Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:21]=1)[C:18]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([OH:20])=[CH:9][CH:10]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C1COCC1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.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>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:21]=1)[C:6]1[CH:7]=[C:8]([OH:20])[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:18]2=[CH:17][C:16]([C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)=[CH:15][CH:14]=1
Reactant: OB(O)c1cccnc1
Reactant: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(Br)cc12
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: ClCCl
Solvent: C1CCOC1
Product: NC1=N[C@]2(CO1)c1cc(O)ccc1Oc1ccc(-c3cccnc3)cc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A 350-mL pressure vessel was charged with (R)-2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthen]-7′-ol (4.00 g, 11.52 mmol), 3-pyridylboronic acid (3.54 g, 28.8 mmol), tetrakis(triphenylphosphine)palladium(0) (1.331 g, 1.152 mmol), THF (57.6 mL), and potassium carbonate (2.0M aq. solution) (28.8 mL, 57.6 mmol). The vessel was sealed and heated to 100° C. and stirred for 2 hours. The layers were partitioned between EtOAc (20 mL) and water (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×20 mL). The combined organic layers were washed with brine (emulsion!), dried over sodium sulfate and filtered with the aid of 10% MeOH/DCM. The filtrate was evaporated to give a yellow solid. This solid was taken up in minimal DCM and sonicated for 5 min. The solid was filtered and washed with DCM (30 mL). Filtering and washing with DCM afforded (S)-2-amino-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol as a pale-yellow solid
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][S:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:28])=[C:23]([CH:27]=3)[C:24](O)=[O:25])=[CH:15][N:16]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[N:31]1[CH:36]=[CH:35][CH:34]=[N:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12]2[S:13][C:14]([CH2:17][S:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:28])=[C:23]([C:24]([N:40]4[CH2:41][CH2:42][N:37]([C:32]5[N:31]=[CH:36][CH:35]=[CH:34][N:33]=5)[CH2:38][CH2:39]4)=[O:25])[CH:27]=3)=[CH:15][N:16]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3]
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: Cc1ccc(SCc2cnc(NC(=O)c3ccc(C(C)(C)C)cc3)s2)cc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1ccc(SCc2cnc(NC(=O)c3ccc(C(C)(C)C)cc3)s2)cc1C(=O)N1CCN(c2ncccn2)CC1
Temperature: 65 °C
Yield: 63 %

Procedure:
A mixture of the product of Example 32, part B (0.250 g, 0.567 mmol), 1-(2-pyrimidyl)piperazine (0.121 g, 0.737 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (0.476 g, 1.08 mmol), 4-methylmorpholine (0.31 mL, 2.82 mmol) in DMF (6 mL) was heated at 65° C. for 5 h. The mixture was then diluted with ethyl acetate, washed with water, 1N NaOH solution, water, and brine. The solution was dried over anhydrous MgSO4 and concentrated under vacuum. The residue was purified using flash column chromatography (ethyl acetate) to provide the desired product (0.210 g, 63%) as a white solid: LC/MS RT=3.94 min; mass spectrum (M+H)+=587.42.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.Cl[CH2:10][C:11](=O)[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:1]=2)[N:4]=1
Reactant: Nc1ccc(Cl)nn1
Reactant: CCOC(=O)CC(=O)CCl
Solvent: CCO
Product: CCOC(=O)Cc1cn2nc(Cl)ccc2n1
Yield: 61.3 %

Procedure:
