Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH:22]([NH:32]C(=O)OC(C)(C)C)[CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])=[N:19][N:18]=4)=[C:13]([NH:40][CH:41]([CH3:43])[CH3:42])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C>C(Cl)Cl>[NH2:32][CH:22]([C:20]1[O:21][C:17]([C:14]2[C:13]([NH:40][CH:41]([CH3:43])[CH3:42])=[CH:12][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]4[N:3]=[CH:2][S:1][C:5]=4[CH:6]=3)=[N:16][CH:15]=2)=[N:18][N:19]=1)[CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:26])[CH3:27]
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)o1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(C(N)CO[Si](C)(C)C(C)(C)C)o1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
tert-butyl (1-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate (56) (200 mg, 0.3 mmol) was dissolved in DCM (10 mL), cooled to −10° C. Added 2,6-lutidine (1.9 mmol, 6 equiv.) and stirred for 15 min. Added TBDMS-Triflate (1.6 mmol, 5 equiv.) in portions, dropwise to the reaction mixture and stirred at −10° C. for 30 min. Gradually, the reaction temperature was raised to room temperature and stirred for 30 min. Diluted the reaction mixture using DCM and quenched by addition of 5% citric acid solution. Extracted the reaction mixture in DCM. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography through silica gel and MeOH: DCM as eluent to provide the desired compound, 5-(5-(1-amino-2-((tert-butyldimethylsilyl)oxy)ethyl)-1,3,4-oxadiazol-2-yl)-N2-(benzo[d]thiazol-6-yl)-N4-isopropylpyridine-2,4-diamine LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.79 min; LCMS (ES-API), m/z 526.9 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][C:4]([C:12]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]#[N:21])[CH:15]=[CH:14][N:13]=2)=[N:3]1.C[Si]([N:26]=[N+:27]=[N-:28])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1>[NH:26]1[C:20]([CH2:19][CH2:18][C:16]2[CH:15]=[CH:14][N:13]=[C:12]([C:4]3[S:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[C:2](=[O:1])[N:3]=3)[CH:17]=2)=[N:21][N:28]=[N:27]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#CCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cc(CCc3nnn[nH]3)ccn2)sc2ccccc12
Yield: 45.5 %

Procedure:
3-[2-(4-Oxo-4H-1,3-benzothiazin-2-yl)-4-pyridyl]propionitrile (0.25 g, 0.85 mmol) and trimethylsilyl azide (0.20 g, 1.7 mmol) were dissolved in toluene (5 ml), and dibutyltin (IV) oxide (0.02 g, 0.08 mmol) was added thereto. The reaction mixture was refluxed for 48 hrs and kept at room temperature. The precipitated crystals were collected by filtration and washed with toluene. The obtained crystals were recrystallized from ethanol to give the titled compound (0.13 g, 44%) as white crystals.
Reaction SMILES: [OH-].[Na+].[CH:3]1([NH:8][S:9]([CH2:12][Br:13])(=[O:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:14][C:15]([Cl:21])([S:19]Cl)[CH:16]([Cl:18])[Cl:17].ClCCl>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[CH:3]1([N:8]([S:19][C:15]([Cl:21])([Cl:14])[CH:16]([Cl:18])[Cl:17])[S:9]([CH2:12][Br:13])(=[O:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=S(=O)(CBr)NC1CCCC1
Reactant: ClSC(Cl)(Cl)C(Cl)Cl
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(CBr)N(SC(Cl)(Cl)C(Cl)Cl)C1CCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
A 5.76 g (0.072 mol) 50% aqueous solution of sodium hydroxide was added slowly to a solution of 8.6 g (0.036 mol) N-cyclopentyl bromomethanesulfonamide, 8.6 g (0.036 mol) 1,1,2,2-tetrachloroethylsulfenyl chloride, and about 0.1 g benzyltriethyl ammonium chloride in 200 mol dichloromethane cooled to 0° C with an ice bath. The reaction mixture was then stirred at 0° C for 2 hours, washed with water, dried over magnesium sulfate and evaporated to give a brown oil. The oil was chromatography over silica gel with dichloromethane/petroleum-ether elution to give 5.5 g (35% yield) of the product, as a grey solid, m.p. 59°-60° C. The elemental analysis for the product is tabulated in Table I under compound No. 9.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:9]([OH:11])=O)[CH:6]([CH3:8])[CH3:7])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[N:39]=[C:38]([OH:40])[C:37]([C:41]([OH:43])=[O:42])=[CH:36][N:35]=2)=[CH:30][CH:29]=1.C(N(CC)CC)C>CN(C)C(=O)C.ClCCl>[C:1]([NH:4][C@@H:5]([C:9]([NH:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]2[N:39]=[C:38]([OH:40])[C:37]([C:41]([OH:43])=[O:42])=[CH:36][N:35]=2)=[CH:32][CH:33]=1)=[O:11])[CH:6]([CH3:7])[CH3:8])(=[O:3])[CH3:2]
Reactant: Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1
Reactant: CC(=O)N[C@@H](C(=O)O)C(C)C
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](C(=O)Nc1ccc(-c2ncc(C(=O)O)c(O)n2)cc1)C(C)C
Temperature: 25 °C
Yield: 49.8 %

