Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[C:14]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=2)[CH:10]=[CH:9][CH:8]=[C:7]4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.Br[C:21]1[CH:22]=[C:23]([C:28]2[N:33]=[C:32]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:31]=[C:30]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[N:29]=2)[CH:24]=[C:25](Br)[CH:26]=1.C([O-])([O-])=O.[K+].[K+].[N:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[C:58]1[CH:63]=[CH:62][C:61](B(O)O)=[CH:60][CH:59]=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.C(O)C.C1(C)C=CC=CC=1>[C:34]1([C:32]2[N:31]=[C:30]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[N:29]=[C:28]([C:23]3[CH:22]=[C:21]([C:61]4[CH:60]=[CH:59][C:58]([C:53]5[CH:54]=[CH:55][CH:56]=[CH:57][N:52]=5)=[CH:63][CH:62]=4)[CH:26]=[C:25]([C:1]4[C:14]5[C:15]6=[C:16]7[C:11](=[CH:12][CH:13]=5)[CH:10]=[CH:9][CH:8]=[C:7]7[CH:6]=[CH:5][C:4]6=[CH:3][CH:2]=4)[CH:24]=3)[N:33]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Brc1cc(Br)cc(-c2nc(-c3ccccc3)nc(-c3ccccc3)n2)c1
Reactant: OB(O)c1ccc(-c2ccccn2)cc1
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-c2nc(-c3ccccc3)nc(-c3cc(-c4ccc(-c5ccccn5)cc4)cc(-c4ccc5ccc6cccc7ccc4c5c67)c3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
In a stream of argon, 0.53 g (2.14 mmol) of 1-pyreneboronic acid, 1.00 g (2.14 mmol) of 2-(3,5-dibromophenyl)-4,6-diphenyl-1,3,5-triazine and 24.7 mg (0.0214 mmol) of tetrakis(triphenylphosphine)palladium were suspended in a mixed solvent composed of 80 mL of toluene and 10 mL of ethanol, and the resultant suspension was heated to 60° C. To the suspension, 8.56 mL (8.56 mmol) of an aqueous 1M K2CO3 solution was gradually added dropwise, and the mixture was stirred for 3 hours. Then the mixture was cooled to room temperature, and 0.64 g (3.21 mmol) of 4-(2-pyridyl)phenylboronic acid wad added. Then the mixture was heated to 70° C. and maintained at that temperature for 3 hours while being stirred. Then the reaction mixture was cooled to room temperature, and was then distilled under a reduced pressure to remove all volatile materials. Methanol was added to the concentrate, and the thus-deposited solid was collected by filtration. The obtained crude product was purified by silica gel chromatography using a hexane/chloroform (1:2) mixed solvent as an eluent to give 0.37 g of the target 4,6-diphenyl-2-[5-(1-pyrenyl)-4′-(2-pyridyl)biphenyl-3-yl]-1,3,5-triazine as a white solid (yield: 26%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([NH:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1)=[O:31]
Reactant: COc1ccccc1C(=O)Cl
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccccc1C(=O)Nc1nc2c(OC)ccc(-c3ccccc3)c2s1

Procedure:
To a solution of 2-amino-4-methoxy-7-phenyl-benzothiazole (200 mg, 0.67 mmol) in THF (10 m) was added DMAP (10 mg, 0.08 mmol), triethylamine (163 □l, 1.17 mmol) and 2-methoxybenzoyl chloride (136 □l, 1 mmol) in THF (2 ml). The mixture was then heated to reflux for 2 h, after cooling, it was partitioned between 1:1 AcOEt/THF (70 ml) and 5% NaHCO3 solution (40 ml). The organic phase was washed with saturated NaCl solution (50 ml), dried with Na2SO4, filtered and the solvent removed under reduced presure. The residue was suspended in ether (10 ml), filtered, washed with ether then dried under vacuum (0.05 mmHg, 60° C.), to afford the title compound was a white solid (260 mg, 85% yield), MS: m/e=390.0 (M+).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][C:4](=[N:6][OH:7])[NH2:5].CCN(CC)CC.[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[C:18]#[CH:19]>C(#N)C>[NH2:5][C:4](=[N:6][O:7][CH:19]=[CH:18][C:17]([O:21][CH2:22][CH3:23])=[O:20])[CH2:3][C:2]([F:9])([F:8])[F:1]
Reactant: C#CC(=O)OCC
Reactant: NC(CC(F)(F)F)=NO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C=CON=C(N)CC(F)(F)F
Temperature: 80 °C

