Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.CO[CH:15](OC)[CH2:16][NH2:17]>C1(C)C=CC=CC=1>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:4]=1[CH:5]=[N:17][CH:16]=[CH:15]2
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: COC(CN)OC
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cccc2ccncc12
Reaction time: 0.5 h
Yield: 7 %

Procedure:
A mixture of 2-trifluoromethylbenzaldehyde (15 g; 86 mmol) and aminoacetaldehyde dimethylacetal (9.37 ml; 86 mmol) in toluene (75 ml) was heated at reflux under Dean/Stark conditions for 2 hours. The cooled reaction mixture was evaporated to dryness and the residue added dropwise to conc. sulfuric acid (200 ml) at 140° C.; after complete addition the heating was continued for 30 mins then the warm mixture was poured over ice. The mixture was filtered and the filtrate basified by the addition of 4N NaOH with cooling. The basic solution was extracted with Et2O (×3), the combined Et2O layers were dried over Na2SO4, filtered and evaporated. The residue was dissolved in DCM and filtered through a short plug of silica and evaporated to give 1.2 g (Yield 7%).
Reaction SMILES: C(OC([N:8]([CH:32]([CH3:34])[CH3:33])[CH2:9][CH2:10][N:11]([CH2:29][C:30]#[CH:31])[S:12]([C:15]1[CH:24]=[CH:23][C:22]2[NH:21][C:20](=[O:25])[C:19]3[NH:26][CH:27]=[CH:28][C:18]=3[C:17]=2[CH:16]=1)(=[O:14])=[O:13])=O)(C)(C)C.[CH2:35]([C:38]([O-:40])=[O:39])[CH2:36][CH3:37].[ClH:41]>C(OCC)C>[CH:32]([NH:8][CH2:9][CH2:10][N:11]([CH2:29][C:30]#[CH:31])[S:12]([C:15]1[CH:24]=[CH:23][C:22]2[NH:21][C:20](=[O:25])[C:19]3[NH:26][CH:27]=[CH:28][C:18]=3[C:17]=2[CH:16]=1)(=[O:14])=[O:13])([CH3:34])[CH3:33].[ClH:41].[CH2:35]([C:38]([OH:40])=[O:39])[CH2:36][CH3:37]
Reactant: C#CCN(CCN(C(=O)OC(C)(C)C)C(C)C)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: CCCC(=O)[O-]
Agent: Cl
Solvent: CCOCC
Product: C#CCN(CCNC(C)C)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Product: CCCC(=O)O

Procedure:
This compound is prepared according to synthesis 139, from 57 mg (0.1 mmol) of 8-{[2-(tert-butoxycarbonyl-isopropyl-amino)-ethyl]-prop-2-ynyl-sulfamoyl}-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate and 2.5 mL (5 mmol) of a 2M solution of hydrochloric acid in diethyl ether to give, after filtration, 42 mg (82%) of 8-[(2-isopropylamino-ethyl)-prop-2-ynyl-sulfamoyl]-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-propyl carboxylate hydrochloride in the form of a white solid.
Reaction SMILES: I.[CH3:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5](SC)[NH:4]1.[NH2:15][CH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1>C(#N)C.C(O)(C(F)(F)F)=O>[CH:16]1([NH:15][C:5]2[NH:4][CH:3]([CH3:2])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:6]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:18][CH2:17]1
Reactant: CSC1=Nc2ccccc2C(C)N1
Reactant: NC1CCc2ccccc21
Agent: I
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CC1NC(NC2CCc3ccccc32)=Nc2ccccc21
Temperature: 85 °C

