Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[S:3][CH2:4][O:5][N:6]=[C:7]([C:30]1[N:31]=[C:32]([NH:35]C=O)[S:33][CH:34]=1)[C:8]([NH:10][CH:11]1[C:28](=[O:29])[N:13]2[C:14]([C:25]([OH:27])=[O:26])=[C:15]([CH2:18][S:19][C:20]3[S:21][CH:22]=[N:23][N:24]=3)[CH2:16][S:17][C@H:12]12)=[O:9].Cl.[CH3:39]O>O1CCCC1>[CH3:39][S:3][CH2:4][O:5][N:6]=[C:7]([C:30]1[N:31]=[C:32]([NH2:35])[S:33][CH:34]=1)[C:8]([NH:10][CH:11]1[C:28](=[O:29])[N:13]2[C:14]([C:25]([OH:27])=[O:26])=[C:15]([CH2:18][S:19][C:20]3[S:21][CH:22]=[N:23][N:24]=3)[CH2:16][S:17][C@H:12]12)=[O:9]
Reactant: COSCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Reactant: CO
Agent: Cl
Solvent: C1CCOC1
Product: CSCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 7-[2-methoxythiomethoxyimino-2-(2-formamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.58 g.), conc. hydrochloric acid (0.405 g.), methanol (8.7 ml.) and tetrahydrofuran (5 ml.) was stirred for 2 hours and 10 minutes at ambient temperature. The solvent was distilled off under reduced pressure and the residue was dissolved in a 10% aqueous solution of sodium hydroxide (pH 7~8.5). An insoluble material was filtered off and the filtrate was adjusted to pH 3.4 with 10% hydrochloric acid under ice-cooling and stirred for 30 minutes. Precipitates were collected by filtration, washed with water and dried to give 7-[2-methylthiomethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.4 g.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([NH:14]C(=O)OC(C)(C)C)[CH3:13])[C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[C:5]2[C:28]1[O:32][N:31]=[C:30]([CH3:33])[N:29]=1.O1CCOCC1>C(Cl)Cl.Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH:12]([NH2:14])[CH3:13])[C:6]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)=[C:5]2[C:28]1[O:32][N:31]=[C:30]([CH3:33])[N:29]=1
Reactant: Cc1noc(-c2c(-c3ccccn3)c(C(C)NC(=O)OC(C)(C)C)nc3ccc(F)cc23)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1noc(-c2c(-c3ccccn3)c(C(C)N)nc3ccc(F)cc23)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of tert-butyl 1-(6-fluoro-4-(3-methyl-1,2,4-oxadiazol-5-yl)-3-(pyridin-2-yl)quinolin-2-yl)ethylcarbamate (0.246 g, 0.547 mmol) in DCM (1.095 mL) and hydrochloric acid, 4M solution in 1,4-dioxane (2.74 mL, 10.95 mmol) was stirred at rt. After 2.5 h, the mixture was partitioned between DCM (50 mL) and water (50 mL). The acidic aq mixture was washed with DCM (30 mL×2) to remove organic impurities. The aq layer was basified to ˜pH 13 with 10 N NaOH (1.5 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with water (100 mL×1), dried over MgSO4, filtered, and concentrated in vacuo to give 1-(6-fluoro-4-(3-methyl-1,2,4-oxadiazol-5-yl)-3-(pyridin-2-yl)-quinolin-2-yl)ethanamine as a light yellow syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59-8.64 (1H, m), 8.29 (1H, dd, J=9.3, 5.6 Hz), 7.83-7.92 (2H, m), 7.76 (1H, dd, J=10.0, 2.7 Hz), 7.50 (1H, d, J=7.8 Hz), 7.44 (1H, ddd, J=7.6, 4.9, 1.2 Hz), 4.03 (1H, q, J=6.7 Hz), 2.38 (3H, s), 2.03 (2H, br. s.), 1.24 (3H, d, J=6.5 Hz); LC-MS (ESI) m/z 350.1 [M+H]+. The light yellow syrup was carried on crude without purification for the next step.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]([OH:20])[CH2:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])(=[O:3])[CH3:2].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:1]([O:4][CH2:5][CH2:6][C:7](=[O:20])[CH2:8][N:9]1[C:10](=[O:19])[C:11]2=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]2[C:13]1=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC(O)CN1C(=O)c2ccccc2C1=O
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(=O)OCCC(=O)CN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of N-(4-acetoxy-2-hydroxybutyl)phthalimide (10.2 g, 36.8 mmol) in CH2Cl2 (185 mL) at 0° C. was treated with molecular seives (18.4 g), N-methylmorpholine oxide (6.46 g, 55.2 mmol), and tetrapropylammonium perruthenate (1.29 g, 3.7 mmol). The mixture was allowed to warm to room temperature over 20 minutes and immediately filtered through silica (using 500 g SiO2 in a coarse glass fritted funnel). The silica was washed with excess diethyl ether (2 L) and concentrated under reduced pressure to afford the desired N-(4-acetoxy-2-oxobutyl)phthalimide (9.22 g, 92%).
Reaction SMILES: C1(C)C=CC(S(O[C@@H:11]2[CH2:30][CH2:29][C@@:28]3([CH3:31])[C@@H:13]([CH2:14][CH2:15][C@@H:16]4[C@@H:27]3[CH2:26][CH2:25][C@@:24]3([CH3:32])[C@H:17]4[CH2:18][CH2:19][C@@H:20]3[C:21](=[O:23])[CH3:22])[CH2:12]2)(=O)=O)=CC=1.Cl>N1C(C)=CC(C)=CC=1C>[CH3:22][C:21](=[O:23])[C@@H:20]1[C@:24]2([CH3:32])[C@H:17]([C@H:16]3[C@H:27]([CH2:26][CH2:25]2)[C@:28]2([CH3:31])[C@H:13]([CH2:12][CH:11]=[CH:30][CH2:29]2)[CH2:14][CH2:15]3)[CH2:18][CH2:19]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Solvent: Cc1cc(C)nc(C)c1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 97 %