11.2 g of 3-amino-6-chloropyridazine was suspended in 150 ml of ethanol; 28.6 g of ethyl 4-chloroacetoacetate was added, followed by heating and refluxing for 24 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was adjusted to pH 7 by the addition of an aqueous solution of sodium hydrogen carbonate, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane:ethyl acetate (2:3). The desired fraction was collected to yield 12.7 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([C@@H:9]([CH:13]2[CH2:15][CH2:14]2)[CH2:10][O:11][CH3:12])[CH:5]=[C:6]([Cl:8])[N:7]=1.[CH3:17][O:18][C:19]1[N:24]=[C:23]([CH3:25])[C:22]([NH2:26])=[CH:21][C:20]=1[CH3:27].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:8][C:6]1[N:7]=[C:2]([NH:26][C:22]2[C:23]([CH3:25])=[N:24][C:19]([O:18][CH3:17])=[C:20]([CH3:27])[CH:21]=2)[C:3](=[O:16])[N:4]([C@@H:9]([CH:13]2[CH2:15][CH2:14]2)[CH2:10][O:11][CH3:12])[CH:5]=1
Reactant: COC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1nc(C)c(N)cc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H](C1CC1)n1cc(Cl)nc(Nc2cc(C)c(OC)nc2C)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.8 %

Procedure:
To a solution of (S)-3,5-dichloro-1-(1-cyclopropyl-2-methoxyethyl)pyrazin-2(1H)-one (4.00 g, 15.2 mmol) from Part G and 6-methoxy-2,5-dimethylpyridin-3-amine (2.31 g, 15.2 mmol) from Part K in THF (76 mL) at 0° C. was added NaHMDS (31.9 mL, 31.9 mmol, 1 M in THF). The reaction mixture was stirred at room temperature for 1 h. The mixture was transferred to a separatory funnel containing saturated aqueous NaHCO3 solution. The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (10% 40% ethyl acetate in hexanes) to afford (S)-5-chloro-1-(1-cyclopropyl-2-methoxyethyl)-3-(6-methoxy-2,5-dimethylpyridin-3-ylamino)pyrazin-2(1H)-one (4.94 g, 86% yield) as a light-brown amorphous solid. Recrystallization from hexanes/ethyl acetate (1:1, 10 mL) to afforded a light-brown crystalline solid: mp 99-100.5° C.; [α]25D −52.3 (c 0.636, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.88 (s, 1H), 6.90 (s, 1H), 4.19-4.14 (m, 1H), 3.92 (s, 3H), 3.74 (dd, JAB10.3, JAX=6.2 Hz, 1H), 3.67 (dd, JBA=10.3, JBX=3.5 Hz, 1H), 3.34 (s, 3H), 2.41 (s, 3H), 2.17 (s, 3H), 1.31-1.24 (m, 1H), 0.80-0.73 (m, 1H), 0.62-0.56 (m, 1H), 0.53-0.47 (m, 1H), 0.36-0.30 (m, 1H); HRMS (ESI) m/e 379.1537 [(M+H)+, calcd for C18H24N4O3Cl 379.1537].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:20])[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)[C:7]=1[F:8].[Li]C(CC)C.CN([CH:29]=[O:30])C.Cl>C1COCC1>[F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:20])[C:3]=1[CH:29]=[O:30]
Reactant: CCCCCc1ccc(-c2cc(C)cc(F)c2F)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2cc(C)c(C=O)c(F)c2F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
Under a nitrogen atmosphere, 8.93 g of the compound (22) having been dissolved in 66 mL of THF was cooled to −78° C., to which 39.0 mL of sec-BuLi (1 M/L) was added, followed by stirring at the same temperature for 2 hours. 3.56 g of DMF having been dissolved in 44 mL of THF was added thereto, followed by stirring at −78° C. for 1 hour, and after increasing the temperature to room temperature, stirring over night. 20 mL of 3N hydrochloric acid was added thereto, and the aqueous layer was extracted with toluene, which was added to the organic layer. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off to obtain 7.61 g of 2,3-difluoro-4-(4-pentylphenyl)-6-methylbenzaldehyde (23).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([OH:10])[N:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br.O>CN(C)C=O.C(OCC)(=O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([O:10][CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[C:23]([F:22])([F:32])[F:33])[N:9]=1)(=[O:3])[CH3:2]
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: CCOC(=O)c1sc(NC(C)=O)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(NC(C)=O)nc1OCc1ccccc1C(F)(F)F
Yield: 61.2 %

Procedure:
Ethyl 2-(acetylamino)-4-hydroxy-1,3-thiazole-5-carboxylate (6.04 g, 26.2 mmol) was dissolved in 100 mL of N,N-dimethylformamide with stirring. Potassium carbonate (3.98 g, 28.8 mmol) was added in a single portion. 2-Trifluoromethylbenzyl bromide (6.58 g, 27.5 mmol) in 20 mL of N,N-dimethylformamide was added via syringe. The reaction was stirred for 16 hours and poured into water and ethyl acetate. The layers were separated, and the organic layer was washed with brine. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Purification by flash chromatography afforded 6.23 g (61%) of ethyl 2-(acetylamino)-4-({[2-(trifluoromethyl)-phenyl]methyl}oxy)-1,3-thiazole-5-carboxylate. 1H NMR (300 MHz, DMSO-d6) δ 12.62 (s, 1H), 7.92 (m, 1H), 7.82-7.71 (m, 2H), 7.58 (m, 1H), 5.60 (s, 2H), 4.19 (q, J=7.2 Hz, 2H), 2.17 (s, 3H), 1.25 (t, J=7.2 Hz, 3H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH2:38])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26].[Br:48][C:49]1[CH:50]=[CH:51][C:52]([NH:58][CH3:59])=[C:53]([CH:57]=1)[C:54](O)=[O:55].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:25]([N:28]1[C:37]2[C:32](=[CH:33][C:34]([NH:38][C:54](=[O:55])[C:53]3[CH:57]=[C:49]([Br:48])[CH:50]=[CH:51][C:52]=3[NH:58][CH3:59])=[CH:35][CH:36]=2)[C:31]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([CH3:39])[CH2:30][C:29]1([CH3:47])[CH3:46])(=[O:27])[CH3:26]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: CNc1ccc(Br)cc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNc1ccc(Br)cc1C(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
HATU condensation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 5-bromo-2-methylaminobenzoic acid (8.4 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 11.
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[C:17](=[N:19][OH:20])[NH2:18])=[O:8])=[CH:3][CH:2]=1.[C:27](O)(=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([C:17]2[N:18]=[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:20][N:19]=2)[N:9]([C:7]([C:4]2[CH:3]=[CH:2][C:1]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:6][CH:5]=2)=[O:8])[CH2:13]1
Reactant: O=C(O)c1ccccc1
Reactant: CON=C1C[C@@H](C(N)=NO)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Product: CON=C1C[C@@H](c2noc(-c3ccccc3)n2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 15, starting from (2S,4EZ)-1-([1,1′-biphenyl]-4-ylcarbonyl)-N′-hydroxy-4-(methoxyimino)-2-pyrrolidinecarboximidamide (Intermediate 8) and benzoic acid, the title compound was obtained in 85% purity by HPLC. MS(ESI+): m/z=439.2.
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:40][C:41]([N:43]([CH3:50])[CH2:44][C@@H:45]1[CH2:49][CH2:48][CH2:47][O:46]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH2:40][CH2:41][N:43]([CH3:50])[CH2:44][C@@H:45]2[CH2:49][CH2:48][CH2:47][O:46]2)=[C:32]([F:37])[CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CN(C[C@@H]1CCCO1)C(=O)CCl
Product: CCN(Cc1ccc(OCCN(C)C[C@@H]2CCCO2)c(F)c1)c1cc(OC)ccc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 20.9 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (15 mg) and 2-chloro-N-methyl-N—[(S)-tetrahydrofuran-2-ylmethyl]acetamide (11 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.4 mg) was obtained.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[CH2:18][CH3:19])[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:35]=[CH:34][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:27][CH:26]=1>>[CH2:32]([O:31][C:29]([C:28]1[CH:34]=[CH:35][C:25]([NH:24]/[C:17](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[CH2:18][CH3:19])=[CH:26][CH:27]=1)=[O:30])[CH3:33]
Reactant: CCOC(CC)=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(N/C(CC)=C2\C(=O)Nc3cc(OC)c(OC)cc32)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-ethyl-methylidene)-5,6-dimethoxy-2-indolinone and ethyl 4-aminobenzoate