Procedure:
4-Methyl-2-methylsulfanyl-3,4-dihydro-quinazoline hydroiodide (31 mg, 0.10 mmol) and (+/−)-1-aminoindane (17 mg, 0.12 mmol) were suspended in acetonitrile (1 ml) and heated in a screw-capped vial to 85° C. (12 h). The product was isolated from the reaction mixture by preparative HPLC (YMC CombiPrep C18 column 50×20 mm, solvent gradient 5-95% CH3CN in 0.1% TFA(aq) over 7.0 min, λ=230 nm, flow rate 40 ml/min) to give the title compound (MS: m/e=264.2 [M+H+]).
Reaction SMILES: S(Cl)([Cl:3])=O.[NH2:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:17]O>>[ClH:3].[CH3:17][O:15][C:14](=[O:16])[C@H:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:5]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
Thionyl chloride (14 mL, 0.19 mol) was slowly added to a vigorously stirred -5° C. suspension of L-phenylalanine (26.28 g, 0.159 mol) in methanol (250 mL). After the addition of thionyl chloride was complete, the resulting homogeneous solution was allowed to warm to room temperature and was left stirring overnight. The reaction solvent was removed in vacuo to produce a white solid. This solid was redissolved in methanol (100 mL) and the resulting solution was reconcentrated in vacuo to produce the product L-phenylalanine methyl ester hydrochloride (mp 158°-159° C. 34.10 g, 0.158 mol, 99.4%). A sample of this material was converted to the N-trifluoroacetylisopropyl ester using standard procedures. The resulting ester was found to contain 0.088% of the D-isomer by gc analysis on a Chirasil-Val™ chiral gc column (obtained from Applied Science). The 1H NMR of this synthetic material was identical with that of a commercial sample.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][CH2:12][OH:13].[CH2:14]([CH:17]([C:23](OCC)=O)[C:18]([O:20]CC)=[O:19])[CH2:15][CH3:16]>>[OH:13][CH2:12][CH2:11][C:4]1[CH:5]=[C:6]([O:9][CH3:10])[CH:7]=[CH:8][C:3]=1[CH2:2][CH:17]([CH2:14][CH2:15][CH3:16])[C:18]([OH:20])=[O:19].[OH:13][CH2:12][CH2:11][CH:4]1[CH2:5][CH:6]([O:9][CH3:10])[CH2:7][CH2:8][CH:3]1[CH2:23][CH:17]([CH2:14][CH2:15][CH3:16])[C:18]([OH:20])=[O:19]
Reactant: COc1ccc(CCl)c(CCO)c1
Reactant: CCCC(C(=O)OCC)C(=O)OCC
Product: CCCC(CC1CCC(OC)CC1CCO)C(=O)O
Product: CCCC(Cc1ccc(OC)cc1CCO)C(=O)O

Procedure:
2-Cyano-2-propyl-6-methoxy-trans-decalin is obtained analogously from 2-(2-bromoethyl-4-methoxycyclohexylmethyl)-valeronitrile (obtainable by chloromethylation of 2-(m-methoxyphenyl)-ethanol to give 2-(2-chloromethyl-5-methoxyphenyl)-ethanol, reaction with diethyl propylmalonate, hydrolysis and decarboxylation to give 2-[2-(2-hydroxyethyl)-4-methoxybenzyl]-valeric acid, hydrogenation to 2-[2-(2-hydroxyethyl)-4-methoxycyclohexylmethyl]-valeric acid, conversion into the amide, reaction with SOBr2 to give 2-(2-bromoethyl-4-methoxy-cyclohexylmethyl)-valeramide and dehydration).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].I[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>O>[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccccc3Cl)c2cc1OC
Temperature: 80 °C
Reaction time: 72 h
Yield: 89.2 %

Procedure:
Toluene (0.7 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.35 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 2-chlorophenyl boronic acid (81 mg) under an argon atmosphere, and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (43 mg, yield 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.O>C(#N)C>[C:14]([O:13][C:12](=[O:18])[NH:11][C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:26])=[CH:3][CH:4]=1)([CH3:15])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl]carbamate (150 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (6 mL) were added benzoyl chloride (84 μL) and triethylamine (101 μL). The mixture was stirred at room temperature overnight and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (212 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:11][C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=3[F:19])=[C:9]([C:20](O)=[O:21])[CH:8]=[N:7][C:6]=12.Cl.[F:24][C:25]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([NH:11][C:12]3[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=3[F:19])=[C:9]([C:20]([N:28]3[CH2:29][CH2:30][C:25]([F:24])([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:26][CH2:27]3)=[O:21])[CH:8]=[N:7][C:6]=12
Reactant: Cc1ccc(F)c(Nc2c(C(=O)O)cnc3c(Br)cnn23)c1
Reactant: FC1(c2ccccc2)CCNCC1
Agent: Cl
Product: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(F)(c4ccccc4)CC3)cnc3c(Br)cnn23)c1
Yield: 29 %