Procedure:
The crude product 3α-toluene-p-sulphonyloxy-5α-pregnan-20-one in 30 mL of collidine was refluxed for 1.0 h. The solution was allowed to cool and then poured into cold dilute hydrochloric acid (200 mL) and extracted three times with CH2Cl2 (100 mL portions). The combined organic phase was dried over magnesium sulfate and concentrated. Flash chromatography on a silica gel bed (100 g) and elution with hexane/ethyl acetate (80:20) gave 4.65 g (97% yield for the two steps) of 5α-pregn-2-ene-20-one.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH:16]=O)[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]>>[Si:1]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][NH:18][CH2:19][CH2:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24])[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CN(C)CCCCN
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(C=O)c1
Product: CN(C)CCCCNCc1cc(CO[Si](C)(C)C(C)(C)C)ccn1

Procedure:
By General Procedure A from 4-{[(tert-butyldimethylsilyl)oxy]methyl}pyridine-2-carbaldehyde and (4-aminobutyl)dimethylamine. Purification by column chromatography (DCM/MeOH (95:5)) gave the title compound as greenish oil. 1H-NMR (300 MHz, CDCl3): δ 8.48 (d, 1H), 7.25 (s, 2H), 7.10 (d, 1H), 4.70 (s, 2H), 3.90 (s, 2H), 2.60 (m, 2H), 2.30 (m, 2H), 2.20 (s, 6H), 1.50 (m, 4H), 1.00 (s, 9H, 0.9 (s, 9H), 0.1 (s, 6H) ppm.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.N1C=CC=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1.N>C(Cl)Cl>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]3[CH:19]=[CH:18][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=3)[CH2:2][CH2:3]2)=[O:35])=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1ccc(CCN2CCNCC2)cc1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1ccc(CCN2CCN(C(=O)Cc3ccc(Cl)cc3)CC2)cc1
Temperature: 20 °C
Reaction time: 4 h

