Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[CH3:22][N:23]1[CH:27]=[C:26]([S:28](Cl)(=[O:30])=[O:29])[N:25]=[CH:24]1>>[CH3:22][N:23]1[CH:27]=[C:26]([S:28]([N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)(=[O:30])=[O:29])[N:25]=[CH:24]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: Cn1cnc(S(=O)(=O)N2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)c1

Procedure:
Compound 79 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-methyl-1H-imidazole-4-sulfonyl chloride and conditions outlined in procedure P. M.p.=256-257° C.; 400 MHz 1H NMR (CDCl3) δ: 8.06-8.03 (m, 1H), 7.64-7.56 (m, 2H), 7.53-7.45 (m, 3H), 3.84-3.78 (m, 5H), 3.30-3.22 (m, 2H), 2.93 (s, 2H), 2.22-2.13 (m, 2H), 2.0-1.90 (m, 2H); LCMS: 446 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=2[C:3]=1[O:14][CH3:15].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[CH:26][C:25]=2[O:36][CH3:37])[C:20]([Cl:38])=[CH:19][N:18]=1.Cl.COCCO>O1CCOCC1>[Cl:38][C:20]1[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)=[CH:26][C:25]=2[O:36][CH3:37])=[N:22][C:17]([NH:1][C:2]2[CH:13]=[CH:12][C:5]3[NH:6][C:7](=[O:11])[CH2:8][CH2:9][CH2:10][C:4]=3[C:3]=2[O:14][CH3:15])=[N:18][CH:19]=1
Reactant: COc1c(N)ccc2c1CCCC(=O)N2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: COCCO
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2OC)CCCC(=O)N3)ncc1Cl
Temperature: 25 °C

Procedure:
Combined 7-Amino-6-methoxy-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (110 mg, 0.00053 mol) Isopropyl alcohol, (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (170 mg, 0.00048 mol), 4 M of Hydrogen chloride in 1,4-Dioxane (200 uL) and 2-Methoxyethanol (5.3 mL, 0.067 mol) in a Radley tube, heat to 110° C. for about 4.5 h. Cool to RT and a solid came out of solution, stirred over night Filtration was followed by washing with 2-methoxyethanol to give a yellow powder. The powder was treated with saturated aq. bicarb, sonicated to break up solids and stirred for 1 h. The yellow solid was filtered and dried overnight. Isolated C as a yellow solid (131.16 mgs, 52%); MP: 248-249° C.; 1H-NMR (dmso, 400 MHz) δ 9.60 (s, 1H), 9.38 (br s, 1H), 9.15 (br s, 1H), 8.32 (s, 1H), 7.50 (d, J=8.3 Hz, 1H), 7.32 (d, J=8.5 Hz, 1H), 6.70 (s, 1H), 6.53-6.48 (m, 2H), 3.80-3.78 (m, 4H), 3.77 (s, 3H), 3.70 (s, 3H), 3.25-3.19 (m, 6H), 2.70-2.68 (m 2H), 2.14-2.10 (m, 2H); LC/MS: 525.36 (M+H).
Reaction SMILES: [NH:1]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:22]([NH:24][C@H:25]([C:31]([NH:33][NH:34]C(OC(C)(C)C)=O)=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])[C@@H:3]([CH3:5])[OH:4].CCOCC>C(O)(C(F)(F)F)=O>[NH:1]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH:16][C@H:17]([C:22]([NH:24][C@H:25]([C:31]([NH:33][NH2:34])=[O:32])[CH2:26][CH2:27][C:28](=[O:30])[NH2:29])=[O:23])[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12])=[O:7])[C@@H:3]([CH3:5])[OH:4]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(C)C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(=O)NN
Reaction time: 0.25 h