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])[OH:4].[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[CH:3]([OH:4])[CH:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1F
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (320 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (497 mg, 78%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:11]2[CH:16]=[C:15]([CH3:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=3)[C:11]3[CH:16]=[C:15]([CH3:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3cccc([N+](=O)[O-])c3)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-methyl-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH:12]([NH2:14])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9]C.[BrH:15]>ClCCl>[BrH:15].[NH2:14][CH:12]([CH3:13])[CH2:11][C:5]1[CH:4]=[C:3]([OH:2])[C:8]([OH:9])=[CH:7][CH:6]=1
Reactant: COc1ccc(CC(C)N)cc1OC
Agent: Br
Solvent: ClCCl
Product: CC(N)Cc1ccc(O)c(O)c1

Procedure:
To 2.0 g of 3A (2.01 mmol) was added 48% HBr, and the mixture was heated on a preheated oil bath for 3 hours under argon atmosphere. The reaction mixture was concentrated under reduced pressure to give thick oil. To the residue, 75 mL of dichloromethane was added and concentrated to dryness under reduced pressure. This was repeated four more times to give 2.3 g of 3B as light pink powder (M+H, 168).
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]([F:23])([F:22])[F:21])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[N:26]1([CH2:32][CH2:33][NH:34][C:35]2[CH:40]=[CH:39][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:37][N:36]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[N:26]1([CH2:32][CH2:33][NH:34][C:35]2[CH:40]=[CH:39][C:38]([C:2]3[CH:25]=[CH:24][C:5]4[C:6]5[N:7]=[C:8]([C:14]6[N:15]([CH2:19][C:20]([F:22])([F:23])[F:21])[N:16]=[CH:17][N:18]=6)[S:9][C:10]=5[CH2:11][CH2:12][O:13][C:4]=4[CH:3]=3)=[CH:37][N:36]=2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: CC1(C)OB(c2ccc(NCCN3CCOCC3)nc2)OC1(C)C
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Product: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(-c3ccc(NCCN4CCOCC4)nc3)ccc1-2

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with (2-Morpholin-4-yl-ethyl)-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-yl]-amine to give 116. MS(ESI+) 558.2. 1H NMR (400 MHz, DMSO) δ 8.41 (d, J=2.1, 1H), 8.32 (d, J=8.4, 1H), 8.29 (s, 1H), 7.79 (dd, J=8.8, 2.4, 1H), 7.45 (dd, J=8.4, 1.7, 1H), 7.30 (d, J=1.6, 1H), 6.59 (dd, J=10.9, 7.1, 2H), 5.87 (q, J=8.7, 2H), 4.41 (t, J=4.9, 2H), 3.64-3.54 (m, 4H), 3.47 (t, J=4.9, 2H), 3.42 (dd, J=12.5, 6.4, 2H), 2.50-2.47, (m, 2H), 2.40-2.44 (m, 4H)
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][CH2:7][C:8]([C@H:10]([C@@H:12]([C@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11])=[O:9].C([O-])(O)=O.[Na+]>CC(C)=O>[CH3:7][C:8]1([CH3:10])[O:11][C@H:10]2[C@@H:12]3[O:13][C:14]([CH3:16])([CH3:12])[O:15][C@:14]3([CH2:16][OH:17])[O:9][C@H:8]2[CH2:7][O:6]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)OC[C@@H]2O[C@@]3(CO)OC(C)(C)O[C@H]3[C@@H]2O1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 132.9 %

Procedure:
