Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH3:30])[CH2:3][N:4]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]2)=[O:6].[Cr](O)(O)(=O)=O.C(O)(C)C>C(O)(=O)C>[C:2]([CH2:3][N:4]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH:16]=[CH:15]2)=[O:6])(=[O:1])[CH3:30]
Reactant: CC(O)CN(CC1CCCCC1)C(=O)CCCCOc1ccc2[nH]c(=O)ccc2c1
Agent: O=[Cr](=O)(O)O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(=O)CN(CC1CCCCC1)C(=O)CCCCOc1ccc2[nH]c(=O)ccc2c1
Reaction time: 1 h
Yield: 35.2 %

Procedure:
In 3 ml of acetic acid is dissolved 0.2 g of 6-{4-[N-(2-hydroxypropyl)-N-cyclohexylmethylaminocarbonyl]butoxy}carbostyril. Thereto is dropwise added 0.3 ml of an aqueous solution containing 0.07 g of chromic acid at room temperature. The mixture is stirred for 1 hour, and 0.3 ml of isopropyl alcohol is added. Acetic acid is removed by evaporation under reduced pressure. The residue is made alkaline with sodium bicarbonate and then extracted with chloroform. The extract is washed with water and dried with anhydrous magnesium sulfate. The solvent is removed by evaporation. The residue is purified by means of a silica gel column chromatography (eluent; chloroform:methanol=20:1) and recrystallized from diethyl ether to obtain 0.07 g of 6-[4-(N-acetylmethyl-N-cyclohexylmethylaminocarbonyl)butoxy]carbostyril.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C:7]2[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[NH:12][C:10](=[O:11])[CH:9](O)[N:8]=2)=[CH:5][CH:6]=1.S(Cl)([Cl:23])=O>CN(C=O)C>[Cl:23][CH:9]1[N:8]=[C:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:10]1=[O:11]
Reactant: O=S(Cl)Cl
Reactant: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1O
Solvent: CN(C)C=O
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2)=NC1Cl
Reaction time: 24 h

Procedure:
Oxazepam (1.0 g) was added in portions to 1.0 ml of freshly distilled thionyl chloride that contained ~50μl of DMF with stirring under N2 atmosphere at ice-bath temperature. As soon as the oxazepam was added to the thionyl chloride, the color turned bright yellow and remained unchanged. After complete addition, the heterogeneous reaction mixture was stirred at 0° for 1 hour and then left in the cold room at ~4° for 24 hours. Excess thionyl chloride was removed on a rotary evaporator. The resulting bright yellow solid was thoroughly mixed with a small amount of anhydrous benzene and then benzene was removed on a rotary evaporator, this was repeated several times to remove thionyl chloride. The residue was then triturated with 3 ml of anhydrous benzene and filtered with suction. The product was dried under vacuum to give 1.1 g of bright yellow solid, m.p. 139°-140° C. decomposition (lit. m.p. 151°-153° dec. and 120°-122° C.).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[N:17]#[C:18][NH2:19]>C(O)(=O)C.C(O)C>[C:18]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:12][CH2:13]1)(=[NH:17])[NH2:19]
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Reactant: N#CN
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1c2c(nc3ccccc13)CCN(C(=N)N)CC2

Procedure:
5 gm (23.6 millimols) of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline were dissolved in 2.7 ml of glacial acetic acid and 20 ml of ethanol, and the solution was stirred at room temperature with 1.12 gm (26.6 millimols) of cyanamide for 72 hours. Thereafter, the product which had crystallized out was dissolved in water and reprecipitated with sodium hydroxide. Yield: 0.6 gm, 10% of theory; m.p. 140° C.
Reaction SMILES: CN1C(C)(C)CC[CH2:4][C:3]1(C)C.C#C.Cl[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16]>CN(C)C1C=CN=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.ClCCl>[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:16])[C:3]#[CH:4]
Reactant: CN1C(C)(C)CCCC1(C)C
Reactant: CCCCOC(=O)Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C#C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CC(=O)OCCCC
Temperature: 40 °C
Yield: 85 %

