Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:15])[C:5]2[S:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[C:13]=1[CH3:14].C([Li])CCC.CN(C)[CH:23]=[O:24].Cl>C(OCC)C>[CH3:11][C:7]1([CH3:12])[C:6]2[C:13]([CH3:14])=[C:2]([CH:23]=[O:24])[CH:3]=[C:4]([CH3:15])[C:5]=2[S:10][CH2:9][CH2:8]1
Reactant: CN(C)C=O
Reactant: Cc1cc(Br)c(C)c2c1SCCC2(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: Cc1cc(C=O)c(C)c2c1SCCC2(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
6-Bromo-3,4-dihydro-4,4,5,8-tetramethyl-2H-1-benzothiopyran (19.8 g, World Patent Application 95/04054) was dissolved in diethyl ether (350 mL) and treated with n-butyllithium (2.5N in hexanes, 42 mL). The mixture was stirred at room temperature for 1 h and then cooled in a dry-ice/acetone bath. Dimethylformamide (16 mL) was added over a period of several minutes and the reaction bath was allowed to warm to -40° C. Hydrochloric acid (1N aqueous, 100 mL) was added and the mixture was allowed to warm to 23° C. The organic phase was separated and washed with saturated aqueous sodium bicarbonate solution (100 mL). The organic phase was dried over magnesium sulfate, filtered, and evaporated under reduced pressure. The residue was subjected to chromatography on silica gel using hexanes/ether (9:1) as eluent to afford the desired compound as a yellow semi-solid (7.7 g). 1H NMR(CDCl3): δ 1.5 (6H), 2.0 (2H), 2.3 (3H), 2.8 (3H), 3.0 (2H), 7.4 (1H), 10.2 (1H).
Reaction SMILES: [C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:17][CH:18]([N:20]([CH3:22])[CH3:21])[CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>CO.O>[C:1]1([C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:17][CH:18]([N:20]([CH3:21])[CH3:22])[CH3:19])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCCCC(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(CC(CCCCC(=O)O)(c1ccccc1)c1ccccc1)N(C)C
Yield: 20.9 %

Procedure:
Ethyl 6,6-diphenyl-8-dimethylaminononanoate (863 mg) was taken up in methanol (7 ml) and treated with 1M KOH in methanol (7.4 ml). The mixture was refluxed under Ar for 2.5 hours, and cooled. The pale yellow solution was concentrated to dryness to provide a clear pale yellow glass. The residue was taken up in H2O (2 ml) and treated dropwise with 1N HCl to pH 6. This solution was then evaporated to dryness and dissolved in 12 ml of methanol to yield a precipitate which was filtered. This procedure was repeated, using 8 ml of methanol, and the filtrates were evaporated to dryness. A 250 mg portion, dissolved in methanol (12 ml), was purified by PTLC. Development with 30% methanol/CHCl3 produced a major band (Rf range 0.12-0.31), which was scraped off the plate and eluted with methanol. The methanolic extracts were evaporated, and the residue was coevaporated twice with toluene (3 ml) to yield 167 mg of 6,6-diphenyl- 8-dimethylaminononanoic acid, as a clear oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@H:5]([CH3:14])[NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[CH2:17][C:18](=[O:20])[CH3:19].C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([N:6]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:17][C:18](=[O:20])[CH3:19])[CH3:14]
Reactant: COC(=O)[C@H](C)NCc1ccccc1
Reactant: CC(=O)CCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@H](C)N(CC(C)=O)Cc1ccccc1
Temperature: 70 °C
Yield: 49.8 %

