified upon standing, this was used in the next step without purification. 1H NMR (400 MHz, CDCl3) δ: 5.23 (1H, br. s), 4.13 (1H, br. s), 2.21 (2H, t, J=7.4 Hz), 1.75-1.90 (1H, m), 1.70-1.50 (3H, m), 1.45 (9H, s), 1.44 (9H, s), 1.50-1.25 (4H, m) MS (ES) C17H31NO6 requires: 345, found: 346 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[C:5]([C:12]([NH:14][CH3:15])=[O:13])[CH:4]=1.N1(C2C=C(C=C([N+]([O-])=O)C=2)C(NC)=O)CCOCC1>>[NH2:9][C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:8]=1)[C:12]([NH:14][CH3:15])=[O:13]
Reactant: CNC(=O)c1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: CNC(=O)c1cc(N2CCOCC2)cc([N+](=O)[O-])c1
Product: CNC(=O)c1cc(N)cc(C(F)(F)F)c1

Procedure:
Utilising the procedure described in Example 86e, but employing α,α,α-trifluoro-N-methyl-5-nitro-m-toluamide (Dean E. Welch, J. Med. Chem. (1969), 12, 299-303) in lieu of 3-(4-morpholinyl)-5-nitro-N-(methyl)-benzamide, afforded the title compound as a beige crystalline solid, m.p. 113-115° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH:10]1[NH:17][CH:13]2[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:19]([C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=1)[C:20]1[CH:32]=[CH:31][C:23]([C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([N:8]1[CH:9]2[CH:10]3[N:17]([CH:19]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)[C:20]4[CH:32]=[CH:31][C:23]([C:24]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=4)[CH:13]([CH:14]1[CH2:15][CH2:16]2)[CH2:12][CH2:11]3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(CC)C(=O)c1ccc(C(Cl)c2cccc(OC)c2)cc1
Reactant: c1ccc(CN2C3CCC2C2CCC3N2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)N2C3CCC2C2CCC3N2Cc2ccccc2)cc1
Yield: 52 %

Procedure:
A mixture formed of 9-benzyl-9,10-diazatricyclo[4.2.1.12,5]decane prepared in Example 2.1 (2.19 mmoles), 4-[chloro-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide obtained in Example 3.1 (1.5 equivalents), anhydrous potassium carbonate (3 equivalents) and acetonitrile (20 ml), is heated at reflux for 3 days. At the end the mixture was filtered under vacuum and the liquid phase recovered. The solvent was evaporated under vacuum and the residual oil purified by flash chromatography. The eluent was ligroin/ethyl acetate 7/3 (v/v). The compound 4-[(10-benzyl-9,10-diazatricyclo-[4.2.1.12,5]dec-9-yl)-(3-methoxyphenyl)methyl]-N,N-diethylbenzamide was obtained. Yield: 52%. IR (nujol) (λ=cm−1) 1680 (C═O); 1H-NMR (CDCl3) δ 1.00-1.30 (m, 6H); 1.60-2.20 (m, 8H); 2.75-2.85 (m, 4H); 3.20-3.36 (m, 2H); 3.37 (s, 2H); 3.40-3.60 (m, 2H); 3.80 (s, 3H); 4.28 (s, 1H); 6.70-6.80 (m, 1H); 7.00-7.40 (m, 10H); 7.55 (d, 2H, J=8.4 Hz). Anal. calc. for C34H41N3O2: C, 77.98; H, 7.89; N, 8.02. Found: C, 77.76; H, 7.91; N, 8.12.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[N:3]=1.[C:8]1([CH:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][C:15](=[O:16])[CH:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:3]=1
Reactant: Cc1nc(N)no1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: Cc1nc(NC(=O)C(c2ccccc2)c2ccccc2)no1

Procedure:
The title compound, white solid, m.p. 153° C. and MS: m/e=293 (M+) was prepared in accordance with the general method of example 44a from 5-methyl-[1,2,4]oxadiazol-3-ylamine (EP 413545) and 2,2-diphenylacetic acid chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:5]([OH:12])=[C:4]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:3]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].[OH-].[Na+]>C(Cl)(Cl)Cl>[C:13]([C:4]1[CH:3]=[C:2]([NH:1][S:18]([CH3:17])(=[O:20])=[O:19])[CH:7]=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[C:5]=1[OH:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: CS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc(NS(C)(=O)=O)cc(C(C)(C)C)c1O
Temperature: 35 °C
Yield: 18 %