Procedure:
0.42 g (0.36 mmol) of tetrakis(triphenylphosphine)palladium(0), 20 mg (0.16 mmol) of 4-dimethylamino-pyridine and 2.87 g (18.5 mmol) of 1,2,2,6,6-penta-methylpiperidine are introduced into 30 ml of dichloromethane in a 60 ml autoclave under argon. Then 10 bar of acetylene are injected, and the autoclave is heated to 40° C. 5 g (36.6 mmol) of n-butyl chloroformate are pumped in over the course of 10 min, and then acetylene is further injected to 20 bar. The amount of acetylene taken up is replenished hourly over the course of 24 h, and, after cooling, the reaction discharge is flushed with nitrogen and the reaction mixture is distilled. n-Butyl propiolate is isolated in 85% yield.
Reaction SMILES: [CH2:1]([NH:3][CH:4]([CH3:23])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2].[BH4-].[Na+].[C:26](O)(=O)[CH3:27]>>[CH2:1]([N:3]([CH2:26][CH3:27])[CH:4]([CH3:23])[CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[C:12]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:13]=3[O:14][C:15](=[O:16])[C:8]=2[CH2:7]1)[CH3:2]
Reactant: CCNC(C)CN1CCc2c(c(=O)oc3cc(OC)ccc23)C1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CCN(CC)C(C)CN1CCc2c(c(=O)oc3cc(OC)ccc23)C1

Procedure:
Prepared by the method described for Example 59 from 3-[2-(ethylamino)propyl]-1,2,3,4-tetrahydro-8-methoxy-5H-[1]benzopyrano[3,4-c]pyridin-5-one (3.0 g, 0.009 moles), glacial acetic acid (20 ml), and sodium borohydride (2.5 g, 0.066 moles). The free base is obtained crystalline. Recrystallization from isopropyl ether gave the product (1.9 g), mp 83°-85° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]2[C:8](=[O:17])[C:9]3[C:14]([C:15](=[O:16])[C:5]=2[CH:4]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.I(O)(=O)(=O)=[O:19].O>C(#N)C>[CH3:1][S:2]([C:3]1[O:7][C:6]2[C:8](=[O:17])[C:9]3[C:14]([C:15](=[O:16])[C:5]=2[CH:4]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:19]
Reactant: CSc1cc2c(o1)C(=O)c1ccccc1C2=O
Reactant: [O-][I+3]([O-])([O-])O
Solvent: CC#N
Solvent: O
Product: CS(=O)c1cc2c(o1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
To a solution of 0.5 gram (2.05 mmoles) of 2-methylthio-naphtho[2,3-b]furan-4,9-dione (prepared in example 7) in 20 mL of acetonitrile at room temperature, 0.49 grams (2.15 mmoles) of periodic acid followed by 2 mg of ferric chloride was added. The mixture was stirred for 10 minutes at room temperature, then 50 mL of water was added, and the resulting mixture was evaporated to remove acetonitrile. The remaining aqueous suspension was filtered, and the obtained solid was washed with water and dried under vacuum. The crude solid product was purified with silica gel chromatograph using dichloromethane/ethyl acetate (9:1) as elution solvent. 0.43 grams of product (yield 80%) was obtained and characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 3.14 (s, 3H), 7.81 (s, 1H), 7.92-7.94 (m, 2H), 8.12-8.17 (m, 2H). Mass (M+H) is 261.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:21])[S:11]([C:14]2[CH:18]=[C:17]([CH:19]=C)[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.I([O-])(=O)(=O)=[O:23].[Na+]>ClCCl.O.C(OCC)(=O)C.O.[Ru](Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH3:21])[S:11]([C:14]2[CH:18]=[C:17]([CH:19]=[O:23])[S:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(S(=O)(=O)N(C)CCc2ccc(F)cc2)cs1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CCc1ccc(F)cc1)S(=O)(=O)c1csc(C=O)c1
Reaction time: 2 h
Yield: 41.8 %