Procedure:
In the same manner as in Example 21, step 5 and using 3-bromo-7-(2-fluoro-5-methylphenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylic acid (333 mg, 0.91 mmol) obtained in step 2 and 4-fluoro-4-phenylpiperidine hydrochloride (296 mg, 1.37 mmol), the title compound (1-39 mg, 29%) was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[NH2:14][CH2:15][CH2:16][CH2:17][NH2:18]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:14][CH2:15][CH2:16][CH2:17][NH2:18]
Reactant: Brc1ccccn1
Reactant: NCCCN
Solvent: c1ccncc1
Product: NCCCNc1ccccn1
Yield: 50.1 %

Procedure:
A mixture of 2-bromopyridine (12.3 mL, 126.7 mmol) and pyridine (13 mL, 161 mmol) in 1,3-diaminopropane (53.5 mL, 640 mmol) was refluxed under nitrogen for 18 hours. The reaction mixture was evaporated under reduced pressure and cooled, and the resulting residue was treated with THF (150 mL) to yield a white precipitate. The precipitate was filtered and washed with additional THF (100 mL). Evaporation of the filtrate afforded an orange oil, which was distilled in vacuo to give N-(2-pyridinyl)-1,3-propanediamine (9.6 g, 50%) as a colorless oil: bp 128-132° C. (2 mmHg).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH:7]=[CH:6][N:5]=[N:4]1.Cl[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)[N:22]=1.O>CN(C)C=O>[N:3]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=4)[N:22]=3)=[CH:16][CH:17]=2)[CH:7]=[CH:6][N:5]=[N:4]1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: FC(F)(F)c1ccc(-c2cccc(CCl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cccc(COc3ccc(CCCCn4ccnn4)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
16 mg (0.39 mmol) of 60% sodium hydride were added at 0° C. to a solution of 80 mg (0.37 mmol) 4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 4.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 100 mg (0.37 mmol) 2-chloromethyl-6-(4-trifluoromethyl-phenyl)-pyridine (WO 2004/007439) were given to the reaction mixture and stirring continued at r.t for 2 days. After addition of 8 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, methanol/water 1:1, and a small amount of ether. The residue was dried at 40° C. to give 101 mg (60%) of the title compound as white powder.
Reaction SMILES: C([CH:4]=[CH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][CH3:17])=[CH:8][CH:7]=1)(O)=O.C(Cl)(Cl)Cl.[Br:22]Br.C(=O)([O-])[O-].[Na+].[Na+]>O.C(Cl)Cl>[Br:22][CH:4]=[CH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([O:16][CH3:17])=[CH:8][CH:7]=1
Reactant: COc1ccc(C=CC(=O)O)c2ccccc12
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C=CBr)c2ccccc12

