Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[S:16]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:20]=3[OH:27])(=[O:18])=[O:17])[CH:9]=2)=[CH:4][CH:3]=1.N(OC(C)(C)C)=O.[N:43]([Si](C)(C)C)=[N+:44]=[N-]>C(#N)C.C1COCC1>[N:1]([C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH2:28][C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[S:16]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:20]=3[OH:27])(=[O:18])=[O:17])[CH:9]=2)=[CH:6][CH:7]=1)=[N+:43]=[N-:44]
Reactant: Nc1ccc(-c2cccc(CN(Cc3ccc(F)cc3)S(=O)(=O)c3cc(Cl)cc(Cl)c3O)c2)cc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: C1CCOC1
Product: [N-]=[N+]=Nc1ccc(-c2cccc(CN(Cc3ccc(F)cc3)S(=O)(=O)c3cc(Cl)cc(Cl)c3O)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
To an ice cold mixture of N-((4′-aminobiphenyl-3-yl)methyl)-3,5-dichloro-N-(4-fluoro-benzyl)-2-hydroxybenzenesulfonamide (0.08 g, 0.15 mmol) in anhydrous acetonitrile (1 mL) and anhydrous THF (1 mL) was added tert-butyl nitrite (0.03 mL, 0.22 mmol) followed by the dropwise addition of azidotrimethylsilane (0.02 mL, 0.17 mmol). The ice bath was removed and the reaction stirred at room temperature. After 1 h, anhydrous THF (0.5 mL) and anhydrous acetonitrile (0.5 mL) were added. After an additional 16 h, the reaction mixture was cooled to 0° C. before tert-butyl nitrite (0.06 mL, 0.44 mmol) and azidotrimethylsilane (0.07 mL, 0.52 mmol) were added. Two hours later, the reaction was quenched with water and extracted twice with chloroform. The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in CHCl3 then passed through a RediSep normal phase silica flash column (4 g) eluting with hexane, followed by CHCl3. The appropriate fractions were concentrated in vacuo to afford the title compound (0.04 g, 50%) as a brown glass. 1H NMR (DMSO-d6) δ 7.80-7.75 (m, 1H), 7.57 (d, J=2.5 Hz, 1H), 7.56-7.45 (m, 3H), 7.32 (t, J=7.7 Hz, 1H), 7.28-7.18 (m, 5H), 7.15-7.03 (m, 3H), 4.51 (s, 2H), 4.49 (s, 2H). MS (ESI): 555.3 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19]Br)[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH3:10][O:11][C:12](=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[F:9])[CH:14]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(COc2ccc(Br)cc2F)c1
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-fluorophenol (10 g, 52.36 mmol), 3-bromomethylbenzoic acid methyl ester (10.9 g, 47.6 mmol), potassium carbonate (9.9 g, 71.4 mmol), and DMF (100 mL) was stirred at room temperature over the weekend, followed by treatment with water. The precipitate was collected by filtration and washed with water and cold MeOH to give 3-(4-bromo-2-fluoro-phenoxymethyl)-benzoic acid methyl ester. LC-MS (ES) calculated for C15H12BrFO3, 338; found m/z 338 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:15])([CH3:14])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[NH:17][C:18](=[NH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C.CCCCCCC>CN(C=O)C>[CH3:14][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])([CH3:15])[CH2:10][C:11]1[O:13][N:25]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:17]=1
Reactant: CC(C)(CC(=O)O)NC(=O)OC(C)(C)C
Reactant: N=C(NO)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(Cc1nc(-c2ccccc2)no1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 15 h
Yield: 67.5 %

Procedure:
A solution of 3-(tert-butoxycarbonylamino)-3-methylbutanoic acid (2.75 g, 12.7 mmol) and N,N′-carbonyldiimidazole (CDI; 2.05 g, 12.7 mmol) in DMF (20.0 mL) was stirred at RT under nitrogen atmosphere for 5 h. N-Hydroxybenzamidine (1.72 g, 12.7 mmol) was added and the reaction mixture was heated to 100° C. and stirred for 15 h. The crude reaction mixture was concentrated in vacuo, poured into ethyl acetate (100 mL) and extracted with water (3×100 mL). The combined aqueous layer was back-extracted with ethyl acetate (100 mL). The combined organic layer was dried over MgSO4, concentrated in vacuo and purified by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) to yield the product as white solid (2.72 g, 8.57 mmol, 67.5%). MS: M=318.1 (M+H)+