Procedure:
A mixture of N-benzylalanine methyl ester hydrochloride (1.00 g, 4.35 mmol), chloroacetone (1.21 g, 13.1 mmol), and sodium hydrogencarbonate (951 mg, 11.3 mmol) in 1,4-dioxane (11 mL) and water (1 mL) was heated at 70° C. for 2 days, then partitioned between EtOAc and 2 M aq. sodium carbonate solution. The organic layer was dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-EtOAc gradient) produced the title compound (540 mg, 50%). Colourless oil, MS: 250.1 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:5][CH:4]=1.[N-:24]=[N+:25]=[N-:26].[Na+]>CN(C=O)C>[N:24]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])=[CH:5][CH:4]=1)=[N+:25]=[N-:26]
Reactant: COCCOCCOCCOCCOCc1ccc(CCl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCOCCOCCOCc1ccc(CN=[N+]=[N-])cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 1-(4-(chloromethyl)phenyl)-2,5,8,11,14-pentaoxapentadecane (1.50 g, 4.33 mmol) in DMF (10 mL) was added NaN3 (337.9 mg, 5.20 mmol). The reaction mixture was stirred overnight at 110° C. The solvent was subsequently evaporated. The residue was then suspended in ethyl acetate and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography to give the desired azide (1.53 g, 4.33 mmol, 90%) as a colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.37 (d, 2H, J=8.0 Hz), 7.30 (d, 2H, J=8.2 Hz), 4.58 (s, 2H), 4.33 (s, 2H), 3.69−3.58 (m, 14H), 3.56−3.52 (m, 2H), 3.37 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 138.6, 134.7, 128.3, 128.2, 72.9, 72.0, 70.7, 70.6, 70.5, 69.7, 68.0, 59.1, 54.6; MS (ESI) m/z calcd for C17H27N3O5 [M+H]+ 353.2 found [M+H2O]+ 371.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=[O:8])[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)=[CH:35][C:34]=1[Pb+3]>C(Cl)(Cl)Cl.Cl>[Br:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=2)=[CH:37][C:38]=1[CH:6]1[C:7](=[O:8])[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5]1=[O:9]
Reactant: Clc1ccc(-c2ccc(Br)c([Pb+3])c2)cc1
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(C)(C)C(=O)C(c2cc(-c3ccc(Cl)cc3)ccc2Br)C1=O
Temperature: 25 °C
Yield: 0.6 %

Procedure:
To a mixture of 2,2,6,6-tetramethylpyran-3,5-dione (0.75 g, 4.9 mmol) and N,N-dimethylaminopyridine (2.52 g, 20.6 mmol) is added anhydrous chloroform (40 ml), followed by stirring at room temperature until dissolution. To this solution is added anhydrous toluene (12 ml), followed by 4-bromo-4′-chlorobiphenyl-3-yllead triacetate (3.25 g, 5.1 mmol) in one portion and the reaction mixture is heated at 80° C. for 2 hours. The mixture is cooled to room temperature, diluted with chloroform (50 ml) and 1M aqueous hydrochloric acid (50 ml), and the mixture is stirred for 5 minutes. The precipitate is removed by filtration, the two phases separated, and the organic phase is washed with brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated in vacuo. The residue is purified by flash column chromatography on silica gel, and fractions containing the desired compound are combined and evaporated to give a residue which is further purified by preparative reverse phase HPLC to give 4-(4-bromo-4′-chlorobiphenyl-3-yl)-2,2,6,6-tetramethylpyran-3,5-dione (0.013 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH:27]([OH:29])[CH3:28].N(C(OCC)=O)=NC(OCC)=O.[CH3:42][O:43][C:44]([C:46]1[S:47][C:48]([N:52]2[CH:56]=[N:55][C:54]([NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[N:53]2)=[CH:49][C:50]=1O)=[O:45]>C1COCC1.CN(C=O)C>[CH3:42][O:43][C:44]([C:46]1[S:47][C:48]([N:52]2[CH:56]=[N:55][C:54]([NH:57][C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)=[N:53]2)=[CH:49][C:50]=1[O:29][CH:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[Cl:20])[CH3:28])=[O:45]
Reactant: COC(=O)c1sc(-n2cnc(Nc3ccccc3)n2)cc1O
Reactant: CC(O)c1ccccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1sc(-n2cnc(Nc3ccccc3)n2)cc1OC(C)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.4 %

Procedure:
Triphenyl phosphine (124 mg, 0.47 mmol, 1.5 Eq.) was added to a stirred solution of 1-(2-Chloro-phenyl)-ethanol (74 mg, 0.47 mmol, 1.5 Eq.) in anhydrous THF (5 mL) at 0° C. under nitrogen. The reaction was stirred at this temperature for 30 minutes, then diethyl azodicarboxylate (75 μL, 0.47 mmol, 1.5 Eq.) was added-dropwise and the reaction stirred at 0° C. for a further 1 hour. 3-Hydroxy-5-(3-phenylamino-[1,2,4]triazol-1-yl)-thiophene-2-carboxylic acid methyl-ester (100 mg, 0.32 mmol, 1.0 Eq.) in anhydrous DMF (2 mL) was added and the reaction stirred for a further 1 hour at 0° C. then allowed to warm to ambient temperature overnight. The crude reaction mixture was partitioned between EtOAc (50 mL) and water (50 mL). The organic phase was washed with water (2×20 mL), dried (MgSO4) and concentrated in vacuo. The crude product was purified by column chromatography (ISCO Companion™, 12 g column, 0-100% EtOAc/petroleum Ether) to give the sub-title compound as an off-white solid (88 mg, 0.19 mmol, 73%); 1H NMR (400 MHz, CDCl3) δ 1.74 (3H, d), 3.93 (3H, s), 5.84 (1H, q), 6.70 (1 h, br s), 6.74 (1H, s), 7.02 (1H, t), 7.21-7.40 (5H, m), 7.51 (1H, d), 7.63 (1H, d), 8.12 (1H, s).
Reaction SMILES: CO.[OH-].[Na+].C([O:8][C:9]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18]C)=[O:17])=[O:12])(=O)C.Cl>O1CCOCC1>[OH:8][C:9]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][C:10]=1[C:11]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([OH:18])=[O:17])=[O:12]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cccc(C)c1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Product: Cc1cccc(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)O)c1O
Temperature: 25 °C
Reaction time: 7 h
Yield: 82.4 %