Procedure:
0.91 Gram of Z-Thr-Asn-Leu-Gln-NHNHBoc was dissolved in 8 ml of TFA, and was allowed to stand at a room temperature for 15 minutes. 80 Milliliters of anhydrous ether was added to this solution and the precipitate formed was collected quickly by filtration, washed with anhydrous ether, then was dried under a reduced pressure in a desiccator containing potassium hydroxide-phosphorus pentoxide as the desiccant, to obtain the desired product.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li+].CC([N-]C(C)C)C.[Br:32][C:33]1[N:38]=[C:37]([CH:39]=O)[CH:36]=[CH:35][CH:34]=1>C1COCC1>[Br:32][C:33]1[CH:34]=[CH:35][CH:36]=[C:37]([CH:39]=[CH:2][O:3][CH3:4])[N:38]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(Br)n1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=Cc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a suspension of (methoxymethyl)triphenylphosphonium chloride (34.5 g, 100.6 mmol) in THF (500 mL) at −10° C. was added LDA (60 mL, 2 mol/L). The mixture was stirred at −10° C. for 1 hour before addition of 6-bromopicolinaldehyde (10 g, 53.8 mmol) in THF (200 mL). The reaction mixture was then allowed to warm to room temperature and stirred at room temperature for 12 hours. The solution was then partitioned between water and ether. The aqueous fraction was separated and extracted twice with ether. The organic layers were washed with brine and dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to give the crude product which was purified by chromatography (petroleum ether:ethyl acetate, 20:1) to give 2-bromo-6-(-2-methoxy-vinyl)-pyridine. (Yield 9.3 g, 80%). LC-MS: [M+H]+ 215.
Reaction SMILES: [CH:1]1[C:6]([C:7](O)=O)=[CH:5][C:4]2[C:10](O[C:13](=O)[C:3]=2[CH:2]=1)=O.C(O)COCCOCCO.C(O)(=O)C1C(=CC(=CC=1)C(O)=O)C(O)=O>>[C:3]1([C:4](=[CH:5][C:6](=[CH:1][CH:2]=1)[CH3:7])[CH3:10])[CH3:13]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Agent: O=C(O)c1ccc(C(=O)O)c(C(=O)O)c1
Solvent: OCCOCCOCCO
Product: Cc1ccc(C)c(C)c1

Procedure:
An improved process for the manufacture of trimellitic acid anhydride having a 97 to 98% anhydride content and having a triethylene glycol color of 170 or less, in yields in the range of 89 to 90% and higher based on the total trimellitic acid produced by catalytic air oxidation of pseudocumene, including the steps of catalytic oxidation of pseudocumene in the presence of acetic acid in an oxidation zone wherein liquid-phase conditions are maintained and wherein the weight ratio of acetic acid to pseudocumene is in the range of about 0.5-5.0:1.0 and the catalyst comprises one or more heavy metal oxidation catalysts comprising zirconium, cobalt, and manganese to provide about 0.1 to about 0.4 weight percent total metals based on pseudocumene and a source of bromine and to provide a total of about 0.1 to about 0.3 weight percent total bromine based on pseudocumene, wherein the total weight ratio of bromine ions to total metal ions is about 0.5 to about 2.0, the zirconium content is about 1 to about 5%, and the manganese content is about 14 to about 60%, each metal by weight of the total metals and wherein the cobalt content is about 35 to about 80 weight percent, temperatures in the oxidation are in a range of about 220° F. to about 480° F., cooling the oxidation reaction effluent to crystallize trimellitic acid, separating and recovering crystallized trimellitic acid from the acetic acid solvent mother liquor, distilling from the acetic acid mother liquor to obtain a mixture of acetic acid and water for concentration of the acetic acid content to provide acetic acid solvent concentrate for recycle to the oxidation and to obtain a bottoms fraction containing high melting solids, heating the crystalline trimellitic acid to convert it to its anhydride and distilling the anhydride to obtain trimellitic acid anhydride product; the improvements comprising conducting the conversion continuously in two series staged dehydration zones with heat removal by evaporation from the liquid in each of the dehydration zones operated at temperatures in a range of about 400° to about 500° F. thereby converting trimellitic acid to its anhydride and evaporating acetic acid solvent, distilling the liquid crude trimellitic anhydride, condensing the vaporized overhead fraction to obtain trimellitic anhydride product, combining the vapor from the first dehydration zone and the acetic acid mother liquor as feed for distilling acetic acid and water mixture therefrom leaving the residue containing high melting solids, combining the residue and the bottom fraction from the distillation of the trimellitic anhydride containing catalyst metals, and continuously adding up to about 50 weight percent of the combined residue and bottom fraction containing high melting solids and catalyst metals to the first dehydration zone.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[C:19](Cl)=O>C1COCC1>[CH3:15][C:16]1[CH:24]=[C:23]([C:25]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:22]=[C:18]([CH3:19])[CH:17]=1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Solvent: C1CCOC1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)cc(C)c3)nc2c1
Reaction time: 0.5 h

