Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[N:3]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.B.O1CCCC1.O>C1COCC1>[Cl:12][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH:4]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH2:3])=[CH:11][CH:10]=1
Reactant: CON=C(Cc1ccc(Cl)cc1)c1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: NC(Cc1ccc(Cl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of oxime geometric isomers 7 (840 mg, 3.23 mmol) in 30 ml dry THF (freshly distilled from sodium/benzophenone ketyl) under nitrogen was added borane-tetrahydrofuran complex (1.0M in THF, 16.2 ml, 16.2 mmol) by syringe at room temperature. The resulting pale yellow solution was refluxed overnight, and cooled in an ice bath. Water (25 ml) was carefully added to quench, followed by 20% NaOH (25 ml). The resulting bi-phasic solution was refluxed with vigorous magnetic stirring overnight. After cooling to room temperature, hexanes (40 ml) were added, and the layers were separated. The aqueous portion was extracted with hexanes (1×40 ml). The combined organic portions were dried over potassium carbonate and concentrated in vacuo to a cloudy, pale yellow syrup. This syrup was purified by column chromatography on 18 g neutral alumina (activity I) using chloroform as eluant to afford the amine as 455.6 mg of a colorless, slightly cloudy syrup (61% yield): Rf 0.36 (5% ET2 NH/CHCl3); IR (CDCl3) 3376 (w), 3316 (w), 3031 (w), 2928 (m), 2856 (w), 1602 (m), 1493 (m), 1451 (m); 1H NMR (CDCl3) δ7.38-7.28 (m, 5H), 7.26 (d, J=8.3 Hz, 2H), 7.09 (d, J=8.3 Hz, 2H), 4.18 (dd, J=8.3, 5.4 Hz, 1H), 2.98 (dd, J=13.4, 5.4 Hz, 1H), 2.84 (dd, J=13.4, 8.4 Hz), 1.50 (br s, 2H); low resolution mass spec. 232 (M+, 22), 215 (37), 125 (54), 106 (100), 89 (49), 79 (100).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH:7]=[CH:8][O:9][C:4]=2[CH:3]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=O.Cl.CO>O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:7]2[C:6](=[O:10])[C:5]3[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][C:4]=3[O:9][CH2:8]2)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: O=c1ccoc2cc(O)ccc12
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(C=C2COc3cc(O)ccc3C2=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After 7-hydroxy-4(4H)-benzopyranone 1.0 g and 3,4-dimethoxybenzaldehyde 1.22 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 40 ml, the mixture was refluxed for 1.5 hours and cooled to room temperature, water 100 ml was added and the mixture was allowed to stand for 30 minutes. The precipitated crystals were filtered.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.Br[CH2:17][CH2:18][N:19]1[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]2[C:20]1=[O:29].C(=O)([O-])O.[Na+]>CN(C)C=O>[C:20]1(=[O:29])[N:19]([CH2:18][CH2:17][N:13]2[CH2:14][CH2:15][CH:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:11][CH2:12]2)[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]12
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 0 °C
Yield: 37.6 %

Procedure:
A mixture of 4-(3-indolyl)piperidine (7.88 g), N-(2-bromoethyl)phthalimide (10.0 g) and sodium hydrogen carbonate (3.64 g) in dry N,N-dimethylformamide (93 ml) was heated at 68°-74° C. for 4 hours. After cooling, the reaction mixture was poured into ice-water (1,000 ml). The resulting precipitate was collected by filtration and washed with methanol to give 1-(2-phthalimidoethyl)-4-(3-indolyl)piperidine (5.53 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[C:3](=[O:18])[CH2:4][C:5](=[O:17])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.CO[CH:22](OC)[N:23]([CH3:25])[CH3:24].Cl.CN>CO>[C:3]([C:4]1[C:5](=[O:17])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=2)=[CH:24][N:23]([CH3:25])[CH:22]=1)(=[O:18])[CH:2]([CH3:19])[CH3:1]
Reactant: CC(C)C(=O)CC(=O)Cc1cccc(C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Agent: CN
Agent: Cl
Solvent: CO
Product: CC(C)C(=O)c1cn(C)cc(-c2cccc(C(F)(F)F)c2)c1=O

