Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[C:11]([F:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[C:9]([F:19])[C:8]=2[F:20])[N:5]=[CH:4][C:3]=1C(OCC)=O.S(=O)(=O)(O)O>O>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([F:13])=[C:11]([F:14])[C:10]([C:15]([F:18])([F:17])[F:16])=[C:9]([F:19])[C:8]=2[F:20])[N:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn(-c2c(F)c(F)c(C(F)(F)F)c(F)c2F)c1N
Agent: O=S(=O)(O)O
Solvent: O
Product: Nc1ccnn1-c1c(F)c(F)c(C(F)(F)F)c(F)c1F
Temperature: 130 °C
Yield: 2.5 %

Procedure:
A stirred mixture of 18.6 grams (0.500 mole) of ethyl 5-amino-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)pyrazole-4-ylcarboxylate, 23 mL of water, and 23 mL of sulfuric acid was heated at 130° C. for six hours. After the reaction mixture was cooled, 75 mL of crushed ice was added. A solid had formed and was collected by filtration; the filtrate was saved. This solid was washed with water and diethyl ether, allowed to dry, and set aside for further purification. To the filtrate was added an aqueous sodium hydroxide solution until a pH of 9.0 was obtained. A solid formed and was collected by filtration. This solid was washed with water and dried to yield 3.8 grams of 5-amino-1-(2,3,5,6-tetrafluoro-4-trifluoromethylphenyl)pyrazole, m.p. 102.5-104.5° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Br)[N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[CH:29]([NH2:31])[CH3:30])[CH:16]=[N:17][CH:18]=1.C(N(CC)C(C)C)(C)C.C(O)(C(F)(F)F)=O>C(O)C>[F:12][C:13]1[CH:14]=[C:15]([C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][C:20]=2[CH:29]([NH:31][C:4]2[N:3]=[C:2]([NH2:1])[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][NH:8]3)[CH3:30])[CH:16]=[N:17][CH:18]=1
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Reactant: CC(N)c1ccc2ccccc2c1-c1cncc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: CC(Nc1nc(N)nc2[nH]cnc12)c1ccc2ccccc2c1-c1cncc(F)c1

Procedure:
A mixture of 2-amino-6-bromopurine (0.030 g, 0.14 mmol), 1-[1-(5-fluoropyridin-3-yl)-2-naphthyl]ethanamine (0.019 g, 0.07 mmol), and N,N-diisopropylethylamine (0.01465 mL, 0.084 mmol) in ethanol (0.2 mL) was heated at reflux under nitrogen overnight. The mixture was evaporated and the resultant residue was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/minute) to give the product as a mixture of rotomers (bis-TFA salt). LCMS calculated for C22H19FN7(M+H)+: m/z=400.2; found: 400.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][C:10]=1[NH:11][CH2:12][CH:13]([O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O)C.C(OC([N:35]=[C:36]=[S:37])=O)C>>[Si:23]([O:22][CH:13]([C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH2:12][N:11]1[C:10]2[CH:9]=[CH:8][NH:7][C:6]=2[C:4](=[O:3])[NH:35][C:36]1=[S:37])([C:26]([CH3:27])([CH3:29])[CH3:28])([CH3:25])[CH3:24]
Reactant: CCOC(=O)N=C=S
Reactant: CCOC(=O)c1[nH]ccc1NCC(O[Si](C)(C)C(C)(C)C)c1ccc(OC)cc1
Product: COc1ccc(C(Cn2c(=S)[nH]c(=O)c3[nH]ccc32)O[Si](C)(C)C(C)(C)C)cc1
Yield: 52.3 %

Procedure:
The title compound (0.07 g, 90%) was prepared in accordance with general method B using 3-{[2-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-methoxyphenyl)ethyl]amino}-1H-pyrrole-2-carboxylic acid ethyl ester (0.13 g, 0.31 mmol) and ethoxycarbonyl isothiocyanate (0.042 mL, 0.37 mmol).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[CH:22]2.Cl.N1C=CC=CC=1>C(OCCO)C>[NH:24]1[C:25]2[C:21](=[CH:20][C:19]([NH:18][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:16]#[N:17])=[CH:27][CH:26]=2)[CH:22]=[CH:23]1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Nc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2ncc(C#N)c(Nc3ccc4[nH]ccc4c3)c2cc1OC