Procedure:
A suspension of 11.41 g (71.7 mmol) of N-acetyl-D-valine and 150 ml of dichloromethane is stirred at room temperature and 7.9 ml (71.7 mmol) of N-methylmorpholine is added. The resulting solution is cooled to -10° C. and 9.3 ml (71.7 mmol) of isobutyl chloroformate is added. The reaction mixture is stirred at -15°±5° C. for 45 min and an ice cold solution of 11.09 g (48 mmol) of 2-(4-aminophenyl)-4-hydroxy-5-pyrimidine carboxylic acid, 7.4 ml (52.8 mmol) of triethylamine, and 200 ml of N,N-dimethylacetamide is added while keeping the temperature below -10° C. The mixture is stirred at 0°-5° C. for 2 hrs and overnight at room temperature. A small amount of solid is filtered and the filtrate is evaporated to dryness. Water is added to the residue and the resulting solid filtered, washed with water, ethyl acetate, and ether and dried to give 8.9 g of 2-[4-(N-acetyl-D-valylamino)phenyl]-4-hydroxy-5-pyrimidine carboxylic acid. A second crop, obtained from the aqueous filtrate, weighs 2.35 g. [α]D23 +4.50 (cl, pH 7).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:26][C:27](Cl)=[O:28]>>[I:1][C:2]1[C:7]([C:27](=[O:28])[CH3:26])=[C:6]([I:8])[CH:5]=[C:4]([I:9])[C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[C:12]([N+:19]([O-:21])=[O:20])[CH:11]=1
Reactant: CC(=O)Cl
Reactant: O=C(O)c1ccc(-c2c(I)cc(I)cc2I)cc1[N+](=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1c(I)cc(I)c(-c2ccc(C(=O)O)c([N+](=O)[O-])c2)c1I

Procedure:
Freidel-Crafts acylation is performed on 2′,4′,6′-triiodo-3-nitrobiphenyl-4-carboxylic acid (6) in the presence of AlCl3 and CH3COCl to yield 2′,4′,6′-triiodo-3′-acetyl-3-nitrobiphenyl-4-carboxylic acid (12).
Reaction SMILES: [Na:1].[CH3:2][C:3]1[C:4]([CH2:21][S:22]([C:24]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]=2)=[O:23])=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][C:12]1(CCC)OC[CH2:15][CH2:14][O:13]1.OCC1O[C:39]2[CH:41]=[CH:42]C=C[C:38]=2[O:37]C1>>[Na:1].[O:37]1[C:38]2[CH:39]=[CH:41][CH:42]=[CH:15][C:14]=2[O:13][CH2:12][CH:11]1[CH2:10][O:9][C:8]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:21][S:22]([C:24]2[NH:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]=2)=[O:23])[C:3]=1[CH3:2]
Reactant: CCCC1(CCOc2ccnc(CS(=O)c3nc4ccccc4[nH]3)c2C)OCCCO1
Reactant: OCC1COc2ccccc2O1
Agent: [Na]
Product: Cc1c(OCC2COc3ccccc3O2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Yield: 3 %