Procedure:
To a solution of 11.05 grams (0.05 mole) of 4-amino-2,6-di-tert-butylphenol in 60 ml of chloroform was added with stirring 5.75 grams (0.05 mole) of methanesulfonyl chloride over a 5-minute period. The reaction mixture was heated to 35° C for 15 minutes followed by the dropwise addition of 8.0 grams (0.05 mole) of a 25% aqueous sodium hydroxide solution and finally heating at 47° C for 30 minutes. After cooling to room temperature, the chloroform layer was separated, washed with water and dried over 4A Molecular Sieves and filtered. The solvent was removed in vacuo, and the residue was washed with hexane leaving 5.8 grams of a crude pink product. Recrystallization from toluene and again from ethylene dichloride gave 2.7 grams of colorless crystals melting at 149°-151° C. (Compound 2)
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23]Br>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH2:23][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: COc1cccc(CBr)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: COc1cccc(CN2N(C3C4CC5CC(C4)CC3C5)C(=O)C2(C)C)c1

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 3-methoxybenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([CH:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4].C([Li])CCC.[C:26](=[O:28])=[O:27]>CCCCC>[CH3:1][O:2][C:3]([C:5]1([C:26]([OH:28])=[O:27])[C:13]2[C:8](=[CH:9][C:10]([CH:14]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCc2cc(C3CCCCCC3)ccc21
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCC
Product: COC(=O)C1(C(=O)O)CCc2cc(C3CCCCCC3)ccc21

Procedure:
melting point 140°-141° C (from pentane), from 10 g of 5-cycloheptyl-1-indanecarboxylic acid methyl ester, 12.8 ml of a 2.6 N solution of butyl-lithium and carbon dioxide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:13]#[N:14])([CH3:12])[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])=[C:5]2[OH:27]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:13]#[N:14])([CH3:12])[C:7](=[O:15])[C:6]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:5]2[OH:27]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C#N)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C#N)C(=O)C(C(=O)NCC(=O)O)=C(O)c2cc(Cl)ccc21
Reaction time: 0.75 h

Procedure:
1,1-Dimethylethyl N((6-chloro-1-cyano-4-hydroxy-1-methyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (0.160 g, 0.41 mmol) was placed in a 25 mL round bottom flask and TFA (20 mL) was added. The mixture was stirred for 45 minutes. TFA was then removed under vacuum, and DCM was used to azeotrope off the remaining TFA (3×) until the oil turned into a solid. MS m/e=335 (M+H)+. Calculated for C15H11ClN2O5 334.04.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[C:4]([NH:16][C:17]2[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=2)[N:3]=1.[O:23]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24]1>>[CH3:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][CH3:13])[C:2]([O:28][CH:25]1[CH2:26][CH2:27][O:23][CH2:24]1)=[N:3][C:4]([NH:16][C:17]1[CH:21]=[C:20]([CH3:22])[NH:19][N:18]=1)=[CH:5]2
Reactant: COc1cc2cc(Nc3cc(C)[nH]n3)nc(Cl)c2cc1OC
Reactant: OC1CCOC1
Product: COc1cc2cc(Nc3cc(C)[nH]n3)nc(OC3CCOC3)c2cc1OC

Procedure:
Similar procedure as described in example 10 was used, starting from (1-Chloro-6,7-dimethoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and tetrahydro-furan-3-ol to give [6,7-Dimethoxy-1-(tetrahydro-furan-3-yloxy)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 371(MH+).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:13][N:14]=[C:15]=[O:16].Cl>N1C=CC=CC=1>[CH2:11]([O:10][C:8]([C:3]1[C:4]([CH3:7])=[N:5][S:6][C:2]=1[NH:1][C:15]([NH:14][CH3:13])=[O:16])=[O:9])[CH3:12]
Reactant: CCOC(=O)c1c(C)nsc1N
Reactant: CN=C=O
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nsc1NC(=O)NC
Temperature: 80 °C

Procedure:
A solution of 5-amino-4-ethoxycarbonyl-3-methylisothiazole (prepared by the method of Goerdeler and Horn, op cit; 3.72 g.) in pyridine (10 ml.) was treated at 80° C. with methyl isocyanate (1.5 ml.) and the mixture was maintained at 80° C. for 6 hours. The mixture was then poured into an excess of dilute aqueous hydrochloric acid to give an off-white precipitate which was filtered off and recrystallised from ethanol to give colourless crystals of 1-(4-ethoxycarbonyl-3-methylisothiazol-5-yl)-3-methylurea (1.6 g.), m.p. 191°-193° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]3[NH:18][CH:19]=[C:20]([CH2:24][C:25]4[CH:26]=[N:27][CH:28]=[N:29][CH:30]=4)[C:21](=[O:23])[N:22]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:31]([F:34])([F:33])[F:32].[CH3:35]CN(C(C)C)C(C)C.CI>ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]3[N:18]([CH3:35])[CH:19]=[C:20]([CH2:24][C:25]4[CH:30]=[N:29][CH:28]=[N:27][CH:26]=4)[C:21](=[O:23])[N:22]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:31]([F:34])([F:32])[F:33]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=c1nc(CCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)[nH]cc1Cc1cncnc1
Solvent: CI
Solvent: CC(Cl)Cl
Product: Cn1cc(Cc2cncnc2)c(=O)nc1CCc1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.8 %