Procedure:
A 0.6 g. portion of impure 5-methyl-1-(3-trifluoromethylphenyl)-2,4-hexanedione was reacted overnight at reflux temperature with N,N-dimethylformamide dimethyl acetal as described in the examples above to obtain 0.8 g. of a dark oil. The oil was dissolved in methanol and reacted with 2 g. of methylamine hydrochloride under reflux for 4 hours. The reaction mixture was evaporated under vacuum to obtain a yellow solid, which was purified as described in Example 10 to obtain 0.09 g. of the desired product, m.p. 104°-105°, showing the following peaks in nmr analysis in DMSOd6 : δ7.6-8.3 (m, 6H, aromatic): 3.7-4.2 (m, 1H, COCH); 3.8 (s, 3H, N--CH3); 1.0-1.2 (d, 6H, CH(CH3)2).
Reaction SMILES: N1([CH:7]=[C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]2)CCCCC1.[CH3:24][C:25](=[O:28])[CH:26]=[CH2:27].C(O)(=O)C>C(O)C>[O:28]=[C:25]1[CH2:24][CH2:7][C:8]2([CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:12][CH2:13]2)[CH:27]=[CH:26]1
Reactant: O=C(OCc1ccccc1)N1CCC(=CN2CCCCC2)CC1
Reactant: C=CC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1C=CC2(CC1)CCN(C(=O)OCc1ccccc1)CC2

Procedure:
To a solution of EXAMPLE 265A (15.88 g) in ethanol (300 mL) was added but-3-enone (3.89 g). The mixture was stirred at reflux overnight. Then acetic acid (30 mL) was added to the mixture which was stirred at reflux again overnight. The mixture was then concentrated under vacuum and the residue was diluted with ethyl acetate (400 mL) and washed with water and brine and dried over Na2SO4. After filtration and evaporation of the solvent, column purification gave the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](=O)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)[CH3:2].[CH:14]1[C:19]([NH:20][NH2:21])=[CH:18][CH:17]=[C:16]([S:22]([NH2:25])(=[O:24])=[O:23])[CH:15]=1.Cl>>[CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([C:7](=[N:21][NH:20][C:19]3[CH:18]=[CH:17][C:16]([S:22]([NH2:25])(=[O:23])=[O:24])=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc2c(c1)NC(=O)C2=O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: CCc1ccc2c(c1)NC(=O)C2=NNc1ccc(S(N)(=O)=O)cc1
Yield: 79 %

Procedure:
The title compound was prepared from 6-ethyl-1H-indole-2,3-dione (Krantz and Young, 1989, U.S. Pat. No. 4,873,232) and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G in 79% yield: 1H NMR (DMSO-d6): δ 1.16 (t, J=7.5 Hz, 3H), 2.60 (q, J=7.5 Hz, 2H), 6.74 (s, 1H), 6.89 (d, J=7.5 Hz, 1H), 7.22 (s, 2H), 7.46 (d, J=7.5 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H), 7.75 (d, J=8.7 Hz, 2H), 11.02 (s, 1H), 12.70 (s, 1H); APCI-MS m/z 343 (M−H)−. Anal. Calcd for C16H16N4O3S.0.32H2O: C, 54.88, H, 4.79; N, 16.00; S, 9.16. Found C, 54.81, H, 4.59; N, 16.06; S, 9.04.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[C:33]([N:2]1[CH2:6][CH2:5][C@@H:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([F:27])=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3]1)(=[O:36])[CH2:34][CH3:35]
Reactant: CCC(=O)Cl
Reactant: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c[nH]c23)c(OCC2CC2)cc1F
Agent: Cl
Product: CCC(=O)N1CC[C@@H](NC(=O)c2c[nH]c3c(-c4cc(OC)c(F)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (R)-pyrrolidin-3-ylamide hydrochloride (example A165) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[CH3:16]O>>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:16])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(CC(=O)O)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cccc(N)c1
Temperature: 0 °C