Procedure:
To a solution of 5-vinylthiophene-3-sulfonic acid[2-(4-fluorophenyl)ethyl]-methyl-amide (328 mg) in dichloromethane (2 mL) was added sodium meta periodate (863 mg) and ruthenium trichloride monohydrate (5 mg) at room temperature. After stirring for 2 hours, this solution was diluted with water and ethyl acetate, and Celite filtration was carried out. The organic layer was separated, after drying with anhydrous sodium sulfate, the residue that was obtained upon removing the solvent by evaporation were purified by silica gel column chromatography (hexane/ethyl acetate) and the title compound (138 mg) was obtained as a yellow oily substance.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][SH:10](=S)=S)=[CH:5][CH:4]=1.[CH:13]1([Mg]Br)[CH2:15][CH2:14]1>C1COCC1.[Cl-].[NH4+].C(OCC)(=O)C>[CH:13]1([S:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=2)[CH2:15][CH2:14]1
Reactant: Br[Mg]C1CC1
Reactant: CSc1ccc(C[SH](=S)=S)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ccc(CSC2CC2)cc1
Temperature: 21 °C
Reaction time: 18 h

Procedure:
To a solution of (4-methylsulfanyl-phenyl)-methanethiol disulfide from Step 1 in THF (50 mL) at 21° C. was added cyclopropylmagnesium bromide (excess) dropwise. The reaction mixture was stirred 18 h at 21° C., then diluted with a saturated ammonium chloride solution and ethyl acetate. The organic extracts were washed (H2O), (brine), dried (MgSO4), filtered and concentrated. Purification by flash chromatography (eluting with hexane/ethyl acetate, 98:2) provided the 1-cyclopropylsulfanylmethyl-4-methylsulfanyl-benzene compound as an oil.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][CH2:14][CH2:15][NH:16][C:17](=[NH:19])[NH2:18])=O)C1C=CC=CC=1.[CH2:23]([S:27]([Cl:30])(=[O:29])=[O:28])[CH2:24][CH2:25][CH3:26].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[ClH:30].[NH:19]=[C:17]([NH:18][S:27]([CH2:23][CH2:24][CH2:25][CH3:26])(=[O:29])=[O:28])[NH:16][CH2:15][CH2:14][CH2:13][C@@H:12]([C:20]([N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:22])[NH2:11]
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCS(=O)(=O)Cl
Reactant: C1CCNC1
Product: CCCCS(=O)(=O)NC(=N)NCCC[C@H](N)C(=O)N1CCCC1
Product: Cl

Procedure:
Starting from (S)-N2-(benzyloxycarbonyl)-arginine, butanesulphonyl chloride and pyrrolidine, the expected product is obtained according to the procedure described in Example 1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11].C(N(CC)CC)C.[C:25](OC(=O)C)(=[O:27])[CH3:26]>ClCCl>[C:25]([O:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCc1ccccc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 22 h

