Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19](OC)=[O:20])[C:11](=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[C:24]1([CH2:30][CH2:31][NH2:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>COCCO>[C:24]1([CH2:30][CH2:31][N:32]2[C:19](=[O:20])[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]3[C:11](=[O:23])[C:10]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[N:4]=[C:3]3[CH2:2]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccccc1-n1c(CCl)nc2ccccc2c1=O
Reactant: NCCc1ccccc1
Solvent: COCCO
Product: O=C1c2ccccc2-n2c(nc3ccccc3c2=O)CN1CCc1ccccc1
Yield: 30.4 %

Procedure:
16.4 g (0.05 mol) of 2-chloromethyl-3-(2-methoxycarbonyl-phenyl)-4H-quinazolin-4-one and 12.1 g (0.1 mol) of 2-phenylethylamine in 100 ml of ethylene glycol monomethyl ether are heated to 100° C. for 5 hours. The solvent is evaporated off on a Rotavapor and 100 ml of water are added to the semi-solid residue. The colourless crystals are filtered off and washed with hot methanol. 5.8 g (30.5% of theory) of 6-(2-phenylethyl)-6,7-dihydro-5H,13H-quinazolino[3,2-a][1,4]benzodiazepine-5,13-dione are obtained.
Reaction SMILES: C(C(C([O-])=O)(O)C(C(C)C)(O)C([O-])=[O:7])(C)C.C(OO)(C)(C)C.[C:23]([C:35]1[CH:36]=[C:37]([CH2:41]/[CH:42]=[CH:43]/[OH:44])[CH:38]=[CH:39][CH:40]=1)#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[C:23]([C:35]1[CH:36]=[C:37]([C@H:41]2[O:7][C@@H:42]2[CH2:43][OH:44])[CH:38]=[CH:39][CH:40]=1)#[C:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCCCC#Cc1cccc(C/C=C/O)c1
Reactant: CC(C)C(O)(C(=O)[O-])C(O)(C(=O)[O-])C(C)C
Agent: [Ti+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: ClCCl
Product: CCCCCCCCCCC#Cc1cccc([C@H]2O[C@@H]2CO)c1
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 916.1 %

Procedure:
To a solution (-)diisopropyltartrate (524 mg) in dry dichloromethane (60 ml) and 4A molecular sieves (1 g) at -20° C. was added titanium(IV) isopropoxide (0.53 ml) followed by t-butylhydroperoxide (3.0M, isooctane) (20 ml). The reaction mixture was stirred for 20 mins at -20° C. and then a solution of trans-3-[3-(1-dodecynyl)phenyl]propene-1-ol (8.88 g) in dichloromethane (20 ml) was added slowly. The mixture was stirred for 1.5 hr and quenched with 25% aqueous sodium hydroxide (6 ml) followed by water (40 ml). The mixture was allowed to warm to room temperature, and was stirred for 30 min. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The organic extracts were combined, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was chromatographed over silica gel (eluted with ethyl acetate/Heptane/1:2). The appropriate fractions were collected and evaporated. The residue was crystallized from heptane to afford 6.5 g (69%) of product, mp 41°-42° C. [α]D25 +33.1° (c. 0.725, chloroform).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[Mn]([O-])(=O)(=O)=[O:13].[K+].[OH2:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10])[C:8]([OH:13])=[O:18]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)c1
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccc([N+](=O)[O-])c(Cl)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
2-Chloro-4-methyl-1-nitro-benzene (1.2 g, 6.99 mmol) in a mixture of water and pyridine (2/1, 30 mL) was heated at 90° C. then potassium permanganate (5.2 g, 32.9 mmol) was added in 4 portions at intervals of 1.5 hours. The reaction mixture was heated at 90° C. for 8 hours and then more potassium permanganate (2 g) was added and the resulting mixture was stirred at 90° C. overnight. More potassium permanganate (2 g) was added and the resulting mixture was stirred at 90° C. for 1 hour, the solid was filtered off on a CELITE™ pad. Water (50 mL) was added to the filtrate; the resulting mixture was acidified until pH<2 and was extracted 3 times with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.19 g (84% yield) of 3-chloro-4-nitro-benzoic acid as a light yellow solid without further purifications
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][N:18]([C:29]2[CH:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[S:31][C:30]=2[C:40]([OH:42])=[O:41])[C:19](=[O:28])[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:19]([N:18]([CH2:17][CH:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1)[C:29]1[CH:33]=[C:32]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[S:31][C:30]=1[C:40]([OH:42])=[O:41])=[O:28]
Reactant: O=C(O)c1sc(-c2ccccc2)cc1N(CC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)c1ccc(Cl)cc1Cl
Agent: [Pd]
Solvent: CO
Product: O=C(O)c1sc(-c2ccccc2)cc1N(CC1CCNCC1)C(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.7 %

