Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[N:17]=[N:18][N:19]([CH2:21][C:22]([N:24]([CH2:36][C:37]([O:39]CC)=[O:38])[CH2:25][C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)=[O:23])[CH:20]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:4])(=[O:3])[NH2:2].[Li+].[OH-]>C1COCC1.O>[S:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([O:14][CH2:15][C:16]3[N:17]=[N:18][N:19]([CH2:21][C:22]([N:24]([CH2:36][C:37]([OH:39])=[O:38])[CH2:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:31]=4)=[O:23])[CH:20]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=[O:3])(=[O:4])[NH2:2]
Reactant: CCOC(=O)CN(Cc1ccc(C(F)(F)F)cc1)C(=O)Cn1cc(COc2ccc3nc(S(N)(=O)=O)sc3c2)nn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1nc2ccc(OCc3cn(CC(=O)N(CC(=O)O)Cc4ccc(C(F)(F)F)cc4)nn3)cc2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 20 mL round bottomed flask equipped with a magnetic stir bar containing THF:H2O (1:1, 10 mL) was placed 139 (176 mg, 0.29 mmol). To this solution LiOH (61 mg, 1.45 mmol) was added and the reaction was allowed to stir at RT for 3 h. After the reaction was done, THF was removed and the aqueous layer was acidified to pH=3 with 6 M HCl. The reaction was then poured into brine (50 mL) and extracted into CHCl3 (3×20 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried over MgSO4 and concentrated in vacuo to afford BD336 (yield not determined) as a colorless solid.
Reaction SMILES: [OH-].[Na+:2].[CH3:3][C:4]1[N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:15][CH:14]=2)[C:7]([C:24]2[CH:41]=[CH:40][C:27]([O:28][C@H:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]([OH:32])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:5]=1>C(O)C>[CH3:3][C:4]1[N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:15][CH:14]=2)[C:7]([C:24]2[CH:25]=[CH:26][C:27]([O:28][C@H:29]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:30]([O-:32])=[O:31])=[CH:40][CH:41]=2)=[CH:6][CH:5]=1.[Na+:2]
Reactant: CCCCCc1ccc(OCCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCc1ccc(OCCCn2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)[O-])cc2)cc1
Yield: 82.9 %

Procedure:
Ethanol (6 ml) and a solution of 1N sodium hydroxide in ethanol (1.10 ml) were added to (2R)-2-(4-{5-methyl-1-[3-(4-pentylphenoxy)propyl]-1H-pyrrol-2-yl}phenoxy)-3-phenylpropanoic acid (640 mg, 1.22 mmol) and the mixture was concentrated. To the residue was added diisopropylether to give the object compound as a solid. 499 mg (yield: 82.9%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21]C(C)(C)C)=[O:20])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:27][N:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:2]2[CH:3]=[CH:4][C:5]([C:8](=[O:26])/[CH:9]=[CH:10]/[C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])=[CH:15][CH:16]=3)=[CH:6][CH:7]=2)[CH2:30][CH2:29]1
Reactant: CN1CCC(N)CC1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(/C=C/C(=O)c2ccc(Br)cc2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CN1CCC(Nc2ccc(C(=O)/C=C/c3ccc(/C=C/C(=O)O)cc3)cc2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 41 %

Procedure:
A mixture of (±)BINAP (435 mg, 0.7 mmol) and Pd2(dba)3 (320 mg, 0.35 mmol) in toluene (10 ml) was heated to 80° C. for 1 h under N2. Then the mixture was cooled down to room temperature and tert-butyl (E)-3-{4-[(E)-3-(4-bromo-phenyl)-3-oxo-propenyl]-phenyl}-acrylate (726 mg, 1.75 mmol), 1-methyl-piperidin-4-ylamine (0.200, 1.75 mmol) and NaOtBu (252 mg, 2.6 mmol) were added. The reaction was refluxed overnight under N2, then the slurry was filtrated (Celite) and the organic filtrate was evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: petroleum ether/AcOEt 1:1). The resulting product was dissolved in DCM (1 ml) and TFA (1 ml) and the solution was stirred at room temperature for 4 h. The solvent was removed in vacuo to give 280 mg of (E)-3-(4-{(E)-3-[4-(1-methyl-piperidin-4-ylamino)-phenyl]-3-oxo-propenyl}-phenyl)-acrylic acid as its trifluoroacetate salt.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:21])[CH2:15][S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)[CH2:29][CH2:28]1)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([C:27]1([C:30]2[CH:35]=[CH:34][C:33]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:21])[CH2:15][S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:4][CH:3]=3)=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:26])[CH3:23]
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)CSC(C)(C)C
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CSC(C)(C)C)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-tert-butylsulfanyl-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1N.S(=O)(=O)(O)[OH:12].S(O)(O)(=O)=O.ClC1C=C(Cl)C(Cl)=CC=1N>>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:6]([Cl:10])=[CH:5][C:3]=1[OH:12]
Reactant: O=S(=O)(O)O
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Product: Oc1cc(Cl)c(Cl)cc1Cl