Procedure:
Using an analogous procedure to that described in Example 141, 248.7 mg (1 mmol) of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 158.6 mg (1.2 mmol) of 5-aminoindole and 115.6 mg (1 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol was refluxed for 0.5 hr. The work up gave 338.7 mg (98.5%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 344.9. HRCIMS: calcd 344.127 for C20H16N4O2 (M+), obsd 344.1277.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Pt](=O)=O>[CH:2]1([O:1][CH2:8][CH:9]2[CH2:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][CH2:17][NH:18]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccnc(COc2ccccc2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(COC2CCCCC2)C1
Reaction time: 6 h
Yield: 73.3 %

Procedure:
Methyl 2-(phenoxymethyl)isonicotinate (2.6 g, 10.69 mmol) was dissolved in acetic acid (50 mL), then platinum(IV) oxide (0.243 g, 1.07 mmol) was added and the mixture hydrogenated in a Büchi hydrogenator at 5 bar and room temperature for 6 h. The catalyst was removed by filtration and the solvent evaporated. The residue was taken up in DCM and the organic phase was washed with satd NaHCO3. The aqueous phase was extracted with DCM and the combined organic phases were filtered through a phase separator and evaporated. Methyl 2-(cyclohexyloxymethyl)piperidine-4-carboxylate (2 g, 73%) was isolated.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]=3[NH:8][C:9]=2[CH:10]=1.O[CH:25]1[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]1>>[C:15]1([C:13]2[CH:12]=[C:11]([C:21]([NH2:23])=[O:22])[C:7]3[NH:8][C:9]4[CH:10]=[C:2]([O:1][CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)[CH:3]=[CH:4][C:5]=4[C:6]=3[N:14]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(O)ccc12
Product: NC(=O)c1cc(-c2ccccc2)nc2c1[nH]c1cc(OC3CCNCC3)ccc12

Procedure:
This was similarly prepared from 7-hydroxy-2-phenyl-5H-pyrido[3,2-b]indole-4-carboxamide and tert-butyl 4-hydroxypiperidine-1-carboxylate. MS (ESI) m/z 387.1 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.35 (1H, br. s.), 8.57 (1H, s), 8.36 (1H, s), 8.28 (2H, d, J=7.02 Hz), 8.12 (1H, d, J=8.55 Hz), 7.84 (1H, s), 7.54 (2H, t, J=7.63 Hz), 7.42 (1H, t, J=7.32 Hz), 7.32 (1H, d, J=2.14 Hz), 6.91 (1H, dd, J=8.85, 2.14 Hz), 4.43-4.57 (1H, m), 3.05 (2H, ddd, J=12.67, 4.27, 4.12 Hz), 2.61-2.74 (2H, m), 1.98-2.11 (2H, m), 1.91 (3H, s), 1.50-1.68 (2H, m).
Reaction SMILES: [C:1]1([C@@H:7]([OH:16])[C@@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH2:23][CH2:22][CH2:21][C:20](=O)[CH:19]=1>C1C=CC=CC=1.CCOCC.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>[CH3:17][C:18]1[CH2:23][CH2:22][CH2:21][C:20]2([O:9][C@H:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:16]2)[CH:19]=1
Reactant: CC1=CC(=O)CCC1
Reactant: O[C@H](c1ccccc1)[C@H](O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: c1ccccc1
Product: CC1=CC2(CCC1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Temperature: 115 °C
Yield: 99.9 %

Procedure:
(1R,2R)-1,2-diphenyl-1,2-ethanediol (150 g, 699 mmol) and 3-methyl-2-cyclohexen-1-one (77 g, 699 mmol) were suspended in benzene (1398 mL) and treated with PPTS (4.39 g, 17.48 mmol). The flask was fitted with a Dean-Stark trap filled with benzene and a condenser. The reaction was heated to 115° C. for 3 days, and then the reaction was cooled to ambient temperature and diluted with ether. The mixture was washed with saturated aq NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated to give a red/orange liquid (214 g, 100% yield). The liquid was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[O:6][C:7]3[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=3[CH2:9][N:10]([C:11]([NH:13][NH2:14])=[O:12])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C1C=CC=CC=1>[C:28]([NH:14][NH:13][C:11]([N:10]1[CH2:9][C:8]2[CH:15]=[CH:16][CH:17]=[CH:18][C:7]=2[O:6][C:5]2[CH:19]=[CH:20][C:2]([Cl:1])=[CH:3][C:4]1=2)=[O:12])(=[O:37])[CH:29]=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C(C=Cc1ccccc1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution containing 1.45 parts of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carboxylic acid hydrazide dissolved in 50 parts by volume of benzene is added successively0.7 part by volume of triethylamine and 0.81 part of cinnamoyl chloride. The resulting reaction mixture is stirred at room temperature for about 48hours, then is washed successively with dilute hydrochloric acid, dilute aqueous sodium hydroxide, water and saturated aqueous sodium chloride. Drying over anhydrous sodium sulfate followed by removal of the solvent bydistillation under reduced pressure affords a residue, which is purified byadsorption on a silicic acid chromatographic column and elution with ethyl acetate-benzene mixtures. The 10% acetate in benzene eluate, upon removal of the solvents, affords 1-cinnamoyl-2-(8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine-10-carbonyl)hydrazine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.FC1C=C([B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)C=CC=1NC1OC2C=CC=CC=2N=1>>[CH3:32][C:27]1([CH3:33])[C:28]([CH3:31])([CH3:30])[O:29][B:25]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[S:10][C:11]4[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=4[N:13]=3)=[CH:4][CH:3]=2)[O:26]1
Reactant: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)c(F)c2)OC1(C)C
Reactant: Brc1ccc(Nc2nc3ccccc3s2)cc1
Product: CC1(C)OB(c2ccc(Nc3nc4ccccc4s3)cc2)OC1(C)C