Procedure:
Into a flask containing 3,3,3-trifluoro-N′-hydroxypropanimidamide (21 mmol, 3 g) in ACN (50 ml), Et3N (21 mmol, 3.5 ml) was added at RT. The resulting mixture was heated at 80° C. and a solution of ethyl propiolate (25.1 mmol, 2.5 g) in ACN (20 ml) was added. The reaction mixture was heated at 80° C. for overnight. The solvent was evaporated and the crude was purified by flash-chromatography. Yield 3.8 g. 1H-NMR (400 MHz; DMSO-d6): δ 1.17 (t, 3H), 3.18 (q, 2H), 4.09 (q, 2H), 5.44 (d, 1H), 6.78 (bs, 2H), 7.70 (d, 1H). LC-MS: [M−1]=239.17.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13].CCCCCCC.CCOC(C)=O>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:14]/[CH:12]=[O:13]
Reactant: O=Cc1cc2ccccc2s1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C/C=C/c1cc2ccccc2s1
Yield: 28.9 %

Procedure:
A solution of benzothiophene-2-carboxaldehyde (3 g, 18.4 mmol) and formylmethylenetriphenylphosphorane (5.62 g, 18.4 mmol) in CH2Cl2 (100 ml) was treated as seen in preparation 1. After a chromatography on silicagel (n-heptane/EtOAc 4/1) pure title compound was obtained (1.00 g, 5.31 mmol, yield 28.9%) as yellow crystals, m.p.=88°.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][C:16]([CH2:18][C:19]([C:21]([F:24])([F:23])[F:22])=[O:20])=O.[NH2:25]/[C:26](/[CH3:32])=[CH:27]\[C:28]([O:30][CH3:31])=[O:29].C(O)(=O)C>CC(O)C>[CH3:32][C:26]1[NH:25][C:16]([CH3:15])=[C:18]([C:19](=[O:20])[C:21]([F:24])([F:23])[F:22])[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:27]=1[C:28]([O:30][CH3:31])=[O:29]
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: COC(=O)/C=C(/C)N
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)C(F)(F)F)C1c1cccc2c(=O)cc(C)oc12

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 143.3 mg (0.93 mmol) of 1,1,1-trifluoroacetylacetone, 61.1 mg (0.53 mmol) of methyl 3-aminocrotonate and 31.9 mg (0.53 mmol) of acetic acid in 5 ml of 2-propanol and heated to reflux under argon for 10 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 22 mg (9.8% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([N:6]([CH3:21])[C:7](=[O:20])[C:8]([CH3:19])([CH3:18])[CH2:9][N:10]2[CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].O.Cl>C(O)C>[CH:13]1([N:10]2[CH2:9][C:8]([CH3:19])([CH3:18])[C:7](=[O:20])[N:6]([CH3:21])[C:5]3[C:11]2=[N:12][C:2]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=2[O:32][CH3:33])=[N:3][CH:4]=3)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CN1C(=O)C(C)(C)CN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(C)C(=O)N2C
Yield: 47.8 %

Procedure:
To a solution of 10-chloro-2-cyclopentyl-4,4,6-trimethyl-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 126; 616 mg, 2.0 mmol) and 4-amino-3-methoxybenzoic acid (378 mg, 2.2 mmol) in ethanol (5 mL) was added water (15 mL) and conc hydrochloric acid (0.335 mL). The mixture was heated under reflux for 36 hours. The reaction was cooled and a brown solid precipitated. This was filtered, dried and triturated under cold acetonitrile and then dried in vacuo to give the product as a pale brown solid (420 mg), 48%)
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:7])[NH:5][N:6]=1.[CH3:8][C:9](=O)[CH2:10][C:11](=O)[CH3:12]>C(O)(=O)C>[CH3:8][C:9]1[CH:10]=[C:11]([CH3:12])[N:6]2[N:5]=[C:4]([OH:7])[N:3]=[C:2]2[N:1]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1n[nH]c(=O)[nH]1
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc(O)nc2n1
Yield: 88.2 %