Procedure:
40 Grams of 2,4,5-trichloroaniline and 200 g of 75% aqueous sulfuric acid solution were charged together with ceramic balls into a ceramic ball mill having one liter capacity. A suspension of fine particles of 2,4,5-trichloroaniline sulfate was prepared by a method similar to that described in Example 5. The suspension was transferred into a beaker having one liter capacity. The ceramic ball mill used was washed with 76 g of 75% aqueous sulfuric acid solution and the washings were also poured into the beaker. Diazotization of 2,4,5-trichloroaniline sulfate in the form of suspension of fine particles was carried out by a method similar to that described in Example 5 except that 15.5 g of sodium nitrite powder was added in 25 minutes. The diazotized solution was then hydrolyzed by a method similar to that described in Example 5. 33.0 g Grams of 2,4,5-trichlorophenol (115° - 120° C/10 mmHg) was obtained. The yield was found to be 82.0%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=1.[Br:18]N1C(=O)CCC1=O>CO>[Br:18][C:5]1[N:4]=[CH:3][C:2]([NH:7][C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:15])[F:16])=[CH:12][CH:13]=2)=[N:1][CH:6]=1
Reactant: FC(F)(F)c1ccc(Nc2cnccn2)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: FC(F)(F)c1ccc(Nc2cnc(Br)cn2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of pyrazin-2-yl-(6-trifluoromethyl-pyridin-3-yl)-amine (0.47 g) was dissolved in 50 Ml MeOH and then charged with N-bromosuccinimide (0.35 g) in a single portion as a solid. The reaction was stirred overnight at room temperature, then concentrated in vacuo. Purification by silica gel chromatography (25% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 6.7 (s, 1 H) 7.5 (s, 1 H) 7.9 (s, 1 H) 8.2 (s, 2 H) 8.6 (s, 1 H); (M+H)+ 320.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22](O)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O.CO.CCCCCC>[O:21]=[C:20]1[C:4]2[C:5]3[C:6](=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]=3[CH:10]=[C:2]([NH:1][C:22](=[O:29])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:3]=2)[CH:17]=[N:18][NH:19]1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C(Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O)c1ccccc1
Yield: 64.6 %

Procedure:
Preparation of example 24 from the title compound of Example 7 (hydrochloride) (23 mg, 0.082 mmol), benzoic acid (11 mg, 0.09 mmol), triethylamine (0.016 mL, 0.115 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N,′,N′-tetramethyluronium hexafluorophosphate (34 mg, 0.090 mmol) in CH2Cl2 (0.3 mL) and N,N-dimethylformamide (0.3 mL) was carried out analogously to Example 11. Silica gel chromatography (10:9:1 hexane:CH2Cl2:methanol followed by 8:5:2 CH2Cl2:hexane:methanol), also in an analogous manner, afforded the title compound (20 mg, 0.053 mmol) as a yellow powder in 64% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:13]([OH:17])[CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:3]([O:8][CH:7]([O:17][CH2:13][CH2:14][CH2:15][CH3:16])[C:6]1[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])[CH2:2][CH2:9][CH3:6]
Reactant: CCCCO
Reactant: O=Cc1cc(F)ccc1[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCOC(OCCCC)c1cc(F)ccc1[N+](=O)[O-]
Yield: 189.2 %

