Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH3:11].[OH:12][CH:13]([CH2:16][OH:17])[CH2:14][NH2:15].C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH2:14][CH:13]([OH:12])[CH2:16][OH:17])=[C:3]([CH3:11])[CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: NCC(O)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc([N+](=O)[O-])ccc1NCC(O)CO
Temperature: 60 °C
Yield: 68.6 %

Procedure:
2 g of 2-fluoro-5-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.4 g of 2,3-dihydroxy-1-propylamine, and 2.14 g of K2CO3. The reaction medium was heated at 60° C. for 15 hours and, after cooling to room temperature, was poured into a water/ice mixture. A yellow precipitate formed, which was filtered off, reslurried in water and then dried over P2O5. 2 g of 3-(4-nitro-2-methylphenylamino)propane-1,2-diol (7) were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:32])[C:7]([CH2:18][NH:19][C:20](=O)[O:21]C3C=CC([N+]([O-])=O)=CC=3)=[CH:8][N:9]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:33][O:34][C:35]([C@H:37]1[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1)=[O:36]>>[CH3:33][O:34][C:35]([CH:37]1[CH2:42][CH2:41][CH:40]([NH:43][C:20]([NH:19][CH2:18][C:7]2[C:6](=[O:32])[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)=[O:21])[CH2:39][CH2:38]1)=[O:36]
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Product: COC(=O)C1CCC(NC(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)CC1

Procedure:
4-[3-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-ureido]-cyclohexane-carboxylic acid methyl ester was prepared starting from intermediate M and trans-4-amino-cyclohexane carboxylic acid methyl ester. MS calcd. for C25H27ClN3O4 [(M+H)+] 468.2, obsd. 468.1.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[F:12].[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[O:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][N:35]=1.ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[F:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]([F:12])[C:5]=1[C:4]1[N:30]=[C:29]([C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[C:26]([O:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([F:42])([F:43])[F:41])=[CH:36][N:35]=3)[CH:27]=2)[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1c(F)cccc1F)S(=O)(=O)c1ccccc1
Reactant: COc1ccc(C#N)cc1Oc1ccc(C(F)(F)F)cn1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: COc1ccc(-c2nc(-c3c(F)cccc3F)nn2C)cc1Oc1ccc(C(F)(F)F)cn1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2,6-difluorobenzohydrazonoyl chloride (0.70 g), 4-methoxy-3-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.80 g), anhydrous iron (III) chloride (0.50 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.30 g of desired compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[F-].[Cs+].CS(O[CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1)(=O)=O>CC(N(C)C)=O>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: [Cs+]
Agent: [F-]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-ol (500 mg, 1.565 mmol) was dissolved in DMA (20 ml). tert-Butyl (4-methanesulfonyloxy)piperidine-1-carboxylate (436.6 mg, 1.565 mmol) and cesium fluoride (236.3 mg, 1.565 mmol) were added, and the mixture was heated to 60° C. with stirring. After 18 hours, tert-butyl 4-methanesulfonyloxypiperidine-1-carboxylate and cesium fluoride were again added in the same quantities to the reaction mixture and heating was continued at 60° C. for a further 18 hours. The solvent was evaporated, and the residue was partitioned between saturated aqueous sodium bicarbonate solution (50 ml) and EtOAc (2×50 ml). The organics were combined, dried over MgSO4 and evaporated. The resulting product was then purified by column chromatography eluting with increasingly polar mixtures of methylene chloride/EtOAc (100/0 to 0/100). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidine-1-carboxylate as a colourless foam (757 mg, 96%); 1H NMR Spectrum: (DMSO-d6): 1.52 (s, 9H), 1.60-1.80 (m, 2H), 2.02-2.20 (m, 2H), 3.20-3.45 (m, 2H), 3.75-3.92 (m, 2H), 4.05 (s, 3H), 4.95 (m, 1H), 7.32-7.45 (m, 2H), 7.55-7.70 (m, 2H), 7.92 (s, 1H), 8.50 (s, 1H), 9.73 (s, 1H); Mass Spectrum: (M+H)+ 503.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:6]3=[CH:5][C:4]=2[CH:3]=1.[CH:17]([N:20]1[CH2:25][CH2:24][CH:23](O)[CH2:22][CH2:21]1)([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>>[CH:17]([N:20]1[CH2:25][CH2:24][CH:23]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[N:7]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:6]4=[CH:5][C:4]=3[CH:3]=2)[CH2:22][CH2:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)N1CCC(O)CC1
Reactant: O=C1NCCCn2c1cc1cc(O)ccc12
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc2n3CCCNC2=O)CC1
Yield: 13 %