Procedure:
To a solution of 5-amino-2,4-dihydro-3H-1,2,4-triazol-3-one (29 g, 0.29 mol) in glacial acetic acid (140 mL) was added pentane-2,4-dione (29 g, 0.29 mol) and the solution was refluxed for 8 hours. The reaction mixture was concentrated under reduced pressure to afford a yellow solid. The solid was filtered and washed with ethanol (200 mL) to give the product (42 g, 80%).
Reaction SMILES: [C:1]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]1(=O)[O:22][C:20](=[O:21])[CH:19]=[CH:18]1.C(OC(=O)C)(=O)C.C(N(CC)CC)C>CC(C)=O.C([O-])(=O)C.[Co+2].C([O-])(=O)C>[C:1]([NH:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20](=[O:21])[CH:19]=[CH:18][C:17]2=[O:22])=[CH:12][N:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(C)OC(=O)NNc1ccc(N)cn1
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)NNc1ccc(N2C(=O)C=CC2=O)cn1
Reaction time: 2 h
Yield: 28.3 %

Procedure:
To a stirred solution of 2-BOC-hydrazino-5-amino pyridine (1 equivalent) in acetone (50 ml/gm) was added maleic anhydride (1.1 equivalents). The reaction mixture was stirred at 25° for 2 hours. To the reaction mixture was added acetic anhydride (1.2 equivalents), cobalt acetate (0.007 equivalents) and triethylamine (0.3 equivalents). The reaction mixture was stirred at 60° for 2 hours. The color of the reaction began as bright yellow and ended as dark yellow. The reaction mixture was concentrated under reduced pressure to give a yellow brown oil. Flash vacuum chromatography (hexanes/ethyl acetate (8/2)) was used to isolate the product. The product was recrystallized in ether/hexane; yield 28.3%; m.p. 182°-184°. IR (KBr): 3400, 3300, 3100, 2990, 1700, 1610, 1500, 1410, 1360, 1320, 1270, 1210, 1150, 1050, 830, 750, 690 cm-1.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4](/[CH:17]=[CH:18]/[CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:6]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1.O>[CH3:1][C:2]1[S:3][C:4](/[CH:17]=[CH:18]/[CH:19]([O:25][C:26](=[O:28])[CH3:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[N:6]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC(O)/C=C/c1sc(C)nc1CCCCCCC(=O)OC
Solvent: c1ccncc1
Solvent: O
Product: CCCCCC(/C=C/c1sc(C)nc1CCCCCCC(=O)OC)OC(C)=O
Reaction time: 24 h

Procedure:
To the solution of 367 mg of 2-methyl-4-(6-carbomethoxy-hexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole (Ic, R1 = CH3) in 4 ml of anhydrous pyridine, 1 ml of acetic anhydride was added. The reaction mixture was allowed to stand for 24 hours at room temperature, diluted with 50 ml of water and extracted with 3 × 15 ml of ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulphate and evaporated in vacuo. The obtained 403 mg of evaporation residue was purified by preparative thin layer chromatography, using a silica gel layer as adsorbent and a mixture of 40 % ethyl acetate and 60 % n-heptane as running solvent. Thus, 290 mg of 2-methyl-4-(6-carbomethoxyhexyl)-5-(3-acetoxy-1-trans-octenyl)-thiazole (Ie, R1 = CH3) of chromatographic purity were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23.[C:22]([O:26][C:27]([NH:29][C@H:30]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:31](O)=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(Cl)Cl.CN(C)C=O>[C:22]([O:26][C:27](=[O:28])[NH:29][C@@H:30]([C:31](=[O:32])[NH:1][C:2]1[CH:3]=[C:4]2[C:20](=[O:21])[NH:19][N:18]=[CH:17][C:6]3=[C:7]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:8][C:9]([CH:10]=1)=[C:5]23)[CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)([CH3:23])([CH3:25])[CH3:24]
Reactant: Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)Nc1cc2c3c(c(-c4ccccc4)[nH]c3c1)C=NNC2=O
Yield: 110.7 %