Procedure:
To a suspension of 33.3 g. (0.146 mol.) of 1-(2-carboxyethenyl)-4-methoxynaphthalene in 500 ml. of chloroform was added dropwise a solution of 8.05 ml. (0.146 mol.) of bromine in 125 ml. of methylene chloride. The solvent was removed, a solution of 31 g. (0.292 mol.) of sodium carbonate in 300 ml. of water was added to the residue and the mixture was refluxed for 2 hours. After cooling, the mixture was extracted with methylene chloride, the layers were separated and the organic phase was washed with water and saturated sodium chloride solution, dried (MgSO4) and evaporated to dryness to give 1-(2-bromoethenyl)-4-methoxynaphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:16][C:17]([O:19]C)=[O:18].[F:21][C:22]1[CH:23]=[CH:24][C:25]([C:33]([F:36])([F:35])[F:34])=[C:26]([CH:32]=1)[CH:27]=[CH:28][C:29](O)=[O:30]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[C:9]1([CH2:14][CH2:13][N:12]([C:29](=[O:30])/[CH:28]=[CH:27]/[C:26]3[CH:32]=[C:22]([F:21])[CH:23]=[CH:24][C:25]=3[C:33]([F:34])([F:35])[F:36])[CH2:11][CH2:10]1)[CH2:8][CH:7]2[CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)C=Cc1cc(F)ccc1C(F)(F)F
Reactant: COC(=O)CC1CC2(CCNCC2)c2c(Cl)cccc21
Product: O=C(O)CC1CC2(CCN(C(=O)/C=C/c3cc(F)ccc3C(F)(F)F)CC2)c2c(Cl)cccc21

Procedure:
The title compound was prepared employing a procedure analogous to that described in Example 1 using methyl 2-(7-chloro-2,3-dihydrospiro[indene-1,4′-piperidine]-3-yl)acetate and 5-fluoro-2-(trifluoromethyl)cinnamic acid followed by a procedure analogous to that described in Example 2. LC-MS Method 1 tR=1.93, min, m/z=496, 498; 1H NMR (CDCl3) 1.20-1.40 (3H), 1.70 (m, 1H), 2.39 (m, 1H), 2.51 (m, 1H), 2.65-3.05 (4H), 3.36 (m, 1H), 3.62 (br s, 1H), 4.06 (d, 1H), 4.79 (d, 1H), 6.83 (d, 1H), 7.0-7.5 (5H), 7.70 (m, 1H), 7.87 (d, 1H).
Reaction SMILES: C(N=C=N[CH:7]([CH3:9])[CH3:8])(C)C.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:18]2[CH2:21][CH:20]([NH2:22])[CH2:19]2)=[CH:13][CH:12]=1.[C:30]1(C)[C:31]([S:36]([CH2:39][C:40](O)=[O:41])(=[O:38])=[O:37])=[CH:32]C=C[CH:35]=1.OC1C2N=NNC=2C=CC=1>ClCCl.CN(C)C=O.CO>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[N:18]2[CH2:19][CH:20]([NH:22][C:40](=[O:41])[CH2:39][S:36]([C:31]3[CH:32]=[CH:9][C:7]([CH3:8])=[CH:35][CH:30]=3)(=[O:38])=[O:37])[CH2:21]2)=[CH:13][CH:12]=1
Reactant: CC(C)N=C=NC(C)C
Reactant: Cc1ccccc1S(=O)(=O)CC(=O)O
Reactant: NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)CC(=O)NC2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)cc1
Reaction time: 17 h