Procedure:
The title compound was synthesized in analogy to example 1, from 9-hydroxy-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one, 1-isopropyl-piperidin-4-ol (commercially available), triphenylphosphine and di-tert-butyl-azodicarboxylate, to give the desired product as a light yellow oil (13%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23][CH3:24])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:4][C:3]=1[F:25].ClCCl.ClC1C=CC=C(C(OO)=[O:37])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[C:21]3[C:16](=[C:17]([CH2:22][S:23]([CH3:24])=[O:37])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH2:9][CH2:10][C:11]#[N:12])=[CH:4][C:3]=1[F:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(CCC#N)c3ccc(Cl)c(F)c3)c[nH]c12
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(CCC#N)c3ccc(Cl)c(F)c3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
300 mg (0.81 mmol) of the compound from Example 152 were introduced into 55 ml of dichloromethane at 0° C., 198 mg (0.81 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, and the solvents were removed in a rotary evaporator. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 266 mg (85% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(O[CH:18]=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>O>[O:8]([C:5]1[N:6]=[CH:7][C:2]([NH:1][CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:3][CH:4]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc(Oc2ccccc2)nc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: O
Product: CCOC(=O)C(=CNc1ccc(Oc2ccccc2)nc1)C(=O)OCC
Temperature: 25 °C

Procedure:
A mixture of 5-amino-2-phenoxypyridine (10.49 g) and diethyl ethoxymethylenemalonate (12.2 g) was boiled under reflux for 2.5 hours. The mixture was cooled to ambient temperature and water (50 ml) was added. The mixture was extracted with dichloromethane to give diethyl 2-(6-phenoxy-3-pyridylaminomethylene)malonate as an oil.
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]([F:21])=[CH:17][CH:16]=3)=[CH:13][S:12][C:11]=2[CH:22]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][O:30][CH3:31]>>[F: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:27]([CH2:28][CH2:29][O:30][CH3:31])[CH2:26][CH2:25][O:24][CH3:23])=[CH:22][C:11]=3[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: Fc1ccc(-c2csc3cc(OCCCCBr)ccc23)cc1
Reactant: COCCNCCOC
Product: COCCN(CCCCOc1ccc2c(-c3ccc(F)cc3)csc2c1)CCOC

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and bis(2-methoxyethyl)amine were converted to yield {4-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-butyl}-bis-(2-methoxy-ethyl)-amine as colorless oil, MS: 432 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:6]=2[CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=[O:21])C=1>CC(C)=O>[NH2:1][C:2]1[C:7]2[C:8](=[O:12])[N:9]([CH3:11])[CH2:10][C:6]=2[CH:5]=[CH:4][N+:3]=1[O-:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CN1Cc2ccnc(N)c2C1=O
Solvent: CC(C)=O
Product: CN1Cc2cc[n+]([O-])c(N)c2C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
A mixture of 4-amino-2-methyl-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (Compound 3108, 62.5 mg, 0.383 mmol) and m-Chloroperbenzoic acid (145 mg, 0.843 mmol) in Acetone (10.0 mL) was stirred at rt for 90 minutes. The reaction mixture was concentrated under reduced pressure to an off white solid. The crude material was purified by silica gel chromatography on the combi-flash Rf system using DCM/7 N NH3 in MeOH (100:0→90:10) as eluent. The fractions containing product were combined and concentrated under reduced pressure to yield a white solid (68.3 mg, 99.5%). 1H NMR (DMSO-d6, 400 MHz): δ=8.19 (d, J=6.57 Hz, 1H), 7.02 (br. s., 2H), 6.82 (d, J=6.57 Hz, 1H), 4.41 (s, 2H), 3.01 (s, 3H). MS (ES+): m/z 180.07 [MH+] (TOF, polar).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(N(C(C)C)CC)(C)C.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: c1c[nH]cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cc(Br)ccc1-n1ccnc1
Yield: 73.7 %