Procedure:
To a mixture of 9.7 g. (37 mmole) ethyl 4-[2-(piperazin-1-yl)-ethyl]-benzoate, 40 ml. methylene chloride and 6.3 g. (80 mmole) anhydrous pyridine is added dropwise at 0° C., in the course of 40 minutes, a solution of 7.0 g. (37 mmole) 4-chlorophenylacetyl chloride in 20 ml. methylene chloride, a cheesy precipitate being formed. After stirring at 20° C. for 4 hours, the reaction mixture is poured into 250 ml. ice water, rendered alkaline with ammonia and extracted several times with methylene chloride. The methylene chloride solution is washed twice with water, dried with anhydrous sodium sulphate and evaporated. After the addition of ligroin, crystallisation occurs. The product is recrystallised from diethyl ether to give 51% of theory of the desired product; m.p. 88°-89° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:27])[CH2:14][C:13]([CH2:16]I)([CH3:15])[S:12][C:11]([NH:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C([SnH](CCCC)CCCC)CCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH3:27])[CH2:14][C:13]([CH3:16])([CH3:15])[S:12][C:11]([NH:18][C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC1(CI)C[C@@](C)(c2ccc(F)c(Br)c2)N=C(NC(=O)c2ccccc2)S1
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)C[C@@](C)(c2ccc(F)c(Br)c2)N=C(NC(=O)c2ccccc2)S1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a solution of N-((4S)-4-(3-bromo-4-fluorophenyl)-6-(iodomethyl)-4,6-dimethyl-5,6-dihydro-4H-1,3-thiazin-2-yl)benzamide (0.13 g, 0.23 mmoles, 1.0 equiv) in toluene (1.5 mL) is added 2-2′-azo-bis-isobutyronitrile (0.006 g, 0.03 mmoles, 0.15 equiv) and tri-n-butyltin hydride. The reaction mixture is stirred at room temperature for 3 h and concentrated under reduced pressure. The solvent is removed under reduced pressure and the residue is purified by silica gel chromatography eluting with a linear gradient of 5% ethyl acetate:hexanes to 20% ethyl acetate:hexanes to give the title compound (25% yield): MS (m/z): 435, 437 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)=[N:9][CH2:10][C:11](=S)[NH:12][C:6]=2[C:5]([Cl:23])=[CH:4][CH:3]=1.[C:24]([NH:32][NH2:33])(=O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[Cl:1][C:2]1[C:7]2[C:8]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=3)=[N:9][CH2:10][C:11]3[N:12]([C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[N:32][N:33]=3)[C:6]=2[C:5]([Cl:23])=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccccc1
Reactant: CC(C)c1ccc(C2=NCC(=S)Nc3c(Cl)ccc(Cl)c32)cc1
Solvent: CCO
Product: CC(C)c1ccc(C2=NCc3nnc(-c4ccccc4)n3-c3c(Cl)ccc(Cl)c32)cc1
Temperature: 250 °C

Procedure:
In the manner given in Example 2, 6,9-dichloro-1,3-dihydro-5-(p-isopropylphenyl)-2H-1,4-benzodiazepine-2-thione is heated in ethanol with benzoic acid hydrazide and the resulting product heated to 250° C. to give 7,10-dichloro-1-phenyl-6-(p-isopropylphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([NH:41][C:42](=[O:46])[CH2:43][CH2:44][CH3:45])=[N:29][N:30]3COCC[Si](C)(C)C)=[CH:26][CH:25]=2)=[CH:20]1.C(OCC)(=O)C>O1CCCC1>[O:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:32]=[C:31]3[C:27]([C:28]([NH:41][C:42](=[O:46])[CH2:43][CH2:44][CH3:45])=[N:29][NH:30]3)=[CH:26][CH:25]=2)=[CH:20]1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccoc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccoc3)ccc12
Temperature: 66 °C

Procedure:
1.95 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 120 mg of N-[6-(furan-3-yl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 5 cm3 of tetrahydrofuran. The reaction medium is heated at about 66° C. for 17 hours. The heating is then stopped and 50 cm3 of ethyl acetate are added. This mixture is washed with 50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2 cm), eluting with ethyl acetate/cyclohexane (30/70 by volume) and collecting 15 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 10 cm3 of diisopropyl ether. This solution is filtered through a sinter funnel to give, after drying (90 Pa; 50° C.), 35 mg of N-[6-(furan-3-yl)-1H-indazol-3-yl]butanamide in the form of a white solid melting at 195° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.C(=O)([O-])[O-].[K+].[K+].[C:26]([NH:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)(=[O:28])[CH3:27].Cl>O.O1CCOCC1>[C:26]([NH:29][C:30]1[CH:35]=[C:34]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)[CH:33]=[CH:32][CH:31]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cccc(-c2ccc(OCc3nc(C(=O)O)cs3)cc2)c1

