Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=O.[CH2:11]([N:13](CC)CC)C.ClC(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[N+:13]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])#[C-:11]
Reactant: O=CCCCCCC(=O)O
Reactant: CCN(CC)CC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: [C-]#[N+]CCCCCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of the above 6-formyl hexanoic acid Wang-resin ester (165 g, 0.16 mol) in dichloromethane (3.2 l) was added triethylamine (222 ml, 1.6 mol), tetrachloromethane (155 ml, 1.6 mol) and triphenylphosphine (168 g, 0.64 mol). The resulting mixture was stirred at room temperature for 16 h under an atmosphere of nitrogen. The resin was filtered off and washed with N,N-dimethylformamide, dichloromethane, methanol, dichloromethane and dried in a vacuum desiccator for 18 h which afforded 6-isocyano-hexanoic acid Wang-resin ester.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[SH:10].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[S:21]([OH:23])=[O:22].Cl>O>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[S:21]([OH:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)O)c1
Reactant: Sc1ccccc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(Sc2ccccc2Br)c(S(=O)O)c1
Temperature: 125 °C

Procedure:
To a solution of NaOH (80.18 g, 2.004 mol) in water (600 ml sonicated and degassed) was added 2-bromothiophenol (108.23 ml, 1.002 mol) and 2-chloro-5-nitro-benzenesulfinic acid (222.11 g, 1.002 mol). The mixture was stirred and heated at 125° C. for 19 hours. The reaction was cooled down at 0° C., and concentrated HCl added dropwise from a dropping funnel while stirring until pH<1. The precipitate formed was filtered, dried in a desiccators overnight and was used without any further purification (417.77 g). m/z (LC-MS, ESP), RT=3.51 min, (M−−1)=372-374, (1:1, bromine isotope ratio present).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][C:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([N+:19]([O-])=O)=[C:12]([O:17][CH3:18])[CH:13]=2)[CH2:8]1)=[O:6].[H][H]>C(O)C.[Pd]>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][C:5]([N:7]1[CH2:16][CH2:15][C:14]2[C:9](=[CH:10][C:11]([NH2:19])=[C:12]([O:17][CH3:18])[CH:13]=2)[CH2:8]1)=[O:6]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CN(C(=O)CCN(C)C)CC2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1cc2c(cc1N)CN(C(=O)CCN(C)C)CC2
Yield: 100 %

Procedure:
A solution of N,N-dimethyl-3-[6-(methyloxy)-7-nitro-3,4-dihydro-2(1H)-isoquinolinyl]-3-oxo-1-propanamine (0.65 g, 2.1 mmol) in ethanol (10 mL) was treated with 10% palladium on carbon (70 mg, Aldrich), and stirred under 60 psi of hydrogen pressure for 16 h in a Fischer-Porter apparatus. The pressure was released, the reaction vessel evacuated, and back-filled with nitrogen twice. The mixture was filtered through celite and the filtrate was concentrated to provide 2-[3-(dimethylamino)propanoyl]-6-(methyloxy)-1,2,3,4-tetrahydro-7-isoquinolinamine (0.58 g, 2.1 mmol, 99%). 1H NMR (400 MHz, DMSO-d6) is complicated due to amide rotomers d ppm 2.14 (s, 6 H), 2.46-2.52 (m, signals beneath DMSO, 4 H), 2.55-2.73 (m, two triplets at 2.58 and 2.69, 2 H), 3.58-3.63 (m, 2 H), 3.72 (s, 3 H), 4.37-4.48 (two singlets at 4.38 and 4.45, 2 H), 4.54-4.61 (two broad singlets at 4.55 and 4.58, 2 H), 6.38-6.42 (two singlets at 6.39 and 6.41, 1 H), 6.56-6.59 (two singlets at 6.56 and 6.57, 1 H); ESIMS (M+H)+=278.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5](N)=[CH:4][C:3]=1[O:9][CH3:10].[OH:11]S(O)(=O)=O.N([O-])=O.[Na+]>O>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([OH:11])=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: COc1cc(N)ccc1C
Reactant: O=S(=O)(O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(O)ccc1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
To a suspension of 4-methyl-3-(methyloxy)aniline (Intermediate 17, 1.86 g) in water (100 mL)/H2SO4 (30 mL, 563 mmol) at 0° C. a solution of sodium nitrite (1.029 g, 14.91 mmol) in water (10 mL) was slowly added and the reaction mixture was stirred for 30 minutes at 0° C. The reaction mixture was slowly added to a solution of H2SO4 98% (20 mL) in Water (80 mL) pre-heated at 90° C. and stirred at this temperature for 1 h. After cooling the mixture was extracted with Et2O (2×200 mL), the organic layer was dried on sodium sulphate, filtered and evaporated to afford the title compound (1.86 g) as a red/brown oil.