Procedure:
A mixture of 2-amino-4,6-dimethoxybenzamide (0.0700 g, 0.36 mmol) and 3,5-dimethylbenzoyl chloride (0.112 g, 0.65 mmol) in THF (5.0 mL) was placed in a microwave reactor at 80° C. for 30 min. The THF was removed under reduced pressure, and the residue was purified via CombiFlash chromatography to yield the expected amide. This material was used directly in the next step. A mixture of the amide and H2O/MeCN (2:1, 5.00 mL) was basified to pH 12 with 2 N NaOH and stirred at 80° C. for 16 h. The mixture was cooled and neutralized with 1 N HCl. The resulting precipitate was collected on a frit, washed with water (5.00 mL) and lyophilized to yield 2-(3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.0395 g, 31% over two steps) as a white solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 7.80 (s, 2H), 7.21 (s, 1H), 6.76 (d, J=2.24 Hz, 1H), 6.53 (d, J=2.21 Hz, 1H), 3.89 (s, 3H), 3.85 (s, 3H), 2.35 (s, 6H); MS (APCI) m/z 311 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:12](I)=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[C:12]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:11][CH:10]=[C:9]([Si:14]([CH3:17])([CH3:16])[CH3:15])[C:3]=1[C:4]([NH:6][CH2:7][CH3:8])=[O:5]
Reactant: CCNC(=O)c1c([Si](C)(C)C)ccc(I)c1Cl
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCNC(=O)c1c([Si](C)(C)C)ccc(-c2ccccc2)c1Cl
Temperature: 90 °C
Reaction time: 24 h
Yield: 59.1 %

Procedure:
To a solution of the compound of Example 239 (0.191 g, 0.5 mmol) and palladium tetrakistriphenylphosphine (23 mg, 0.02 mmol) in toluene (10 mL) was added 2 M sodium carbonate (0.5 mL) and phenyl boronic acid (73 mg, 0.6 mmol). The mixture was heated at 90° C. for 30 h, additional portions of catalyst (20 mg) and 2 M sodium carbonate (0.5 mL) were added and heating was continued for 24 h. The cool reaction was diluted with CH2Cl2 and washed with 2 M sodium carbonate (50 mL with 5 mL conc NH4OH). The organic layer was dried (MgSO4) and concentrated. The crude product was purified by RC (ethyl acetate/hexanes) and recrystallization from hexanes to afford the title compound as white needles (98 mg, 59%). m.p. 134-135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:24][CH2:25][CH2:26][CH2:27][C:28](O)=[O:29])[N:9]=2)=[CH:4][CH:3]=1.O[N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2N=N1.Cl.C(N=C=NCCCN(C)C)C.NC1C=CC=CC=1>O.C(N(CC)CC)C.CN(C)C=O>[C:36]1([NH:32][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]23)[CH:37]=[CH:38][CH:39]=[CH:40][CH:35]=1
Reactant: On1nnc2ccccc21
Reactant: CCc1cc2c(s1)-n1c(C)nnc1C(CCCCC(=O)O)N=C2c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc2c(s1)-n1c(C)nnc1C(CCCCC(=O)Nc1ccccc1)N=C2c1ccc(Cl)cc1
Yield: 80.4 %