Procedure:
4-{[(2-Carboxy-5-phenyl-thiophen-3-yl)-(2,4-dichloro-benzoyl)-amino]-methyl}-piperidine-1-carboxylic acid benzyl ester (124 mg, 0.2 mmol) was dissolved in MeOH (2 mL) and treated with 10% Pd/C (200 mg) under H2 balloon. The reaction was stirred at room temperature for 18 h and the mixture was filtered on celite. The solution was evaporated to a residue that was purified by reverse-phase HPLC to provide 3-[(2,4-Dichloro-benzoyl)-piperidin-4-ylmethyl-amino]-5-phenyl-thiophene-2-carboxylic acid (17.3 mg, 18% yield). 1H NMR (CD3OD, 300 MHz): 7.55 (d, 1H), 7.50 (m, 2H), 7.27-7.39 (m, 4H), 7.25 (s, 1H), 7.18 (dd, 1H), 4.12 (m, 1H), 3.75 (m, 1H), 3.43 (m, 2H), 2.96 (q, 2H), 2.65 (d, 2H), 2.05 (m, 1H), 1.62 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N+:16]([O-])=O)[CH:14]=2)[NH:9][CH:8]=1)[NH2:5].O.O.[Sn](Cl)Cl>CN(C=O)C.O.C([O-])(O)=O.[Na+].CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH2:16])[CH:14]=2)[NH:9][CH:8]=1)[NH2:5]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](N)Cc1c[nH]c2ccc(N)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 148.9 %

Procedure:
The 5-nitrotryptophan methyl ester intermediate of example 47 (0.400 g, 0.72 mmol) was dissolved in DMF (3 mL). Water (0.1 mL) and tin dichloride dihydrate (0.812 g, 3.6 mmol) were added and the mixture heated at 60° C. for 3 h and stirred overnight at room temperature. The reaction mixture was diluted with water (50 mL), saturated aqueous NaHCO3 (20 mL) and EtOAc (50 mL). The mixture was vigorously stirred for 5 min and filtered to remove solids (wash cake with 50 mL of EtOAc). The organic layer from the filtrate was washed with water (3×50 mL) and brine (50 mL), and subsequently dried over MgSO4. Volatiles were removed under reduced pressure and the residue was triturated with TBME (10 mL) to give the 5-aminotryptophan methyl ester derivative as a white solid (0.250 g).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[Cl-].C([Al+]CC)C.[CH3:17][C:18]1([C:25](Cl)=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>ClCCl>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:25]([C:18]3([CH3:17])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:26])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC1(C(=O)Cl)CCCCCC1
Reactant: Brc1cnc2[nH]ccc2n1
Agent: CC[Al+]CC
Agent: [Cl-]
Solvent: ClCCl
Product: CC1(C(=O)c2c[nH]c3ncc(Br)nc23)CCCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32.4 %