Procedure:
Preparation of example 118 from the title compound of Example 7 (hydrochloride) (43 mg, 0.138 mmol), (R)-tert-butoxycarbonylamino-3-phenyl-propionic acid (44 mg, 0.166 mmol), triethylamine (0.058 mL, 0.414 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (63 mg, 0.166 mmol) in CH2Cl2 (0.4 mL) and N,N-dimethylformamide (0.4 mL) was carried out analogously to Example 11. Silica gel chromatography (eluted with 1:1 hexane:acetone), also in an analogous manner, afforded the title compound (80 mg) as a yellow powder contaminated with an unknown impurity. The compound was carried on without further purification to Example 115.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([Cl:17])[CH:8]=2)=[N:5][N:6]=1.[CH2:18]([C:20]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=[O:23])[CH3:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>CN(C)C=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>[Cl:17][C:9]1[CH:8]=[C:7]([C:4]2[S:3][C:2]([C:27]3[C:20]([CH2:18][CH3:19])=[C:21]([CH:24]=[CH:25][CH:26]=3)[CH:22]=[O:23])=[N:6][N:5]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH:14]([CH3:16])[CH3:15]
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)Oc1ccc(-c2nnc(Br)s2)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1c(C=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(Cl)c2)s1
Temperature: 130 °C
Yield: 28.3 %

Procedure:
To a suspension of 2-bromo-5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazole (D10) (0.5 g), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (D5) (0.468 g) and tripotassium phosphate (0.795 g) in N,N-dimethylformamide (DMF) (10 mL) and Pd(Ph3P)4 (0.173 g). The reaction mixture was degassed and then the reaction vial was sealed and heated under microwave at 130° C. for 10 min. Water was then added to the reaction mixture. The mixture was extracted with EA. The combined organic solution was dried over anhydrous sodium sulphate. After filtration and concentration, the residue was purified by column chromatography to give 3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,3,4-thiadiazol-2-yl)-2-ethylbenzaldehyde (D11) (164 mg). MS (ES): C20H19ClN2O2S requires 386. found 387.1 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11]([O:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[C:19]([CH3:21])[CH:20]=1)(=[O:13])=[O:12].[CH2:23](O)[CH2:24][CH2:25][OH:26].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11]([O:14][C:15]1[CH:16]=[C:17]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[O:22][CH2:23][CH2:24][CH2:25][OH:26])(=[O:12])=[O:13]
Reactant: OCCCO
Reactant: COc1ccc(OC)c(S(=O)(=O)Oc2cc(C)cc(O)c2)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(OC)c(S(=O)(=O)Oc2cc(C)cc(OCCCO)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 500 mg (1.54 mmol) of 3-(2,5-dimethoxyphenylsulfonyloxy)-5-methylphenol, as prepared in the preceding step, 1.1 mL (15 mmol) of 1,3-propanediol and 808 mg (3.08 mmol) of triphenylphosphine in 12 mL of anhydrous tetrahydrofuran was added 485 mg (3.08 mmol) of diethyl azodicarboxylate dropwise over 15 min. After stirring at ambient temperature for 1 h, the reaction mixture was concentrated to a yellow syrup. The resulting mixture was flash chromatographed on 40 g of silica gel with 50-75% ethyl acetate-hexane to afford a mixture of the desired product and triphenylphosphine oxide. Chromatography on 35 g of silica gel with 4% acetone-dichloromethane afforded 483 mg (82% yield) of the title compound as a colorless resin: 1H-NMR (300 MHz; CDCl3) δ 7.34 (d, 1 H, J=3.1 Hz), 7.15 (dd, 1 H, J=9.1, 3.1 Hz), 7.03 (d, 1 H, J=9.1 Hz), 6.59 (m, 1 H), 6.53 (m, 1 H), 6.48 (t, 1 H, J=2.1 Hz), 4.01 (t, 2 H, J=6.0 Hz), 3.97 (s, 3 H), 3.81 (dd, 2 H, J=11.2, 5.8 Hz), 3.76 (s, 3 H), 2.25 (s, 3 H) and 1.98 (pentet, 2 H, J=6.0 Hz).
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:42](COCC[Si](C)(C)C)[CH:41]=[N:40][C:5]=2[C:6]([CH2:31][C:32]2[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=2[Cl:39])=[N:7][C:8]=1[NH:9][C:10]1[C:15]([F:16])=[CH:14][C:13]([N:17]2[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]2)=[C:12]([CH3:30])[CH:11]=1)#[N:2].S(=O)(=O)(O)[OH:52]>O>[Cl:38][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:39])[C:32]=1[CH2:31][C:6]1[C:5]2[N:40]=[CH:41][NH:42][C:4]=2[C:3]([C:1]([NH2:2])=[O:52])=[C:8]([NH:9][C:10]2[CH:11]=[C:12]([CH3:30])[C:13]([N:17]3[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]3)=[CH:14][C:15]=2[F:16])[N:7]=1
Reactant: Cc1cc(Nc2nc(Cc3c(Cl)cccc3Cl)c3ncn(COCC[Si](C)(C)C)c3c2C#N)c(F)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(Nc2nc(Cc3c(Cl)cccc3Cl)c3nc[nH]c3c2C(N)=O)c(F)cc1N1CCNCC1
Temperature: 90 °C

