Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CC[O-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[NH2:1][C:2]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: ClCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc2ccccc2n1Cc1ccccc1
Temperature: 25 °C
Yield: 38.9 %

Procedure:
To a solution of 2-aminobenzimidazole (2) (Aldrich, 6 g., 45 mmol) in EtOH (10 mL) was added EtONa (21% in EtOH, 16.83 mL, 45 mmol) and benzyl chloride (5.70 mL, 50 mmol) and the brown solution was refluxed for 3 days under N2 gas. After cooling to room temperature, the reaction mixture was filtered through celite and concentrated in vacuo. The resulting brown solid was filtered hot in 300 mL acetone and crystallized from approximately 100 mL of acetone, and gave 3 as brown crystals (3.91 g., 39%). Recrystallization of the mother liquor afforded additional 3 as brown crystals (0.70 g., 7%). 1H-NMR (DMSO-d6) δ 5.27 (s, 2H), 6.61 (s, 2H), 6.82 (t, J=8.8 Hz, 1H), 6.93 (t, J=6.4 Hz, 1H), 7.05 (d, J=8.0 Hz, 1H), 7.15 (d, 7.2 Hz, 1H), 7.20 (d, 6.8 Hz, 2H), 7.24 (d, 7.6 Hz, 1H), 7.31 (t, 7.6 Hz, 2H); 13C-NMR (DMSO-d6) 45.11, 108.30, 115.19, 118.49, 120.88, 127.39, 127.66, 128.91, 134.60, 137.64, 143.34, 155.46.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8](B(O)O)[CH:7]=[CH:6][C:5]=12.I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[N:3]1[O:2][N:1]=[C:5]2[CH:6]=[CH:7][C:8]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[N:20][C:21]=4[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=3)=[CH:9][C:4]=12
Reactant: OB(O)c1ccc2nonc2c1
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
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: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc3nonc3c2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of Benzo[c][1,2,5]oxadiazole-5-boronic acid (18 mg, 0.11 mmol) in EtOH (3.3 ml) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 ml). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 ml) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA44. ESI-MS (M+H)+ m/z calcd 296.1, found 296.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[F:9].[N+]([C:13]1[CH:18]=CC=C[CH:14]=1)([O-])=O.S(=O)(=O)(O)O>OCC(CO)O>[Br:1][C:2]1[C:3]([F:9])=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]=[CH:18][CH:13]=[CH:14]2
Reactant: Nc1ccc(Br)c(F)c1
Reactant: O=[N+]([O-])c1ccccc1
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: Fc1c(Br)ccc2ncccc12
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-3-fluoro-phenylamine (100 g, 526 mmol), ferrous sulfate (30 g), glycerol (200 g), nitrobenzene (40 g) and concentrated sulfuric acid (100 mL) were heated gently. After the first vigorous reaction, the mixture was heated to reflux for 5 hours. Nitrobenzene was evaporated in vacuo. The aqueous solution was acidified with glacial acetic acid and dark brown precipitate separated, which was purified by flash chromatography (silica gel, petroleum/ethyl acetate=12/1) to return a mixture of 6-bromo-5-fluoro-quinoline and 6-bromo-7-fluoro-quinoline as a white solid (80 g, 68%). This mixture was heated to reflux in petroleum ether. The solution was cooled to r.t., filtered and dried to return 6-bromo-7-fluoro-quinoline as a white solid. To the solution was added HCl/MeOH, and a white solid precipitated from the solution. The solid was filtered and basified. The resulting precipitate was collected by filtration and dried to obtain 6-bromo-5-fluoro-quinoline as white solid. 1H-NMR (DMSO-d6, 300 MHz): 9.0 (d, 1H), 8.5 (d, 1H), 8.0 (m, 1H), 7.8 (d, 1H), 7.7 (m, 1H); MS: m/z 228 [M+H+]+.