Procedure:
3-Aminophenylacetic acid (15.5 g, 0.10 mol) was suspended in methanol (150 mL) and cooled to 0° C. Thionyl chloride (11.2 mL, 0.15 mol) was added dropwise under stirring. A clear orange solution was obtained, which was stirred for 4 hours, then evaporated. The solid residue was partitioned between ethyl acetate (150 mL) and saturated sodium bicarbonate (150 mL) and the organic phase washed with saturated sodium bicarbonate (100 mL), and brine and dried (Na2SO4). Methyl 3-aminophenylacetate was isolated as a brown oil. (14.1 g, 83%). 1H NMR (500 MHz, CDCl3) δ 7.12 (1H, dd), 6.7-6.6 (3H, m), 3.71 (3H, s), 3.55 (2H, s).
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][NH:9][C:10]([CH:12]2[CH2:15][CH2:14][CH2:13]2)=O)=[N:6][N:5]=[CH:4][NH:3]1>P(Cl)(Cl)(Cl)=O>[CH:12]1([C:10]2[N:6]3[C:7]([C:2](=[O:1])[NH:3][CH:4]=[N:5]3)=[CH:8][N:9]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: O=C(NCc1nnc[nH]c1=O)C1CCC1
Solvent: O=P(Cl)(Cl)Cl
Product: O=c1[nH]cnn2c(C3CCC3)ncc12
Temperature: 0 °C

Procedure:
A crude solution of cyclobutanecarboxylic acid (5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)amide (1.33 g, 6.39 mmol) in phosphorus oxychloride (POCl3) (10 mL) was heated to 55° C. The reaction was heated for 2 h then concentrated in vacuo and the crude oil was cooled to 0° C. in an ice-bath and quenched with 2M NH3 in isopropanol (IPA) until slightly basic. This crude reaction mixture was concentrated in vacuo and was partitioned between DCM and H2O and separated. The aqueous layer was extracted with DCM (3×) and the combined organic fractions were dried over sodium sulfate (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by chromatography on silica gel [eluting with 5% MeOH in DCM], resulting in the title compound as an off-white solid; 1H NMR (DMSO-d6, 400 MHz) δ 1.86-1.96 (m, 1H), 2.00-2.13 (m, 1H); 2.26-2.46 (m, 4H); 3.87-4.00 (m, 1H); 7.71 (s, 1H); 7.87 (d, J=3.6 Hz, 1H); 11.7 (brs, 1H); MS (ES+): m/z 191.27 (100) [MH+], HPLC: tR=2.06 min (MicromassZQ, polar—5 min).
Reaction SMILES: [NH+]1C=CN[CH:2]=1.[N:6]1([C:11]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=3[S:13](=[O:25])(=[O:24])[N:12]=2)[CH:10]=[CH:9]N=C1.C(N)(C)C>>[CH:10]([NH:6][C:11]1[NH:16][C:15]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:14]=2[S:13](=[O:25])(=[O:24])[N:12]=1)([CH3:9])[CH3:2]
Reactant: c1c[nH+]c[nH]1
Reactant: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=C(n1ccnc1)N2
Solvent: CC(C)N
Product: CC(C)NC1=NS(=O)(=O)c2cc([N+](=O)[O-])ccc2N1