Procedure:
The same procedure as in the steps (8c) to (8g) of Example 8 was repeated using 2-hydroxymethyl-1,4-benzodioxane to obtain the title compound (141 mg, total yield: 3%) as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[CH:2]([C:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:4]=1)=[O:1]
Reactant: NS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccccc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: NS(=O)(=O)c1ccc(-n2nc(C=O)cc2-c2ccccc2)cc1
Reaction time: 6 h
Yield: 70.5 %

Procedure:
To a solution of alcohol 8b (3 g, 9.1 mmol) and 3 g of powdered 4 Å molecular sieves in 150 mL of DCM, was added PCC (2.94 g, 13.7 mmol) at room temperature. After 6 hours, the reaction mixture was filtered through a 0.75-in. pad of Celite. The filtrate was concentrated in vacuo then the residue was purified by column chromatography to afford the titled compound (2.1 g, 70%) as a white solid. mp 177.3-179.8° C. 1H NMR (300 MHz, DMSO-d6): δ 10.03 (s, 1H), 7.88 (d, J=8 Hz, 2H), 7.61-7.49 (m, 4H), 7.48-7.37 (m, 3H), 7.35-7.26 (m, 2H), 7.20 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=O)([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.[F:33][C:34]([F:60])([F:59])[C:35]1[CH:36]=[C:37]([CH:56]=[CH:57][CH:58]=1)[CH2:38][NH:39][C:40](=[O:55])[C:41]1[CH:46]=[CH:45][N:44]=[C:43]([C:47]2[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=2[NH2:54])[CH:42]=1>ClCCl.CN(C)C1C=CN=CC=1>[F:60][C:34]([F:33])([F:59])[C:35]1[CH:36]=[C:37]([CH:56]=[CH:57][CH:58]=1)[CH2:38][NH:39][C:40]([C:41]1[CH:46]=[CH:45][N:44]=[C:43]([C:47]2[CH:52]=[C:51]([Cl:53])[CH:50]=[CH:49][C:48]=2[NH:54][C:14]([C:13]2[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=2)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:20])=[O:16])[CH:42]=1)=[O:55]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: Nc1ccc(Cl)cc1-c1cc(C(=O)NCc2cccc(C(F)(F)F)c2)ccn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(Cl)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.7 %

Procedure:
Into a 100-mL round bottom flask, was placed a solution of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid (210 mg, 0.71 mmol, 1.20 equiv) in dichloromethane (35 mL), EDC.HCl (170.6 mg, 0.89 mmol, 1.50 equiv), 4-dimethylaminopyridine (108.8 mg, 0.89 mmol, 1.50 equiv), and N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-chlorophenyl)isonicotinamide (240 mg, 0.59 mmol, 1.00 equiv). The resulting solution was stirred for 6 h at 25° C. in an oil bath. The resulting solution was diluted with 100 mL of dichloromethane and washed with 2×50 mL of aqueous NH4Cl and brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 350 mg (86%) of product as a yellow solid.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])C.[CH:27]1([NH2:30])[CH2:29][CH2:28]1>>[CH:27]1([NH:30][C:4]([C:6]2[N:7]=[N:8][C:9]([O:12][CH2:13][C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:5])[CH2:29][CH2:28]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1ccc(OCc2c(-c3cccc(F)c3)noc2C)nn1
Product: Cc1onc(-c2cccc(F)c2)c1COc1ccc(C(=O)NC2CC2)nn1
Yield: 83 %

