Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[CH:11][CH:10]=1)=[O:2].S([CH2:36][N+:37]#[C-:38])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CO>[O:2]1[C:1]([C:3]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])=[CH:11][CH:10]=2)=[CH:38][N:37]=[CH:36]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=CC1=C(c2ccc(NC(=O)c3c(F)cccc3F)cc2)CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(Nc1ccc(C2=C(c3cnco3)CCCC2)cc1)c1c(F)cccc1F
Yield: 65 %

Procedure:
The solution of Compound 100 (60 mg, 0.17 mmol), tosylmethylisocyanide (38 mg, 0.19 mmol) and K2CO3 (50 mg, 0.36 mmol) in MeOH (5 mL) were heated at 90° C. for 40 min before it was filtered and concentrated. The residue was dissolved in EtOAc (10 mL) and H2O (10 mL). The organic phase was collected, dried and concentrated. Column chromatography afforded Compound 23 (47, 65%). 1H NMR (300 MHz, CDCl3) δ 7.64-7.59 (m, 4 H), 7.46-7.40 (m, 1 H), 7.12 (d, J=8.7 Hz, 2 H), 7.01 (t, J=8.1 Hz, 2 H), 6.21 (s, 1 H), 2.49-2.40 (m, 4 H), 1.84-1.76 (m, 4 H); ESMS cacid (C22H18F2N2O2): 380.1; found: 381.1 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10][CH2:11]Br.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C)C=O>[C:13]1([S:19][CH2:11][CH2:10][CH2:9][CH2:8][Br:7])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCCCCBr
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCCSc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Potassium carbonate (5.64 g) and 1,4-dibromobutane (5.88 g) were added to a solution of thiophenol (3 g) in dimethylformamide (40 ml), and the mixture was stirred at 50° C. for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried and the solvent was evaporated under reduced pressure to give 6.67 g of 4-phenylthiobutyl bromide.
Reaction SMILES: [CH2:1]([Li:5])[CH2:2][CH2:3][CH3:4].[CH3:6][C:7]1[CH:8]=[N:9][C:10]2CCCC[C:15]=2[CH:16]=1>CCCCCC.O1CCCC1>[Li:5][CH:1]1[C:10]2[N:9]=[CH:8][C:7]([CH3:6])=[CH:16][C:15]=2[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc2c(c1)CCCC2
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]C1CCCc2cc(C)cnc21
Reaction time: 0.5 h

Procedure:
A solution of n-butyl-lithium (15% w/w, 36 ml, 0.05 mole) in hexane was added portionwise to a stirred solution of 3-methyl-5,6,7,8-tetrahydroquinoline (7.3 g, 0.05 mole) in dry tetrahydrofuran (50 ml.) at 0° under nitrogen. After the addition the solution was stirred for 0.5 hour to give a dark red solution of 8-lithio-3-methyl-5,6,7,8-tetrahydroquinoline.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[CH3:24][O:25][CH2:26][CH2:27][NH:28][CH2:29][CH3:30]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:28]([CH2:29][CH3:30])[CH2:27][CH2:26][O:25][CH3:24])=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: CCNCCOC
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Product: CCN(CCCCOc1ccc2c(-c3ccc(Br)cc3)c(C)sc2c1)CCOC

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and N-(2-methoxy-ethyl)-ethylamine were converted to yield {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-ethyl-(2-methoxy-ethyl)-amine as yellowish oil, MS: 476 (MH+,1Br).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([NH2:38])[CH2:37][CH2:36]2)=[CH:31][CH:30]=1>C1COCC1>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2([NH:38][C:2]3[N:7]=[C:6]([O:8][CH2:9][C:10]([F:11])([F:12])[F:13])[N:5]=[C:4]([NH:14][C:15]4[CH:16]=[CH:17][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[CH:26][CH:27]=4)[N:3]=3)[CH2:36][CH2:37]2)=[CH:33][CH:34]=1
Reactant: NC1(c2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Yield: 37.8 %