Procedure:
3-(Imidazol-1-yl)-7-nitro-4H-1,2,4-benzothiadiazine 1,1-dioxide imidazolium salt was treated with isopropylamine according to the general procedure Method A to give the title compound; m.p. 311-313° C.; IR (KBr): 3363, 3221, 2980, 1657, 1646,1615, 1601, 1572, 1532, 1494, 1339, 1284, 1267, 1155, 1106 cm−1; 1H-NMR (DMSO-d6, HMDS; d ppm): 1.10 (d, 6H, 2×CH3), 3.90 (m, 1H, NH—CH), 7.35 (m, 2H, 5-H+NH—CH), 8.35 (m, 2H, 6-H+8-H), 10.90 (bs, 1H, NH).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([OH:7])=O)[CH3:3].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CN(C=O)C.[NH2:35][CH:36]1[CH2:42][C:41]([CH3:44])([CH3:43])[C:40]2[CH:45]=[CH:46][C:47]([N+:49]([O-:51])=[O:50])=[CH:48][C:39]=2[NH:38][C:37]1=[O:52]>CCOCC>[CH3:1][N:2]([CH3:3])[CH2:4][C:5]([NH:35][CH:36]1[CH2:42][C:41]([CH3:44])([CH3:43])[C:40]2[CH:45]=[CH:46][C:47]([N+:49]([O-:51])=[O:50])=[CH:48][C:39]=2[NH:38][C:37]1=[O:52])=[O:7]
Reactant: CC1(C)CC(N)C(=O)Nc2cc([N+](=O)[O-])ccc21
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CN(C)CC(=O)NC1CC(C)(C)c2ccc([N+](=O)[O-])cc2NC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethylamino-acetic acid (0.124 g, 1.20 mmol), EDCl (0.461 g, 2.41 mmol), HOBT (0.276 g, 2.05 mmol) and DMF (1.00 mL, 12.9 mmol) were stirred at rt for 30 minutes, followed by the addition of TEA (0.235 mL, 1.68 mmol) and 3-Amino-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one (0.300 g, 1.20 mmol). The reaction mixture was stirred at rt for 3 h, diluted with ether and washed with water. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. Title compound was isolated as a white solid (80 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([N+:16]([O-:18])=[O:17])[C:12](O)=[N:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])O.[Na+].P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:12]1[C:11]([N+:16]([O-:18])=[O:17])=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)=[CH:14][N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cc(-c2ccc(Cl)c(Cl)c2)cnc1O
Agent: O=C([O-])O
Agent: [Na+]
Product: O=[N+]([O-])c1cc(-c2ccc(Cl)c(Cl)c2)cnc1Cl
Temperature: 120 °C

Procedure:
A mixture of 1.6 g of 5-(3,4-dichlorphenyl)-2-hydroxy-3-nitropyridine (starting material G4) and 10 ml of phosphorous oxychloride is heated under reflux to 120° C. for 3 hours. After cooling the mixture is carefully added to ice/water, then neutralized with sodium hydrogencarbonate and extracted three times with ethyl acetate. The combined organic phases are evaporated to dryness and the residue is chromatographed on a silica gel column (ethylacetate/petroleum ether 1:20). Concentration of the chromatographically pure fractions gives 0.88 g of the title compound as yellow crystals. The mass spectrum shows the molecular peak M+ at 302 Da.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:8]([O-])=O)[CH:5]=[CH:6][CH:7]=1.[S:11]([O-:14])([O-:13])=[O:12].[Na+].[Na+].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][C:7]=1[S:11]([OH:14])(=[O:13])=[O:12]
Reactant: O=S([O-])[O-]
Reactant: O=[N+]([O-])c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccc(S(=O)(=O)O)c(Cl)c1
Reaction time: 1.5 h

Procedure:
A mixture of 31.5 grams of 3-chloronitrobenzene, 450 milliliters of 5N-sodium sulphite solution and 500 milliliters of 2N sodium hydroxide solution was refluxed with stirring for 90 minutes, acidified with concentrated hydrochloric acid, and refluxed for 1 hour. On cooling and diluting with water a solid crystallised out which was filtered and washed with water to give 9.9 grams of 2-chlorosulphanilic acid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([C:14]1[CH:15]=[C:16]([CH2:21][CH:22]([O:26][CH2:27][CH3:28])[C:23]([OH:25])=[O:24])[CH:17]=[CH:18][C:19]=1[OH:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C=O)C.[CH2:34](O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[CH2:34]([O:24][C:23](=[O:25])[CH:22]([O:26][CH2:27][CH3:28])[CH2:21][C:16]1[CH:17]=[CH:18][C:19]([OH:20])=[C:14]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)O
Reactant: OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(Cc1ccc(O)c(Cc2ccccc2)c1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49 %