Reaction SMILES: N[C:2]1C(N)=NC=CN=1.C[O:10][C:11]1[CH:19]=[C:18]([O:20][CH2:21][C:22]#[CH:23])[CH:17]=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].OC1C=C(O)C=CC=1C(OC)=O.C(Cl)C#C>>[OH:10][C:11]1[CH:19]=[C:18]([O:20][CH2:21][C:22]#[CH:23])[CH:17]=[CH:16][C:12]=1[C:13]([O:15][CH3:2])=[O:14]
Reactant: Nc1nccnc1N
Reactant: C#CCOc1ccc(C(=O)O)c(OC)c1
Agent: C#CCCl
Agent: COC(=O)c1ccc(O)cc1O
Product: C#CCOc1ccc(C(=O)OC)c(O)c1

Procedure:
A mixture of 11 g of 2,3-diaminopyrazine (IIa), 20.6 g of 2-methoxy-4-propargyloxybenzoic acid [m.p. 142°; obtainable by reacting methyl 2,4-dihydroxybenzoate with propargyl chloride to give methyl 2-hydroxy-4-propargyloxybenzoate (m.p. 100°), reacting the latter with methyl iodide to give methyl 2-methoxy-4-propargyloxybenzoate (m.p. 88°), and hydrolysing the latter] and 300 ml of POCl3 is boiled for 2 hours. The mixture is evaporated to dryness, ice-water is added to the residue, and the mixture is rendered alkaline with K2CO3 solution. The precipitated 2-(2-methoxy-4-propargyloxyphenyl)-1,3,4,7-tetraazaindene is filtered off. M.p. 189°-190°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][NH:14][CH2:15][C@H:9]12)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:23][C:24](ON1C(=O)CCC1=O)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]2[CH2:13][N:14]([C:24]([O:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:25])[CH2:15][C@H:9]12)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2CNC[C@@H]21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H]2CN(C(=O)OCc3ccccc3)C[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(3aR,6aR)-Hexahydro-pyrrolo[3,4-b]pyrrole-1-carboxylic acid tert-butyl ester (3.0 g, 12.5 mmole) and N-(benzyloxycarbonyloxy)-succinimide (3.42 g, 13.7 mmole) were mixed in 15 ml of dichloromethane. The mixture was stirred at room temperature overnight and then concentrated under vacuum to provide the crude product The residue was purified by flash chromatography (20% ethyl acetate in hexane) to provide the title compound. 1H NMR (CDCl3) δ ppm 7.29-7.43 (m, 5H) 5.13 (s, 2H) 4.15-4.33 (m, 1H) 3.39-3.74 (m, 5H) 3.20-3.37 (m, 1H) 2.84-2.96 (m, 1H) 1.92-2.03 (m, 1H) 1.66-1.82 (m, 1H) 1.46 (s, 9H). MS: (M+H)+=347.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=[CH:9][C:10]1[O:14][CH:13]=[CH:12][CH:11]=1)[C:6]([CH3:8])=O)[CH3:2].[CH2:16]([O:18][C:19](=[O:24])[CH2:20][C:21](=[NH:23])[NH2:22])[CH3:17].C(O)(C)C>C(O)C>[CH2:16]([O:18][C:19]([C:20]1[CH:9]([C:10]2[O:14][CH:13]=[CH:12][CH:11]=2)[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])=[C:6]([CH3:8])[NH:22][C:21]=1[NH2:23])=[O:24])[CH3:17]
Reactant: CCOC(=O)CC(=N)N
Reactant: CCOC(=O)C(=Cc1ccco1)C(C)=O
Solvent: CC(C)O
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1ccco1
Yield: 78 %

Procedure:
Upon boiling a solution of 10.4 g of 2-furfurylideneacetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours, 2-amino-6-methyl-4-(fur-2-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 183°C (isopropanol) is obtained. Yield: 78% of theory.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.[CH:10](=[O:13])[CH2:11][CH3:12].C(O)(=O)C(O)=O>O>[OH:13][CH:10]([C:4]1([CH3:9])[C:5](=[O:8])[C:6]([OH:7])=[C:2]([CH3:1])[O:3]1)[CH2:11][CH3:12]
Reactant: CCC=O
Reactant: CC1=C(O)C(=O)C(C)O1
Agent: O=C(O)C(=O)O
Solvent: O
Product: CCC(O)C1(C)OC(C)=C(O)C1=O