Procedure:
As described for example 52, 6-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-pyridazine-3-carboxylic acid ethyl ester (143 mg, 0.4 mmol) was converted, using cyclopropylamine instead of ethanolamine, to the title compound (122 mg, 83%) which was obtained as an off white solid. MS: m/e=369.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.CO[CH:14]1[CH2:18][CH2:17][CH:16](OC)O1.Cl.ClC1C=CN=CC=1.O1CCOCC1>C(OCC)C>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:14]=[CH:18][CH:17]=[CH:16]2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Agent: Cl
Agent: Clc1ccncc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(Cl)nc1-n1cccc1

Procedure:
The reaction is carried out in the same way as in Stage B of Example 90 but starting from 15.40 g (0.0887 mol) of 6-chloro-3-nitro-2-aminopyridine and by using 12.9 g (0.0976 mol; 1.1 eq) of 2,5-dimethoxytetrahydrofuran, 14.64 g (0.0976 mol; 1.1 eq) of 4-chloropyridine hydrochloride and 300 cm3 of 1,4-dioxane. The solution is brought to reflux for 6 h. At the end of the reaction, the precipitate is taken up in ethyl ether.
Reaction SMILES: I[C:2]1[O:10][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([NH2:11])[C:4]=2[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[NH2:31][C:32]1C2C(=CC=C(C#N)C=2)C=CN=1>CN1CCCC1=O.[C-]#N.[Zn+2].[C-]#N.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:11][C:5]1[C:4]2[CH:3]=[C:2]([C:32]#[N:31])[O:10][C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: Nc1nccc2oc(I)cc12
Reactant: N#Cc1ccc2ccnc(N)c2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Solvent: CN1CCCC1=O
Product: N#Cc1cc2c(N)nccc2o1

Procedure:
This compound was prepared from 2-iodo-furo[3,2-c]pyridin-4-ylamine (5.2 g), zinc cyanide (3.6 g), triphenylphosphine (2.1 g) and palladium acetate (1.8 g) in 75 mL of N-methyl-pyrrolidone using the procedure described for 1-amino-isoquinoline-7-carbonitrile. Yield: 2.0 g (64%); yellow solid; m.p. 280° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:15]=[N:16][N:17](CC2C=CC(OC)=CC=2)[CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)(C(F)(F)F)=O>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[N:4][C:3]=1[C:14]1[CH:15]=[N:16][NH:17][CH:18]=1
Reactant: COc1ccc(Cn2cc(-c3nc(Nc4ncccn4)sc3Cl)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Clc1sc(Nc2ncccn2)nc1-c1cn[nH]c1
Temperature: 120 °C
Reaction time: 0.13 h
Yield: 78.8 %

Procedure:
According to Scheme 7, Step 2: A mixture of 5-chloro-4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine (0.33 mmol, 130 mg) in TFA (1 mL) was stirred for 8 minutes at 120° C. under microwave activation. The reaction mixture was neutralized with a saturated aqueous solution of Na2CO3 and extracted with AcOEt. The combined organic layers were dried over MgSO4, were filtered and were evaporated under reduced pressure. The crude compound was purified by flash chromatography with silica gel using DCM/MeOH (96:4) as eluent to afford 5-chloro-4-(1H-pyrazol-4-yl)-N-(pyrimidin-2-yl)thiazol-2-amine (0.26 mmol, 74 mg, 81%) as a beige solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=O)[C:7]([NH2:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:14]([NH2:16])=O>>[N+:1]([C:4]1[CH:12]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:13]=[CH:14][NH:16][C:9]2=[O:11])([O-:3])=[O:2]
Reactant: NC=O
Reactant: Nc1ccc([N+](=O)[O-])cc1C(=O)O
Product: O=c1[nH]cnc2ccc([N+](=O)[O-])cc12