Procedure:
A first stock solution was prepared consisting of 2-(4-iodo-phenoxymethyl) -thiazole-4-carboxylic acid ethyl ester (of intermediate 2; 1.56 g, 4 mmol), bis(tri -cyclohexyl-phosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 140 mg, 0.21 mmol), and dioxane (approximately 82 mL). A second stock solution was prepared consisting of potassium carbonate (1.66 g, 12 mmol) and water (approximately 8.2 mL). The solutions were sonicated and degassed by bubbling nitrogen gas through them. 4 mL of the first stock solution and 0.4 mL of the second stock solution were added to a reaction vial containing 3-acetamidobenzeneboronic acid (ASDI Incorporated, Newark, Del.; 107 mg, 0.6 mmol). The mixture was heated in a microwave oven at 170 degrees for 25 min. 1 M HCl (0.1 mL) was added to each vial, and the solution were passed through silica gel columns (1 g of silica), and washed with dimethylacetamide (2×1 mL). The solution was evaporated to dryness to give 2-(3′-acetylamino-biphenyl-4-yloxymethyl) -thiazole-4-carboxylic acid. Mass spectrum MH+=369.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]4[O:22][C:21]([CH3:24])([CH3:23])[C:20](=[O:25])[C:19]=4[C:26]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[C:31]1[CH:32]=[CH:33][C:34]([F:37])=[N:35][CH:36]=1>>[F:37][C:34]1[N:35]=[CH:36][C:31]([C:20]2([OH:25])[C:19]3[C:26]([CH3:27])=[C:15]([N:12]4[CH2:11][CH2:10][N:9]([C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)[CH2:14][CH2:13]4)[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]=3[O:22][C:21]2([CH3:24])[CH3:23])=[CH:32][CH:33]=1
Reactant: Fc1ccc(Br)cn1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)(c3ccc(F)nc3)C(C)(C)O4)CC2)cc1
Yield: 67 %

Procedure:
Using 4-(4-methoxyphenyl)-1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-on-5-yl)piperazine and 5-bromo-2-fluoropyridine obtained in Reference Example 13, the title compound was obtained in the same manner as in Example 33. Yield 67% mp. 129–131° C. (hexane-ethyl acetate).
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.[OH:17][C@H:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1.[F:30][C:31]([F:35])([F:34])[CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:30][C:31]([F:35])([F:34])[CH2:32][O:17][C@@H:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: OCC(F)(F)F
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](OCC(F)(F)F)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
Di-tert-butyl azodicarboxylate (2.96 g, 12.83 mmol) was added to an ice cooled mixture of tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate (2 g, 10.70 mmol), 2,2,2-trifluoroethanol (10.70 g, 106.95 mmol) and triphenylphosphine (3.37 g, 12.83 mmol) in THF (24 mL). The mixture was stirred at 70 C for 16 h. The mixture was concentrated under vacuum and the residue was purified by FCC, eluting with a gradient of EtOAc in heptane. The white solid collected was washed with heptane and the filtrate was concentrated to afford the title compound (1.263 g, 44%), which was used without further purification. Method B HPLC-MS: MH+ requires m/z=270 Found: m/z=214 (M minus tert-butyl), Rt=2.02 min (82%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([S:26]([NH2:25])(=[O:28])=[O:27])=[CH:30][CH:31]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(S(N)(=O)=O)cc3)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-[6-methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-pyrimidine (example E.83) (0.150 g, 0.381 mmol) and commercially available (4-aminosulfonylphenyl)boronic acid [CAS-No. 613660-87-0] (0.130 g, 0.457 mmol) according to the general procedure VI. Obtained as a white solid (0.045 g, 25%). MS (ISP) 471.1 [(M+H)+].
Reaction SMILES: C([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[CH:16]1)[C:12]([NH2:14])=[O:13])C1C=CC=CC=1.CCO[C:36]([CH3:38])=[O:37]>CO.[OH-].[OH-].[Pd+2]>[CH3:16][C:17]([CH3:20])([CH3:18])[C@H:38]([NH:14][C:12](=[O:13])[C@H:11]([N:15]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[CH:16]1)[CH2:10][C:9]([OH:8])=[O:32])[CH2:36][OH:37]
Reactant: CCOC(C)=O
Reactant: NC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[C@@H](CO)NC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Reaction time: 3 h
Yield: 95 %

Procedure:
A mixture of N-(1-benzyloxycarbonyloxy-3,3-dimethylbut-2(R)-yl))-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester (140 mg, 0.212 mmol) and Pd(OH)2 (60 mgof 20% Pd by content) in MeOH (1 mL) and EtOAc (9 mL) was stirred under H2 atmosphere for 3 hours. The catalyst was filtered onto Celite and rinsed with 10% MeOH/CHCl3 (75 mL). The filtrate was concentrated in vacuo to provide a yellow solid, which was precipitated from hot CHCl3solution with hexane to furnish 68 mg(95%) of N-[2,2-dimethyl-1(S)-(hydroxymethyl)propyl]-3(R)-(3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid as a yellow solid, mp 192-4° C. 1H NMR (CD3OD): δ 8.56 (d, 1H, J=5.9 Hz), 7.78-7.60 (m, 7H), 7.37 (t, 1H, J=1.9 Hz), 6.96 (t, 1H, J=2.5 Hz), 6.54 (t, 1H, J=1.6 Hz), 5.22 (dd, 1H, J=2.5 Hz), 3.83-3.70 (m, 2H), 3.45-3.40 (m, 1H), 3.22 (d, 1H, J=7.5 Hz), 3.02 (dd, 1H, J=7.2, 16.8 Hz), 0.90 (s, 9H). IR (KBr): 3405, 2960, 1718, 1656, 1602, 1560, 1408, 1364, 1203, 922, 818, 783 cm−1. HRFABMS: Calculated for C25H29N3O4Cs (M+Cs+): 568.1212. Found: 568.1189. Anal. Calculated for C25H29N3O4.0.10CHCl3: C, 67.38; H, 6.55; N, 9.39. Found: C, 67.69, H, 6.90; N, 9.65.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH2:12]([N:16]=[C:17]=[S:18])[CH2:13][CH2:14][CH3:15].O>CN(C)C=O>[CH2:12]([N:16]1[C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=[C:17]1[SH:18])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN=C=S
Reactant: COC(=O)c1ccccc1N
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(S)nc2ccccc2c1=O
Reaction time: 8 h