Reaction SMILES: C(OC([N:8]([C:29]1[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][N:30]=1)[C:9]1[CH:10]=[C:11]([C:16]2[S:20][C:19]([CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[N:18][CH:17]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)=O)(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O.ClCCCl>[CH3:27][C:22]([CH3:28])([CH2:21][C:19]1[S:20][C:16]([C:11]2[CH:10]=[C:9]([NH:8][C:29]3[N:34]=[C:33]([C:35]([F:38])([F:36])[F:37])[CH:32]=[CH:31][N:30]=3)[CH:14]=[C:13]([CH3:15])[CH:12]=2)=[CH:17][N:18]=1)[C:23]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)C(C)(C)Cc1ncc(-c2cc(C)cc(N(C(=O)OC(C)(C)C)c3nccc(C(F)(F)F)n3)c2)s1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C(C)(C)Cc1ncc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
The product from Step 2 (390 mg, 0.708 mmol) was dissolved in CH2Cl2 (8 mL)/TFA (2 mL) and stirred at room temperature for 90 min. The reaction was subsequently diluted with 1,2-DCE and evaporated to dryness. The residue was redissolved in EtOAc, washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and evaporated. Flash chromatography (0-50% ethyl acetate in hexanes) afforded 293 mg (92%) of methyl 2,2-dimethyl-3-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]propanoate as a yellow gum. MS ESI: [M+H]+ m/z 451.0. 1H NMR (600 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.80 (d, J=4.9, 1H), 8.00-7.88 (m, 2H), 7.43 (s, 1H), 7.25 (d, J=4.9, 1H), 7.13 (s, 1H), 3.61 (s, 3H), 3.19 (s, 2H), 2.29 (s, 3H), 1.18 (s, 6H). rhSYK activity=+++
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH:18](O)([CH3:20])[CH3:19].C[O-].[Na+].[CH2:25](Cl)[C:26]#[CH:27]>CO.[Fe](Cl)(Cl)Cl>[CH2:19]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:27][C:26]#[CH:25])=[CH:15][CH:16]=2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1)[C:18]#[CH:20]
Reactant: CC(C)O
Reactant: C#CCCl
Reactant: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl[Fe](Cl)Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C#CCOc1ccc(C(C)(C)c2ccc(OCC#C)cc2)cc1

Procedure:
228 g bisphenol A, 300 ml isopropanol, 360 g of a 30% solution of sodium methanolate in methanol, 0.05 g iron-(III) chloride and 200 g propargyl chloride are mixed. An exothermic reaction takes place, most of the product having been formed (TLC verification) by the time the reaction is over (approx. 15 minutes). The reaction mixture is left to react for 4 hours and is then filtered and concentrated. 275 g of the product (characterized by NMR spectroscopy) are obtained.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5](O)(=O)[CH3:6].[C:9]1([NH:15][NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(O)C>[C:9]1([N:15]2[CH:6]=[C:5]3[C:2]([C:1](=[O:3])[NH:15][C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=43)=[N:16]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(=O)Cl
Reactant: NNc1ccccc1
Reactant: CC(=O)O
Solvent: CCO
Product: O=c1[nH]c2ccccc2c2cn(-c3ccccc3)nc12

Procedure:
Acetyl chloride (26 mL, 364 mmol), acetic acid (30 mL), and phenylhydrazine (36 mL, 364 mmol) were added sequentially to a suspension of material from Part A (37 g, 182 mmol) in ethanol (910 mL). The reaction mixture was heated at reflux for 18 hours. A white solid was isolated by filtration and washed with ethanol. Analysis of this material by 1H NMR indicated that this material was a 1:1 mixture of starting material and product. The solid was triturated with refluxing acetonitrile to provide 2-phenyl-2,5-dihydro-4H-pyrazolo[3,4-c]quinolin-4-one as a white powder, mp>250° C. MS (APCI) m/z 262 (M+H)+; Anal. calcd for C16H11N3O: C, 73.55; H, 4.24; N, 16.08. Found: C, 73.44; H, 4.21; N, 16.20.
