Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:21][CH2:22][CH2:23][CH2:24]O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:20][CH2:24][CH2:23][CH2:22][OH:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]/[CH:6]=[CH:7]\[CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCCCO
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCC(=O)OCCCO

Procedure:
A solution of z,z,z-octadeca-6,9,12-trienoic acid (150 g) in methylene chloride (500 ml) was added dropwise to a mixture of 1,3-dihydroxypropane (205 g), 1,3-dicyclohexylcarbodiimide (130 g) and 4-(N,N-dimethylamino)pyridine (87 g) in methylene chloride (2500 ml) at room temperature under nitrogen. When tlc indicated that the reaction had gone to completion the reaction mixture was filtered. The filtrate was washed with dilute hydrochloric acid, water and saturated sodium chloride solution. The solution was dried, concentrated and purified by dry column chromatography to yield 1-(z,z,z-octadeca-6,9,12-trienoyloxy)-3-hydroxypropane as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:20])=[C:5]([CH3:19])[C:6]2[O:11][C:10]([CH2:13][C:14](O)=[O:15])([CH3:12])[CH2:9][CH2:8][C:7]=2[C:17]=1[CH3:18].S(Cl)([Cl:23])=O>CN(C)C=O.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:4]([CH3:20])=[C:5]([CH3:19])[C:6]2[O:11][C:10]([CH2:13][C:14]([Cl:23])=[O:15])([CH3:12])[CH2:9][CH2:8][C:7]=2[C:17]=1[CH3:18]
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)O)O2
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CC(=O)Cl)O2

Procedure:
To a solution composed of 3.34 g of (3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acetic acid, 2 drops of N,N-dimethylformamide and 50 ml of benzene was added 0.87 ml of thionyl chloride, and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was evaporated under reduced pressure to remove the low-boiling substances. The above procedure gave (3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)acetyl chloride in a quantitative yield of 3.56 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])(=[O:13])=[O:12])[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:22][C:23]1[S:24][CH:25]=[C:26]([C:28]([NH:30][C:31]2[C:32]3[C:36]([CH:37]=[C:38](B4OC(C)(C)CC(C)(C)O4)[CH:39]=2)=[N:35][N:34](C2CCCCO2)[CH:33]=3)=[O:29])[N:27]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[S:11]([NH:10][C:4]1[CH:3]=[C:2]([C:38]2[CH:37]=[C:36]3[C:32]([CH:33]=[N:34][NH:35]3)=[C:31]([NH:30][C:28]([C:26]3[N:27]=[C:23]([CH3:22])[S:24][CH:25]=3)=[O:29])[CH:39]=2)[CH:7]=[N:6][C:5]=1[O:8][CH3:9])(=[O:13])=[O:12]
Reactant: Cc1nc(C(=O)Nc2cc(B3OC(C)(C)CC(C)(C)O3)cc3nn(C4CCCCO4)cc23)cs1
Reactant: COc1ncc(Br)cc1NS(=O)(=O)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ncc(-c2cc(NC(=O)c3csc(C)n3)c3cn[nH]c3c2)cc1NS(=O)(=O)c1ccc(F)cc1F
Temperature: 140 °C
Yield: 15.5 %

Procedure:
N-[5-Bromo-2-(methyloxy)-3-pyridinyl]-2,4-difluorobenzenesulfonamide (39 mg, 0.104 mmol), 2-methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (50 mg, 0.104 mmol), Pd(dppf)Cl2 (8 mg, 10.36 μmol) and sodium carbonate (44 mg, 0.415 mmol) were added to a microwave vial, followed by 1,4-Dioxane (0.5 mL) and Water (0.5 mL) and the reaction mixture was heated in the microwave at 140° C. for 20 min. After cooling, the mixture was then passed through a 1 g silica cartridge and washed with DCM:methanol. The solvent was evaporated by blow down under nitrogen. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v) and passed through a 1 g C18 cartridge, washing with acetonitrile, then evaporated by blow down. The residue was dissolved in 1.6 ml DMSO:methanol (1:1, v/v) and purified by MDAP (Method E). This MDAP purification step was then repeated to afford the title compound (9 mg).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[NH:5][N:4]=1.I[C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[F:13][C:2]([F:1])([F:12])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[N:4]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: O=C(O)c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Temperature: 130 °C
Reaction time: 3.25 h
Yield: 104.4 %