Procedure:
Methanol (2 mL), dioxane (4 mL), and a 2 mol/L aqueous solution of sodium hydroxide (0.77 mL) were added to the obtained methyl 2-(2-acetoxy-3-methylbenzamido)-4-phenylbenzoate (0.062 g), followed by stirring at room temperature for 7 hours. The reaction mixture was adjusted to a pH of 1.1 with 6 mol/L hydrochloric acid. The solid substance was collected by filtration to obtain 0.044 g of 2-(2-hydroxy-3-methylbenzamido)-4-phenylbenzoic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=4[F:25])=[C:11]3[C:10](I)=[N:9]2)=[CH:5][CH:4]=1.[CH3:29][N:30]1[C:34]([Sn](CCCC)(CCCC)CCCC)=[CH:33][N:32]=[CH:31]1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[F:25][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:9]=[C:10]([C:34]3[N:30]([CH3:29])[CH:31]=[N:32][CH:33]=3)[C:11]=12)[NH2:24]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncn1C
Reactant: COc1ccc(Cn2nc(I)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2nc(-c3cncn3C)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Temperature: 100 °C
Yield: 78.3 %

Procedure:
4-(1-(4-Methoxybenzyl)-3-iodo-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (300 mg, 0.612 mmol, prepared in Example 7, step B), 1-methyl-5-(tributylstannyl)-1H-imidazole (681 mg, 1.84 mmol) (Org. Proc. Res. & Dev., 2003, 7(5), 676-683), tetrakis (triphenylphosphine) palladium (0) (141 mg, 0.122 mmol) and toluene (5 mL) were charged in a 25 mL, single-neck, round-bottomed flask. The reaction mixture was stirred at 100° C. until the starting material had been consumed (2 days). Then the reaction was cooled to room temperature and then partitioned between EtOAc (50 mL) and water (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude product. The crude product was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 100/1 to 10/1, v/v) to afford product (213 mg, 78.3%). LRMS (APCI pos): >95% purity, 254 nm, m/e 445 (M+1). 1H NMR (400 MHz, CDCl3 δ 8.32 (d, 1H), 7.71 (m, 1H), 7.50 (m, 1H), 7.36 (m, 2H), 6.96 (m, 1H), 6.83 (m, 2H), 6.52 (m, 1H), 6.46 (m, 1H), 6.28 (d, 1H), 5.65 (s, 2H), 3.92 (s, 3H), 3.77 (s, 3H), 3.67 (s, 2H, NH2),
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][OH:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:28]1[CH:29]=[CH:30][C:31]2[N:32]([C:34](=[O:56])[N:35]([C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[N:36]=2)[N:33]=1>CN(C)C=O>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:28]3[CH:29]=[CH:30][C:31]4[N:32]([C:34](=[O:56])[N:35]([C:37]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)[N:36]=4)[N:33]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=c1n(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2ccc(Cl)nn12
Reactant: OCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1n(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc2ccc(OCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.7 %

Procedure:
0.326 g of 4-(diphenylmethoxy)-1-piperidinepropanol was dissolved in 3 ml of N,N-dimethylformamide; 0.044 g of 60% oily sodium hydride was added, followed by stirring at room temperature for 1 hour. 0.326 g of 6-chloro-2-triphenylmethyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was added, followed by stirring at room temperature for 14 hours. After ice water was added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol (95:5). The desired fraction was collected and concentrated to yield 0.58 g of 6-[3-[4-(diphenylmethoxy)piperidino]propoxy]-2-triphenylmethyl[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one as an oily substance. 0.58 g of the oily substance obtained was dissolved in 10 ml of acetone; 467 mg of p-toluenesulfonic acid hydrate was added, followed by refluxing under heating in an oil bath for 5 hours. After cooling, the acetone was mostly distilled off under reduced pressure; to the residue, an aqueous solution of sodium hydrogen carbonate was added; the reaction mixture was extracted with ethyl acetate-tetrahydrofuran (2:1); the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (85:15:1). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with ethyl acetate, and dried, to yield 0.137 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[N+:16]([O-])=O>C(O)C.O1CCCC1.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[NH2:16]
Reactant: COc1ccnc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccnc(-c2ccc(F)c(N)c2)c1
Yield: 100.1 %