Procedure:
A stirred mixture of 7.6 g (0.05 mole) methyl anthranilate and 5.8 g (0.05 mole) n-butyl isothiocyanate in 45 ml dimethylformamide was heated at reflux for 11/2 hours, stirred overnight, then heated for 6 hours and then stirred at ambient temperature over the weekend. The reaction mixture was poured into 200 ml water (at 20° C.) to give a precipitate. The mixture was chilled and then filtered. The precipitate was washed three times with water; the filtrate was set aside. A small amount of ethanol was drained through the filter cake once. The solid was washed twice with hexane and air-dried overnight to give the above-identified product, as a solid, melting point 167°-172° C.
Reaction SMILES: [Na].Cl.[NH2:3][OH:4].[CH3:5][CH2:6][O:7][C:8]([C:10]([NH2:12])=S)=[O:9]>C(O)C>[CH3:5][CH2:6][O:7][C:8](/[C:10](/[NH2:12])=[N:3]/[OH:4])=[O:9]
Reactant: NO
Reactant: CCOC(=O)C(N)=S
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)/C(N)=N/O
Reaction time: 8 h

Procedure:
A solution of 8.98 gm. (0.39 mole) of sodium in 180 ml. of anhydrous ethanol is added to a solution of 26.8 gm. (0.386 mole) of hydroxylamine hydrochloride in 270 ml. of hot ethanol. The precipitate is removed by filtration. To the stirred filtrate is added 34.2 gm. (0.26 mole) of ethyl 2-thiooxamate. The yellow solution is allowed to stand overnight. The solution is evaporated to dryness in vacuo and the residue recrystallized from diethyl ether. There is obtained 21.2 g. (68%) of a yellow solid melting at 99°-101° C.
Reaction SMILES: [Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:23])([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].CC(C)[O-].[Al+3:28].CC(C)[O-].CC(C)[O-].O>C(O)(C)C>[Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([CH3:23])([CH3:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4].[Al+3:28].[Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH3:23])[CH3:22])=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4].[Cl:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH3:23])[CH3:22])=[CH:9][CH:8]=1)[C:3]([O-:5])=[O:4]
Reactant: CC(C)(COc1ccc(CC(Cl)C(=O)O)cc1)c1ccccc1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(COc1ccc(CC(Cl)C(=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
In 30 ml of isopropanol is dissolved 3.05 g of 2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)phenyl]propionic acid, and 0.62 g of aluminum isopropoxide is added to the solution. The mixture is stirred at room temperature for 3 hours. Then, 0.5 ml of water is added to the mixture and the mixture is further stirred for 1 hour. The resulting precipitates are collected by filtration, washed with water and isopropanol and dried. The procedure gives 2.0 g of Aluminum 2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)-phenyl]propionate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[C:16]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:15]=3)[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:34][C:35]1[N:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1>>[F:27][C:26]([F:29])([F:28])[CH2:25][O:24][C:16]1[CH:15]=[C:14]([C:12]2[CH:11]=[C:10]([C:30]([F:33])([F:32])[F:31])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:38]4[CH:37]=[N:36][C:35]([NH2:34])=[N:40][CH:39]=4)[CH:7]=[CH:6][CH:5]=3)[N:13]=2)[CH:19]=[CH:18][C:17]=1[C:20]([F:23])([F:22])[F:21]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: FC(F)(F)COc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F
Product: Nc1ncc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)c(OCC(F)(F)F)c4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-[3-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-6-trifluoromethyl-pyrimidine (example E.55) (0.273 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.19 g, 68%). MS (ISP) 560.2 [(M+H)+]; mp 250° C.