Procedure:
A mixture of 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole (950 mg, 5.0 mmol), 4-iodobenzoic acid (1.24 g, 5.0 mmol), N,N-dimethylglycine (20 mol %, 103 mg, 1.0 mmol), copper (I) iodide (10 mol %, 95 mg, 0.5 mmol) and potassium carbonate (1.45 g, 10.5 mmol) in dimethylsulfoxide (15 ml) was stirred at 130° C. in an oil bath under argon for 3.25 hours. The reaction mix was then filtered under vacuum and the filtrate separated between ethyl acetate and water. The aqueous layer was retained and acidified to approximately Ph2 using 5M aqueous HCl. The aqueous fraction was then washed 3 times with ethyl acetate. The organic layers were combined and dried over sodium sulphate, and the solvent was removed by rotary evaporation to give the title compound as a brown solid (1.62 g, 100%).
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)[S:16][C:17]=3[F:18])[CH:10]=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[F:18][C:17]1[S:16][C:15]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)=[N:14][C:13]=1[C:11]1[CH:12]=[N:8][NH:9][CH:10]=1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4cccc(C)n4)sc3F)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Nc2nc(-c3cn[nH]c3)c(F)s2)n1
Yield: 50 %

Procedure:
According to Scheme 6 Step 4: A solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-fluorothiazol-2-yl)-6-methylpyridin-2-amine (0.24 mmol, 95 mg) in TFA (3 mL) was microwaved for 8 minutes at 140° C. After evaporation of the solvent, the reaction mixture was neutralized with a solution of NaOH (1 M). The aqueous phase was extracted with DCM and with AcOEt. The organic phase was dried over MgSO4, was filtered and was concentrated. The resulting crude product was washed with Et2O to yield 5-fluoro-N-(6-methylpyridin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine (0.12 mmol, 33 mg, 50%) as a beige solid.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:17][C:18]#[N:19].[NH4+]>BrC1C=CC=CC=1>[C:11]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][NH:10][C:18]([NH2:19])=[S:17])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: Brc1ccccc1
Product: NC(=S)NCCC(c1ccccc1)c1ccccc1
Yield: 58.7 %

Procedure:
A solution of 3,3-diphenylpropylamine (4.00 g, 18.9 mmol) and ammonium thiocyanate (1.60 g, 20.8 mmol) in bromobenzene (30 mL) was refluxed for 1 hour. After cooling, the solid precipitate was recovered, rinsed with diethyl ether, water, and ethanol, and dried to provide 3.00 g (yield 59%) of the title compound.
Reaction SMILES: Cl.CCO[CH:5](OCC)[CH2:6][Cl:7].[CH2:11]([O:13][C:14]([NH:16][NH2:17])=[O:15])[CH3:12]>O>[CH2:11]([O:13][C:14](=[O:15])[NH:16][N:17]=[CH:5][CH2:6][Cl:7])[CH3:12]
Reactant: CCOC(=O)NN
Reactant: CCOC(CCl)OCC
Agent: Cl
Solvent: O
Product: CCOC(=O)NN=CCCl
Temperature: 30 °C
Reaction time: 0.25 h

Procedure:
60 ml water and 0.8 ml of concentrated hydrochloric acid were heated to 90° C. in a three times tubulated round bottom flask of 250 ml contents equipped with a stirrer, thermometer and reflux condenser. The reaction mass was then reacted with 15.2 g of chloroacetaldehydediethylacetal and was subjected to stirring for 15 minutes at 90° to 100° C. The mass was then cooled to 30° C. and a solution of 12.5 g of hydrazinoformic acid ethylester in 40 ml water was added within a period of 10 minutes. There formed a white crystal slurry. After further stirring for 15 minutes the mass was subjected to suction. The separated crystals were washed with 30 ml icewater and were dried in vacuum at room temperture until the weight remained constant. There were obtained white crystals.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@H:10]1[CH2:40][CH2:41][CH2:42][N:43]=[N+]=[N-])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:11][C@@H:10]1[CH2:40][CH2:41][CH2:42][NH2:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCCC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NCCC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 8 h

Procedure:
To a nitrogen flushed solution of 3-(2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl)propyl azide (3 g, 4.94 mmol) in CH3OH (100 mL) was added 10% Pd/C (525 mg). The resulting mixture was allowed to stir under a balloon of H2 overnight. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated to give the title compound. 1H NMR (CDCl3) δ 1.48 (m, 1H), 1.59 (m, 1H), 2.23 (m, 1H), 2.30 (m, 2H), 3.66-3.76 (m, 5H), 4.00 (m, 1H), 4.09 (m, 1H), 4.38 (d, J=10.0, 1H), 4.50 (d, J=12.1, 1H), 4.61 (d, J=11.7, 1H), 4.68 (d, J=11.8, 1H), 4.70 (d, J=12.0, 1H), 4.79 (d, J=10.0, 1H), 4.86 (d, J=11.2, 1H), 5.02 (d, J=11.2, 1H), 7.00 (m, 2H), 7.25-7.40 (m, 18H), 8.06 (s, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[CH2:7]([O:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([C:27]([O:29]CC)=O)[C:22]([O:24]CC)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:27](=[O:29])[CH:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:22]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6])=[O:24]
Reactant: NCCCCN
Reactant: CCOC(=O)C(CCCCCCOCc1ccccc1)C(=O)OCC
Product: NCCCCNC(=O)C(CCCCCCOCc1ccccc1)C(=O)NCCCCN
Temperature: 90 °C