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a mixture of 1.0 g of 2,5-dimethyl-4-hydroxy-3-(2H)-furanone, 5 g of propanal and 20 ml of water were added 0.2 g of oxalic acid and the mixture was stirred at room temperature for 25 hours and then extracted three times with chloroform. The chloroform extract was evaporated and the residue purified by column chromatography on polyamide using ether-pentane 10/90 as the eluent. Pure 2-(1-hydroxypropyl)-2,5-dimethyl-4-hydroxy-3-(2H)-furanone was obtained, which was recrystallized from ether-pentane 50/50; solid mass at room temperature.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.C1C=CC=CC=1.C1([Li])C=CC=CC=1.[CH2:23]([N:26]=[C:27]=[S:28])[CH:24]=[CH2:25]>O>[CH2:23]([NH:26][C:27](=[S:28])[CH:3]([O:2][CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH:24]=[CH2:25]
Reactant: COCc1ccccn1
Reactant: C=CCN=C=S
Agent: [Li]c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: C=CCNC(=S)C(OC)c1ccccn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 9.95 g. (0.081 mole) of 2-(methoxymethyl)pyridine in 80 ml. of dry benzene is added dropwise to a chilled solution of 40 ml. (0.084 mole) of phenyl lithium in 80 ml. of dry benzene. The mixture is stirred at 0°C. for 1 hour after the addition is complete. Then 8.02 g. of allyl isothiocyanate in 50 ml. of benzene is added dropwise and the mixture is allowed to come to room temperature gradually. The mixture is then diluted with 500 ml. of water and acidified with 10% hydrochloric fractions The layers are separated and the organic layer is washed several times with water. The aqueous layers are combined, neutralized with 10% aqueous sodium hydroxide solution and then brought to pH 9 5% aqueous sodium bicarbonate solution, then extracted with chloroform. The chloroform extracts are washed once with brine and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on a silica gel column, eluting with ethyl acetate. The fraction, containing the product are combined and evaporated and the residue is recrystallized from ethyl acetate/hexane to give N-allyl-2-methoxy-2-(2-pyridyl)thioacetamide, m.p. 59.5°-60°C.
Reaction SMILES: C[O-].[Na+].CO.[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC1C=C(C)C=C(C)C=1S([O-])(=O)=O.[NH2:27][N:28]1[CH:33]=[CH:32][C:31]([C:34]([O:36]C)=[O:35])=[CH:30][C:29]1=[NH2+:38]>O>[C:7]1([C:6]2[N:38]=[C:29]3[CH:30]=[C:31]([C:34]([OH:36])=[O:35])[CH:32]=[CH:33][N:28]3[N:27]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)c1ccn(N)c(=[NH2+])c1
Agent: C[O-]
Agent: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccn2nc(-c3ccccc3)nc2c1
Reaction time: 1 h

Procedure:
Sodium methoxide (10.9 ml, a 5 M methanol solution) and benzaldehyde (3.3 ml) were added to a methanol (100 ml) solution of the 1-amino-4-(methoxycarbonyl)pyridin-2(1H)-iminium 2,4,6-trimethylbenzenesulfonate (10 g) obtained in (Example 3.18) <Step 3>, and the obtained mixture was then stirred for 1 hour. Thereafter, water (5 ml) was added to the reaction solution, and the mixed solution was then stirred at 40° C. for 30 minutes. Thereafter, methanol was distilled away under reduced pressure, water (50 ml) and methyl tert-butyl ether (50 ml) were then added to the residue, followed by stirring the mixture. An organic layer was separated from a water layer, and the water layer was then washed with methyl tert-butyl ether (50 ml) again. The water layer was adjusted to pH 4 by addition of 4 N hydrochloric acid (10 ml), and a mixed solution of methylene chloride and methanol (95:5, 50 ml) was then added thereto. Insoluble substances were removed by filtration, and an organic layer was then separated from a water layer. The water layer was extracted with a mixed solution of methylene chloride and methanol (95:5, 50 ml) twice. Organic layers were then combined, and the solvent was then distilled away under reduced pressure. The obtained residue was successively triturated with methyl tert-butyl ether (50 ml) and methanol (50 ml). The obtained solid was washed with methanol (20 ml), and was then dried at 50° C. under reduced pressure, so as to obtain the title compound (3.2 g) in the form of a brown solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8].