Procedure:
(±)-5-(4-(4-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)valeric acid (0.50 g) and 1-hydroxybenzotriazole (0.17 g) are added to dry dimethylformamide (20 ml) and the mixture is stirred under ice-cooling. Thereto is added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.24 g), and then triethylamine (0.23 g) and aniline (0.10 g) are added. The mixture is stirred at room temperature for 4 days. After the completion of the reaction, water (100 ml) is added and the mixture is extracted with ethyl acetate. The organic layer is washed with 6N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate:methanol=10:l) and crystallized from ethyl acetate and isopropyl ether to give 0.47 g of (±)-N-phenyl-5-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepin-6-yl)pentaneamide as white powdery crystals, melting point 238°-240° C.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:22]1([CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:29][CH2:30][CH2:31][C:32](O)=[O:33])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:35]1([CH:28]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:29][CH2:30][CH2:31][C:32]([N:19]2[CH2:20][CH2:21][N:16]([CH2:15][C:2]3([CH3:1])[CH2:6][C:5]4[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=4[O:3]3)[CH2:17][CH2:18]2)=[O:33])[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Reactant: O=C(O)CCCC(c1ccccc1)c1ccccc1
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(C(=O)CCCC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 86 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and 5,5-diphenylvaleric acid, the procedure of Example 10 was otherwise repeated to provide the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([C:21](O)=[O:22])[C:12]3[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=3[N:14]=2)[CH:6]=[CH:7][CH:8]=1.[NH2:24][CH2:25][C:26]1[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C([O-])(O)=O.[Na+]>CS(C)=O.CO.C(Cl)Cl>[CH3:32][C:31]1[CH:30]=[C:29]([CH3:33])[NH:28][C:27](=[O:34])[C:26]=1[CH2:25][NH:24][C:21]([C:11]1[C:12]2[CH:17]=[N:16][N:15]([CH:18]([CH3:20])[CH3:19])[C:13]=2[N:14]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][OH:1])[CH:4]=2)[CH:10]=1)=[O:22]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3cccc(CO)c3)nc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(CO)c3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.3 %

Procedure:
A mixture of 6-(3-(hydroxymethyl)phenyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (0.65 g, 2.09 mmol), 3-(aminomethyl)-4,6-dimethylpyridin-2(1H)-one (0.64 g, 4.18 mmol) and PYBOP (1.63 g, 3.13 mmol) in DMSO (5 mL) was stirred at room temperature for 12 hr. After completion of the reaction, saturated NaHCO3 solution was added to it and extraction was carried out using 20% MeOH/DCM. The combined organic layers were washed with water; dried over anhydrous Na2SO4; filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give a white solid (0.71 g, 81.4%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[CH3:10][O-:11].[Na+].O>CO.C(COC)OC>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH2:5][O:11][CH3:10])[CH:3]=1
Reactant: BrCc1cccc(Br)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CO
Product: COCc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of 3-bromobenzylbromide (15.0 g) in methanol-dimethoxyethane (30 ml+10 ml) was added sodium methylate (4.9 g) under cooling with ice and the mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into water. The reaction mixture was extracted with ether. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and the solvent was evaporated to give the title compound (12.1 g) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)[F:30].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([F:30])=[N:18][CH:17]=[C:16]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cncc(OCc3cccc(Cl)c3)n2)CC1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2nc(OCc3cccc(Cl)c3)cnc2F)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 6′-(3-chloro-benzyloxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (1-1b) (600 mg, 1.49 mmol) in acetonitrile (12.4 ml) at 0° C. under a nitrogen atmosphere was treated with Selectfluor™ ([1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]-octane bis(tetrafluoroborate)]) (526 mg, 1.49 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was partitioned between CH2Cl2 and water. The organic phase was washed twice with water, twice with saturated aqueous NaHCO3 solution and twice with brine, dried over MgSO4 (anhydrous), filtered and concentrated in vacuo. The residue was purified by flash chromatography (CHCl2-EtOAc 99:1 to 95:5). Three compounds were obtained in the following elution order: difluorinated material (160 mg, 25%), Intermediate I-3i (32 mg, 5%) and Intermediate I-3i′ (141 mg, 22%). The structures of the two monofluorinated products were assigned by nuclear Overhauser effect (nOe) experiments.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=O)[CH:15]=3)[N:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:19]1[CH2:23][C:22](=[O:24])[NH:21][C:20]1=[O:25]>>[C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH:17]=[C:23]4[S:19][C:20](=[O:25])[NH:21][C:22]4=[O:24])[CH:15]=3)[N:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccc2ncnc(-c3ccccc3)c2c1
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)C(=Cc2ccc3ncnc(-c4ccccc4)c3c2)S1