Procedure:
To a large excess of 1,4-diaminobutane (85 g, 0.964 mol) at 90° C. under argon was slowly added (over 2 hours) B2 (10.50 g, 0.030 mol). The solution was heated at 90° C. overnight and the excess diamine distilled off under reduced pressure (0.1 mBar, 28° C.) to quantitatively yield the title compound as a pale yellow low melting point solid. C24H42N4O3 requires 434. Found DCl: M++1 435. I.R. 1664 cm−1 (CO2). δH (CDCl3) 1.15-1.40 (10H, br m, (CH2)3CH2CH, NH2), 1.40-1.60 (10H, br m, (CH2)2CH2NH2, CH2CH2O), 1.76 (2H, q, CH2CH), 2.63 (4H, t, CH2NH2), 2.93 (2H, t, CH2CH), 3.16 (4H, q, CH2NH), 3.37 (2H, t, CH2OCH2Ph), 4.42 (2H, s, CH2Ph), 7.26 (5H, m, Ph), 7.61 (2H, t, CONH). δC (CDCl3) 25.7 (1C, CH2(CH2)2CH), 26.6 (2C, CH2CH2NH2), 28.8, 29.4 (2C, CH2CH2CH, CH2CH2O), 30.6 (2C, CH2CH2NH), 32.7 (1C, CH2CH), 39.0 (2C, CH2NHCO), 41.4 (2C, CH2NH2), 54.7 (1C, CHCO), 70.1, 72.6 (2C, CH2OCH2), 127.2 (1C, CH(CH)2C), 127.3 (2C, CHC), 128.0 (2C, CHCHC), 138.5 (1C, CCH2O), 171.0 (2C, CONH).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Br:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#N>C(#N)C>[Br:13][C:10]1[C:11]2[O:12][C:14]([C:15]([CH3:20])([CH3:19])[CH3:16])=[N:1][C:2]=2[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=1
Reactant: COC(=O)c1cc(N)c(O)c(Br)c1
Reactant: CC(C)(C)C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)c1cc(Br)c2oc(C(C)(C)C)nc2c1
Temperature: 150 °C
Yield: 19.3 %