[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17](Cl)(=[O:19])=[O:18]>>[Cl:9][C:10]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=1[S:17]([NH:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[C:3]=1[Br:8])(=[O:19])=[O:18]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Product: Cc1noc(NS(=O)(=O)c2cccc(Cl)c2Cl)c1Br
Yield: 75 %

Procedure:
2,3-Dichloro-N-(4-bromo-3-methyl-5-isoxazolyl)benzenesulfonamide was prepared from 5-amino-4-bromo-3-methylisoxazole and 2,3-dichlorobenzenesulfonyl chloride according to the procedures described in Example 45. The crude product was purified by recrystallization from ethyl acetate/hexanes to give a crystalline solid, m.p. 166°-169° C., yield 75%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([O:42][CH:43]([CH3:45])[CH3:44])=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([O:42][CH:43]([CH3:44])[CH3:45])=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CC(C)Oc1ccc(N)c2c1CN(C)C2=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(OC(C)C)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-Amino-2-methyl-4-(propan-2-yloxy)-2,3-dihydro-1H-isoindol-1-one (Compound 207A). MS (ES+): m/z 638.26 (100) [MH+]; HPLC: tR=1.21 min (UPLC, purity).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(Cl)Cl.[C:17](Cl)(=[O:21])[C:18](Cl)=[O:19]>C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:13])[CH:11]=[C:10]([CH3:12])[C:9]2[C:4]3=[C:5]([C:17](=[O:21])[C:18](=[O:19])[N:3]13)[CH:6]=[CH:7][CH:8]=2
Reactant: CC1=CC(C)(C)Nc2ccccc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1=CC(C)(C)N2C(=O)C(=O)c3cccc1c32
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1,2-dihydro-2,2,4-trimethylquinoline (34.6 g., 0.2 mole) in 50 ml. dry methylene chloride was added slowly dropwise to oxalyl chloride (26.4 g., 0.21 mole) in 300 ml. dry methylene chloride. Addition required 45 min., and when complete the resultant solution was stirred at ambient temperature 4 hrs. and refluxed 2 hrs. The dark red solution was freed of solvent at reduced pressure and the very dark solid residue taken up in chloroform. Dilution with ligroine and chilling produced a total yield of 32.6 g. (71.8%); m.p. 170°-176° C. A sample repeatedly recrystallized from toluene-ligroine (1:4) melted at 176°-177.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-])=[O:2].O.NN>O1CCCC1.[Rh]>[C:7]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([NH:1][OH:2])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccccc2)cc1
Agent: [Rh]
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: ONc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 99.5 %

Procedure:
To a mixture of 4-nitrobiphenyl (400 mg, 2.008 mmol) and 5% rhodium on carbon (15 mg, 0.146 mmol) in tetrahydrofuran (15 ml), hydrazine hydrate (0.200 ml, 2.61 mmol) was added, and gas evolution was observed. The reaction mixture was stirred at RT for 25 minutes, then it was partitioned between diethyl ether (90 ml) and brine (20 ml), and the phases were separated. The aqueous phase was extracted with diethyl ether (90 ml), and the combined organic extracts were dried (Na2SO4) and concentrated to give 370 mg of the desired compound (89% purity) and about. The mixture was used as such for the next step.