Reaction SMILES: [OH:1][C:2]([CH3:10])([CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.CN(C)C=O.[CH3:21][Si:22]([CH3:26])([CH3:25])OCl>O>[CH3:10][C:2]([O:1][Si:22]([CH3:26])([CH3:25])[CH3:21])([CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(C)(O)CCC=C
Reactant: C[Si](C)(C)OCl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCC(C)(CCC=C)O[Si](C)(C)C

Procedure:
To a mixture of 50 g. of 4-hydroxy-4-methyl-oct-1-yn-7-ene and 61.3 g. of imidazole in 100 ml. of dimethylformamide at 0° C., is added, with stirring, 49.1 g. of trimethylsilyloxy chloride. The mixture is stirred at room temperature overnight and poured into petroleum ether and water. The organic layer is washed with water and saturated sodium bicarbonate solution and dried over magnesium sulfate. The solvent is removed and the residue distilled (74°-78° C., 1.5 mm.) to give the product as a colorless liquid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1Cl.[CH3:15][SH:16].[OH-].[Na+]>CS(C)=O.O>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[S:16][CH3:15]
Reactant: O=[N+]([O-])c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CS
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc([N+](=O)[O-])cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a stirred solution containing 45.1 g (0.20 mole) of 3-(trifluoromethyl)-4-chloronitrobenzene and 15 g (0.30 mole) of methyl mercaptan in 150 ml of DMSO was added dropwise at ambient temperature a solution containing 8.0 g (0.20 mole) of sodium hydroxide in 20 ml of water. This addition was exothermic to 60° C. After one hour, the reaction mixture was poured into ice water. The product was filtered and dried to give 45.0 g (95%) of yellow solid; m.p. 50° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](F)[C:14]=2[N+:20]([O-:22])=[O:21])[CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[NH2:32])=[CH:27][CH:26]=1.C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH:31]([NH:32][C:15]2[C:14]([N+:20]([O-:22])=[O:21])=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:4]2[CH:3]=[C:2]([F:1])[CH:11]=[CH:10][C:5]=2[C:6]([O:8][CH3:9])=[O:7])[C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(C(N)c2ccc(OC)cc2)cc1
Reactant: COC(=O)c1ccc(F)cc1Oc1cccc(F)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC(=O)c1ccc(F)cc1Oc1cccc(NC(c2ccc(OC)cc2)c2ccc(OC)cc2)c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
To a solution of EXAMPLE 44A (3.82 g) and bis(4-methoxyphenyl)methanamine (4.51 g) in N-methyl-2-pyrrolidinone (65. ml) was added N-ethyl-N-isopropylpropan-2-amine (4.30 ml) and the mixture was heated at 100° C. for 24 hours. The crude product, isolated by concentration, was purified on silica gel, eluted with a 10, 25, 65% ethyl acetate in hexane step gradient.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[C:2]1=O)[CH2:8]2.C(O)C.C1(C)C=CC(S([CH2:24][N+:25]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+]>COCCOC>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:24]#[N:25])[CH2:8]2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1C2CC3CC(C2)CC1C3
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: N#CC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 77.1 %

Procedure:
To a solution of 2-adamantanone (6.24 g, 41.50 mmol) in anhydrous 1,2-dimethoxyethane (150 mL) was added anhydrous ethanol (3.6 mL, 61.00 mmol) and p-toluenesulfonylmethyl isocyanide (10.0 g, 51.50 mmol) at 0° C. Potassium tert-butoxide (7.03 g, 62.70 mmol) was added in portions over 35 minutes under nitrogen atmosphere. The reaction mixture was stirred for 3.5 hours at ambient temperature. The mixture was filtered through a pad of diatomaceous earth that was washed with ethyl acetate (200 mL). The filtrate was washed with brine (2×200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to dryness. The residue was purified by column chromatography with a gradient of 0-10% ethyl acetate in hexanes to afford the title compound (5.16 g, 77% yield) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 2.88 (s, 1H), 2.15-2.11 (m, 4H), 1.92-1.85 (m, 4H), 1.75-1.70 (m, 6H); MS (ES−) m/z 162.2 (M+1).