Procedure:
To a slurry of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (3.6 g, 8.89 mmol) and 1-(4-chlorophenyl)cyclopropanamine (1.491 g, 8.89 mmol) in THF (50 mL) was stirred for 5 h at 80° C. The precipitate was filtrated through a plug washing with THF to give acrude product that was purified by Biotage eluting with 4/1-hexane/ethyl acetate to give 1.8 g of tert-butyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate as a solid. LC-MS (Condition A), MS m/z (M++H) 536.0. A solution of above tert-butyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (4 g, 7.46 mmol) and HCl in dioxane (7.46 ml, 4 M) was stirred for 4 h. Concentration gav 3.58 g of the desired product as a solid, LC-MS (Condition A), MS m/z (M++H) 480.05.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[I:13]Cl.S(=O)(O)[O-].[Na+]>C(O)(=O)C>[I:13][C:12]1[C:2]([F:1])=[CH:3][C:4]2[O:9][CH2:8][C:7](=[O:10])[NH:6][C:5]=2[CH:11]=1
Reactant: O=C1COc2cc(F)ccc2N1
Reactant: ClI
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1COc2cc(F)c(I)cc2N1
Yield: 94.9 %

Procedure:
7-Fluoro-2H-1,4-benzoxazin-3(4H)-one (15.8 g) was mixed with iodine monochloride (15.6 g) in acetic acid (150 ml) and heated to reflux for 36 h. The cooled mixture was treated with saturated aqueous sodium bisulfite until the color was dissipated. The solid was filtered and washed well with water. The solid was air dried and dried further by dissolution in dimethylformamide (100 ml) and evaporated to dryness under reduced pressure to give the desired product (26.3 g) contaminated with some starting material. (The reaction can be taken to completion by addition of more iodine monochloride and refluxing for 24 h longer. ) The crude product was used in Step B.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.Cl.[NH2:23][CH2:24][C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1)[OH:26]>>[Cl:33][C:29]1[CH:28]=[C:27]([C@@H:25]([OH:26])[CH2:24][NH:23][CH:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:21]=[CH:20][C:11]([CH2:12][CH:13]4[S:17][C:16](=[O:18])[NH:15][C:14]4=[O:19])=[CH:10][CH:9]=3)[CH2:4][CH2:3]2)[CH:32]=[CH:31][CH:30]=1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Reactant: NC[C@H](O)c1cccc(Cl)c1
Agent: Cl
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)c4cccc(Cl)c4)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) and (1R)-2-amino-1-(3-chloro-phenyl)-ethanol (which was obtained in Example 1) according to the procedure of Example 73 as a pale yellowish solid; mp>195–198° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.60 (m, 2 H), 1.85–2.10 (m, 2 H), 2.60–3.50 (m, 7 H), 3.65 (brd, J=12.5 Hz, 2 H), 4.63 (dd, J=9.5, 4.1 Hz, 1 H), 4.74 (dd, J=8.8, 3.1 Hz, 1 H), 6.86 (d, J=8.7 Hz, 2 H), 7.05 (d, J=8.7 Hz, 2 H), 7.20–7.50 (m, 4 H); MS (ES) m/z: 460.0 (MH+); HRMS Calcd. for C23H26ClN3O3S (M+): 459.1383. Found: 459.1376.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[O:8])[C@H:4]([CH2:20][N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:3]1.N1C=CC=CC=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:33][S:34]([O:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[O:8])[C@H:4]([CH2:20][N:21]2[CH2:25][CH2:24][NH:23][C:22]2=[O:26])[CH2:3]1)(=[O:36])=[O:35]
Reactant: O=C1NCCN1C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CN2CCNC2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-4-hydroxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methyl pyrrolidine (1.60 g), pyridine (0.43 ml) and N,N-dimethylaminopyridine (0.54 g) in dichloromethane (20 ml) was added methanesulfonyl chloride (0.37 ml) under ice-cooling and the mixture was stirred under the same condition for 1 hour and then allowed to stand at ambient temperature for 3 hours. The reaction mixture was washed successively with 1N hydrochloric acid, aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of chloroform and methanol (9:1 V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(2-oxoimidazolidin-1-yl)methylpyrrolidine (1.90 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].Cl.[CH3:14][O:15][C:16](=[O:26])[CH2:17][C:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>ClCCl>[CH3:14][O:15][C:16](=[O:26])[CH2:17][C:18]1([CH2:24][NH:25][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)CC1(CN)CCCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CC1(CNC(=O)c2ccccc2[N+](=O)[O-])CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
To a mixture of 2-nitrobenzoyl chloride (0.3 mL, 2.05 mmol) and (1-aminomethyl-cyclohexyl)-acetic acid methyl ester hydrochloride (500 mg, 2.25 mmol) (prepares according to example A) in dichloromethane (10 mL) is added DIPEA (0.75 mL, 4.02 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated and the resulting residue is purified by flash chromatography with 50% EtOAc in Hexane as the eluent to afford the desired {1-[(2-nitro-benzoylamino)-methyl]-cyclohexyl}-acetic acid methyl ester (680 mg, 99%).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=O>C(O)C.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:13][CH2:12][C:11]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH2:10][CH2:9]1
Reactant: c1ccc(CN2CCC3(CCCCc4ccccc43)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O=CO
Product: c1ccc2c(c1)CCCCC21CCNCC1
Yield: 65.6 %