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.[O-:16][CH2:17][CH3:18].[Na+].O>C(O)C>[CH2:17]([O:16][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH3:18]
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cc(C(F)(F)F)ccc1C#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.6 %

Procedure:
To a solution of 2-nitro-4-trifluoromethyl-benzonitrile (4.052 g, 18 mmol) in ethanol (25 mL) were added sodium ethoxide solution (13.4 mL, 36 mmol, 21% wt in ethanol) dropwise over 30 min. The reaction mixture was stirred at room temperature for 1 h. Water (50 mL) was added and the resulting mixture was stirred for 15 min. The solid was filtered off, washed with water and dried under vacuum for 3 d to give 2-ethoxy-4-trifluoromethyl-benzonitrile as a beige solid (2.85 g, 74%). It was used without further purification.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([C:18]3[CH2:19][CH2:20][S:21](=[O:25])(=[O:24])[CH2:22][CH:23]=3)=[C:13]([F:26])[CH:12]=2)[CH2:6]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C(#N)C>[O:25]=[S:21]1(=[O:24])[CH2:20][CH:19]=[C:18]([C:14]2[C:15]([F:17])=[CH:16][C:11]([N:7]3[CH2:6][C@H:5]([CH2:4][NH2:1])[O:9][C:8]3=[O:10])=[CH:12][C:13]=2[F:26])[CH2:23][CH2:22]1
Reactant: [N-]=[N+]=NC[C@@H]1CN(c2cc(F)c(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: NC[C@H]1CN(c2cc(F)c(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5S)-5-(Azidomethyl)-3-[4-(1,1-dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3,5-difluorophenyl]-1,3-oxazolidin-2-one (WO 01/81350 A1) (7 g, 18.2 mmol) was dissolved in water (15 ml) and acetonitrile (150 ml). Triphenylphosphine (5.73 g, 21.9 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours. The solvent was evaporated and the residue purified by flash column chromatography on silica gel with 5% methanol in dichloromethane. The fractions containing product were evaporated to near dryness and treated with ethereal HCl to precipitate the hydrochloride salt of the title compound as a white solid (5.03 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.[C:10]([CH:15]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:12][CH2:13][CH3:14])=[O:11]>O1CCOCC1.[O-2].[Mn+4].[O-2]>[Cl:1][C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:15]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCc1cnc(Cl)cn1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cnc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a solution of (5-chloro-2-pyrazinyl)methanol (11.0 g) in dioxane (110 mL) was added manganese(IV) oxide (26.5 g) and (carbethoxymethylene)triphenylphosphorane (29.2 g). After stirring for 2 hours at room temperature, a resulting precipitate was filtered and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel to give ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (11.0 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C:14](=[O:17])[CH2:15][CH3:16])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[CH:7][CH:6]=2.N1C=CC=CC=1.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCCC1>[Cl:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([NH:13][C:14](=[O:17])[CH2:15][CH3:16])[C:2]([NH:1][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:11]2
Reactant: CCC(=O)Nc1nc2ccc(Cl)cc2nc1N
Reactant: CCCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCC(=O)Nc1nc2cc(Cl)ccc2nc1NC(=O)CC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of 50 parts of 3-amino-6-chloro-2-propionamidoquinoxaline in 1000 parts of pyridine was cooled to 5° in an ice bath. A solution of 96 parts of hexanoyl chloride in 88 parts of tetrahydrofuran was added as quickly as possible with good cooling to prevent the temperature from rising above 25°. The reaction mixture was stirred for 10 minutes and then poured into 2500 parts of ice water. The yellow gum which separated was removed by filtration and washed with water and then dissolved in 2700 parts of methylene chloride. The methylene chloride solution was washed in succession with 1000 parts each of water, 5% aqueous hydrochloric acid, water, 10% aqueous sodium carbonate, and water. The methylene chloride solution was dried (MgSO4) and evaporated. The residue was recrystallized from 1:4 ethyl acetate-benzene, the solid filtered off, and washed with ether to yield 8 parts of 6-chloro-3-hexanamido-2-propionamidoquinoxaline, m.p. 158°-160°, as a colorless solid.