Procedure:
A suspension of 2-bromo-5H-pyrrolo[2,3-b]pyrazine (100 mg, 0.505 mmol) in anhydrous dichloromethane (10 ml) was cooled to 0° C. under N2. Diethyl aluminum chloride (1M in hexanes, 1.50 ml, 1.50 mmol) was added quickly, and the reaction mixture was stirred for 30 minutes. 1-Methyl-cycloheptanecarbonyl chloride (882 mg, 5.05 mmol) was added dropwise, and the reaction mixture was refluxed overnight. The reaction mixture was cooled to 0° C. and quenched with saturated aqueous NaHCO3. The biphasic solution was concentrated, and the remaining aqueous solution was extracted with ethyl acetate. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a pale brown solid. The residue was purified by silica gel chromatography using 19-74% EtOAc in hexanes as eluant providing 55 mg (32%) of (2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-(1-methyl-cycloheptyl)-methanone as a white solid. MP 197.7-198.2° C., M+H=336.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:15])[CH2:11][CH2:12][CH:13]=[CH2:14])=[CH:6][CH:5]=1.N1C2C(=CC=CC=2)C=CC=1>CCOCC>[Br:1][CH2:14][CH:13]1[CH2:12][CH2:11][CH:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)[O:15]1
Reactant: BrBr
Reactant: C=CCCC(O)c1ccc(Cl)cc1
Solvent: c1ccc2ncccc2c1
Solvent: CCOCC
Product: Clc1ccc(C2CCC(CBr)O2)cc1
Yield: 18.1 %

Procedure:
16 g (0.1 mole) of bromine are added dropwise to 17.3 g (0.1 mole) of 5-(4-chlorophenyl)-pent-1-en-5-ol in 50 ml of absolute ether at 0° C. When the addition has ended, 13 g (0.1 mole) of quinoline are added, whereupon the temperature rises to 15° C. and quinoline hydrobromide precipitates. The precipitate is filtered off with suction, the filtrate is evaporated in vacuo and the residue is heated on a waterbath for 1 hour. After cooling, the residue is taken up in ether, the mixture is washed with 15% strength hydrochloric acid and with water, dried over sodium sulphate and concentrated in vacuo and the residue is distilled under a high vacuum. 5 g (18% of theory) of 2-bromomethyl-5-(4-chlorophenyl)tetrahydrofuran of boiling point 145° C./0.13 mbar are obtained. ##STR111##
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=O)[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1.[NH:21]([C:23]([NH:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=1)=[S:24])[NH2:22].CN(C)C=O>Cl.O>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:22][NH:21][C:23]([NH:25][C:26]3[CH:34]=[CH:33][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=3)=[S:24])[CH3:16])[C:10]=2[OH:18])=[CH:5][CH:4]=1
Reactant: NNC(=S)Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(=NNC(=S)Nc1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Yield: 89.3 %

Procedure:
1-[5-(4-trifluoromethylphenyl)-1-methyl-4-hydroxy-1H-pyrazol-3-yl]ethanone (0.1694 mmol, HPLC purity 80%, 60.2 mg) and 4-hydrazinocarbonothioylaminobenzoic acid (0.1694 mmol, 35.8 mg) were stirred with dimethylformamide (3 mL) and three drops of concentrated hydrochloric acid at room temperature for 8.5 hours. After addition of water, the precipitated yellow solid was recovered by filtration, washed with water and dried by means of a vacuum pump. Chloroform/n-hexane was added to the resulting solid, and the precipitated solid was recovered by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (72.2 mg, yield 89%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[BrH:16]>>[C:1]1([CH2:7][CH2:8][CH2:9][Br:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br
Reactant: OCCCc1ccccc1
Agent: O=S(=O)(O)O
Product: BrCCCc1ccccc1
Temperature: 0 °C

Procedure:
To 3.2 g of 3-phenyl-1-propanol, were added 1.2 g of concentrated sulfuric acid and 6.08 g of 47% aqueous solution of hydrobromic acid, and the resultant solution was heated for 5 hours at 140-150° C. Then, the solution was poured into ice-water and extracted with ethyl acetate. The organic layer resulted was dried with anhydrous magnesium sulfate, and the solvent used was distillated under reduced pressure, thereby affording 4.3 g of 3-phenyl-1-bromopropane.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.IC.[C:17](=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C1CCC(c2ccc(O)cc2)CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1ccc(C2CCC(=O)CC2)cc1
Yield: 126.9 %