Procedure:
To a solution of 4-bromo-1-fluoro-2-nitrobenzene (1.12 mL; 9.09 mmol; 1 eq) and diisopropylethylamine (1.58 mL; 9.09 mmol; 1 eq;) in anhydrous acetonitrile (80 mL) is added imidazole (620 mg; 9.09 mmol; 1 eq) under argon. The reaction mixture is allowed to stir under reflux for 65 hours until complete consumption of starting material. The crude mixture is concentrated under vacuum and the resulting powder dissolved in ethyl acetate (60 mL). The organic phase is then washed with water (50 mL), brine (50 mL) and dried over sodium sulfate to provide an orange powder after concentration under vacuum. Further purification by flash chromatography on silica gel (ethyl acetate/cyclohexane 9:1) afforded the title compound (1.81 g; 6.7 mmol; 74%) as an orange powder.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=O)C.C[O-].[Na+].Cl.[NH2:16][C:17]([NH2:19])=[NH:18].Cl>CO.CN(C)C=O>[NH2:19][C:17]1[NH:18][C:7]2=[CH:8][CH:9]=[CH:10][C:6]2=[C:4]([OH:3])[N:16]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)C1CCCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1nc(O)c2cccc-2[nH]1
Yield: 18 %

Procedure:
A solution of 2-ethoxycarbonyl cyclopentanone (114 ml, 0.77mol) and N,N-dimethylformamide (40 ml) was added dropwise to a mixture solution of sodium methoxide(83.2 g, 0.44 mol) and N,N-dimethylformamide(80 ml), while maintaining the temperature of the reaction system below 0° C. A solution of guanidine HCl salt(81 g, 0.85 mol) and methanol(127 ml) was added to the above reaction mixture and then was heated to reflux for 14 hours. The reaction mixture was neutralized by conc. HCl and the resulting solid was filtered and dried under reduced pressure to give 20.69 g of titled compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2([OH:38])[C:19]3[CH:20]=[CH:21][C:22]([O:24][CH2:25][O:26][CH3:27])=[CH:23][C:18]=3[O:17][CH2:16][CH:15]2[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=2)=[CH:10][CH:9]=1.[I-:39].[Na+].O>C(C(C)=O)C>[OH:38][C:14]1([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:39])=[CH:9][CH:10]=2)[C:19]2[CH:20]=[CH:21][C:22]([O:24][CH2:25][O:26][CH3:27])=[CH:23][C:18]=2[O:17][CH2:16][CH:15]1[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][O:36][CH3:37])=[CH:30][CH:29]=1
Reactant: [I-]
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCCCCCl)cc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCCCCI)cc2)cc1
Temperature: 25 °C
Yield: 74.6 %

Procedure:
4-[4-(5-Chloropentyloxy)phenyl]-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (167 mg, 0.3 mmol) and sodium iodide (139 mg, 0.9 mmol) were dissolved in methyl ethyl ketone (5 ml) and then refluxed for 12 hours. The reaction solution was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The concentrate was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 142 mg (yield: 75%) of the title compound as a colorless oil.
Reaction SMILES: [Cl-].[Li+].[CH2:3]([N:9]1[CH:14]=[C:13](I)[C:12]([CH3:16])=[C:11]([N+:17]([O-:19])=[O:18])[C:10]1=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:21]1([Sn](CCCC)(CCCC)CCCC)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.C(OCC)(=O)C>[CH2:3]([N:9]1[CH:14]=[C:13]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]([CH3:16])=[C:11]([N+:17]([O-:19])=[O:18])[C:10]1=[O:20])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCn1cc(I)c(C)c([N+](=O)[O-])c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCn1cc(-c2ccccc2)c(C)c([N+](=O)[O-])c1=O
Yield: 72.2 %