Procedure:
A solution of 29.0 g of the product from Example 1 and 24 ml triethylamine in 290 ml of dichloromethane was cooled to 0° C. and treated with 13 ml acetic anhydride. The reaction mixture was stirred at room temperature for 22 hours. Dichloromethane (200 ml) was added and the organic layer washed with three 50 ml portions of water and one portion of brine. Drying the organic layer over magnesium sulfate followed by concentrating in vacuo gave the crude product. Purification by silica gel chromatography (elution with hexanes-ethyl acetate, 70:30) affoded 19.5 g of pure 2-[2-(acetyloxy)ethyl]-N-(1,1-dimethylethyl)benzenesulfonamide as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[N:9][C:10]([O:12][Si:13]([CH3:16])([CH3:15])[CH3:14])=[CH2:11])[CH:5]=[CH:6][CH:7]=1.[Cl:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:36]/[C:37]3[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=3[CH3:44])/[C:23](=[O:35])[N:24]2[CH2:27][O:28][CH2:29][CH2:30][Si](C)(C)C)=[CH:20][CH:19]=1.CO>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:26]=[C:25]2[NH:24][C:23](=[O:35])[C:22]3([CH:36]([C:37]4[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:38]=4[CH3:44])[CH2:12][C:10](=[O:11])[NH:9][CH:8]3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:21]2=[CH:20][CH:19]=1.[CH3:27][O:28][CH:29]([Si:13]([CH3:14])([CH3:15])[CH3:16])[CH3:30]
Reactant: C=C(N=Cc1cccc(Cl)c1)O[Si](C)(C)C
Reactant: Cc1ccc(F)cc1/C=C1\C(=O)N(COCC[Si](C)(C)C)c2cc(Cl)ccc21
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(C)[Si](C)(C)C
Product: Cc1ccc(F)cc1C1CC(=O)NC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C

Procedure:
To a toluene (12 ml) solution of 1-(3-chlorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 1b in toluene (50 mL) was added E/Z-6-chloro-3-(5-fluoro-2-methyl-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one (0.30 g, 0.72 mmol) prepared in example 146a. The reaction tube was then placed into the cavity of a focused monomode microwave reactor and the contents of the flask were irradiated for 35 min at 135° C. After the solution was cooled to room temperature, methanol (25 mL) was added. The reaction solutions were concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:3) to give racemic (2′S,3S,4′R)-6-chloro-2′-(3-chlorophenyl)-4′-(5-fluoro-2-methyl-phenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a yellow solid (0.45 g)
Reaction SMILES: C(Cl)(Cl)Cl.CCCCCC.C[O:12][C:13](=[O:34])[CH2:14][C:15]1[CH:33]=[CH:32][C:18]2[C:19]3(OCC[O:28]3)[C:20]3[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=3[CH:22]=[CH:23][C:17]=2[CH:16]=1>CC(C)=O.CCCCCC>[CH:16]1[C:17]2[CH:23]=[CH:22][C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[C:19](=[O:28])[C:18]=2[CH:32]=[CH:33][C:15]=1[CH2:14][C:13]([OH:34])=[O:12]
Reactant: COC(=O)Cc1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Solvent: CCCCCC
Product: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
2.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d] cyclohepten-2-yl)propionic acid methyl ester is stirred in 25 ml. of 1:1 concentrated sulfuric acid:water for 12 hours. The mixture is poured into water and extracted with ethyl acetate and the extract is washed, dried and evaporated to afford a 70% yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionic acid, m.p. (chloroform-hexane) 138°-139°C.; m.p. (acetone-hexane) 113°-115°C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetic acid methyl ester gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5°C.
Reaction SMILES: [CH3:1][C:2]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:40]([O:42][C:43]1[CH:62]=[CH:61][C:46]([O:47][CH:48]2[CH2:51][N:50]([C:52]3[CH:57]=[CH:56][C:55]([C@@H:58]([NH2:60])[CH3:59])=[CH:54][CH:53]=3)[CH2:49]2)=[CH:45][CH:44]=1)[CH3:41]>CN(C=O)C>[CH2:40]([O:42][C:43]1[CH:62]=[CH:61][C:46]([O:47][CH:48]2[CH2:49][N:50]([C:52]3[CH:57]=[CH:56][C:55]([C@@H:58]([NH:60][C:6]([C:2]4([CH3:1])[CH2:3][CH2:4][CH2:5]4)=[O:8])[CH3:59])=[CH:54][CH:53]=3)[CH2:51]2)=[CH:45][CH:44]=1)[CH3:41]
Reactant: CCOc1ccc(OC2CN(c3ccc([C@H](C)N)cc3)C2)cc1
Reactant: CC1(C(=O)O)CCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1ccc(OC2CN(c3ccc([C@H](C)NC(=O)C4(C)CCC4)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 0.011 g (0.10 mmol) 1-methyl-cyclobutanecarboxylic acid in 1 mL DMF are added 0.035 mL (0.20 mmol) DIPEA and 0.032 g (49.1 mmol) TBTU. The mixture is stirred for 15 min at rt. Subsequently 0.031 g (0.10 mmol) (S)-1-{4-[3-(4-ethoxy-phenoxy)-azetidin-1-yl]-phenyl}-ethylamine (X.1) are added and stirring is continued for 12 h at rt. The mixture is directly purified by HPLC to yield the desired product.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][N:5]=[C:4]2[CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14](B4OC(C)(C)C(C)(C)O4)=[CH:13][C:12]=3[N:3]12.[Br-].[CH2:27]([CH:34]1[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH:37]=[C:36](OS(C(F)(F)F)(=O)=O)[CH2:35]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[CH2:27]([CH:34]1[N:39]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:38][CH:37]=[C:36]([C:14]2[CH:15]=[CH:16][C:11]3[O:10][CH2:9][C:4]4=[N:5][NH:6][C:7](=[O:8])[CH:2]([CH3:1])[N:3]4[C:12]=3[CH:13]=2)[CH2:35]1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC1C(=O)NN=C2COc3ccc(B4OC(C)(C)C(C)(C)O4)cc3N21
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1C(=O)NN=C2COc3ccc(C4=CCN(C(=O)OC(C)(C)C)C(Cc5ccccc5)C4)cc3N21
Temperature: 90 °C
Yield: 99 %