Procedure:
0.031 cm3 of diisopropylcarbodiimide, a solution of 30 mg of 1-[bis(4-chlorophenyl)methyl]azetidin-3-ylamine in 0.5 cm3 of anhydrous dichloromethane, and 3 cm3 of anhydrous dichloromethane are added to a solution of 85.7 mg of toluenesulfonylacetic acid, 27 mg of hydroxybenzotriazole in solution in 0.5 cm3 of dimethylformamide under an inert argon atmosphere, at a temperature in the region of 23° C. After 17 hours at a temperature in the region of 23° C., the reaction mixture is loaded onto a 3-cm3 SPE cartridge containing 1 g of SCX phase preconditioned with methanol. After washing with twice 5 cm3 of methanol and then 4 cm3 of 0.1 N ammoniacal methanol, the expected product is eluted with 4 cm3 of 1 N ammoniacal methanol. The fraction containing the expected product is evaporated under an air stream at a temperature in the region of 45° C. and then dried under reduced pressure (1 mbar) at a temperature in the region of 40° C. N-{1-[bis(4-chlorophenyl)methyl]-azetidin-3-yl}-2-(toluene-4-sulfonyl)acetamide is obtained in the form of a yellow lacquer [1H NMR spectrum (500 MHz, CDCl3, δ in ppm): 2.85 (t, J=7 Hz: 2H); 3.07 (s: 3H); 3.48 (t, J=7 Hz: 2H); 4.24 (s: 1H); 4.49 (mt: 1H); 7.19 (broad d, J=6 Hz: 1H); from 7.20 to 7.40 (mt: 8H); 8.40 (s: 1H)].
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[CH:14][S:15][C:3]=12.[I:16]N1C(=O)CCC1=O>>[OH:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[CH:13]=[C:14]([I:16])[S:15][C:3]=12
Reactant: CCOC(=O)c1cnc2ccsc2c1O
Reactant: O=C1CCC(=O)N1I
Product: CCOC(=O)c1cnc2cc(I)sc2c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
To a stirring solution of ethyl 7-hydroxythieno[3,2-b]pyridine-6-carboxylate (Elliot, R. L, O'Hanlon, P. J., Rogers, N. H. Tetrahedron 43 (14) 3295-3302 (1987)) (2.50 g, 10.96 mmol) in trifluomethanesulfonic acid (50 mL) at 0° C. was added N-iodo succinimide (2.46 g, 10.96 mmol) portion wise. The mixture was stirred for 1 hour, allowing the solution to warm to ambient temperature. Ice (50 g) was added and the resulting aqueous extracted with CH2Cl2 (3×100 mL). The organic layers were combined, dried over MgSO4 and solvent removed to afford 2.92 g title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:28]([O:29][CH3:30])=[CH:27][C:5]2[NH:6][C:7](=[O:26])[C:8]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=4)=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.Br[CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][O:34]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>C(OCC)(=O)C>[CH3:30][O:29][C:28]1[C:2]([O:1][CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[CH:3][C:4]2[NH:10][C:9]3[CH:11]=[C:12]([C:15]4[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:24][CH3:25])[CH:16]=4)[CH:13]=[CH:14][C:8]=3[C:7](=[O:26])[NH:6][C:5]=2[CH:27]=1
Reactant: COc1cc2c(cc1O)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Reactant: BrCC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCC1CCCCO1)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A mixture of Example 476I (40 mg, 0.098 mmol), 2-bromomethyl-tetrahydro-2H-pyran (0.13 mL, 0.98 mmol), K2CO3 (136 mg, 0.98 mmol) and DMF (2 mL) was heated at 100° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel with 49:1 dichloromethane/methanol to provide 23 mg (47%) of the desired product. MS (ESI) m/e 506 (M+H)+; 1H NMR (300 MHz, DMSO-d6) 9.66 (s, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.53 (d, J=1.7 Hz, 1H), 7.35 (dd, J=1.7, 8.5 Hz, 1H), 7.26-7.31 (m, 2H), 6.69 (s, 1H), 6.64 (s, 1H), 4.03 (s, 3H), 3.72-3.94 (m, 3H), 3.67 (s, 3H), 3.60 (m, 1H), 3.39 (m, 1H), 1.82 (m, 1H), 1.64 (m, 1H), 1.41-1.55 (m, 3H), 1.27 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].CCN(C(C)C)C(C)C.[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21](Cl)=[O:22]>ClCCl.CC#N>[F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][C:21](=[O:22])[C:20]1[C:19]([Cl:18])=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:28]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccncc1F
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccncc1F)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a cooled (0° C.) mixture of 3-fluoropyridin-4-amine (1.0 g, 8.9 mmol) and DIPEA (2.7 mL, 18 mmol) in dichloromethane (20 mL) and MeCN (10 mL) was added a solution of 2,6-dichlorobenzoyl chloride (2.1 g, 9.8 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was partitioned between EtOAc (30 mL) and sat. NaHCO3 (30 mL). The aqueous layer was extracted with EtOAc (2×15 mL) and then the combined organic extracts were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc) to afford N-(3-fluoropyridin-4-yl)-2,6-dichlorobenzamide (1.2 g, yield: 47%). 1H NMR (400 MHz, DMSO) δ 11.21 (s, 1H), 8.59 (d, J=2.8, 1H), 8.41 (d, J=5.4, 1H), 8.21 (dd, J=6.7, 5.4, 1H), 7.77-7.33 (m, 3H). LCMS (ESI) m/z: 285.2 [M+H+]
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:2]1[O:4][CH2:3]1.[OH2:11]>[OH-].[Na+].C(O)(=O)CCCCCCCCCCC>[CH2:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:2]([CH2:3][OH:11])[OH:4]
Reactant: O
Reactant: CCCCCOCC1CO1
Agent: CCCCCCCCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCCCCOCC(O)CO
Temperature: 90 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
In a four-necked 300-ml flask, 100 g (0.69 mole) of amyl glycidyl ether obtained in Example 1, 25 g (1.39 mole) of water, 2.31 g (0.028 mole) of 48% sodium hydroxide and 5.54 g (0.028 mole) of lauric acid were charged, followed by heating to 90° C. while stirring under a nitrogen gas atmosphere. The stirring was continued for 8 hours. After excess water was distilled off, the residue was distilled under reduced pressure (100° C., 0.133 kPa), whereby 110 g (0.59 mole) of amyl glyceryl ether was obtained (yield: 86%, purity: 99%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]([CH2:17][C@@H:18]([NH:23]C(OC(C)(C)C)=O)[C@@H:19]([CH3:22])[CH2:20][CH3:21])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1.[ClH:32]>CCOC(C)=O>[ClH:32].[CH3:1][O:2][C:3](=[O:31])[CH2:4][N:5]([CH2:17][C@@H:18]([NH2:23])[C@@H:19]([CH3:22])[CH2:20][CH3:21])[CH2:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](CN(CC(=O)OC)Cc1cccc2ccccc12)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](N)CN(CC(=O)OC)Cc1cccc2ccccc12
Reaction time: 1 h