Procedure:
A mixture of bis(triphenylphosphine)Pd(II) chloride (0.014 g), lithium chloride (0.067 g), 1-hexyl-5-iodo-4-methyl-3-nitro-2-pyridone (0.15 g, 0.41 mmol) and phenyltributyltin (0.11 mL, 0.62 mmol) in THF (15 mL) was heated under reflux for 2 days. The mixture was cooled, diluted with ethyl acetate, and washed with aqueous potassium fluoride and water. The organic phase was dried, filtered and evaporated. Chromatography of the residue over silica gel (petroleum ether/methylene chloride 1/1 to methylene chloride is gradient) gave 1-hexyl-4-methyl-3-nitro-5-phenyl-2-pyridone (0.093 g, 72%).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[S:27][C:26](Cl)=[N:25][C:24]=34)=[O:18])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1>CO.[Pd]>[CH3:1][C:2]1[S:3][C:4]([C:29]2[CH:30]=[C:31]([CH3:35])[CH:32]=[CH:33][CH:34]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[S:27][CH:26]=[N:25][C:24]=34)=[O:18])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CNC(=O)c3cccc4sc(Cl)nc34)C[C@@H]3C[C@@H]32)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2[C@H](CNC(=O)c3cccc4scnc34)C[C@@H]3C[C@@H]32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-Chloro-benzothiazole-4-carboxylic acid [(1S,3S,5S)-2-(2-methyl-5-m-tolyl-thiazole-4-carbonyl)-2-aza-bicyclo[3.1.0]hex-3-ylmethyl]-amide (4.2 mg) is added to a suspension of Pd/C (10%, 10.0 mg) in MeOH (1.0 mL). The mixture is stirred at RT under a hydrogen atmosphere (1 bar) for 3 h. After filtration through celite and washing with MeOH the solvents are removed in vacuo to give the desired product. LC-MS (acidic): tR=1.01 min; [M+H]+=489.1.
Reaction SMILES: C([O:3][C:4](=[O:29])/[CH:5]=[C:6](\[CH3:28])/[CH:7]=[CH:8]/[C:9]1[CH2:13][CH2:12][CH2:11][C:10]=1[C:14]1[CH:23]=[CH:22][C:21]2[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)C.[OH-].[Na+]>C1COCC1.CCO>[CH3:28]/[C:6](/[CH:7]=[CH:8]/[C:9]1[CH2:13][CH2:12][CH2:11][C:10]=1[C:14]1[CH:23]=[CH:22][C:21]2[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)=[CH:5]\[C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)/C=C(C)/C=C/C1=C(c2ccc3c(c2)C(C)(C)CCC3(C)C)CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(/C=C/C1=C(c2ccc3c(c2)C(C)(C)CCC3(C)C)CCC1)=C\C(=O)O
Reaction time: 48 h

Procedure:
1.32 g of (2E,4E)-3-Methyl-5-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclopent-1-enyl]-penta-2,4-dienoic acid ethyl ester was dissolved in 13 ml of THF/EtOH=1/1 and treated with 5.6 ml of 3N NaOH. The mixture was kept for 48 h at ambient temperature and then poured onto crushed ice/HCI. Extraction with AcOEt, washing with H2O, drying over Na2 SO4, evaporation of the solvent, and recrystallization from AcOEt afforded 803 mg of the title compound as yellow crystals of mp. 195°-196°(dec.).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:10]([F:12])[F:11])=[CH:5][CH:4]=1.[CH2:13]([NH:20][C:21]([C:23]1[S:24][C:25]([N:29]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:30]2=[O:36])=[CH:26][C:27]=1[CH3:28])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([NH:20][C:21]([C:23]1[S:24][C:25]([N:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([O:9][CH:10]([F:12])[F:11])=[CH:5][CH:4]=3)=[CH:31][C:30]2=[O:36])=[CH:26][C:27]=1[CH3:28])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: FC(F)Oc1ccc(CBr)cc1
Reactant: Cc1cc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccccc1
Product: Cc1cc(-n2ccc(OCc3ccc(OC(F)F)cc3)cc2=O)sc1C(=O)NCc1ccccc1
Yield: 35 %

Procedure:
Following the procedure as described in Example 9, making variations only as required to use 1-(bromomethyl)-4-(difluoromethoxy)benzene in place of 2-cyclopropylethyl 4-methylbenzenesulfonate to react with N-benzyl-5-(4-hydroxy-2-oxopyridin-1(2H)-yl)-3-methylthiophene-2-carboxamide, the title compound was obtained as a pinkish solid in 35% yield: mp 178-180° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.55 (t, J=6.0 Hz, 1H), 8.16 (d, J=8.0 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H) 7.38-7.20 (m, 9H), 6.28 (dd, J=7.9, 2.7 Hz, 1H), 6.14 (d, J=2.7 Hz, 1H), 5.16 (s, 2H), 4.41 (d, J=6.0 Hz, 2H), 2.42 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 166.1, 162.4, 160.9, 150.8, 139.6, 138.8, 137.2, 135.1, 132.4, 129.9, 128.2, 127.3, 127.4, 127.1, 126.6, 120.6, 118.7, 116.2, 102.5, 97.3, 69.2, 42.5, 15.5; MS (ES+) m/z 497.3 (M+1).
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[CH:7][C:8]=1[Cl:9].Cl[CH2:12][CH2:13][CH2:14][OH:15]>>[Cl:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[Cl:9])[O:10][CH2:12][CH2:13][CH2:14][OH:15]
Reactant: OCCCCl
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: [Na]
Product: OCCCOc1ccc(Cl)c(Cl)c1
Yield: 90 %