Procedure:
A solution of 1'-benzylspiro[6,7,8,9-tetrahydro-5H-benzocyclohepten-5,4'-piperidine] (526 mg, 1.7 mmol) in ethanol (100 ml), containing formic acid (6 ml), was hydrogenated at 50 p.s.i. in the presence of palladium hydroxide on carbon (Pearlman's catalyst) (250 mg, 50% (w/w)) for 6 hours. The solution was filtered and the solvents removed in vacuo. The residue was taken up in ethyl acetate (50 ml) and washed with 10% (w/v) potassium hydroxide in water (50 ml). The organic phase was separated and the aqueous layer extracted once more with ethyl acetate (50 ml). The combined organic layers were dried (MgSO4) and the solvents removed in vacuo to give spiro [6,7,8,9-tetrahydro-5H-benzocyclohepten-5,4'-piperidine] (240 mg, 65%), which was used without further purification.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[F:5][C:6]1[C:11]2[NH:12][C:13](=[O:15])[O:14][C:10]=2[CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1.N12CCCN=C1CCCCC2>CN(C=O)C>[F:5][C:6]1[C:11]2[N:12]([CH:2]([CH3:4])[CH3:3])[C:13](=[O:15])[O:14][C:10]=2[CH:9]=[C:8]([N+:16]([O-:18])=[O:17])[CH:7]=1
Reactant: O=c1[nH]c2c(F)cc([N+](=O)[O-])cc2o1
Reactant: CC(C)I
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(C)n1c(=O)oc2cc([N+](=O)[O-])cc(F)c21

Procedure:
Prepared from 2-iodopropane (0.76 ml, 7.57 mmol), 4-fluoro-6-nitro-1,3-benzoxazol-2(3H)-one (EXAMPLE 86, Step 5, 1.2 g, 6.06 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.13 ml, 7.57 mmol) in DMF (10 ml) according to the method of EXAMPLE 86, Step 6 (0.87 g, 60%); mp 122-3° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:14]1([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:23]1[CH2:24][CH2:25][N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:21][CH2:22]1)=[O:5]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1F
Product: O=C(c1cc([N+](=O)[O-])ccc1F)N1CCN(c2ccccc2)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 2-Fluoro-5-nitro-benzoyl chloride and 1-phenyl-piperazine (70%, orange solid, MS (m/e): 330.1 (M+H, 100%)
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C([O:18][C:19](=[O:48])[CH2:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC)=[O:37])[CH:31]=2)=[O:29])[CH:25]=[CH:24][C:23]=1[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]Br)C>CCCCCC.C(OCC)(=O)C>[C:36]([C:32]1[CH:31]=[C:30]([C:28]([C:26]2[CH:25]=[CH:24][C:23]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][O:1][C:2]3[CH:12]=[CH:11][C:5]4[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=4[C:3]=3[CH2:13][CH2:14][CH3:15])=[C:22]([CH2:21][CH2:20][C:19]([OH:48])=[O:18])[CH:27]=2)=[O:29])[CH:35]=[CH:34][CH:33]=1)([OH:38])=[O:37]
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Reactant: CCOC(=O)CCc1cc(C(=O)c2cccc(C(=O)OCC)c2)ccc1CCCCCCBr
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCCCCc2ccc(C(=O)c3cccc(C(=O)O)c3)cc2CCC(=O)O)ccc2c1OCCC2=O
Yield: 32.6 %

Procedure:
Starting with 0.169 g (0.82 mmol) of 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one and 0.425 g (0.82 mmol) of 2-(6-bromohexyl)-5-[[3-(ethoxycarbonyl)phenyl]carbonyl]benzenepropanoic acid ethyl ester, the title compound (0.157 g; 34.7% overall yield) was obtained as a white solid, mp 137°-139° C. (recrystallized from hexane-ethyl acetate), using the procedure of example 22.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:34][C:35]1[CH:40]=[C:39](B(O)O)[CH:38]=[CH:37][N:36]=1>>[Cl:34][C:35]1[CH:40]=[C:39]([N:17]2[C:18]3[C:14](=[CH:13][C:12]([C:10]([N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]4)=[O:11])=[CH:20][CH:19]=3)[CH:15]=[C:16]2[C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH2:25][CH2:24]2)=[O:22])[CH:38]=[CH:37][N:36]=1
Reactant: CC(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Reactant: OB(O)c1ccnc(Cl)c1
Product: CC(C)C(=O)N1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2ccnc(Cl)c2)CC1
Yield: 43 %