Procedure:
A solution of N-[2(S)-(t-Butoxycarbonylamino)-3(S)-methylpentyl]N(1-naphthylmethyl) glycine methyl ester from example 1 step E (5.90 g, 13.8 mmol) in EtOAc (100 ml) was saturated with gaseous hydrogen chloride. The resulting solution was allowed to stand at room temperature for 1 hr. The solvent was evaporated in vacuo to afford the title compound as a white solid.
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Cl)[CH3:13]>O>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][O:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH3:3])=[CH:6][CH:7]=1)[CH3:13]
Reactant: COc1ccc(O)cc1
Reactant: CCOC(CCl)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCOC(COc1ccc(OC)cc1)OCC
Yield: 47.1 %

Procedure:
Potassium hydroxide pellets (22.4 g) and molten p-methoxyphenol (50 g) were heated with stirring to a temperature in the range from 90° to 100° C. until a clear solution was obtained. Chloroacetaldehyde diethylacetal (120 g) was added at such a rate to maintain the temperature in the range from 90° to 100° C. and after stirring for a further 15 minutes water was removed from the flask as an azeotrope with chloroacetaldehyde diethylacetal, the water and acetal were separated and the acetal was returned to the reaction mixture. Azeotropic distillation was continued until the temperature of the vapour reached 140°-150° C. and then the reaction mixture was heated under reflux for a further 6 hr. Water (200 ml) was added to the cooled mixture which was then extracted with chloroform (2×200 ml). The chloroform extracts were washed with aqueous 2N sodium hydroxide (100 ml) to remove unreacted phenols and the chloroform layer was dried over Na2SO4 and the solvent removed by distillation under reduced pressure. The crude product was distilled under reduced pressure to give, as a third fraction, p-methoxyphenoxyacetaldehyde diethyl acetal (45.6 g) of b.p. 180°-194° C. at 44 mm the product being characterized by p.m.r. spectroscopy.