Procedure:
To a solution of methyl 3-amino-5-bromo-4-hydroxybenzoate (2.00 g, 4.06 mmol, 50% purity), 2,2-dimethylpropanoic acid (0.83 g, 8.13 mmol), and solid support triphenylphosphine (75% by weight; 4.26 g, 12.2 mmol) in acetonitrile (20 mL) was added trichloroacetonitrile (815 μL, 8.13 mmol). The mixture was heated in a microwave reactor for 10 min at 150° C. The mixture was cooled to ambient temperature, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→70% hexanes/ethyl acetate) gave the title compound (245 mg). LC-MS [M]=312.1.
Reaction SMILES: [Cl:1][C:2]([Cl:47])([Cl:46])[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:34]([O:36]CC)=[O:35])=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:13]2)=[O:8])([CH3:5])[CH3:4].[OH-].[Na+].Cl.N1C=CN=C1.CC([Si](Cl)(C)C)(C)C.[NH4+].[Cl-].C([O-])([O-])=O.[K+].[K+]>CCO.CCOC(C)=O.C1COCC1.O.CO>[Cl:47][C:2]([Cl:1])([Cl:46])[C:3]([O:6][C:7]([N:9]1[CH:14]2[C:15]([C:34]([OH:36])=[O:35])=[C:16]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH2:24][CH2:25][O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:28])[CH3:29])[CH:19]=3)[CH2:17][CH:10]1[CH2:11][N:12]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:13]2)=[O:8])([CH3:5])[CH3:4]
Reactant: CCOC(=O)C1=C(c2cc(CCCO[Si](C)(C)C(C)(C)C)no2)CC2CN(C(=O)OC(C)(C)C)CC1N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC2CC(c3cc(CCCO[Si](C)(C)C(C)(C)C)no3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C(Cl)(Cl)Cl
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of compound C3 (1.03 g, 1.40 mmol) in EtOH (10 mL) and aq. 1M NaOH (10 mL) was stirred at 80° C. for 5 h. The mixture was allowed to cool to rt, and was then diluted with EtOAc. This mixture was acidified with aq. 1M HCl until a pH between 3 and 4 was obtained. The layers were separated, then the aq. phase was extracted with EtOAc (2×). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude product was dissolved in DMF (20 mL). Imidazole (381 mg, 5.6 mmol) and TBDMS-Cl (527 mg, 3.5 mmol) were added. The mixture was stirred overnight. Aq. sat. NH4Cl was added and the resulting suspension was extracted with heptane (3×). The combined org. extracts were dried over MgSO4, filtered, and concentrated to yield a yellow oil. This crude product was dissolved in THF (15 mL), MeOH (5 mL) and H2O (5 mL), and K2CO3 (97 mg) was added. The mixture was stirred at rt for 2.5 h and was concentrated to half under reduced pressure. The residue was then diluted with Et2O to produce a clear yellow sol. This yellow sol. was washed with aq. sat. NH4Cl. The aq. phase was extracted with Et2O (2×), and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude title compound (950 mg, 95%) was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH2:11][CH2:12][CH3:13])[C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].Br[CH:21]([F:23])[F:22].O>CN(C)C=O>[F:22][CH:21]([F:23])[O:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][CH2:11][CH2:12][CH3:13])[C:3]=1[C:4]#[N:5]
Reactant: CCCSc1cccc(O)c1C#N
Reactant: FC(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCSc1cccc(OC(F)F)c1C#N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
10.8 g (56 mmol) of 2-hydroxy-6-propylsulfanylbenzonitrile were dissolved in 120 ml of dimethylformamide, and 15.5 g (0.11 mol) of anhydrous potassium carbonate were added. Then, at room temperature, 8.2 g of bromodifluoromethane were passed in, and the mixture was stirred at room temperature for 5 hours. Then 15.5 g (0.11 mol) of anhydrous potassium carbonate and 7.2 g of bromodifluoromethane were added, and the mixture was stirred at room temperature overnight. The reaction mixture was worked up by pouring into water and extracting twice with methyl tert.-butyl ether. The organic phase was separated, washed several times with water and concentrated. The solid has been dried in vacuo at 50° C. Yield: 12.3 g of an oily residue.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O[N:8]=[C:9]([C:14](=[O:34])[CH:15]([O:30]C(=O)C)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:10](OC)=[O:11].[ClH:35]>O1CCCC1>[ClH:35].[NH2:8][CH:9]([CH:14]([OH:34])[CH:15]([OH:30])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:10][OH:11]
Reactant: CCCCCCCCCCCCCCC(OC(C)=O)C(=O)C(=NO)C(=O)OC
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCC(O)C(O)C(N)CO
Temperature: 60 °C

Procedure:
0.275 mol of lithium aluminum hydride was introduced, under argon, with continual stirring, into tetrahydrofuran. The solution was then cooled to a temperature of 0° C., and 0.055 mol of methyl 2-hydroxyimino-3-oxo-4-acetoxyoctadecanoate was slowly added. The reaction mixture was then gradually heated to 60° C. At the end of the reaction, marked by the disappearance of the starting materials, the reaction mixture was hydrolysed while cold with a hydrochloric acid solution. A precipitate formed, which was filtered off, and then the solvent was evaporated under vacuum. After crystallizing from a mixture of ethyl ether and acetonitrile, a white solid was obtained which, filtered and dried, gave 14.2 g of 2-aminooctadecane-1,3,4-triol hydrochloride in the form of a white powder.
Reaction SMILES: C([O:3][C:4](=O)[N:5]([C:13]1[CH:18]=[C:17]([C:19]2[N:20](COCC[Si](C)(C)C)[CH:21]=[CH:22][N:23]=2)[N:16]=[C:15]([NH2:32])[C:14]=1[N+:33]([O-])=O)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.N1C=CN=C1.Cl>[Ni].C(O)(=O)C.O1CCOCC1>[NH2:32][C:15]1[C:14]2[NH:33][C:4](=[O:3])[N:5]([CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:13]=2[CH:18]=[C:17]([C:19]2[NH:20][CH:21]=[CH:22][N:23]=2)[N:16]=1
Reactant: CCOC(=O)N(Cc1ccccc1)c1cc(-c2nccn2COCC[Si](C)(C)C)nc(N)c1[N+](=O)[O-]
Agent: [Ni]
Agent: Cl
Agent: c1c[nH]cn1
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Nc1nc(-c2ncc[nH]2)cc2c1[nH]c(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.9 %