Procedure:
Dissolve 5-fluoro-2-nitrobenzaldehyde (9.43 g, 55.81 mmol), 1-butanol (12.41 g, 167.4 mmol) and 4toluenesulfonic acid monohydrate (0.9 g, 4.7 mmol) in toluene (84 mL). Heat the reaction mixture to reflux, and remove the water using a Dean-Stark apparatus. Continue to heat the reaction mixture for 3 hours. Add water and extract the aqueous layer with ethyl acetate. Combine the organic layers and dry over anhydrous sodium sulfate. Filter, concentrate under reduced pressure and purify by flash column chromatography (1% v/v triethylamine buffered silica gel, 5% ethyl acetate/hexane) to obtain 15.8 g (95%) of the title compound as colorless oil.
Reaction SMILES: I[CH2:2][CH3:3].C[O-].[Na+].[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:19][OH:20])[C:16]([OH:18])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH2:19][O:20][CH2:2][CH3:3])[C:16]([OH:18])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.8 %

Procedure:
To a suspension of sodium hydride (17.73 g, 702 mmol) in THF (600 mL) at 0° C. was added MeOH (18 mL) dropwise. The mixture was stirred at RT for 1 h to yield a sodium methanolate solution. Iodoethane (25.5 mL, 316 mmol) and a portion of the sodium methanolate solution (120 mL) were added to a solution of (S)-2-(tert-butoxycarbonylamino)-3-hydroxypropanoic acid (18 g, 88 mmol) in THF (600 mL). After stirring at RT for 1 h, the remaining sodium methanolate solution (480 mL) was added, followed by additional iodoethane (9.9 mL, 123 mmol). The mixture was stirred at RT overnight. The mixture was subsequently concentrated and the residue was dissolved in water. The aqueous layer was washed with ether (250 mL), acidified to pH 2 using 1N HCl, and extracted with EtOAc (3×300 mL). The combined organic layers were washed with 1M Na2S2O3 (300 mL), dried, and concentrated. The resulting crude material was reconstituted in MeOH, DCM and DMF (total volume: 50 mL) and purified via reverse phase preparative HPLC. The fractions were collected and the ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3, washed with EtOAc (2×200 mL), dried over Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation to yield the title compound as a clear oil (1.81 g, 9%). [M+H] calc'd for C10H19NO5, 234. found, 234.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][N:23]=1)[CH:19]=[O:20])([O-:3])=[O:2].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:27]=[C:28]([Mg]Cl)[CH:29]=[CH:30][CH:31]=1.C([O-])(O)=O.[Na+]>C1COCC1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[C:16]1[CH:17]=[C:18]([CH:19]([C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([C:25]([F:35])([F:34])[F:24])[CH:31]=2)[OH:20])[CH:21]=[CH:22][N:23]=1)([O-:3])=[O:2]
Reactant: FC(F)(F)c1cccc([Mg]Cl)c1
Reactant: O=Cc1ccnc(-c2cc(N3CCCCC3)ccc2[N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(C(O)c2cccc(C(F)(F)F)c2)ccn1
Temperature: 0 °C

Procedure:
To a −78° solution of 110 mg of 2-(2-nitro-5-(piperidin-1-yl)phenyl)isonicotinaldehyde in 4 mL of THF was added 0.82 mL of a 1.0 M solution of 3-(trifluoromethyl)phenylmagnesium chloride in THF. After 5 min the solution was warmed to 0° C. and treated with 10 mL of a saturated aqueous solution of NaHCO3. The mixture was extracted with ethyl acetate and the organic extracts were washed with water and then with brine. The solution was dried (Na2SO4) and the solvent was evaporated. The residue was purified by silica gel chromatography eluting with 1:1 ethyl acetate/hexanes to give 123 mg of product. MS (ES, m/z) 458.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10]N(CC)CC)[CH:5]=[CH:4][C:3]=1[C:16](=[O:21])[C:17](=[CH2:20])[CH2:18][CH3:19].ClC1C=C(OC[CH2:31][CH2:32][N:33]([CH2:36]C)[CH2:34][CH3:35])C=CC=1C(=O)CCC>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:36][N:33]([CH2:34][CH3:35])[CH2:32][CH3:31])[CH:5]=[CH:4][C:3]=1[C:16](=[O:21])[C:17](=[CH2:20])[CH2:18][CH3:19]
Reactant: CCCC(=O)c1ccc(OCCCN(CC)CC)cc1Cl
Reactant: C=C(CC)C(=O)c1ccc(OCCN(CC)CC)cc1Cl
Product: C=C(CC)C(=O)c1ccc(OCCCN(CC)CC)cc1Cl