Procedure:
A mixture of 5-nitroanthranilic acid (2 g, 14.6 mmol) and formamide (2.9 ml, 72 mmol) is irradiated at 150 C in a microwave (power: 60 W) until TLC shows completion of reaction (20 minutes). After cooling, the reaction mixture is rinsed with ethyl acetate and evaporated under reduced pressure. The crude is purified by flash chromatography (silica gel; ethyl acetate/hexanes) to give the above product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[Cl-].[Al+3].[Cl-].[Cl-].C(S)CCCCCCC>ClCCl>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([F:10])[C:3]=1[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)CCc1c(F)cc(OC)cc1F
Agent: CCCCCCCCS
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CCc1c(F)cc(O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.7 %

Procedure:
A solution of ethyl 3-(2,6-difluoro-4-methoxyphenyl)propanoate (1.17 g, 4.79 mmol), aluminum chloride (1.9 g, 14.2 mmol) and 1-octanethiol (1.7 mL, 9.80 mmol) in dichloromethane (20 mL) was stirred from under ice-cooling to room temperature for 4 hr. The reaction mixture was poured into ice water, and the mixture was stirred for 1 hr. The mixed solution was extracted with dichloromethane, washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:10-1:5) to give the title compound (1.0 g, yield 91%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH:6]=1>C(OCC)(=O)C.[Pt]>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([NH2:14])=[CH:12][CH:13]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Cn2cc(Cl)cn2)cc1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: Nc1ccc(Cn2cc(Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.4 %

Procedure:
To a solution of 4-chloro-1-(4-nitrobenzyl)-1H-pyrazole (0.750 g, 3.16 mmol) in ethyl acetate (30 mL) was added Pt/C (0.038 g, 0.19 mmol). The mixture was stirred at rt for 48 h, filtered through celite, washed with ethyl acetate, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.357 g, 43%) as a peach solid. MW=207.66. 1H NMR (CDCl3, 500 MHz) δ 7.41 (s, 1H), 7.26 (s, 1H), 7.07-7.01 (m, 2H), 6.65-6.59 (m, 2H), 5.09 (s, 2H), 3.74 (s, 2H); APCI MS m/z 207 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:9]1([C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: Nc1ccc(-c2ccccc2)cn1
Yield: 49.2 %

Procedure:
2-Amino-5-bromopyridine (5.0 g, 28.90 mmol), phenylboronic acid (7.05 g, 57.80 mmol), dichlorobis(triphenylphosphine)palladium(II) (1.01 g, 1.45 mmol), and 2M Na2CO3(aq) (24 mL, 48 mmol) were combined in 150 mL of dimethoxyethane and heated to reflux for 1 hour. Upon cooling, the reaction mixture was diluted with EtOAc and washed with H2O and brine. The solvent was removed to give an amber oil which was chromatographed on silica gel eluting with hexanes/ethyl acetate (1:1) to afford 5-phenylpyridin-2-amine (2.42 g) as a tan solid.
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1.[Sn](Cl)(Cl)(Cl)Cl.O>C1(C)C=CC=CC=1.ClC(Cl)C.CCCCCC>[NH2:17][C:16](=[C:6]([C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[C:7]([O:9][CH3:10])=[O:8])[C:15]1[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: COC(=O)CC(=O)C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(Cl)Cl
Product: COC(=O)C(C(=O)C(C)C)=C(N)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 60.2 %

Procedure:
75.09 g of methyl isobutyrylacetate (0.50 mol, concentration 96%) and 61.8 g of 4-fluorobenzonitrile (0.50 mol, concentration 98%) were dissolved in 500 ml of toluene and treated with 144.72 g of tin tetrachloride (0.55 mol, concentration 99%) at room temperature over the course of 15 min. After half an hour at room temperature, the mixture was heated to 80° C. After 3 h, the suspension was cooled to 10° C. and treated with 500 ml of water. The mixture was diluted with 100 ml of dichloroethane and the phases were separated. The organic phase was washed with 2×100 ml of 1N sodium hydroxide solution. After concentration in vacuo, 125.5 g of crude product were obtained in the form of a yellowish solid. The solid was dissolved in 160 ml of n-hexane under reflux and filtered hot. The product precipitated from the filtrate on cooling. By filtering through a frit and washing the filter cake with 130 ml of n-hexane, 79.8 g of methyl 2-[1-amino-1-(4-fluorophenyl)methylene]-4-methyl-3-oxopentanoate were obtained in the form of a spectroscopically pure solid.
Reaction SMILES: Cl.Cl[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[CH:21])[CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:22]([O-:24])=[O:23].[CH3:25][O-:26].[Na+]>O>[C:20]([C:16]1[CH:15]=[C:14]([NH:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([O:26][CH3:25])=[C:4]([N+:22]([O-:24])=[O:23])[CH:5]=3)[N:10]=[CH:9][N:8]=2)[CH:19]=[CH:18][CH:17]=1)#[CH:21]
Reactant: C[O-]
Reactant: C#Cc1cccc(Nc2ncnc3cc(Cl)c([N+](=O)[O-])cc23)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c([N+](=O)[O-])cc23)c1