Procedure:
To the product of Example 51D (190 mg, 0.26 mmol) at 0° C. was added concentrated sulfuric acid (3 mL) and water (0.6 mL) and the mixture was heated at 90° C. for 20 minutes. After quenching with water (20 mL) and adjusting to pH 8 with saturated sodium bicarbonate solvent, the mixture was extracted with 4/1 dichloromethane/methanol (3×100 mL). The organic layers were collected, dried over anhydrous sodium sulfate, filtered, concentrated and purified by preparative HPLC using a gradient of 10/90 to 75/25 acetonitrile/water (containing 0.1% trifluoroacetic acid) to give the title compound. 1H NMR (DMSO-d6, 300 MHz): δ 13.63 (s, 1H), 11.98 (s, 1H), 9.63 (s, 1H), 8.64 (m, 3H), 7.90 (d, 1H), 7.83 (s, 1H), 7.56 (d, 2H), 7.39 (t, 1H), 6.90 (d, 1H), 4.74 (s, 2H), 3.25 (m, 4H), 2.95 (m, 4H), 2.07 (s, 3H). MS: 528 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][Sn](CCCC)(CCCC)CCCC.C([Li])CCC.[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:38]2[C:43]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[O:51][CH3:52])=[C:42]([O:53][CH2:54][CH2:55][OH:56])[N:41]=[C:40](S(C)(=O)=O)[N:39]=2)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[C:24]([C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH:37][C:38]2[C:43]([O:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[O:51][CH3:52])=[C:42]([O:53][CH2:54][CH2:55][OH:56])[N:41]=[C:40]([CH2:5][O:4][CH2:3][O:2][CH3:1])[N:39]=2)(=[O:35])=[O:36])=[CH:30][CH:29]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CCCC[Sn](CCCC)(CCCC)COCOC
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(S(C)(=O)=O)nc1OCCO
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COCOCc1nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c(Oc2ccccc2OC)c(OCCO)n1
Reaction time: 0.07 h