Procedure:
A solution of 4-(4-hydroxyphenyl)cyclohexanone (5 g) and iodomethane (0.828 ml) in N,N-dimethylformamide (50 ml) was treated with potassium carbonate (4.36 g) at room temperature for 28 hours. Water was poured into the reaction mixture. And the resulting precipitate was collected by filtration and washed with isopropanol and diisopropyl ether to give 4-(4-methoxyphenyl)cyclohexanone (6.815 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:17]=1[OH:18])[C:8]([C:10]1[CH:14]=[CH:13][NH:12][CH:11]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH2:26][CH2:27][CH3:28]>CN(C)C=O>[CH2:25]([N:12]1[CH:13]=[CH:14][C:10]([C:8](=[O:9])[C:7]2[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:17]([OH:18])=[C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=2)=[CH:11]1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCBr
Reactant: CC(C)(C)c1cc(C(=O)c2cc[nH]c2)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1ccc(C(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)c1
Reaction time: 1 h

Procedure:
2 G (6.6 mmol) of 3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole were added to a cooled, stirred suspension of 0.69 g of sodium hydride (50% in mineral oil) in 50 ml of anhydrous dimethylformamide under nitrogen. After 1 hour at 20° C., 0.8 ml of n-butyl bromide was added. Stirring was continued for an additional 18 hours at room temperature. The reaction mixture was poured over a 10% HCl-ice mixture, then extracted three times with 250 ml ethyl acetate. The organic layer was washed five times with 200 ml water, dried and evaporated to dryness. The residue was purified on a silica column (200 g) eluting with hexane:ethyl acetate (9:1). Crystallization from acetone-hexane gave 1.52 g of N-n-butyl-3-(3,5-di-t-butyl-4-hydroxybenzoyl)pyrrole (mp 101°-103° C.).
Reaction SMILES: Br.[NH2:2][C:3]1[NH:7][N:6]=[C:5]([CH3:8])[C:4]=1[Br:9].[C:10]([CH:13]1[CH2:18][CH2:17][O:16][C:14]1=[O:15])(=O)[CH3:11]>C(O)C>[Br:9][C:4]1[C:5]([CH3:8])=[N:6][N:7]2[C:14]([OH:15])=[C:13]([CH2:18][CH2:17][OH:16])[C:10]([CH3:11])=[N:2][C:3]=12
Reactant: CC(=O)C1CCOC1=O
Reactant: Cc1n[nH]c(N)c1Br
Agent: Br
Solvent: CCO
Product: Cc1nc2c(Br)c(C)nn2c(O)c1CCO
Temperature: 25 °C
Yield: 31.5 %

Procedure:
A solution of 5-amino-4-bromo-3-methylpyrazole hydrobromide (13 g, 51 mmol) and α-acetyl-γ-butyrolactone (6.8 g, 53 mmol) in ethanol (65 mL) was heated under reflux for nine hours. After cooling to room temperature, the resulting crystals were collected by filtration, to give the title compound (4.6 g) as white crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH3:35])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[CH3:36][O:37][C:38]1[CH:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][O:53][CH3:54])[CH2:47][CH2:46]2)[CH:42]=[CH:41][C:39]=1[NH2:40].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C(F)(F)F.N>CO.C(Cl)Cl>[F:32][C:26]1[CH:27]=[CH:28][CH:29]=[C:30]([F:31])[C:25]=1[NH:24][C:22](=[O:23])[C:21]1[CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:40][C:39]3[CH:41]=[CH:42][C:43]([N:45]4[CH2:50][CH2:49][N:48]([CH2:51][CH2:52][O:53][CH3:54])[CH2:47][CH2:46]4)=[CH:44][C:38]=3[O:37][CH3:36])[N:7]=2)[CH:18]=[CH:19][C:20]=1[O:34][CH3:35]
Reactant: COCCN1CCN(c2ccc(N)c(OC)c2)CC1
Reactant: COc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N
Solvent: ClCCl
Solvent: CO
Solvent: OCC(F)(F)F
Product: COCCN1CCN(c2ccc(Nc3nccc(-c4c(-c5ccc(OC)c(C(=O)Nc6c(F)cccc6F)c5)nc5ccccn45)n3)c(OC)c2)CC1
Temperature: 100 °C
Yield: 66.7 %