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@@H:5]1[N:16]1[CH2:21][C:20]([F:23])([F:22])[CH2:19][CH2:18][C:17]1=[O:24])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][C@H:4]1[CH2:8][N:7]([CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:6][C@@H:5]1[N:16]1[CH2:21][C:20]([F:23])([F:22])[CH2:19][CH2:18][C:17]1=[O:24]
Reactant: [N-]=[N+]=N[C@H]1CN(Cc2ccccc2)C[C@@H]1N1CC(F)(F)CCC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: N[C@H]1CN(Cc2ccccc2)C[C@@H]1N1CC(F)(F)CCC1=O
Temperature: 25 °C
Yield: 100.2 %

Procedure:
To a solution of the product of Step 7 (8.50 g, 25.3 mmol) in tetrahydrofuran (85 mL) was added triphenylphosphine (6.65 g, 25.3 mmol) and H2O (0.91 g, 50.7 mmol). The solution was stirred at reflux for 3 hours and then cooled to room temperature and concentrated. The residue was dissolved in 4.0 N aqueous HCl (200 mL) and extracted with chloroform (200 mL). The aqueous layer was basified to pH 10 with concentrated aqueous ammonium hydroxide solution and the resulting mixture was extracted with chloroform (2×300 mL). The combined organic extracts were dried over sodium sulfate and concentrated to afford 7.84 g (99%) of the product as a solid. MS m/z 310.3 (AP+100).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][OH:25])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[CH3:37]N(C)C=O.[H-].[Na+].CI>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][O:25][CH3:37])=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: CN(C)C=O
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2CO)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COCc1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a mixture of {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methanol (0.30 g) and N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 0.030 g) at 0° C. After stirring the reaction mixture at 0° C. for 30 min, methyl iodide (0.11 g) was added to the reaction mixture, and the mixture was further stirred at room temperature for 3 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give 2-(2-furyl)-4-{[2-methoxy-4-({[4-(methoxymethyl)-1-phenyl-1H-pyrazol-3-yl]oxy}methyl)phenoxy]methyl}-5-methyl-1,3-oxazole as colorless crystals (0.20 g, yield 65%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 121-122° C.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC(C)=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][C:34]1[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:44])([F:43])[F:42])=[CH:36][N:35]=1)[C:28]#[N:29].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:24][C:25]1[CH:26]=[C:27]([C:28]2[N:2]([CH3:1])[N:3]=[C:4]([C:5]3[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:12])[N:29]=2)[CH:30]=[CH:31][C:32]=1[O:33][C:34]1[C:39]([Cl:40])=[CH:38][C:37]([C:41]([F:44])([F:42])[F:43])=[CH:36][N:35]=1
Reactant: N#Cc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=C(Cl)c2c(F)cccc2Cl)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)c(Cl)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
A mixture of N-methyl-N-(p-toluenesulfonyl)-2-chloro-6-fluorobenzohydrazonoyl chloride (0.90 g), 3-chloro-4-(3-chloro-5-trifluoromethylpyridine-2-yloxy)benzonitrile (0.80 g), anhydrous iron (III) chloride (0.40 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (100 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 0.60 g of desired compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]#N)=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2].CN(C)[CH:19]=[O:20].[BH4-].[Na+].COCCl>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][O:20][CH3:19])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(=O)Nc1ccc(SC#N)cc1[N+](=O)[O-]
Agent: COCCl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: COCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Reaction time: 1 h

Procedure:
2.37 G. of 1-acetamido-2-nitro-4-thiocyanatobenzene in 10 ml. dimethylformamide is treated at 20°-25° C under nitrogen, with 0.38 g. of sodium borohydride. After one hour 1.6 ml. of chloromethyl methyl ether is added, and the mixture kept at 20°-30° C for a further 3 hours. Water is then added and the product filtered off. Recrystallization from cyclohexane gives 1-acetamido-2-nitro-4-methoxymethylthiobenzene.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][C:32]1[O:36][C:35]([C:37]2([NH2:40])[CH2:39][CH2:38]2)=[N:34][CH:33]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:35]6[O:36][C:32]([CH3:31])=[CH:33][N:34]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: Cc1cnc(C2(N)CC2)o1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)o5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.5 mmol, 1 eq), 1-(5-methyloxazol-2-yl)cyclopropanamine (0.082 g, 0.6 mmol, 1.1 eq), EDCI.HCl (0.105 g, 0.54 mmol, 1.1 eq), HOBT (0.067 g, 0.5 mmol, 1.0 eq) and TEA (0.21 ml, 1.5 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water. The organic layer was separated, washed with water and concentrated to give the crude product which was purified by Prep. TLC (20 mm thickness) using 5% methanol/DCM as an eluent. Yield: 25 mg (25%) 1H NMR (400 MHz, DMSO-d6): δ 1.25-1.28 (m, 2H), 1.40-1.44 (m, 2H), 2.21 (d, J=1.2 Hz, 3H), 2.29 (s, 3H), 2.82 (d, J=4.8, 3H), 6.66 (d, J=1.2 Hz, 1H), 7.38-7.44 (m, 4H), 7.57 (d, J=1.2, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.81-7.83 (s and m, 2H), 7.98-8.01 (m, 2H), 8.47 (q, J=4.8 Hz, 1H), 9.28 (s, 1H). LCMS: (ES+) m/z=524.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].[CH3:14]O>CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH3:14])=[O:6]
Reactant: CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Yield: 96 %

Procedure:
A mixture of 3-fluoro-4-nitrobenzoic acid(2.07 g, 11.2 mmol) and cH2SO4(0.5 ml) in MeOH(10 ml) was refluxed for 8 h. The solvent was evapolated. The residue was dissolved in AcOEt and washed with saturated NaHCO3 aqueous solution, water, brine, dried (Na2SO4), and concentrated to give 2.14 g(96%) of ivory solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24]Br)[CH:7]=1)[CH3:2].[CH3:27][CH:28]([SH:30])[CH3:29].[H-].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][S:30][CH:28]([CH3:29])[CH3:27])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Reactant: CC(C)S
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSC(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[3-(2-Bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester (0.4 g, 0.94 mmol), 2-propanethiol (0.11 mL, 1.13 mmol), and sodium hydride (60% in mineral oil; 0.05 g, 1.13 mmol) were combined in 1,4-dioxane and stirred at room temperature for 30 minutes. The mixture was worked-up to give [3-(2-isopropylsulfanylmethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester, which was then reduced to the amine as described in Example 3, Step 5 to provide [3-(4-amino-2-isopropylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester The amine was then treated with pivaloyl chloride according to Example 3, Step 6 to provide {3-[4-(2,2-dimethyl-propionylamino)-2-isopropylsulfanylmethyl-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester according to the procedure described in Example 3, Step 7 provided the acid.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O[CH2:5][C@H:6]1[C@@H:9]([NH:10][C:11](=[O:27])[CH:12]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:28])[NH:7]1)(=O)=O.[I-:36].[Na+]>CC(C)=O>[C:23]([O:22][C:20]([NH:19][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:11]([NH:10][C@H:9]1[C:8](=[O:28])[NH:7][C@H:6]1[CH2:5][I:36])=[O:27])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2NC(=O)[C@@H]2NC(=O)C(NC(=O)OC(C)(C)C)c2ccccc2)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)N[C@H]1C(=O)N[C@H]1CI)c1ccccc1