Procedure:
##STR150## (1) To a solution of methoxymethyloxymethyltributyltin (655 mg) in tetrahydrofuran (6 ml) is added dropwise a 1.63M solution of n-butyl lithium in n-hexane (1.09 ml) at -78° C. The mixture is stirred at the same temperature for four minutes, and thereto is added a solution of 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxyphenoxy)-2-methylsulfonylpyrimidin-4-yl]benzenesulfonamide obtained in Reference Example 10-(1) (200 mg) in tetrahydrofuran (2 ml), and the mixture is stirred for 40 minutes. To the mixture is added an aqueous ammonium chloride solution, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried, and evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=100:1~50:1) to give 4-tert-butyl-N-[6-(2-hydroxyethoxy)-2-methoxymethyloxymethyl-5-(2-methoxy-phenoxy)pyrimidin-4-yl]benzenesulfonamide (111 mg) as a colorless caramel.
Reaction SMILES: C(OC1C(F)=CC(Br)=C2C=1C([CH2:21][C:22]([OH:24])=[O:23])=CN2C)C1C=CC=CC=1.[Br:25][C:26]1[CH:27]=[C:28]2[O:41][CH2:40][CH2:39][O:38][C:29]2=[C:30]2[C:34]=1[N:33]([CH2:35][CH2:36][CH3:37])[CH:32]=[CH:31]2>>[Br:25][C:26]1[CH:27]=[C:28]2[O:41][CH2:40][CH2:39][O:38][C:29]2=[C:30]2[C:34]=1[N:33]([CH2:35][CH2:36][CH3:37])[CH:32]=[C:31]2[CH2:21][C:22]([OH:24])=[O:23]
Reactant: CCCn1ccc2c3c(cc(Br)c21)OCCO3
Reactant: Cn1cc(CC(=O)O)c2c(OCc3ccccc3)c(F)cc(Br)c21
Product: CCCn1cc(CC(=O)O)c2c3c(cc(Br)c21)OCCO3
Yield: 74 %

Procedure:
Following the procedure (step 3, scheme 333) used to prepare compound 33-4, compound 40-3 gave compound 40-4 in 74% yield as a yellow solid. LCMS: calc 353.0 found 353.9 [MH]+.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[CH:6]=1.[OH-].[K+].O>C1COCC1.CO>[CH3:12][C:7]1[CH:6]=[C:5]([C:4]#[CH:3])[CH:10]=[C:9]([CH3:11])[CH:8]=1
Reactant: Cc1cc(C)cc(C#C[Si](C)(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc(C)cc(C)c1
Reaction time: 1 h
Yield: 82.7 %

Procedure:
A solution of crude 1-trimethylsilyl-2-(3,5-dimethylphenyl)acetylene (105 mmol, theoretical maximum) in THF (70 mL) and MeOH (280 mL) was cooled in an ice/water bath during addition of 8N KOH (16 mL, 128 mmol) and water (25 mL) and the reaction was then removed from ice/water bath. After 1 h, approximately half of the organic solvent was removed in vacuo. Hexanes (1 L) and water (400 mL) were added. The organic layer was washed with saturated brine, dried (Na2SO4), and concentrated to give 11.3 g of 1-(3,5-dimethylphenyl)acetylene as a brown oil:
Reaction SMILES: [CH2:1]([C:8]#[N:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][C:11](C)([O-])[CH3:12].[K+].[CH3:16][N:17]([CH:19]=O)C>>[C:2]1([CH:1]([C:11]2[CH:12]=[CH:19][N:17]=[CH:16][CH:10]=2)[C:8]#[N:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: N#CCc1ccccc1
Reactant: CN(C)C=O
Agent: [K+]
Product: N#CC(c1ccccc1)c1ccncc1

Procedure:
The compound was prepared substantially in accordance with the procedure detailed in Example 12A, using the compound of Example 15A, benzyl cyanide (3.3 ml, 28.7 mmol) and potassium t-butoxide (6.44 g, 57.4 mmol) in 60 ml of DMF.
Reaction SMILES: [O:1]=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].O.[C:9]1(C)C=CC(S(O)(=O)=O)=C[CH:10]=1>C(O)C>[CH2:9]([O:4][C:3](=[O:5])[C:2](=[O:1])[CH2:6][CH3:7])[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCC(=O)C(=O)O
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(=O)CC
Temperature: 25 °C
Yield: 16662.4 %

Procedure:
2-Oxo-butyric acid (10.0 g, 97.2 mmol) was dissolved in ethanol (100 mL) and p-toluene sulfonic acid mono hydrate (0.1 g) was added. The reaction mixture was heated to reflux for 48 h. After cooling the reaction mixture to room temperature, the ethanol was removed under reduced pressure to give 11.4 g of 2-oxo-butyric acid ethyl ester.