Procedure:
The title compound was prepared following the method of Example 20 using {2-amino-3-nitro-6-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyridin-4-yl}-benzyl-carbamic acid ethyl ester (174 mg) and Raney nickel (5 mg) in acetic acid (3 ml). This gave initially the SEM protected imidazole compound. Hydrogen chloride in dioxane (4 M, 1 ml) was then added drop-wise and the solution left to stir at room temperature for 24 hours. The reaction mixture was then transferred to a microwave vial (Biotage, 2-5 ml) and heated under microwave irradiation for 10 minutes at 110° C. (Biotage, Initiator 8). The reaction mixture was evaporated then re-dissolved in methanol and the solution loaded onto a cation-exchange cartridge (Bakerbond, sulphonic acid bonded-phase, 1 g). The cartridge was washed with methanol (2×5 ml) to remove impurities and then the product released by eluting with ammonia in methanol (2 M, 5 ml). The desired fractions were combined and evaporated to a brown solid. This was triturated with isopropanol and the solid collected by filtration then washed with more isopropanol, providing the title compound (28 mg) as a pale brown solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 5.02 (s, 2 H) 5.58 (s, 2 H) 6.91 (s, 1 H) 7.06 (s, 1 H) 7.11 (s, 1 H) 7.25-7.36 (m, 5 H) 10.53 (s, 1 H) 11.99 (s, 1 H). LCMS Rt=1.52 m/z 307 [MH]+hm
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[O:3][C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1nc2ccccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nc3ccccc3o2)CC1

Procedure:
A mixture of 52.5 mmol 2-chlorobenzoxazol, 53.6 mmol piperazine-1-carboxylic acid tert-butyl ester and 63 mmol of potassium carbonate in 60 ml of acetonitrile was refluxed for 16 hours. The reaction mixture was concentrated, diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated to yield the title compounds as a slightly orange solid. MS (m/e): 304.2 (M+H+)
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25](=[O:27])[CH3:26])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[CH3:28][N:29]([CH:31](OC)OC)[CH3:30]>CO>[CH3:28][N:29]([CH3:31])/[CH:30]=[CH:26]/[C:25]([C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)=[O:27]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CO
Product: CN(C)/C=C/C(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Yield: 77.6 %

Procedure:
A mixture of 1-(1-trityl-1H-imidazol-4-yl)ethanone (81.0 g, 230 mmol) and DMF-DMA (77.0 mL, 575 mmol) in MeOH (500 mL) was heated to reflux for 72 h. The mixture was then allowed to cool to RT and was then cooled to 0° C. the suspension was filtered and the filter cake was dried in vacuo at 40° C. to give the title compound (72.7 g) that was used as it is in the next step. UPLC-MS: MS 408.3 (M+H+); UPLC rt 1.08 min.
Reaction SMILES: [CH2:1]1[CH2:6][CH2:5][C:4]([CH2:11][NH2:12])([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[Si](C)(C)C.Cl[C:26]([O:28][CH:29]([Cl:31])[CH3:30])=[O:27]>ClCCl>[Cl:31][CH:29]([O:28][C:26]([NH:12][CH2:11][C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2][CH2:1][CH2:6][CH2:5]1)=[O:27])[CH3:30]
Reactant: CC(Cl)OC(=O)Cl
Reactant: NCC1(CC(=O)O)CCCCC1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Cl)OC(=O)NCC1(CC(=O)O)CCCCC1
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
In a 5-liter, 3-neck, round bottom flask containing dichloromethane (1.6 L) is added gabapentin (120.4 g, 0.704 mol) followed by triethylamine (294 mL, 2.11 mol). Chlorotrimethylsilane (178 mL, 1.40 mol) is slowly added while maintaining the reaction temperature below 15° C. and the resulting suspension is stirred for 30 min. 1-Chloroethyl chloroformate (100 g, 0.704 mol) is then added slowly while maintaining the temperature below 15° C. After the addition is complete, additional triethylamine (88 mL, 0.63 mol) is added and the resulting suspension is stirred at room temperature for 30 min. The resulting silyl ester is converted via acidic work-up to the corresponding acid by washing the reaction mixture with water (2×1 L), followed by 1N HCI (2×2 L) then brine (2×500 mL). After drying over anhydrous sodium sulfate and removal of the solvent in vacuo, the crude product (190 g) is obtained as an orange oil and used in Step B without further purification. 1H NMR (CDCI3, 400 MHz): δ 1.41-1.57 (m, 10H), 1.78 (d, 3H), 2.33 (s, 2H), 3.27 (d, 2H), 5.42 (br. s, 1H), 6.55 (q, 1H).