Procedure:
Following the general method as outlined in Example 1, starting from 4-Phenyl-quinazoline-6-carbaldehyde (intermediate 13) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][N:7]2[C:13](=[O:14])[C@H:12]3[CH2:15][CH2:16][CH2:17][C@H:11]3[N:10]([C:18](=[O:31])[CH2:19][N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[C:9]3[CH:32]=[CH:33][CH:34]=[CH:35][C:8]2=3)=[CH:4][CH:3]=1.[C:38]1([C@@H:44]([N:46]=[C:47]=[O:48])[CH3:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(OCC)(=O)C.C(OCC)C>[C:38]1([C@@H:44]([NH:46][C:47](=[O:48])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:7]3[C:13](=[O:14])[C@H:12]4[CH2:15][CH2:16][CH2:17][C@H:11]4[N:10]([C:18](=[O:31])[CH2:19][N:20]4[C:21](=[O:30])[C:22]5=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]5[C:24]4=[O:25])[C:9]4[CH:32]=[CH:33][CH:34]=[CH:35][C:8]3=4)=[CH:36][CH:37]=2)[CH3:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1
Reactant: C[C@H](N=C=O)c1ccccc1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)Nc1ccc(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)cc1)c1ccccc1
Yield: 53 %

Procedure:
Using (3aR*,10aS*)-9-(4-aminobenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one and (S)-1-phenylethyl isocyanate, the title compound was synthesized in otherwise the same manner as Example 26. Yield 53%, m.p. 156°-160° C. (ethyl acetate-diethyl ether).
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:24][C:23](=[O:25])[N:22](CC3C=CC(OC)=CC=3)[S:21]2(=[O:36])=[O:35])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.C([SiH](C)C)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:24][C:23](=[O:25])[NH:22][S:21]2(=[O:35])=[O:36])=[CH:16][CH:15]=1)[C:10]([OH:12])=[O:11]
Reactant: COc1ccc(CN2C(=O)CN(c3ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc3)S2(=O)=O)cc1
Agent: C[SiH](C)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccc(N2CC(=O)NS2(=O)=O)cc1)C(=O)O
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
The title A compound, (S)-2-t-butoxycarbonylamino-3-(4-[5-(4-methoxy-benzyl)-1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl]-phenyl)-propionic acid (84.5 mg, 0.163 mmol) is dissolved in TFA (3.26 mL) containing t-butyidimethylsilane (0.081 mL, 0.498 mmol) at RT. The reaction is monitored by reverse phase HPLC (YMC CombiScreen Pro C18, 50×4.6 mm I.D., particle size S-5 micron, 12 nM) eluting at 3 mL/min with a gradient of 90:10 (0.1% TFA in water:MeCN) to 10:90 over 7.0 min. The starting material has a retention time of 3.85 min. After 20 min at RT, the reaction is heated at 80° C. for an additional 45 min. A new peak by HPLC has a retention time of 0.52 min, corresponding to the desired product. The reaction is cooled, filtered through florisil to remove a black precipitate and concentrated on a Savant Speedvac. The resulting residue is triturated with Et2O to give a white solid. This material is purified on a preparative reverse phase HPLC column (YMC CombiPrep Pro C18, 50×20 mm I.D., particle size S-5 micron, 12 nM) in two equal aliquots and eluted at 30 ml/min with a gradient of 100:0 (0.1% TFA in water:MeCN) to 70:30 over 5.0 min, then to 10:90 by 7 min. Fractions containing product are combined and concentrated on a Savant Speedvac, then triturated with 10% dimethylsulfoxide (DMSO) in MeCN to yield (S)-2-amino-3-[4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-propionic acid as a white solid: [M−1]−=298.0.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:9])([CH3:8])[N:5]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.[CH3:24][C:25]([Si:28](Cl)([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1>>[Si:28]([O:1][CH2:2][C@H:3]1[O:7][C:6]([CH3:8])([CH3:9])[N:5]([C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[C@H:4]1[CH2:17][C:18]1[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=1)([C:25]([CH3:27])([CH3:26])[CH3:24])([CH3:30])[CH3:29]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccncc2)[C@@H](CO)OC1(C)C
Agent: c1c[nH]cn1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2ccncc2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C

Procedure:
The title compound was synthesized in manner analogous to that described in Example 407, using (4S,5S)-tert-butyl 5-(hydroxymethyl)-2,2-dimethyl-4-(pyridin-4-ylmethyl)oxazolidine-3-carboxylate in the presence of TBSCl and imidazole, and was used without further purification.