Reaction SMILES: C([Al:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][CH:7]([CH3:9])[CH3:8])C(C)C.[C:14]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[OH:26])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:20]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][Al:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Reactant: Oc1ccccc1-c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)C[Al](CC(C)C)Oc1ccccc1-c1ccccc1

Procedure:
In a manner analogous to that described in Example 1, 16 g of triisobutylaluminum and 13.72 g of 2-phenyl-phenol are reacted in absolute toluene to afford (2-biphenylyloxy)diisobutylaluminum and this is then reacted with 20.52 g of pyridine-N-oxide-2-thiol to yield the title compound. The isolation of the product is carried out in an analogous manner. The yield of (2-biphenylyloxy)bis(2-pyridinethiolato)aluminum N,N'-dioxide, an almost white powder, is 33.4 g, about 92.5% of theory. Upon heating it sinters from about 174° C. and melts at 236°-238° C.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:39])[N:11]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21](OCCCCCCCCC3OCCO3)[CH:20]=1)[CH2:12][C:13]1[CH:18]=CC=[CH:15][CH:14]=1)[CH2:2]2.[C:40](=[O:43])([O-])[O-].[K+].[K+].[CH2:46]1[CH2:50][O:49][CH2:48][CH2:47]1>Cl>[N:1]12[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8]1)[C@@H:3]([O:9][C:10](=[O:39])[N:11]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:12][C:13]1[CH:14]=[CH:15][CH:46]=[C:50]([O:49][CH2:48][CH2:47][CH2:23][CH2:24][CH2:19][CH2:20][CH2:21][CH2:22][CH:40]=[O:43])[CH:18]=1)[CH2:2]2
Reactant: O=C([O-])[O-]
Reactant: C1CCOC1
Reactant: O=C(O[C@H]1CN2CCC1CC2)N(Cc1ccccc1)c1cccc(OCCCCCCCCC2OCCO2)c1
Agent: Cl
Agent: [K+]
Product: O=CCCCCCCCCOc1cccc(CN(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (R)-quinuclidin-3-yl(3-(8-(1,3-dioxolan-2-yl)octyloxy)phenyl)(phenyl)methylcarbamate (0.66 g, 1.23 mmol) in THF (10 mL), 2M hydrochloric acid was added (20 mL). The reaction mixture was stirred at RT for 3 hours. To the reaction mixture was added 10% aqueous potassium carbonate, and the mixture extracted with DCM (×3). The combined organic extracts were washed poured through a hydrophobic cartridge, and concentrated under reduced pressure to afford the title compound (0.64 g, quantitative yield). The material was used directly in the next step with no further purification.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25].O>O1CCCC1>[CH3:23][S:24]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)(=[O:26])=[O:25]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 5 h
Yield: 96.1 %

Procedure:
t-butyl 4-hydroxymethyl-1-piperidinecarboxylate (5.00 g, 23.2 mmol)was dissolved in tetrahydrofuran (75 ml). To the solution were added triethylamine (2.83 g) and methanesulfonyl chloride (3.19 g) under ice cooling, and the mixture was stirred at 0° C. for 5 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate twice. The organic layer was washed with 1N-hydrochloric acid and a saturated aqueous solution of sodium hydrogencarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid materials were washed with hexane to give the titled compound (6.55 g, 22.3 mmol, Yield 96%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[N:12]=[C:13]4[C:19]([C:20](O)=[O:21])=[CH:18][NH:17][C:14]4=[N:15][CH:16]=3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[Si:43]([O:50][CH2:51][C:52]([CH3:55])([NH2:54])[CH3:53])([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]>CN(C1C=CN=CC=1)C.CN(C=O)C.O>[Si:43]([O:50][CH2:51][C:52]([NH:54][C:20]([C:19]1[C:13]2[C:14](=[N:15][CH:16]=[C:11]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=4)[NH:8][N:7]=3)[N:12]=2)[NH:17][CH:18]=1)=[O:21])([CH3:55])[CH3:53])([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]