Procedure:
Oxalyl chloride (0.364 g, 2.87 mmol) was added dropwise to a mixture of 3-(3-benzyl-4-hydroxy-phenyl)-2-ethoxy-propionic acid (0.345 g, 1.15 mmol) and a catalytic amount of DMF in dry DCM (2.0 mL). The mixture was stirred for 17 h at room temperature before the excess oxalyl chloride was evaporated in vacuo. The remaining carboxylic acid chloride was redissolved in dry DCM (3.0 mL) and benzyl alcohol (0.15 g, 1.38 mmol) was added under nitrogen atmosphere. After stirring for 24 h at room temperature the solvent was removed in vacuo and the resulting oil was purified by column chromatography using DCM/MeOH (96:4) as the eluent to afford the title compound as an oil (0.22 g, 36.8%). Mass Spectrum: M−H+ 388.94.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[F:9][C:10]1[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][C:11]=1[N+:20]([CH3:23])([CH3:22])[CH3:21].FC(F)(F)C(O)=O>O>[F:1][C:2]([F:8])([F:7])[S:3]([O-:6])(=[O:5])=[O:4].[C:16]([C:14]1[CH:13]=[CH:12][C:11]([N+:20]([CH3:22])([CH3:21])[CH3:23])=[C:10]([F:9])[CH:15]=1)([OH:18])=[O:17]
Reactant: COC(=O)c1ccc([N+](C)(C)C)c(F)c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[N+](C)(C)c1ccc(C(=O)O)cc1F

Procedure:
A solution of 4.00 g (11.1 mmol) 10, 96 ml dest. water and 96 ml trifluoroacetic acid was refluxed for 2 days. The reaction mixture was evaporated, dried by use of oil pump vacuum over night and treated with diethyl ether. The resulting solid was filtered, washed extensively with diethyl ether and dried by oil pump vacuum. The solid crude product 11 was obtained in 92% yield (3.54 g, 10.2 mmol) and crude compound 11 was used for the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22]([O:24][CH2:25][CH2:26]Br)[CH3:23].O>CN(C)C=O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:23][CH2:22][O:24][CH2:25][CH3:26])[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CCOCCBr
Reactant: Clc1ncnc2cc(-c3ccco3)[nH]c12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCn1c(-c2ccco2)cc2ncnc(Cl)c21

Procedure:
To a solution of 4-chloro-6-(2-furyl)-5H-pyrrolo[3,2-d]pyrimidine (220 mg) in N,N-dimethylformamide (1.2 mL) was added cesium carbonate (489 mg) under ice-cooling, and the mixture was stirred under ice-cooling for 15 min. 2-Bromoethyl ethyl ether (0.169 mL) was added and the mixture was stirred at room temperature for 2 days. Cesium carbonate (326 mg) and 2-bromoethyl ethyl ether (0.113 mL) were added and the mixture was stirred at room temperature for 1 day. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (60 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent, hexane:ethyl acetate=4:1→1:4) to give the title compound (76 mg).
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[Cl:7][CH2:8][CH2:9][N:10]=[C:11]=[O:12]>C1COCC1>[Cl:7][CH2:8][CH2:9][NH:10][C:11]([NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[O:12]
Reactant: NCC(F)(F)F
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: O=C(NCCCl)NCC(F)(F)F
Yield: 93.8 %

Procedure:
A solution of 2,2,2-trifluoroethanamine (0.469 g, 4.74 mmol) and chloroethylisocyanate (0.50 g, 4.74 mmol) in THF (10 mL) was stirred at RT for 2 h, then concentrated to dryness. The residue was treated with DCM, concentrated to dryness and dried to afford 1-(2-chloroethyl)-3-(2,2,2-trifluoroethyl)urea (910 mg, 94%). 1H NMR (400 MHz, DMSO-d6): δ 6.67 (t, J=6.5 Hz, 1 H), 6.41 (m, 1 H), 3.80 (m, 2 H), 3.57 (t, J=6.2 Hz, 2 H), 3.32 (m, 2 H); MS (ESI) m/z: 205.0 (M+H+).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([CH2:28]O)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:44]=[N+:45]=[N-:46])(C2C=CC=CC=2)=O)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[N:44]([CH2:28][C:26]1[N:27]=[C:23]([N:21]2[CH2:22][CH:19]([O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:20]2)[S:24][CH:25]=1)=[N+:45]=[N-:46]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CO)cs2)C1)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 98.6 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-hydroxymethyl-1,3-thiazol-2-yl)azetidine (1.02 g, 2.39 mmol) (obtained as described in Reference Example 2(2)) in tetrahydrofuran (50 ml) were added diphenylphosphoryl azide (0.8 ml, 3.71 mmol), triphenylphosphine (950 mg, 3.62 mmol) and 40% diethylazodicarboxylate in toluene solution (1.32 g, 3.59 mmol) in an ice bath under an atmosphere of nitrogen. The mixture was stirred in an ice bath for 2 hours. After checking the completion of the reaction, the mixture was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (8:1) as the eluant to afford 1-(4-azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (1.06 g, yield 99%) as colorless syrup.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[C:8]([CH:14]=1)[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])(=[O:3])[CH3:2].[N+:24]([O-])([OH:26])=[O:25]>C(O)(=O)C>[C:1]([C:4]1[C:5]([N+:24]([O-:26])=[O:25])=[CH:6][C:7]([S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])=[C:8]([CH:14]=1)[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccc(Sc2ccc(F)cc2F)c(NS(C)(=O)=O)c1
Solvent: CC(=O)O
Product: CC(=O)c1cc(NS(C)(=O)=O)c(Sc2ccc(F)cc2F)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 1 h
Yield: 85.3 %