Procedure:
A suspension of 2-fluoro-5-(4-methoxypyridin-2-yl)nitrobenzene (0.2 g) in ethanol (4 ml) and tetrahydrofuran (3 ml) was hydrogenated over palladium on carbon (10% w/w, 50% wet, 60 mg) under a hydrogen atmosphere for 5 hours. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give 2-fluoro-5-(4-methoxypyridin-2-yl)aniline (176 mg).
Reaction SMILES: C[Al](C)C.[CH3:5][O:6][CH2:7][CH2:8][NH2:9].[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]=1[CH2:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][N:25]=1.O>O1CCOCC1>[CH3:5][O:6][CH2:7][CH2:8][NH:9][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([O:23][CH2:22][C:12]2[C:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[N:14][O:15][C:11]=2[CH3:10])=[N:25][CH:26]=1
Reactant: COCCN
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Agent: C[Al](C)C
Solvent: C1COCCO1
Solvent: O
Product: COCCNC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
A solution of trimethylaluminium (2 M in toluene, 2.0 mL, 4.0 mmol) was added dropwise (exothermic) to a solution of 2-methoxyethylamine (300 mg, 4.0 mmol) in dioxane (3 mL) and the resulting mixture was stirred at room temperature for 1 h. Then a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (310 mg, 1.0 mmol) in dioxane (3 mL) was added. The resulting mixture was then heated at 85-95° C. for 4 days and then cooled to room temperature and then poured into water and extracted with ethyl acetate which was then washed with brine, dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 9:1) afforded the title compound (280 mg, 76%) which was obtained as a colourless oil. MS: m/e=368.1 [M+H]′.
Reaction SMILES: [O:1]=[C:2]([CH2:16][C@@H:17]([O:23][C:24]([O:26][CH2:27][C:28]([Cl:31])([Cl:30])[Cl:29])=[O:25])[C@@H:18]([CH3:22])[CH2:19][CH:20]=[CH2:21])[C:3]([CH3:15])([CH3:14])[C@@H:4]([OH:13])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].N1C=CN=C1.[CH2:37]([Si:39](Cl)([CH2:42][CH3:43])[CH2:40][CH3:41])[CH3:38].O>CN(C)C=O>[O:1]=[C:2]([CH2:16][C@@H:17]([O:23][C:24]([O:26][CH2:27][C:28]([Cl:29])([Cl:30])[Cl:31])=[O:25])[C@@H:18]([CH3:22])[CH2:19][CH:20]=[CH2:21])[C:3]([CH3:14])([CH3:15])[C@@H:4]([O:13][Si:39]([CH2:42][CH3:43])([CH2:40][CH3:41])[CH2:37][CH3:38])[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: C=CC[C@H](C)[C@@H](CC(=O)C(C)(C)[C@@H](O)CC(=O)OC(C)(C)C)OC(=O)OCC(Cl)(Cl)Cl
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C=CC[C@H](C)[C@@H](CC(=O)C(C)(C)[C@H](CC(=O)OC(C)(C)C)O[Si](CC)(CC)CC)OC(=O)OCC(Cl)(Cl)Cl

Procedure:
A solution of tert-butyl (3S,7R,8S)-5-oxo-3-hydroxy-4,4,8-trimethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-10-undecenoate (1.7 g), imidazole (0.48 g), and triethylsilyl chloride (0.68 g) in 5 mL of dimethylformamide is stirred for 2 hours at ambient temperature, then poured into water and extracted with ether. The extract is washed with sat. aq. NaCl, dried over MgSO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[C:18](Cl)(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:18]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)(=[O:20])[CH3:19]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 2-amino-5-nitropyridine (4.0 g, 28.8 mmol ) in dichloromethane (15 ml) were added 176 mg (31.6mmol) of 4-N,N'-dimethylaminopyridine (DMAP), 4.41 ml of triethylamine (31.6 mmol) and 2.16 ml (31.6 mmol) of acetyl chloride in turn, and the mixture was stirred at room temperature for 1 hour. A 1M aqueous solution of potassium carbonate was added to the mixed suspension to neutralize it. Extraction with chloroform was repeated three times, and the extract was dried over magnesium sulfate. The solvent was removed, and the residue was subjected to silica gel column chromatography (eluent: chloroform). Recrystallization from chloroform-hexane gave 2.14 g of the intended product as a flesh-colored powder (yield: 49%).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[CH3:6][O:7][C:8]1[CH:12]=[CH:11][S:10][CH:9]=1.O=P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:6][O:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: COc1ccsc1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccsc1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 43.4 %