Reaction SMILES: C([N:8]1[CH2:11][CH:10]([N:12]([CH3:18])[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)[CH2:9]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][N:12]([C:13]1[S:14][CH:15]=[CH:16][N:17]=1)[CH:10]1[CH2:9][NH:8][CH2:11]1
Reactant: CN(c1nccs1)C1CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(c1nccs1)C1CNC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
A solution of 166 mg (0.62 mmol) of 1-Boc-3-(methyl(thiazol-2-yl)amino)azetidine in DCM (5 ml) was combined with 2.5 ml of TFA and stirred for 3 h at RT. The mixture was then evaporated under a vacuum. The residue was redissolved with water and washed with ether. The aqueous phase was adjusted to pH 11 with a 20% strength aq. NaOH soln. and saturated with common salt. The mixture was then extracted with chloroform and the organic phase was dried over MgSO4 and filtered. After removal of the solvents under a vacuum, 102 mg (0.60 mmol, 97%) of 3-(methyl(thiazol-2-yl)amino)azetidine were obtained.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[N:8]2.C([O-])([O-])=O.[K+].[K+].O1CCO[CH2:23][CH2:22]1>O>[CH2:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[N:8]2)[CH:22]=[CH2:23]
Reactant: C1COCCO1
Reactant: COc1cnc2cccc(CBr)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C=CCc1cccc2ncc(OC)nc12
Temperature: 110 °C
Reaction time: 48 h
Yield: 74 %

Procedure:
A suspension of 8-(bromomethyl)-2-methoxy-quinoxaline (8.0 g; prepared according to WO 2008/078305) and K2CO3 (8.74 g) in dioxane (154 mL) and water (20 mL) was degassed by bubbling N2 through for 20 min and treated with Pd(dppf)Cl2.DCM complex (1:1) (521 mg) and vinylboronic anhydride pyridine complex (5.12 g). The reaction was further stirred at 110° C. for 2 days and partitioned between water and ether. The org. phase was washed with water and brine, dried over MgSO4, concentrated under reduced pressure and purified by CC (Hex/EA 9:1 to 4:1), affording a yellow liquid (4.70 g, 74% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([S:12]([CH3:15])(=[O:14])=[O:13])=[N:9][C:5]2=[N:6][C:7]=1[I:8].C(N(CC)CC)C.Cl[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[N:9]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:5]2=[N:6][C:7]=1[I:8]
Reactant: C[Si](C)(C)CCOCCl
Reactant: CS(=O)(=O)c1nc2nc(I)c(Cl)cc2[nH]1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1c(S(C)(=O)=O)nc2cc(Cl)c(I)nc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-5-iodo-2-(methylsulfonyl)-1H-imidazo[4,5-b]pyridine (for preparation see WO 2012116145; 1.5 g) and triethylamine (875 μL) are dissolved in tetrahydrofurane (12 mL), cooled to 0° C. and treated with (2-(chloromethoxy)ethyl)trimethylsilane (SEM-CI; 890 μL). The mixture is stirred for 30 minutes while warming to room temperature. Then the mixture is partitioned between saturated aqueous NH4Cl and ethylacetate. The organic phase is washed with water and brine. After drying (MgSO4) the solvents are evaporated in vacuo to give the title compound. LC (method 1): tR=1.22 min; Mass spectrum (ESI+): m/z=488 [M+H]+.