Reactant: CC(C)(N)CO[Si](C)(C)C(C)(C)C
Reactant: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)O)c4n3)n[nH]c2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(-c3cnc4[nH]cc(C(=O)NC(C)(C)CO[Si](C)(C)C(C)(C)C)c4n3)n[nH]c2c1
Reaction time: 16 h
Yield: 46.1 %

Procedure:
To a stirred solution of 2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.34 mmol), EDCI (130 mg, 0.68 mmol), DMAP (83 mg, 0.68 mmol) and DIEA (88 mg, 0.68 mmol) in 6 mL of DMF was added 1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-amine (138 mg, 0.68 mmol) in one portion at room temperature, then the mixture was stirred for 16 hours. The reaction mixture was poured into 40 mL of water, filtered and the filter cake was washed with petroleum ether to give crude N-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-2-(6-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (75 mg, 46.0%) as a pale yellow solid. MS: (M+H)+=479.2.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[CH:6][C:7]=1Cl.[CH2:11]([SH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(O)(C)C>[CH2:11]([S:18][C:7]1[CH:6]=[N:5][N:4]([CH3:9])[C:3](=[O:10])[C:2]=1[Cl:1])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: SCc1ccccc1
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cn1ncc(SCc2ccccc2)c(Cl)c1=O
Reaction time: 8 h
Yield: 59.4 %

Procedure:
35.8 g (200 millimoles) of 4,5-dichloro-2-methylpyridazin-3(2H)-one are suspended in 300 ml of isopropanol and the suspension is colled to -20° C. A solution of 24.8 g (200 millimoles) of benzyl mercaptan and 20.2 g (200 millimoles) of triethylamine in 200 ml of isopropanol is added dropwise at this temperature, after which stirring is continued for 1 hour at -10° C. and overnight at room temperature. The resulting precipitate is filtered off under suction, washed with isopropanol and water and dried under reduced pressure to give 31.7 g (60%) of a product of melting point 102°-104° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH2:12][NH:13][CH2:14][CH2:15][C:6]2=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]12[CH2:38][CH2:37][CH2:36][C:34]3[C:35]1=[C:30]([CH:31]=[CH:32][CH:33]=3)[NH:29][C:28]2=[O:39]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[CH2:12][N:13]([CH2:23][CH2:24][CH2:25][CH2:26][C:27]34[CH2:38][CH2:37][CH2:36][C:34]5[C:35]3=[C:30]([CH:31]=[CH:32][CH:33]=5)[NH:29][C:28]4=[O:39])[CH2:14][CH2:15][C:6]2=1
Reactant: COc1ccc2[nH]c3c(c2c1)CCNC3
Reactant: O=C1Nc2cccc3c2C1(CCCCBr)CCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3c(c2c1)CCN(CCCCC12CCCc4cccc(c41)NC2=O)C3
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
A 295 mg (1.46 mmol) portion of 6-methoxy-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole and 404 mg (2.91 mmol) of potassium carbonate were added to 7 ml of DMF solution containing 300 mg (0.97 mmol) of 2a-(4-bromobutyl)-2a,3,4,5-tetrahydro-1H-benz[cd]indol-2-one and stirred overnight at room temperature. The reaction solution was extracted with ethyl acetate and washed with water. After drying (Na2SO4), the solvent was removed by evaporation under a reduced pressure and the thus obtained oil was purified by a silica gel column chromatography (80 cc; elution by chloroform-methanol=15:1) and recrystallized from acetone-diisopropyl ether to obtain 369 mg of the title compound (88% in yield).