Procedure:
Chlorosulfonic acid (ClSO3H, 2.31 g, 19.62 mmol) was slowly added at 0° C. to a solution of 3-methoxythiophene (2.29 g, 19.62 mmol) in CHCl3 (80 ml) The resulting mixture was stirred at 0° C. for 30 min. The solvent was evaporated under reduced pressure, at room temperature, the residue was suspended in POCl3 (15 ml, 156.96 mmol), and PCl5 (8.2 g, 39.24 mmol) was added slowly. The reaction was stirred at 60° C. for 18 h, then cooled to room temperature and poured onto crushed ice (200 g). The aqueous mixture was extracted with CHCl3 (2×150 ml) and the combined organic layers was dried (MgSO4). The solid was removed by filtration and the filtrate was concentrated to give 3-methoxy-2-thiophenesulfonyl chloride as a brown oil (1.81 g, 43% yield).
Reaction SMILES: [NH2:1][C:2](=[N:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][N:17]3C(=O)C4=CC=CC=C4C3=O)[CH:11]=2)[N:9]=1)[NH2:3].O.NN>C(O)C>[NH2:17][CH2:16][C:12]1[CH:11]=[C:10]([C:8]2[N:9]=[C:5]([N:4]=[C:2]([NH2:3])[NH2:1])[S:6][CH:7]=2)[CH:15]=[CH:14][N:13]=1
Reactant: NC(N)=Nc1nc(-c2ccnc(CN3C(=O)c4ccccc4C3=O)c2)cs1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1cc(-c2csc(N=C(N)N)n2)ccn1
Yield: 97.1 %

Procedure:
A mixture of 2-(diaminomethyleneamino)-4-(2-phthalimidomethylpyridin-4-yl)thiazole (1.57 g) and hydrazine hydrate (0.63 g) in ethanol (25 ml) was refluxed for two hours. The resulting precipitate was filtered off and washed with methanol (20 ml). The two organic layer was combined and evaporated in vacuo to give 4-(2-aminomethylpyridin-4-yl)-2-(diaminomethyleneamino)thiazole (1.00 g).
Reaction SMILES: Cl[S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3].[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C(Cl)Cl>[CH3:10][N:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3]
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: CNc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)CS(=O)(=O)N(C)c1ccccc1

Procedure:
Chlorine gas was passed through a suspension of 230 g of ice, CH12Cl2 (457 ml) and methyl thioglycolate (86 ml, 942 mmol), cooling with an ice/water bath to maintain an internal temperature below 30° C. After approximately six hours, the yellow/green color of the dissolved chlorine persisted for 30 minutes after gas flow was stopped and passing additional chlorine gas was no longer exothermic. The cooling bath was then removed and the biphasic mixture was allowed to stir at ambient temperature for 1 h before being sparged with nitrogen for 20 minutes. The layers were then separated and the organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure to provide the intermediate methyl (chlorosulfonyl)acetate (160 g, 927 mmol) as a yellow oil. A portion of the intermediate methyl (chlorosulfonyl)acetate (100 g, 579 mmol) was added dropwise as a solution in CH2Cl2 (290 ml) to a stirring −15° C. solution of N-methylaniline (124 g, 1159 mmol) dissolved in CH2Cl2 (290 ml). The rate of addition was adjusted to maintain the internal temperature below 5° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature over the course of 2 h and 1M HCl (1000 mL) was added and the aqueous phase was extracted with dichloromethane (2×500 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting oil was seed crystallized to afford a brown solid. Recrystallization from hot ethanol (320 mL) provided the title compound as an off-white solid. 1H NMR (600 MHz, DMSO-D6) δ 7.40 (m, 4H); 7.31 (m, 1H); 4.30 (s, 2H); 3.65 (s, 3H); 3.26 (s, 3H). LRMS (APCI) calculated for C25H21N4O3S [M+H]+, 244.1. found 244.0.