Procedure:
A mixture of methyl-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one (prepared from the corresponding bromide (Preparation #1, Step D) following similar procedure as describe in Example #109, Step B, 0.103 g, 0.3 mmol), tert-butyl 6-benzyl-4-(trifluoromethylsulfonyloxy)-5,6-dihydropyridine-1(2H)-carboxylate (0.253 g, 0.6 mmol), Pd(dppf)Cl2—CH2Cl2 complex (0.073 g, 0.09 mmol) and K2CO3 (0.124 g, 0.9 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL) was heated at 90° C. for 10 h. The reaction was cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by PTLC (eluting with 50% EtOAc in petroleum ether) to give tert-butyl 6-benzyl-4-(1-methyl-2-oxo-1,2,3,5-tetrahydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-9-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.147 g, 99%). LC/MS (Table 1, Method 2) Rt=1.308 min; MS m/z: 489 [M+H]+.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[NH:52]1[CH2:56][CH2:55][CH2:54][CH:53]1[CH2:57][C:58]1[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=2[O:60][C:59]=1[CH2:67][CH2:68][CH2:69][OH:70]>CN1C(=O)CCC1.O>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:18]([N:52]1[CH2:56][CH2:55][CH2:54][CH:53]1[CH2:57][C:58]1[C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=2[O:60][C:59]=1[CH2:67][CH2:68][CH2:69][OH:70])=[O:20])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: OCCCc1oc2ccccc2c1CC1CCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: O
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(O)cc1)C(=O)N1CCCC1Cc1c(CCCO)oc2ccccc12
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
A solution containing Boc-L-tyrosine (577 mg, 2.1 mmol) and HATU (716 mg, 1.8 mmol) in anhydrous NMP (6 mL) was treated with NMM (0.3 mL, 2.7 mmol) at ambient temperature. After 10 min, a solution containing 61 (429 mg, 1.7 mmol) in NMP (5 mL) was added. After 2 d, the reaction mixture was diluted with water and the product was extracted with diethyl ether. The combined ether extracts were washed with water and dilute aqueous NaHCO3, brine, dried over anhydrous Na2SO4, filtered and concentrated. The crude product was purified by flash silica gel chromatography (10% MeOH/DCM) to afford 821 mg (92%) of 62 as a pale yellow foam. 1H NMR (CDCl3, 300 MHz) δ8.54 (br 2, 1H), 7.66-7.63 (m, 1H), 7.36-7.32 (m, 1H), 7.21-7.06 (m, 5H), 6.83 (d, J=8.4 Hz, 2H), 5.58 (d, J=9.0 Hz, 1H), 4.64-4.56 (m, 1H), 4.34-4.31 (m, 1H), 3.92-3.88 (m, 1H), 3.70 (app t, J=5.7 Hz, 2H), 3.51-3.26 (m, 1H), 3.18-2.79 (m, 4H), 2.01-1.97 (m, 2H), 1.69-1.47 (m, 1H), 1.42 (s, 9H) ppm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[C:10](OC(=O)C)(=[O:12])C>C(O)=O>[CH:10]([NH:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1)=[O:12]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: O=CO
Product: O=CNc1nc(Cl)cc(Cl)n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A 250 ml. three necked flask was fitted with a mechanical stirrer, a thermometer, and a reflux condenser with drying tube. To the flask was charged 70 ml. of a 98% formic acid and 3.85 g (0.025 mole) of 2-amino-4,6-dichloropyrimidine as prepared in example 1. Acetic anhydride, 30 ml. was added slowly with stirring to maintain temperature below 50° C. When the addition of acetic anhydride was complete, the mixture was heated for 6 more hours at 50° C and then allowed to stand overnight at room temperature. Excess formic acid and acetic anhydride were evaporated under vacuum. The solid residue was crystallized from 15 ml. of ethyl alcohol. There was obtained 3.7 g of 2-formamido-4,6-dichloropyrimidine (PY-24) in the form of white crystals, melting point, 142°-144° C, yield 77%.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1.N.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2nc(C)cc(O)n2)cc1
Agent: N
Product: COc1ccc(-c2nc(C)cc(Cl)n2)cc1
Reaction time: 0.5 h