Reaction SMILES: CO[C:3]1[CH:13]=[CH:12][C:11]([O:14]C)=[CH:10][C:4]=1[CH:5]=[CH:6][C:7]([OH:9])=[O:8].ClC(Cl)C.B(Br)(Br)Br>>[OH:14][C:11]1[CH:10]=[C:4]2[C:3](=[CH:13][CH:12]=1)[O:8][C:7](=[O:9])[CH:6]=[CH:5]2
Reactant: COc1ccc(OC)c(C=CC(=O)O)c1
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Product: O=c1ccc2cc(O)ccc2o1
Temperature: 83 °C
Reaction time: 15 h
Yield: 118.8 %

Procedure:
Equip a 3-L, three-neck, round-bottom flask equipped with a large blade mechanical stirrer, a thermocouple, a Claisen adapter, an addition funnel, and a reflux condenser. Add 2,5-dimethoxycinnamic acid (102.8 g, 493 mmol, 1.0 equiv) and dichloroethane (1.5 L). Add boron tribromide (247.4 g, 987 mmol, 2.0 equiv) dropwise over 45 min while keeping the temperature below 40° C. Rapidly stir the resulting mixture and heat gradually to 83° C. over 45 min, monitoring the temperature increase and gas evolution, Stir for 6 h at reflux then for 15 h at 76° C. Cool the resulting mixture to room temperature and quenched carefully with water (450 mL). Filter the solid, wash with heptane and dry under vacuum to afford 6-hydroxy coumarin (95 g) as a light brown solid which is used without further purification. Equip a 2-L, three-neck, round-bottom flask with a magnetic stir bar and a thermocouple. Add 6-hydroxy coumarin (39.8 g, 245 mmol, 1.0 equiv), anhydrous acetonitrile (700 mL) and N,N-diisopropylethylamine (200 mL, 1.15 mol, 4.7 equiv). Add chloromethyl methyl ether (40.0 mL, 527 mmol, 2.1 equiv) dropwise over 30 min while keeping the temperature below 40° C. Stir the resulting mixture at room temperature for 3 h, then add an additional equiv of chloromethyl methyl ether. Stir at room temperature for 15 h, then quench the reaction mixture with saturated aqueous ammonium chloride (500 mL) and extracted with ethyl acetate. Combine the organic extracts and dry over anhydrous magnesium sulfate, filter and concentrate under reduced pressure. Purify the residue by column chromatography on silica gel (30-50% ethyl acetate/heptane) to afford a light yellow solid. Suspend the solid in a mixture of ethyl acetatefleptane (150 mL, 10:90), filter and dry to afford 6-methoxymethoxy coumarin 17a (25.6 g, 50%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J=7.8 Hz, 1H), 7.30-7.12 (m, 3H), 6.41 (d, J=7.8 Hz, 1H), 5.20 (s, 2H), 3.48 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 161.2, 154.0, 149.5, 143.5, 121.6, 119.6, 118.1, 117.3, 113.8, 95.3, 56.4; IR (KBr) 1714 (s), 1570 (s), 1491 (m), 1447 (m), 1266 (s), 1154 (s), 1070 (s), 1017 (s) cm−1; ESI MS m/z 207 [C11H10O4+H]+.