Procedure:
Preparation analogously to Example 70 by the reaction of 3,4-dichlorophenol sodium salt with 3-chloro-1-propanol to give 3-(3,4-dichlorophenoxy)-1-propanol (m.p. 40°-43°; yield about 90%), which is converted quantitatively into 3-(3,4-dichlorophenoxy)-propyl 1-methanesulphonate (m.p. 41°-43°) and is reacted with excess 5-amino-5-desoxy-1.4;3.6-dianhydro-L-iditol 2-nitrate in boiling ethanol. Isolation as hydrochloride. Yield, after recrystallisation from ethanol: 56%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[CH:24]([O:27][C:28]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[CH:30][N:29]=1)([CH3:26])[CH3:25]>>[CH:24]([O:27][C:28]1[C:33]([C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][C:11]4[S:10][C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)=[N:8][C:7]=4[C:6]=3[CH:23]=2)=[CH:32][CH:31]=[CH:30][N:29]=1)([CH3:26])[CH3:25]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: CC(C)Oc1ncccc1B1OC(C)(C)C(C)(C)O1
Product: CC(C)Oc1ncccc1-c1ccc2c(c1)-c1nc(-c3ncnn3C(C)C)sc1CCO2
Yield: 59 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and 2-isopropoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine were reacted to give 239 (0.102 g, 59%). 1H NMR (400 MHz, DMSO) δ 8.53 (d, J=2.2, 1H), 8.23-8.03 (m, 2H), 7.75 (dd, J=7.3, 1.8, 1H), 7.56 (dd, J=8.4, 2.2, 1H), 7.20-7.00 (m, 2H), 5.72 (dt, J=13.3, 6.6, 1H), 5.35 (dt, J=12.3, 6.2, 1H), 4.43 (t, J=4.9, 2H), 3.47 (t, J=4.9, 2H), 1.50 (d, J=6.6, 6H), 1.29 (d, J=6.2, 6H). MS (ESI(+)): m/z 448.1 (M+H)
Reaction SMILES: [Br:1][CH2:2][C:3](Cl)=[O:4].[Cl:6][C:7]1[CH:8]=[C:9]([CH:14]2[CH2:18][NH:17][CH2:16][CH:15]2[N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[C:24]([F:32])[CH:23]=2)[CH3:20])[CH:10]=[CH:11][C:12]=1[Cl:13].C(N(CC)CC)C>C1COCC1>[Br:1][CH2:2][C:3]([N:17]1[CH2:16][CH:15]([N:19]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[C:24]([F:32])[CH:23]=2)[CH3:20])[CH:14]([C:9]2[CH:10]=[CH:11][C:12]([Cl:13])=[C:7]([Cl:6])[CH:8]=2)[CH2:18]1)=[O:4]
Reactant: O=C(Cl)CBr
Reactant: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CNCC1c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(Cc1ccc(C(F)(F)F)c(F)c1)C1CN(C(=O)CBr)CC1c1ccc(Cl)c(Cl)c1
Yield: 70 %

Procedure:
To a stirred solution of bromo-acetyl chloride (0.146 ml, 1.75 mmol) in THF (15 ml) at RT was added over 1 hour a solution of [(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-(3-fluoro-4-trifluoromethyl-benzyl)-methyl-amine (Intermediate VIII-1, 0.70 g, 1.66 mmol) and triethyl amine (0.25 ml, 1.83 mmol) in THF (10 mL). The reaction was stirred over night, quenched by addition of an aqueous solution of NaHCO3, and the product extracted with EtOAC. Purification by flash chromatography (SiO2, EtOAc/Hx 1:1) yielded 0.63 g (70%) of the title compound as a white solid. ES-MS m/e: 542.6 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:28]=[N:29][CH:30]=[C:31]([CH:35]=1)[C:32]([NH2:34])=[O:33]>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[CH:28]=[N:29][CH:30]=[C:31]([CH:35]=3)[C:32]([NH2:34])=[O:33])=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: NC(=O)c1cncc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NC(=O)c1cncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (400 mg, 1.13 mmol) and 5-bromonicotinamide [CAS 28733-43-9; commercially available] (204 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (140 mg, 26%). MS (ISP) 476.2 [(M+H)+]; mp 285–287° C.