Procedure:
A mixture of 5'-acetyl-2'-(2,4-difluorophenylthio)methanesulfonanilide (1 g) and nitric acid (248 mg) in acetic acid (5 ml) was stirred at 80° C. for 1 hour. The reaction mixture was evaporated to dryness. The residue was washed with ethanol to give yellow crystals of 5'-acetyl-2'-(2,4-difluorophenylthio)-4'-nitromethanesulfonanilide (0.96 g).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]#[N:16])=[CH:9][C:8]=1[CH2:17][CH:18]([CH3:20])[CH3:19])(=O)=O.[CH2:23]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([C:30]1[CH:31]=[C:32]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]#[N:16])=[CH:9][C:8]=2[CH2:17][CH:18]([CH3:20])[CH3:19])[CH:33]=[CH:34][C:35]=1[O:36][CH3:37])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1ccc(B(O)O)cc1Cc1ccccc1
Reactant: CC(C)Cc1cc(CCC#N)ccc1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(-c2ccc(CCC#N)cc2CC(C)C)cc1Cc1ccccc1
Temperature: 80 °C
Yield: 52.1 %

Procedure:
490 mg (1.46 mmol) Trifluoro-methanesulfonic acid 4-(2-Cyanoethyl)-2-isobutyl-phenyl ester (6), 505 mg (2.09 mmol, 1.4 eqv) crude 3-Benzyl-4-methoxy-benzene-1-boronic acid (22) and 169.4 mg (0.15 mmol, 0.1 eqv) Pd(Ph3P)4 were dissolved in 20 ml DME/EtOH (9+1). 1.46 ml (2.92 mmol, 2 eqv) of a 2 M aq. Na2CO3-solution was added to this yellow solution and the resulting mixture was heated at 80° C. for 17 h. After concentrating the mixture in vacuo the residue was taken up in water and extracted with CH2Cl2. The comb. org. fractions were dried over MgSO4 and evaporated. Column chromatography (Hexanes/EtOAc (3+1)) yielded 290.8 mg (0.76 mmol, 52%) 24 as a clear oil: Rf (Hexanes/EtOAc (3+1)) 0.34; 1H NMR (400 MHz, CDCl3) δ 0.63 (d, 6H, J=6.70 Hz), 1.55 (m, 1H), 2.35 (d, 2H, J=7.33 Hz), 2.57 (t, 2H, J=7.45 Hz), 2.88 (t, 2H, J=7.45 Hz), 3.79 (s, 3H), 3.92 (s, 2H), 6.82 (d, 1H, J=8.34 Hz), 6.92 (d, 1H, J=2.15 Hz), 6.96-7.20 (m, 9H); LRMS (EI) m/z 383 (13), 335 (15), 293 (23), 214 (17), 187 (21), 161 (20), 160 (100), 145 (35), 144 (35), 105 (50), 91 (58), 77 (11); HRMS (EI) Calcd. for C27H29NO: 383.224914. Found: 383.225267.