Procedure:
The title compound was synthesized in analogy to example 5, after stirring for 6.5 days at 35° C., from 1-{4-[5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carbonyl]-piperazin-1-yl}-2-methyl-propan-1-one (example 31) and 2-chloropyridine-4-boronic acid to afford the desired product as light-brown foam (43%). MS (ISP): 565.4 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][NH:4][C:5](=[O:25])[NH:6][C:7]1[CH:8]=[C:9]([C:13]2[N:17]3[CH:18]=[CH:19][C:20]([C:22]([NH2:24])=[O:23])=[CH:21][C:16]3=[N:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1.CC(O[CH:33](N(C)C)[N:34]([CH3:36])[CH3:35])(C)C.CCOCC>CN(C=O)C>[CH3:33][N:34]([CH3:36])/[CH:35]=[N:24]/[C:22]([C:20]1[CH:19]=[CH:18][N:17]2[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([NH:6][C:5]([NH:4][CH2:3][C:2]([F:1])([F:26])[F:27])=[O:25])[CH:8]=3)=[CH:14][N:15]=[C:16]2[CH:21]=1)=[O:23]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: NC(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)/C=N/C(=O)c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Reaction time: 1 h
Yield: 74.2 %

Procedure:
To a stirred solution of 3-[3-[3-(2,2,2-trifluoroethyl)ureido]-phenyl}imidazo[1,2-a]pyridine-7-carboxylic acid amide (20 mg, 0.053 mmol) in dry DMF (0.5 ml) was added Bredereck's reagent (25 μl, 0.12 mmol) and the reaction mixture stirred for 1 h. Et2O was added to the reaction and the resulting precipitate filtered off. The precipitate was redissolved in MeOH, transferred to a flask and the solvent removed in vacuo to afford a pale yellow solid (17 mg). MS: [M+H]+433.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH2:17]([N:24]([CH:29]([CH3:31])[CH3:30])[C:25](=[O:28])[CH:26]=[CH2:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:27][CH2:26][C:25]([N:24]([CH:29]([CH3:30])[CH3:31])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:28])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(=O)N(Cc1ccccc1)C(C)C
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)N(Cc1ccccc1)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 5 mmole), N-benzyl-N-isopropyl-2-propenamide (1.0 g, 5 mmole) (prepared from acryloyl chloride and benzylisopropylamine), and triethylamine (0.05 ml) in methanol was stirred for 60 hours at room temperature. The reaction mixture was concentrated in vacuo to an oil. Chromatography on silica gel gave the title compound.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].C([O:23][C:24](=O)[CH2:25][CH:26]([OH:30])[CH2:27][C:28]#[N:29])C>O1CCCC1>[C:28]([CH2:27][CH:26]([OH:30])[CH2:25][C:24](=[O:23])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:29]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CC(O)CC#N
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(=O)CC(O)CC#N
Temperature: -55 °C

Procedure:
To a vessel containing 265 kg of 16.8% n-butyllithium is added a mixture of 80 kg of diisopropylamine in 80 L of tetrahydrofuran maintaining the temperature at less than 20° C. The solution is cooled to −55° C., and 85 kg of tert-butyl acetate is added maintaining the temperature at −50°±5° C. A solution of 25 kg of R 4-cyano-3-hydroxybutanoic acid ethyl ester in 55 L of tetrahydrofuran is then added, and the temperature is allowed to warm to −20° C. for at least 20 minutes. The solution is then quenched by transferring to aqueous hydrochloric acid. The organic layer is separated and the aqueous layer re-extracted with ethyl acetate. The combined organic layers are concentrated by vacuum distillation to afford crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]#[N:12].[CH2:13](N)[CH2:14][NH2:15]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][C:11]1[NH:15][CH2:14][CH2:13][N:12]=1
Reactant: Cc1ccc(F)c(CC#N)c1Cl
Reactant: NCCN
Product: Cc1ccc(F)c(CC2=NCCN2)c1Cl