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 2 g (3.98 mmol) of product from Example 20, 6 g (40 mmol) of sodium iodide and 150 ml of acetone is thoroughly degassed with argon and then heated at 55°-60° for seven hours. The mixture is cooled to room temperature and the acetone is evaporated. The residue is partitioned between ethyl acetate and water. The organic phase is separated and washed with aqueous sodium thiosulfate and saline. The dried solution is evaporated to give 1.48 g (81%) of the title product.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]#[C:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=2)[CH:6]=[CH:5][N:4]=1.[I-].[NH2:20][N+:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][N:21]3[N:20]=2)[CH:6]=[CH:5][N:4]=1
Reactant: N[n+]1ccccc1
Reactant: CSc1nccc(C#Cc2ccnc(SC)n2)n1
Agent: [I-]
Solvent: CC#N
Product: CSc1nccc(-c2nn3ccccc3c2-c2ccnc(SC)n2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
2-(Methylsulfanyl)-4-{[2-(methylsulfanyl)-4-pyrimidinyl]ethynyl}pyrimidine (0.1 g, 0.37 mmol) was dissolved in acetonitrile (5 mL). To this solution was added 1-aminopyridinium iodide (81 mg, 0.37 mmol) and 1,8-diazobicyclo[5.4.0]undec-7-ene (0.056 mL, 0.37 mmol) and the resulting mixture was stirred at room temperature overnight The resulting reddish suspension was concentrated in vacuo. Ethyl acetate and water were added to this residue. The phases were separated and the aqueous phase extracted with additional ethyl acetate. The organics were combined, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (1:1 ethyl acetate:hexane) gave 95 mg (71%) of 2,3-bis[2-(methylsulfanyl)-4-pyrimidinyl]pyrazolo[1,5-a]pyridine as a solid. 1H NMR (CDCl3): δ 8.64 (d, 1H), 8.53 (d, 1H), 8.41 (d, 1H), 8.31 (d, 1H), 7.56 (d, 1H), 7.37 (t, 1H), 7.13 (d, 1H), 7.00 (t, 1H), 2.59 (s, 3H), 2.37 (s, 3H); MS m/z 367 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(C(C)C)CC)(C)C.[CH2:25]([O:32][CH2:33][C:34](Cl)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[CH2:25]([O:32][CH2:33][C:34]([N:12]1[CH2:13][CH2:14][CH2:15][N:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:10][CH2:11]1)=[O:35])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Clc1ccc(N2CCCNCC2)c(Cl)c1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(COCc1ccccc1)N1CCCN(c2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 452 %

Procedure:
To a solution of 1-(2,4-dichloro-phenyl)-[1,4]diazepane (0.11 g, 0.45 mmol) in dichloromethane (5 mL) was added diisopropyl-ethylamine (0.082 mL, 0.47 mmol) and benzyloxyacetyl chloride (0.086 g, 0.47 mmol). The solution was stirred at room temperature for 1 h. The residue was chromatographed on silica gel using dichloromethane/ethyl acetate from 100% to 95% dichloromethane in a gradient fashion, to obtain the title compound as a gum (0.80 g, 46%). 1H NMR (300 MHz, CDCl3): δ 7.33 (m, 6H), 7.14 (m, 1H), 6.96 (m. 1H), 4.64 (m, 2H), 4.21 (m, 2H), 3.79 (m, 2H), 3.65 (m, 2H), 3.19 (m, 4H), 2.04 (m, 2H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:53])[CH3:52])[CH:46]([OH:58])[CH2:45]2)[CH:7]([CH3:60])[CH2:6][CH2:5][C:4]1=[O:61])[CH3:2].[CH2:62](OC(=N)C(Cl)(Cl)Cl)[CH:63]=[CH2:64].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:59])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][Si:51]([C:54]([CH3:57])([CH3:56])[CH3:55])([CH3:52])[CH3:53])[CH:46]([O:58][CH2:64][CH:63]=[CH2:62])[CH2:45]2)[CH:7]([CH3:60])[CH2:6][CH2:5][C:4]1=[O:61])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O[Si](C)(C)C(C)(C)C)C(O)C3)C(C)CCC1=O)C(C)CC2OC
Reactant: C=CCOC(=N)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Product: C=CCOC1CC(C=C(C)C2OC(=O)C3CCCCN3C(=O)C(=O)C3(O)OC(C(OC)CC(C)CC(C)=CC(CC)C(=O)CCC2C)C(OC)CC3C)CCC1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"(tert-butyldimethylsiloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (186 mg in 6 ml 33% methylene chloride in cyclohexane) allyltrichloroacetimidate (62 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifluoromethanesulfonic acid (5 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 24 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by flash chromatography on silica gel (ethyl acetate: hexane (1:4)+1% methanol) gave the title compound (80 mg).
