Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:15][C:6]2[N:7]=[C:8]([NH:10][C:11]([NH:13][CH3:14])=[O:12])[S:9][C:5]=2[C:4]([CH3:17])([CH3:16])[CH2:3]1.[CH2:19]1[O:24][CH2:23]OCO1.S(=O)(=O)(O)O.[OH-].[Na+]>O>[CH3:1][C:2]1([CH3:18])[CH2:15][C:6]2[N:7]=[C:8]([N:10]3[C:11](=[O:12])[N:13]([CH3:14])[CH2:23][O:24][CH2:19]3)[S:9][C:5]=2[C:4]([CH3:17])([CH3:16])[CH2:3]1
Reactant: CNC(=O)Nc1nc2c(s1)C(C)(C)CC(C)(C)C2
Reactant: C1OCOCO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1COCN(c2nc3c(s2)C(C)(C)CC(C)(C)C3)C1=O
Temperature: 5 °C
Reaction time: 16 h

Procedure:
Sulfuric acid, 85% concentration (40 grams) was charged into a glass reaction vessel fitted with a mechanical stirrer and a thermometer and was cooled to about 5° C. N-(5,5,7,7-tetramethyl-4,5,6,7-tetrahydrobenzothiazol-2-yl)-N'-methylurea (4.1 grams; 0.015 mole) and s-trioxane (1.4 grams, 0.015 mole) were added portionwise, with stirring, to the cold sulfuric acid. Stirring was continued for a period of about 16 hours at a temperature of about 20°-25° C. The reaction mixture was then diluted 1:1 with water and neutralized with aqueous 40% sodium hydroxide. The neutralized mixture was filtered and the solid obtained was washed with 3-100 ml portions of water and air dried to yield the desired product 3-(5,5,7,7-tetramethyl-4,5,6,7-tetrahydro-benzothiazol-2-yl)-5methyltetrahydro-1,3,5-oxadiazin-4-one as a solid having a melting point of 138°-140° C. Elemental analysis: Theory: C: 58.22%; H: 7.49%; N: 13.58%; Found: C:57.53%; H: 7.57%; N: 13.61 %.
Reaction SMILES: C([NH2:4])(C)C.Cl.[C:6]([O:10][C:11]([NH:13][CH:14]([CH2:21][CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32])[C:23](=O)[CH3:24])[C:15](OC(C)C)=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7]>O.CS(C)=O>[CH3:24][C@H:23]1[NH:4][C:15](=[O:16])[CH:14]([NH:13][C:11](=[O:12])[O:10][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:21][C@H:22]1[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH3:32]
Reactant: CC(C)N
Reactant: CC(=O)C(CC(NC(=O)OC(C)(C)C)C(=O)OC(C)C)c1ccccc1C
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccccc1[C@@H]1CC(NC(=O)OC(C)(C)C)C(=O)N[C@@H]1C
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 20728 %

Procedure:
To a solution of NaBO3.4H2O (10 g, 0.026 mol) in H2O (180 g) was charged isopropylamine (30 g, 0.25 mmol) dropwise at 20° C. After the mixture was stirred for 30 min, the pH was adjusted to 10.3-10.5 by 6M HCl. PLP (1 g, 6.4 mmol) and ATA-412 (25 g) was charged to the solution at 20° C. After the above mixture was stirred for 1 h, a solution of 36 (50 g, 4.7 mmoL) in DMSO (250 mL) was added slowly at 20° C. The solution was heated to 55° C. and stirred for 24 h. After the reaction was complete, the reaction was quenched by isopropyl alcohol (100 mL), and then partitioned with water and IPAc. The organic phase was dried over Na2SO4 and concentrated. The crude residual was further purified by flash chromatography on silica gel (5-20% EtOAc/PE) to give 37 (16.5 g, 40% yield). 1H (DMSO-d6, 400 MHz): δ 7.83 (s, 1H), 7.18-7.13 (m, 4H), 4.06 (br, 1H), 3.67-3.51 (m, 2H), 2.30 (d, 3H), 1.99 (t, 1H), 1.36 (s, 9H), 0.82 (m, 3H); MS (ESI) m/e [M+H]+: 319.2
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6](=[O:12])[CH2:7][C:8]([CH2:10]Cl)=[O:9].Cl>C(#N)C.O.C(O)(=O)C>[CH3:4][O:5][C:6](=[O:12])[CH2:7][C:8]([CH2:10][O:2][CH3:1])=[O:9]
Reactant: COC(=O)CC(=O)CCl
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CC#N
Product: COCC(=O)CC(=O)OC
Temperature: 70 °C
Reaction time: 0.41 h
Yield: 91.7 %