Procedure:
(7-Chloro-6-nitroquinazolin-4-yl)-(3-ethynyl-phenyl)-amine hydrochloride (100 mg, 0.306 mmol and dry sodium methoxide (120 mg, 2.22 mmol) were stirred in 2 mL of dry 2-methylpyrrolidin-1-one for 8 hours at 30° C. To the cooled reaction mixture 0.93 mL of 3N and 1 mL of water were added. The mixture was diluted with 60 mL of water and extracted with two time 60 mL of ethyl acetate. The pooled organic layers were washed with three times 50 mL of water and 50 mL of brine, dried with magnesium sulfate, filtered and vacuum evaporated to afford the title product as a solid; 80 mg (82%); mp 213°-218° C. dec.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9](=[CH:14][C:15]1[CH:16]=[N:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])=[CH:19][CH:20]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>[Pd].CO>[C:1]([O:5][C:6]([NH:8][CH:9]([CH2:14][C:15]1[CH:16]=[N:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=2[F:28])=[CH:19][CH:20]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(=Cc1ccc(-c2cccc(F)c2F)nc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(Cc1ccc(-c2cccc(F)c2F)nc1)NC(=O)OC(C)(C)C
Yield: 89.2 %

Procedure:
10% Palladium on carbon (10 mg) was added to a mixture of methyl 2-[(tert-butoxycarbonyl)amino]-3-[6-(2,3-difluorophenyl)pyridin-3-yl]acrylate (70 mg, 0.2 mmol) in methanol (3 mL) and acetic acid (0.5 mL, 9 mmol). The reaction was shaken in parr shaker under H2 at 60 Psi for 5 h. The reaction was complete by LC-MS, this was filtered and concentrated under reduced pressure to give crude methyl 2-(tert-butoxycarbonylamino)-3-(6-(2,3-difluorophenyl)pyridin-3-yl)propanoate (0.07 g, 100%) as an oil. Analytical LCMS (M+H)+: m/z=393.0.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][N:8]1[S:13](=[O:15])(=[O:14])[NH:12][C:11]([O:16][CH2:17][CH3:18])=[N:10][C:9]1=O.P(Cl)(Cl)([Cl:22])=O>ClCCCl>[Cl:22][C:9]1[N:8]([CH3:7])[S:13](=[O:15])(=[O:14])[N:12]=[C:11]([O:16][CH2:17][CH3:18])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC1=NC(=O)N(C)S(=O)(=O)N1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC1=NS(=O)(=O)N(C)C(Cl)=N1
Yield: 96.5 %

Procedure:
50 parts of phosphorus pentachloride were introduced into a stirred mixture of 41.4 parts of 6-methyl-3-ethoxy-6H-1,2,4,6-thiatriazin-5-one-1,1-dioxide in 100 parts of 1,2-dichloroethane and 100 parts of phosphorus oxychloride at room temperature. The reaction mixture was stirred under reflux for 12 hours and then evaporated down under reduced pressure, giving 43.5 parts (96.5% of theory) of 5-chloro-6-methyl-3-ethoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide, of melting point 75°-80° C.