24 mL of sulfuric acid were added dropwise, with vigorous stirring, to 100 mL of acetone cooled to 0-5° C., at a rate such that the reaction temperature remained below 20° C. 5 g of L-sorbose were added to the reaction mixture, and stirring was allowed to continue for 4 h at room temperature. The reaction mixture was allowed to stand at room temperature overnight, and was cooled to -8° C. (ice-NaCl bath). The cooled reaction mixture was neutralized to pH 8 with saturated NaHCO3 at a rate such that the reaction temperature remained below 0° C. The resulting mixture containing precipitated Na2SO4 was allowed to warm to room temperature and the Na2SO4 was filtered and washed twice with dry acetone. Combined organic filtrate and washings were concentrated in vacuo at 20° C., and the resulting oily residue was extracted with chloroform (5×10 mL). The chloroform extract was dried (MgSO4) and evaporated to afford a viscous gum which crystallized (mp.=59-61° C.) upon standing. Recrystallization (benzene) of the above crystallized gum afforded 4.8 g (67%) of the above-titled compound as fine crystals: mp.=76-77° C. (lit. 77-78° C. (T. Reichstein et al., Helv. Chim. Acta, 1934, 17, 331); 1H NMR (CDCl3) δ1.35 (s, 6H), 1.45 (s, 3H), 1.52 (s, 3H), 2.50 (br. s, 1H, OH), 3.75-3.90 (m, 2H, 6-H2), 4.05-4.15 (m, 3H), 4.33 (d, 1H, 3H), 4.5 (d, 1H, J≈1H, 1-H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:26])=[C:9]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)(=[O:14])=[O:13])[N:10]=2)[CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][C:35]=1[C:42]([F:45])([F:44])[F:43]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH3:26])=[C:9]([N:11]([CH2:38][C:37]3[CH:40]=[CH:41][C:34]([F:33])=[C:35]([C:42]([F:45])([F:43])[F:44])[CH:36]=3)[S:12]([C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:19][CH:20]=3)(=[O:14])=[O:13])[N:10]=2)[CH:7]=1
Reactant: Fc1ccc(CBr)cc1C(F)(F)F
Reactant: Cc1c(NS(=O)(=O)c2ccc(-n3cccn3)cc2)nc2ccc(Cl)cn12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(N(Cc2ccc(F)c(C(F)(F)F)c2)S(=O)(=O)c2ccc(-n3cccn3)cc2)nc2ccc(Cl)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
To a solution of compound 16-C (0.011 g, 0.27 mmol) in DMF (0.5 mL) was added Na2CO3 (0.0057 g, 0.054 mmol) and 4-fluoro-3-trifluoromethylbenzyl bromide (0.0077 g, 0.03 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water, and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography, eluting with a hexanes-EtOAc gradient to give Compound 102 (0.011 g, 72%) as a white solid; MS m/z (M+H+) 564.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:35])[CH3:34])[CH:28]=[CH:29][CH:30]=4)[CH2:21][CH2:20]3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[C:27]([NH:31][C:32](=[O:36])[CH:33]([CH3:34])[CH3:35])[CH:28]=[CH:29][CH:30]=5)[CH2:21][CH2:20]4)=[CH:15][CH:16]=3)[CH:11]=[CH:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cccc(I)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4c(ccn4-c4cccc(Cl)c4)c3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 1-chloro-3-iodobenzene and N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 486.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Te:11](Cl)(Cl)Cl)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[PH2](O)=O>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([Te:11][Te:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc([Te](Cl)(Cl)Cl)cc1OC
Agent: O=[PH2]O
Solvent: CCO
Product: COc1ccc([Te][Te]c2ccc(OC)c(OC)c2)cc1OC

Procedure:
3,4-Dimethoxyphenyltellurium trichloride (37.2 g=0.1 mole) was dissolved in absolute ethanol (500 ml), and the slightly turbid solution was filtered. To the rapidly stirred solution was added, at room temperature, 50% aqueous hypophosphorous acid (30 ml, ≃0.3 mole) as rapidly as possible. There was a brief appearance of a brown solution color, before the entire solution set to a mass of black fibrous crystals. The product was collected after 15 minutes by filtration using rubber dam to compact the highly solvated crystal mass. The product was washed with water and then air dried to yield 25.2 g, 95% of theory, black fibrous crystals, m.p. 134°-136° C. Recrystallization from isopropanol raised the m.p. to 136°-139° C. C, H and Te elemental analyses were in agreement with the structural formula.