Procedure:
5-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide (Intermediate Example 2) (100 mg, 0.2 mmol), 2-(methyloxy)-4-{4-[2-(methyloxy)ethyl]-1-piperazinyl}aniline (Example 238, step A) (48 mg, 0.18 mmol), and p-toluenesulfonicacid (93 mg, 0.49 mmol) were weighed into a 20 mL vial. 1 mL of trifluoroethanol was added and the mixture was heated to 100° C. for 72 h. 2 mL of 2 N ammonia in MeOH was added. The solvent was rotovaped down. The residue was taken up in 3 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-absorbed solids were purified by flash chromatography to give the title compound (85 mg, 0.12 mmol, 64%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.78 (s, 1H), 9.36 (s, 1H), 8.45 (s, 1H), 8.20 (d, J=5.50 Hz, 1H), 8.10 (d, J=2.20 Hz, 1H), 7.77 (dd, J=8.80, 2.20 Hz, 1H), 7.69 (d, J=9.17 Hz, 1H), 7.34-7.46 (m, 3H), 7.28 (d, J=8.80 Hz, 1H), 7.18 (t, J=8.07 Hz, 2H), 6.90-6.98 (m, 1H), 6.67 (d, J=2.57 Hz, 1H), 6.52 (d, J=5.13 Hz, 1H), 6.45-6.51 (m, 1H), 3.98 (s, 3H), 3.79 (s, 3H), 3.46 (t, J=5.87 Hz, 2H), 3.24 (s, 3H), 3.10-3.17 (m, 4H), 2.53-2.58 (m, 4H), 2.51 (t, J=5.87 Hz, 2H); MS (ESI): 721 [M+H]+.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]O)[N:10]2[CH:17]=1)[CH3:6]>C(Cl)Cl>[ClH:3].[CH2:5]([C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][Cl:3])[N:10]2[CH:17]=1)[CH3:6]
Reactant: CCc1cn2c(CO)cccc2n1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCc1cn2c(CCl)cccc2n1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
To a mixture solution consisting of 8.8 ml (120.0 mmol) of thionyl chloride and 10 ml of methylene chloride was added, 4.23 g (24.0 mmol) of 2-ethyl-5-hydroxymethylimidazo[1,2-a]pyridine with small portions. The reaction mixture was stirred for one hour at room temperature. Then, the solvent and excess volume of thionyl chloride were distilled off under reduced pressure. To the residual white solid was added 30 ml of toluene. The mixture was stirred well, and the solvent was distilled off under reduced pressure. This process repeated twice to give 5.44 g of a crude product (99.0%, white solid), which was used for the subsequent reaction without purification.
Reaction SMILES: C(OP([CH2:9][C:10]([O:12][Si](C)(C)C)=[O:11])(OCC)=O)C.C([Li])CCC.[N+:22]([C:25]1[CH:54]=[C:53]([N+:55]([O-:57])=[O:56])[CH:52]=[CH:51][C:26]=1[O:27][CH2:28][C:29]([F:50])([F:49])[C:30]([F:48])([F:47])[C:31]([F:46])([F:45])[C:32]([F:44])([F:43])[CH2:33][O:34][C:35]1[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=1)([O-:24])=[O:23]>O1CCCC1.CCCCCC.O>[N+:22]([C:25]1[CH:54]=[C:53]([N+:55]([O-:57])=[O:56])[CH:52]=[CH:51][C:26]=1[O:27][CH2:28][C:29]([F:49])([F:50])[C:30]([F:47])([F:48])[C:31]([F:45])([F:46])[C:32]([F:43])([F:44])[CH2:33][O:34][C:35]1[CH:36]=[CH:37][C:38]([CH:39]=[CH:9][C:10]([OH:12])=[O:11])=[CH:41][CH:42]=1)([O-:24])=[O:23]
Reactant: CCOP(=O)(CC(=O)O[Si](C)(C)C)OCC
Reactant: O=Cc1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)COc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: O=C(O)C=Cc1ccc(OCC(F)(F)C(F)(F)C(F)(F)C(F)(F)COc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
To a mixture of trimethylsilyl diethylphosphonoacetate (2.97 g) in anhydrous tetrahydrofuran (100 mL) at 0° C. is added 1.6 M solution of butyllithium in hexane (6.9 mL). The reaction is stirred for 2 hrs. at room temperature and then treated with 4-[6-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5-octaflurohexyloxy]benzaldehyde (5.32 g) in anhydrous tetrahydrofuran (30 mL). The mixture is stirred for a further 2 hrs., diluted with water and extracted with ethyl ether. The extracts are washed with water and brine, dried (MgSO4), concentrated, and purified by crystallization to give 4-[6-(2,4-dinitrophenoxy)-2,2,3,3,4,4,5,5-octaflurohexyloxy]cinnamic acid. The acid is converted to the methyl ester by treatment with diazomethane in ether solution.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:10](C(OC(C)(C)C)=O)[N:11]3[C:15]=2[CH2:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1.Cl[S:30]([OH:33])(=O)=[O:31].[NH3:34]>C(Cl)(Cl)Cl.ClC(Cl)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:23]3[CH:28]=[CH:27][C:26]([S:30]([NH2:34])(=[O:33])=[O:31])=[CH:25][CH:24]=3)=[CH:10][N:11]3[C:15]=2[CH2:14][CH2:13][CH2:12]3)=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: N
Reactant: CC(C)(C)OC(=O)c1c(-c2ccccc2)c(-c2ccc(Cl)cc2)c2n1CCC2
Solvent: CC(Cl)Cl
Solvent: ClC(Cl)Cl
Product: NS(=O)(=O)c1ccc(-c2cn3c(c2-c2ccc(Cl)cc2)CCC3)cc1
Temperature: 2.5 °C
Reaction time: 12 h