Procedure:
2-(2-Chloro-6-fluoro-3-methyl-benzyl)-4,5-dihydro-1H-imidazole was prepared from (2-chloro-6-fluoro-3-methylphenyl)-acetonitrile and ethylene diamine in analogy to Example 19 b): off-white solid; MS (ISP): 227.0 ((M+H)+.).
Reaction SMILES: C1(OC2C=CC=CC=2)C=CC=CC=1.[N+:14]([C:17]1[CH:22]=[CH:21][C:20](Cl)=[CH:19][C:18]=1[C:24]([F:27])([F:26])[F:25])([O-:16])=[O:15].[CH3:28][C:29]1([CH3:36])[NH:33][C:32](=[O:34])[NH:31][C:30]1=[O:35]>>[F:25][C:24]([F:27])([F:26])[C:18]1[CH:19]=[C:20]([N:31]2[C:30](=[O:35])[C:29]([CH3:36])([CH3:28])[NH:33][C:32]2=[O:34])[CH:21]=[CH:22][C:17]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1C(F)(F)F
Reactant: CC1(C)NC(=O)NC1=O
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CC1(C)NC(=O)N(c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)C1=O
Temperature: 200 °C
Yield: 21 %

Procedure:
The following were introduced into 383.52 ml of phenyl oxide: 225.60 grams of 2-nitro-5-chloro-trifluoromethylbenzene, described in the German Patent No. DRP 637,318, 128.10 grams of 5,5-dimethylhydantoin described in Beil., Vol. 24, 289 and 198.53 grams of cuprous oxide. The mixture was heated to 200° C. for 24 hours, then cooled to 20° C. and filtered. The residue was rinsed with phenyl oxide, then extracted with ethyl acetate. The ethyl acetate phase was concentrated to dryness under reduced pressure at 60° C. and the residue was taken up in ammoniacal dichloroethane. The crystals obtained were dried at 60° C. to obtain 66.55 grams of crude product which, after purification from aqueous ethanol yielded 62.55 grams of purified desired product.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([NH:30][C:31]([NH:33][C:34]4[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:41])=[O:32])=[N:25][CH:26]=[N:27]3)=[CH:22][C:21]=2[O:42][CH3:43])[CH2:12][CH2:11]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([C:24]([NH:30][C:31]([NH:33][C:34]4[C:35]([Cl:41])=[CH:36][CH:37]=[CH:38][C:39]=4[Cl:40])=[O:32])=[N:25][CH:26]=[N:27]3)=[CH:22][C:21]=2[O:42][CH3:43])[CH2:12][CH2:11]1
Reactant: COc1cc2c(NC(=O)Nc3c(Cl)cccc3Cl)ncnc2cc1OCCCN1CCC(CNC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1cc2c(NC(=O)Nc3c(Cl)cccc3Cl)ncnc2cc1OCCCN1CCC(CN)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 58.6 %

Procedure:
A mixture of 1-{7-[3-(4-tert-butoxycarbonylaminomethylpiperidin-1-yl)propoxy]-6-methoxyquinazolin-4-yl}-3-(2,6-dichlorophenyl)urea (0.075 g), trifluoroacetic acid (0.35 ml) and chloroform (1.5 ml) was stirred at ambient temperature for 40 minutes. The mixture was evaporated and the residue was stirred under a 1N aqueous sodium hydroxide solution (3 ml) for 1 hour. The resultant solid was isolated and dried. There was thus obtained the title compound (0.037 g); NMR Spectrum: (DMSOd6) 1:12 (m, 3H), 1.62-1.7 (m, 2H), 1.9 (t, 2H), 2.0 (m, 4H), 2.38-2.54 (m, 4H), 2.92 (m, 2H), 3.3 (m, partially obscured by a water signal), 3.95 (s, 3H), 4.26 (t, 2H), 7.28 (s, 1H), 7.41 (t, 1H), 7.62 (d, 2H), 8.06 (s, 1H), 8.66 (s, 1H); Mass Spectrum: M+H+ 533 and 535.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:12])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
0.072 mol (12.6 g) of 4-chloro-2-nitrophenol, 40 ml of acetone and 9.72 g of potassium carbonate are introduced into a 250 ml three-necked flask equipped with a stirring system, a thermometer and a condenser. The mixture is brought to 40° C and 9.72 g of dimethyl sulphate are then added drop by drop; the mixture is heated under reflux for 5 hours; the potassium sulphate is separated; the acetone solution is concentrated under reduced pressure and the 4-chloro-2-nitroanisole is precipitated. It is separated and then crystallized in a water/acetone mixture.