Procedure:
6.5 g of 4-hydroxy-2-(4-methoxyphenyl)-6-methylpyrimidine prepared in reference example 1 (3) was added to 30 ml of phosphorus oxychloride, and the mixture was refluxed with stirring for 30 minutes. The reaction mixture was cooled and poured into diluted ammonia solution and the precipitated crystals were filtered off. The crystals were dissolved in chloroform. After the chloroform layer was washed twice with water, it was dried with anhydrous magnesium sulfate and was evaporated in vacuo. The residue was crystallized with n-hexane and filtered off. Whereby 5.1 g of crystals was obtained. Melting point is 80° to 81° C.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[N:4]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:3]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:11]([C:7]1[CH:6]=[C:5]2[C:10]([C:2]([C:25]3[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=3)=[N:3][N:4]2[CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=1)([O-:13])=[O:12]
Reactant: OB(O)c1ccncc1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc([N+](=O)[O-])cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1nc(-c2ccncc2)c2ccc([N+](=O)[O-])cc21
Temperature: 120 °C
Yield: 83.1 %

Procedure:
To a microwave vial was added 3-iodo-6-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (1.2 g, 2.9 mmol, WO 2010/027500, Intermediate 57, Step B), pyridine-4-boronic acid (0.704 g, 5.72 mmol), and Pd(PPh3)4 (0.165 g, 0.143 mmol), 1,4-dioxane (25 mL) and an aqueous solution of Na2CO3 (2 M, 6.3 mL, 12.6 mmol). The vial was sealed and the mixture was heated in a microwave at about 120° C. for about 40 min. The mixture was diluted with EtOAc (100 mL) and water (25 mL) and the layers separated. The aqueous layer was extracted with EtOAc (15 mL). The combined extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (80 g silica gel) eluting with 20 to 80% EtOAc/heptane to provide 6-nitro-3-(pyridin-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0.893 g, 84%): LC/MS (Table 2, Method c) Rt=3.02 min.; MS m/z: 371 (M+H)+.