Procedure:
tert-Butyl 1-(4-chlorophenyl)-2-phenyl-6,7-dihydro-5H-pyrrolizine-3-carboxylate (190 mg, 0.5 mmol) is taken up in CHCl3 (10 ml), the solution is cooled to 0-5° C. in an ice bath, and a solution of chlorosulphonic acid (1 ml, 1.75 g, 15 mmol) in CHCl3 (20 ml) is then slowly added dropwise (IT<10° C., 15 min). The mixture is then stirred at RT for 12 h, a solution of NH3 in dichloroethane (40 ml) saturated in the cold is added and it is stirred at RT for a further 12 h. It is then treated with ice water (5 ml), and the phase mixture is sucked through a G3 frit. The CHCl3 phase is separated from the now clear aqueous phase in a separating funnel. The filter residue is washed with a little water and CHCl3 and dried in vacuo. The dried solid substance is crystallized from MeOH: 0.13 g (70%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[NH:31][C:32](=[NH:44])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:32]([NH:44][O:26][C:25]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:29][CH:28]=1)=[O:27])(=[NH:31])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCC(=N)NO
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(=O)O)cc1)Cc1ccc(C(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCCCCCCCCCC(=N)NOC(=O)c1ccc(CN(Cc2ccc(C(F)(F)F)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 23.8 %

Procedure:
To a solution of 4-({(tert-butoxycarbonyl)[4-(trifluoromethyl)benzyl]amino}methyl)-benzoic acid (102 mg, 0.25 mmol), N-hydroxydodecanimidamide (70 mg, 0.33 mmol) and DMAP (3 mg, 0.03 mmol) in anhydrous DCM (15 mL) was added EDC (62 mg, 0.33 mmol) and the resulting reaction mixture was stirred at RT for 14 h. Evaporation of the solvents gave an oil. This crude product was purified by column chromatography over silica gel (AcOEt/c-Hex 80/20) to give the title compound as a colorless oil (36 mg, 24%). 1H NMR (CDCl3, 300 MHz) δ 8.01 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 7.40-7.20 (m, 4H), 4.88 (br s, 2H), 4.51 (s, 2H), 4.42 (s, 2H), 2.36 (t, J=8.2 Hz, 2H), 1.75-1.59 (m, 2H), 1.49 (s, 9H), 1.45-1.16 (m, 16H), 0.89 (t, J=7.0 Hz, 3H). HPLC (Condition A), Rt: 5.42 min (HPLC purity: 96.1%).