Procedure:
N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzothiazol-2-amine was prepared from N2-(4-bromophenyl)-1,3-benzothiazol-2-amine (0.909 g, 2.98 mmol) in a manner similar to that used for N2-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,3-benzoxazol-2-amine. The compound was formed as an off-white powder (0.321 g, 31%). RP-HPLC (25 to 100% CH3CN in 0.1 N aqueous ammonium acetate over 10 min at 1 mL/min using a Hypersil HS C18, 250×4.6 mm column) tr=13.82 min., 92%; m/z 351 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.C(Cl)(=O)C(Cl)=O.Cl.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][CH:28]=1.C(N(CC)CC)C>O1CCCC1.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([NH:26][C:27]3[CH:28]=[CH:29][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=3)=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: COC(=O)Cc1ccc(N)cc1
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccc(NC(=O)c2sc3ccc(OC)cc3c2OC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (500 mg, 2.0 mmoles) in 20 mL of dry tetrahydrofuran is added oxalyl chloride (262 μL, 3.0 mmoles) followed by one drop of dimethylformamide. The HCl salt of methyl 4-aminophenylacetate (605 mg, 3.0 mmoles) is added, followed by triethylamine (1.4 mL, 10 mmoles). The mixture is stirred at room temperature overnight. The mixture is partitioned between ethyl acetate and 1N HCl. The organic layer is washed with water, then brine. The organic layer is next dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude product is purified by flash chromatography, eluting with a gradient of 1:1 ethyl acetate:hexane to only ethyl acetate to provide 692 mg (84%) of product; mp 111°-113° C.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH2:6])(=[O:3])[CH3:2]>[Pt].C(O)(=O)C>[C:1]([O:4][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH3:6])(=[O:3])[CH3:2]
Reactant: C=COC(C)=O
Agent: [Pt]
Solvent: CC(=O)O
Product: CC(=O)OC(C)OC(C)=O

Procedure:
The procedure of Example 17 was repeated except that 4.5 g of platinum (5%) supported on activated carbon was used in place of palladium supported on activated carbon. GC analysis showed that vinyl acetate was formed with considerable amount of acetic acid and 8.28 g of ethylidene diacetate.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[C@H:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[O:32])[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CNCCN1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCNCC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazine (Aldrich) to give the title compound. LC-MS: 593.2 [(M+H)+]
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH2:10][CH:11]([C:18]1([CH3:23])[CH2:22][CH2:21][CH2:20][CH2:19]1)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C>C1COCC1.C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]([C:18]2([CH3:23])[CH2:19][CH2:20][CH2:21][CH2:22]2)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: CCOC(=O)CC(N)C1(C)CCCC1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CC(Nc1nc(Cl)ncc1F)C1(C)CCCC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a solution of 2,4-dichloro-5-fluoro-pyrimidine (0.184 g, 1.100 mmol) and racemic ethyl 3-amino-3-(1-methylcyclopentyl)propanoate, 33a, (0.199 g, 1.000 mmol) in THF (10 mL) and ethanol (1 mL) was added triethylamine (0.307 mL, 2.200 mmol). The reaction mixture was stirred at 70° C. for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was purified via silica gel chromatography (25% EtOAc/Hexanes) to afford 180 mg of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.88 (d, J=2.7 Hz, 1H), 5.54 (d, J=9.2 Hz, 1H), 4.74-4.54 (m, 1H), 4.08 (q, J=7.2 Hz, 2H), 2.68 (dd, J=14.8, 3.7 Hz, 1H), 2.46 (dd, J=14.8, 9.3 Hz, 1H), 1.69 (dd, J=12.8, 8.8 Hz, 4H), 1.63-1.50 (m, 2H), 1.46-1.38 (m, 1H), 1.37-1.23 (m, 1H), 1.23-1.14 (m, 3H), 1.00 (s, 3H). LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.54 minutes (M+H) 330.17.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH:5]1[CH2:8][CH:7]([C:9]2[CH:10]=[C:11]([C:15]#[C:16][Si](C(C)C)(C(C)C)C(C)C)[CH:12]=[CH:13][CH:14]=2)[CH2:6]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[C:46]1[CH:51]=[CH:50][C:49]([O:52][CH:53]([F:55])[F:54])=[CH:48][CH:47]=1.C(N(CC)CC)C>C1COCC1.[Cu](I)I.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>[F:54][CH:53]([F:55])[O:52][C:49]1[CH:50]=[CH:51][C:46]([C:16]#[C:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH:7]3[CH2:6][CH:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:8]3)[CH:10]=2)=[CH:47][CH:48]=1
Reactant: FC(F)Oc1ccc(Br)cc1
Reactant: COCCC1CC(c2cccc(C#C[Si](C(C)C)(C(C)C)C(C)C)c2)C1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCCC1CC(c2cccc(C#Cc3ccc(OC(F)F)cc3)c2)C1
Yield: 91.7 %