Procedure:
This compound is prepared by essentially the same method as described in Example 1 Step B except that the 1-[2-chloro-4-(2-diethylaminoethoxy)phenyl]-1-butanone of Example 1 Step B is replaced by an equimolecular quantity of 1-[2-chloro-4-(3-diethylaminopropoxy)phenyl]-1-butanone. The product is obtained as a yellow oil upon distillation in vacuo (0.4 mm.).
Reaction SMILES: C(O[C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]2[NH:15][CH:16]=[CH:17][N:18]=2)=[CH:9][CH:8]=1)C.[CH3:20][NH2:21]>>[CH3:20][NH:21][C:4](=[O:19])[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]2[NH:18][CH:17]=[CH:16][N:15]=2)=[CH:11][CH:12]=1
Reactant: CN
Reactant: CCOC(=O)COc1ccc(Cc2ncc[nH]2)cc1
Product: CNC(=O)COc1ccc(Cc2ncc[nH]2)cc1
Reaction time: 24 h

Procedure:
A solution of 4-(1-imidazolylmethyl)phenoxyacetic acid ethyl ester (1.02 g) in 33% ethanolic methylamine was allowed to stand for 24 hour. The solution was evaporated and the residue was crystallised from ethyl acetate/petrol to give N-methyl-4-(1-imidazolylmethyl)phenoxyacetamide (0.61 g), m.p. 124°-125° C. Found: C, 63.44, H, 6.21, N, 17.25. C13H15N3O2 requires: C, 63.66, H, 6.16, N, 17.13%.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([OH:21])=O)=[CH:16][C:15]=3[C:22]=2[CH3:23])[CH2:7][CH2:6]1.C(N(C(C)C)CC)(C)C.[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Cl:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:2]([Cl:1])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]([N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[O:21])=[CH:16][C:15]=3[C:22]=2[CH3:23])[CH2:7][CH2:6]1
Reactant: C1COCCN1
Reactant: Cc1c(N2CCN(Cc3c(Cl)cccc3Cl)CC2)ccc2oc(C(=O)O)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(N2CCN(Cc3c(Cl)cccc3Cl)CC2)ccc2oc(C(=O)N3CCOCC3)cc12
Reaction time: 0.25 h
Yield: 42.2 %

Procedure:
To a solution of 5-[4-(2,6-Dichloro benzyl)-piperazine-1-yl]-4-methyl-benzofuran-2-carboxylic acid (0.07 g, 0.00017 mol) in anhydrous DMF (275 ml) was added diisopropyl ethyl amine (0.08 ml, 0.0005 mol) and morpholine (0.16 ml, 0.00018 mol) under nitrogen atmosphere. The reaction mixture was stirred for 15 minutes, added Py-BOP (0.11 g, 0.0002 mol) and stirred for 1 hour. The completion of the reaction was confirmed by TLC. The reaction mixture was quenched into ice water. The solid separated was filtered. After drying under vacuum, the crude product was isolated as white solid. The crude product was purified by Prep HPLC using a Zorbax C-18 column with mobile phase 0.1% trifluoroacetic acid in water (A)/Acetonitrile (B) with a flow rate of 20 ml/min to yield {5-[4-(2,6-dichlorobenzyl)piperazine-1-yl]-4-methyl-benzofuran-2-yl}-morpholin-4-yl-methanone (35 mg, 43%).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].Cl[C:12]([O:14][CH3:15])=[O:13].[OH-].[Na+]>O>[NH2:10][C:8](=[N:9][C:12](=[O:13])[O:14][CH3:15])[O:7][CH3:6]
Reactant: COC(=O)Cl
Reactant: COC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)N=C(N)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 52 parts of 2-methylpseudourea hydrogen sulfate in 250 parts of water at 0°-5°C is added 31 parts of methyl chloroformate followed by dropwise addition of 74 parts of 50% sodium hydroxide. The reaction mass is stirred at room temperature for 3 hours and then extracted with methylene chloride. The methylene chloride extract is dried and the solvent evaporated. The residue is triturated with hexane to give 23 parts of methy N-(1-amino-1-methoxy-methylene)-carbamate melting at 36°-39.5°C.
Reaction SMILES: [C:1]1([N:11]2[C:15]([SH:16])=[N:14][N:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]1([N:11]2[C:15]([S:16][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:14][N:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: Sc1nnnn1-c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CSc1nnnn1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.5 %