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][C:10]([CH2:15][CH3:16])([CH2:13][CH3:14])[CH2:11][OH:12])(=[O:8])=[O:7])C.[H-].[Na+].Cl[C:20]1[C:21]([CH3:29])=[CH:22][C:23]2[N:24]([CH:26]=[CH:27][N:28]=2)[N:25]=1.Cl>O1CCCC1>[CH2:15]([C:10]([CH2:13][CH3:14])([CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:11][O:12][C:20]1[C:21]([CH3:29])=[CH:22][C:23]2[N:24]([CH:26]=[CH:27][N:28]=2)[N:25]=1)[CH3:16]
Reactant: CCC(CC)(CO)CS(=O)(=O)N=CN(C)C
Reactant: Cc1cc2nccn2nc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(COc1nn2ccnc2cc1C)CS(N)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
To a solution of 1.38 g of 3-(N,N-dimethylaminomethyl-ene)aminosulfonyl -2,2-diethyl-1-propanol in 30 ml of tetrahydrofuran, 0.23 g of 60% oily sodium hydride was added, followed by stirring at room temperature for 1 hour. To the reaction mixture, 0.74 g of 6-chloro-7-methylimidazo [1,2-b]pyridazine was added, followed by refluxing under heating conditions for 1 hour. After cooling, the reaction mixture was neutralizedwith 1 N hydrochloric acid and extracted with ethyl acetate-tetrahydrofuran(1:1). After the extract was washed with water and dried over MgSO4, the solvent was distilled off under reduced pressure. To the residue was added 14 ml of 6 N hydrochloric acid, followed by stirring at 110° C. for 30 minutes. After cooling, the mixture was concentrated under reduced pressure, and the residue adjusted to a pH of 7 by addition of aqueous solution of sodium hydrogen carbonate and then extracted with ethyl acetate. After saline washing, the extract was dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue subjected to column chromatography using 100 g of silica gel, eluted with chloroform-methanol (5:1), and crystallized from a mixed solvent of methanol and ethyl acetate, to yield 1.19 g of the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]2[N:5]([CH:18]=[N:19][CH:20]=2)[C:6]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1.C(N(CC)C(C)C)(C)C.Br[CH2:31][CH2:32][O:33][CH3:34]>C(#N)C>[Cl:2][C:3]1[C:4]2[N:5]([CH:18]=[N:19][CH:20]=2)[C:6]([N:12]2[CH2:17][CH2:16][N:15]([CH2:31][CH2:32][O:33][CH3:34])[CH2:14][CH2:13]2)=[C:7]([C:9](=[O:11])[CH3:10])[CH:8]=1
Reactant: CC(=O)c1cc(Cl)c2cncn2c1N1CCNCC1
Reactant: COCCBr
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1CCN(c2c(C(C)=O)cc(Cl)c3cncn23)CC1
Yield: 57.1 %

Procedure:
1-(8-Chloro-5-piperazin-1-ylimidazo[1,5-a]pyridine-6-yl)ethanone hydrochloride (16 mg, 0.052 mmol), N,N-diisopropylethylamine (27 μL, 0.16 mmol) and 1-bromo-2-methoxyethane (4.9 μL, 0.052 mmol) were stirred in acetonitrile (1.0 mL) for 22 hours at 65° C. Purification by preparative LCMS (pH 10) gave the desired compound (10 mg, 60%). LCMS calculated for C16H22ClN4O2 (M+H)+: m/z=337.1. found: 336.9.