Procedure:
{3-[3-(2-methoxy-ethyl)-cyclobutyl]-phenylethynyl}-triisopropyl-silane (1.00 g, 2.70 mmol) was dissolved in THF (5 ml) and treated with a 1M solution of tetrabutylammonium fluoride (TBAF) in THF (5 ml) at room temperature. The crude product obtained from aqueous work-up was placed in a CEM snap top microwave vial and combined with 1-Bromo-4-Difluoromethoxybenzene (1.20 gm, 5.38 mmol), copper iodide (70 mg, 0.262 mmol), tetrakis(triphenylphosphine)palladium (140 mg, 0.120 mmol) and triethylamine (5.8 g, 98 mmol). The vial was quickly agitated then irradiated in a CEM Explorer™ microwave instrument for 30 minutes at 80° C. Purification by column chromatography (gradient; 0%-10% EtOAc in hexanes) afforded an oil 882 mg (46%). This material was used in next step without further characterization.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH:23]([NH:26][CH2:27][CH2:28][CH2:29][OH:30])([CH3:25])[CH3:24]>>[OH:30][CH2:29][CH2:28][CH2:27][N:26]([CH:23]([CH3:25])[CH3:24])[C:18]([C:12]1[S:13][C:14]2[CH2:15][CH2:16][O:17][C:8]3[CH:7]=[C:6]([C:4]4[CH:3]=[N:2][NH:1][CH:5]=4)[CH:22]=[CH:21][C:9]=3[C:10]=2[N:11]=1)=[O:20]
Reactant: CC(C)NCCCO
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CC(C)N(CCCO)C(=O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 3-(isopropylamino)propan-1-ol to give 290. MS: (ESI+)=413.1
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=CC=1CC(OCC)=O)(=[O:4])=[O:3].C([N:21]=[C:22]=[O:23])CCC>>[CH2:5]([S:2]([NH:1][C:22]([NH2:21])=[O:23])(=[O:3])=[O:4])[CH2:10][CH2:9][CH3:8]
Reactant: CCCCN=C=O
Reactant: CCOC(=O)Cc1ccccc1S(N)(=O)=O
Product: CCCCS(=O)(=O)NC(N)=O

Procedure:
Following the procedure of Example 1, ethyl o-aminosulfonylbenzeneacetate was reacted with n-butyl isocyanate to form the N-(n-butyl)sulfonylurea derivative; m.p. 140°-142°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:11][C:10]=1[N:26]([S:32]([NH:35]C(OC(C)(C)C)=O)(=[O:34])=[O:33])[CH2:27][C:28]([O:30][CH3:31])=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>Cl.O1CCOCC1>[NH2:35][S:32]([N:26]([C:10]1[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17](=[O:25])[O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:27][C:28]([O:30][CH3:31])=[O:29])(=[O:33])=[O:34]
Reactant: COC(=O)CN(c1ccc(OCC(=O)OCC[Si](C)(C)C)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)CN(c1ccc(OCC(=O)OCC[Si](C)(C)C)cc1OCc1ccccc1)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of methyl N-(2-(benzyloxy)-4-{2-oxo-2-[2-(trimethylsilyl)ethoxy]ethoxy}phenyl)-N-{[(tert-butoxycarbonyl)amino]sulfonyl}glycinate (50 mg, 0.08 mmol) in HCl/dioxane (3 mL, 4.0 M) is stirred at RT for 30 min. The solvent is removed under reduced pressure and water is added. The mixture is extracted with EtOAc and the organic phase dried over magnesium sulfate. The solvent is removed under reduced pressure to give the title compound.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[NH:20]1[CH:24]=[N:23][N:22]=[N:21]1>>[N:20]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=2)[CH:24]=[N:23][N:22]=[N:21]1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Reactant: c1nnn[nH]1
Product: CN(C(=O)Oc1ccc(Cn2cnnn2)cc1)c1ccccc1
Yield: 6 %