Procedure:
A mixture of 1-(Naphthalen-1-yl)-1H-tetrazole-5-thiol (235 mg, 1.03 mmol), ethyl bromoacetate (189 mg, 1.13 mmol) and potassium carbonate (171 mg, 1.24 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Water was then added to the reaction mixture and the precipitate that formed collected to give ethyl 2-(1-(naphthalen-1-yl)-1H-tetrazol-5-ylthio)acetate as a solid (306 mg, 94%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.O[NH:25][C:26](=[NH:37])[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](=[O:36])(=[O:35])[NH2:34])[CH:28]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]4[O:23][N:37]=[C:26]([C:27]5[CH:28]=[C:29]([S:33]([NH2:34])(=[O:35])=[O:36])[CH:30]=[CH:31][CH:32]=5)[N:25]=4)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: N=C(NO)c1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Product: NS(=O)(=O)c1cccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(Cl)cc5)nc34)n2)c1

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) (171 mg, 0.5 mmol) and N-hydroxy-3-sulfamoyl-benzamidine [CAS-No. 9000-88-7] (161 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (dichloromethane) as a light yellow solid (200 mg, 77%). MS (ISP) 521.2 [(M+H)+]; mp 247° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[O:13][CH2:14][CH:15]1[CH2:20][CH2:19][N:18]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:17][CH2:16]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc(COc2cccc(OCC3CCNCC3)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1CCC(COc2cccc(OCc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-{[3-(Benzyloxy)phenoxy]methyl}piperidine hydrochloride (1.5 g) was dissolved in chloroform (30 mL), and diisopropyl ethylamine (3.13 mL) and methanesulfonyl chloride (0.52 mL) were added thereto under ice-cooling, followed by stirring at room temperature for 2 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction liquid, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was powdered and purified from chloroform/hexane to obtain 4-{[3-(benzyloxy)phenoxy]methyl}-1-(methylsulfonyl)piperidine (1.508 g).
Reaction SMILES: [CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1.Cl.Cl[CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40]>>[CH3:1][N:2]([CH3:33])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:26][CH:25]=2)[C:11]([CH:13]2[C:22]3[C:17](=[C:18]([O:23][CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH2:14]2)=[O:12])=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(O)cccc32)cc1
Reactant: CN(C)CCCCl
Agent: Cl
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCCCN(C)C)cccc32)cc1
Yield: 63.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(4-dimethylaminophenyl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.66 g) and 3-chloro-N,N-dimethylpropylamine hydrochloride (0.32 g) as starting materials, N-[(4-dimethylaminophenyl)-methyl]-5-[3-(dimethylamino)propoxy]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.5 g) was obtained. Oxalic acid was added to this compound. By recrystallization from isopropyl alcohol, N-[(4-dimethylaminophenyl)methyl]-5-[3-(dimethylamino)propoxy]-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide oxalate ⅘ hydrate (0.18 g) was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1.ClC1C=CC=C(C(OO)=[O:18])C=1.CCCCCCC>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][C:6]([Br:9])=[CH:5][N:4]=1)=[O:18]
Reactant: CSc1ncc(Br)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CCCCCCC
Product: CS(=O)c1ncc(Br)cn1
Yield: 90 %

Procedure:
The title compound was prepared by oxidation of 2-methylthio-5-bromopyrimidine by m-chloroperbenzoic acid in chloroform as described in Example 39; yield 90%, m.p. 90° C. (n-heptane). 1H NMR (CDCl3): δ2.91 (Me),. 8.90 (H-4, H-6).