Procedure:
To the solution of 2-[2-(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)ethyl]-5-(5-pyrimidinylmethyl)-4(1H)-pyrimidinone (200 mg, 0.411 mmol) in dichloroethane (5 ml) was added DIPEA (0.143 ml, 0.822 mmol). It was stirred at rt for 30 min, mixed with MeI (0.031 ml, 0.493 mmol) dropwise, then stirred at r.t. overnight. Purification via MDAP then afforded the title compound (16 mg, 7.8%). LCMS: rt=3.04 min, [M+H+]=501
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]=2[C:18]([OH:20])=O)=[CH:4][CH:3]=1.Cl.[NH2:22][CH2:23][C:24]1[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[NH:10][C:9]=2[C:18]([NH:22][CH2:23][C:24]2[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=2)=[O:20])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnc(CN)cn1
Reactant: O=C(O)c1[nH]c(-c2cccs2)cc1-c1ccc(F)cc1
Agent: Cl
Product: COC(=O)c1cnc(CNC(=O)c2[nH]c(-c3cccs3)cc2-c2ccc(F)cc2)cn1
Yield: 76 %

Procedure:
This material was prepared using a method substantially similar to that of Example 5 from 3-(4-fluorophenyl)-5-(2-thienyl)-1H-pyrrole-2-carboxylic acid and methyl 5-(aminomethyl)pyrazine-2-carboxylate hydrochloride, yielding the title compound. Methyl 5-[({[3-(4-fluorophenyl)-5-(2-thienyl)-1H-pyrrol-2-yl]carbonyl}amino)methyl]pyrazine-2-carboxylate: Yield 76%; 1H-NMR (500 MHz, δ ppm, CDCl3) 9.47 (sb, 1H), 9.07 (s, 1H), 8.64 (s, 1H), 7.47 (dd, J=8.3 Hz, J′=5.5 Hz, 2H), 7.24 (d, J=4.5 Hz, 1H), 7.21 (d, J=3.0 Hz, 1H), 7.16 (t, J=8.6 Hz, 2H), 7.06 (dd, J=4.5 Hz, J′=4.1 Hz, 1H), 6.64 (t, J=4.6 Hz, 1H), 6.40 (d, J=2.9 Hz, 1H), 4.72 (d, J=5.2 Hz, 2H), 4.04 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:20][O-:21].[Na+]>C1(C)C=CC=CC=1.CO>[CH2:13]([O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([O:21][CH3:20])[CH:11]=[CH:10]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[O-]
Reactant: Clc1ccc2cccc(OCc3ccccc3)c2n1
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc2cccc(OCc3ccccc3)c2n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
The crude 2-chloro-8-benzyloxyquinoline from above was dissolved in toluene (10 mL) and added to a stirred 25 wt % solution of NaOMe in MeOH (50 mL). The reaction solution was heated with stirring overnight at 70° C. After cooling to room temperature, the reaction solution was poured onto ice and extracted with toluene. The combined organic extracts were dried (MgSO4) and concentrated in vacuo to give a colorless oil (6.14 g, 92%). The product was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12](=[O:19])[N:11]([CH2:20][C:21]([OH:23])=O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][NH2:46]>>[NH:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34]=[C:33]1[NH:41][CH2:42][CH2:43][CH2:44][CH2:45][NH:46][C:21](=[O:23])[CH2:20][N:11]1[CH2:10][CH2:9][CH:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:24])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[C:12]1=[O:19]
Reactant: NCCCCNc1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)CC1CCN(CC(=O)O)C(=O)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)CC1CCN(CC(=O)NCCCCNc2nc3ccccc3[nH]2)C(=O)c2ccccc21

Procedure:
Analogously to Example IX, compound 3 was reacted with 1.0 g (3.1 mmol) of compound 9 and the reaction product was purified by column chromatography (eluent: diethyl ether/MeOH/ammonia, 40/10/2.5), 0.78 g of white amorphous powder; ESI-MS [M+H+]: 520.