Procedure:
The title compound was prepared in 6% yield as an oil using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and tetrazole. 1H NMR (400 MHz; CDCl3): δ 3.42 (br s, 3H), 5.57 (s, 2H), 7.17 (br s, 2H), 7.26-7.42 (m, 7H), 8.52 (s, 1H); HPLC-MS: m/z=332.0 (M+23); Rt=3.24 min.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][N:20]=3)[CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:29]([O:31][NH2:32])[CH3:30].C([O-])(=O)C.[Na+].O>ClCCl.C(O)C>[CH2:29]([O:31][N:32]=[C:1]([C:5]1[C:10](=[O:11])[CH2:9][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][N:20]=3)[CH:13]=2)[CH2:7][C:6]=1[OH:27])[CH2:2][CH3:3])[CH3:30]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2cccc(Oc3ccc(SC)cn3)c2)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2cccc(Oc3ccc(SC)cn3)c2)CC1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 2.1 g (0.0055 mol) of 2-propionyl-3-hydroxy-5-(3-(5-(methylthio)-2-pyridyloxy)phenyl)cyclohex-2-en-1-one, 0.45 g (0.0061 mol) of ethoxyamine hydrochloride and 0.50 g (0.0061 mol) of sodium acetate in 8 mL of dichloromethane and 12 mL of absolute ethanol was stirred under a nitrogen atmosphere at room temperature for about 20 hours. The reaction mixture was poured into 100 mL of water and extracted thrice with 10 mL portions of dichloromethane. The solvent extracts were combined, dried over MgSO4, filtered through silica gel and the solvent removed by evaporation leaving a residue which solidified upon standing. Recrystallization of the residue from hexane gave the above named product in a yield of 2.2 g (94 percent of theoretical). The product melted at 75°-78° C.; 1H NMR (CDCl3): δ1.08-1.52 (m, 6H, both --CH2CH3 's), 2.45 (s, 3H, --SCH3), 2.60-3.65 (m, 7H, --CH(CH2)2 and --CH2CH3), 6.80-7.55 (m, 5H, ArH's), 7.75 (dd, J=9 Hz and 2H, 1H, ArH), 8.18 (d, J=2 Hz, ArH), 15.1 (br s, 1H, enol H) (Compound 4).
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]2=[N:6][C:5]=1[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1.[N:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH2:27])[N:22]=1>>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]2[N:8]([C:4]([CH2:3][NH:27][C:23]3[N:22]=[N:21][CH:26]=[CH:25][N:24]=3)=[C:5]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[N:6]=2)[CH:9]=1
Reactant: Cc1ccc(-c2nc3ccc(C)cn3c2CCl)cc1
Reactant: Nc1nccnn1
Agent: Cl
Product: Cc1ccc(-c2nc3ccc(C)cn3c2CNc2nccnn2)cc1

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 139 from 3-(chloromethyl)-6-methyl-2-p-tolylimidazo[1,2-a]pyridine hydrochloride and 1,2,4-triazin-3-amine. m/e+ 331 for C19H19N6 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ 8.60 (d, J=2.2 Hz, 1H), 8.04 (s, 1H), 8.00 (d, J=2.2 Hz, 1H), 7.86 (s, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.53 (d, J=9.1 Hz, 1H), 7.22 (d, J=8.0 Hz, 2H), 7.05 (dd, J=1.4, 9.1 Hz, 1H), 5.11 (s, 2H), 2.37 (s, 3H), 2.27 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([O:11]CC)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl>>[Cl:1][C:2]1[C:10]2[S:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1nc2cccc(Cl)c2s1
Agent: Cl
Product: O=c1[nH]c2cccc(Cl)c2s1
Yield: 38 %

Procedure:
Prepared analogous to Example 5 from 7-chloro-2-ethoxy-benzothiazole and concentrated hydrochloric acid with a yield of 38% of theory. M.p.: 202°-203° C. (after recrystallization from methanol and from diisopropyl ether).