Procedure:
77.4 g of sodium methylate, 97 percent, was suspended in 100 g of acetonitrile at ambient temperature. To this well-stirred suspension, 101.9 g of 97.5 percent 4-chloroacetoacetic acid methyl ester was added by drops through a drip funnel with a drop counter over a 5 to 6 minute period under N2 atmosphere. The temperature rose and was kept by means of cooling at 68° to 70° C. As soon as the heat development slackened, the cooling water was turned off and the reaction mass was heated with 70° C. hot water. This pastelike, mustard-yellow reaction mixture continued to be stirred at 70° C. for 24 to 25 minutes and, with stirring, was then slowly introduced into a solution of 6 g of glacial acetic acid and 215 g of water cooled in an ice bath. At the same time, 37.4 percent hydrochloric acid was introduced drop by drop from a burette. At the same time, the pH was measured by means of a glass electrode and kept between 4.5 and 8 by adjusting the addition rate of the reaction mixture and/or HCl. At the end of the neutralization, the pH was 6.1±0.1. For the neutralization, 56.4 ml of hydrochloric acid were used (37.4 percent) and the temperature was kept at 30° to 35° C. The neutralized mixture was put into a separating funnel. After standing a short time, the resultant layers were separated. The aqueous layer was extracted once with 200 ml and then twice each time with 100 ml of acetonitrile. The united organic phases were concentrated in a rotary evaporator at 30° to 35° C. and ≃20 torr up to a constant weight. The solvent evaporated off was regenerated and used with the next batch. The raw product was distilled at 0.5 to 1.5 torr/90° C. 4-methoxyacetoacetic acid methyl ester was obtained in a yield of 91.7 percent, based on the amount of chloroester used. The purity of the product was 98.8 percent.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.N1(C2C=C[C:23]([CH:24]=[O:25])=CC=2)C=CC=N1>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:14]=[CH:13][C:10](/[CH:11]=[CH:23]/[CH:24]=[O:25])=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: O=Cc1ccc(-c2ccncc2)cc1
Product: O=C/C=C/c1ccc(-c2ccncc2)cc1

Procedure:
The title compound was prepared by a procedure analogous to Reference Example 30 by substituting 4-(4-pyridinyl)-benzaldehyde (prepared as described in WO 9828264) for the 4-(1H-pyrazol-1-yl)-benzaldehyde of Reference Example 30. MS 210 (M+H)+.
Reaction SMILES: O[CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][NH:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7].[Cr](Cl)([O-])(=O)=[O:17].[NH+]1C=CC=CC=1.C(OCC)(=O)C.C(Cl)Cl>C(Cl)Cl>[O:17]=[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:10]1[CH2:2][CH2:3][NH:4][C:5](=[O:9])[CH:6]([CH3:8])[CH3:7]
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CC(C)C(=O)NCC(O)c1ccccc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)C(=O)NCCC1C=CC=CC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.7 %

Procedure:
A mixture of N-(2-hydroxy-2-phenyl-ethyl)-2-methyl-propanamide (15.0 g, 72 mmol), prepared in the previous step, and pyridinium chlorochromate (23.7 g, 110 mmol) in 300 ml of methylene chloride was stirred at room temperature for 5 hours. The reaction was filtered and the filtrate concentrated under reduced pressure to give a dark residue. Chromatography of the residue on silica gel (230-400 mesh) using ethyl acetate-methylene chloride as the eluent gave N-(2-oxo-phenyl-ethyl)-2-methyl-propanamide (6.07 g, 41%) as a light green solid, mp 88-93° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[N:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38](O)=[O:39])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.C(Cl)CCl.[CH:50]1([S:53]([NH2:56])(=[O:55])=[O:54])[CH2:52][CH2:51]1.C1CCN2C(=NCCC2)CC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([O:18][CH:19]3[CH2:36][CH:35]4[N:21]([C:22](=[O:42])[N:23]([CH3:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]=[CH:29][CH:30]5[C:32]([C:38]([NH:56][S:53]([CH:50]6[CH2:52][CH2:51]6)(=[O:55])=[O:54])=[O:39])([NH:33][C:34]4=[O:37])[CH2:31]5)[CH2:20]3)[C:15]3[C:10](=[C:11]([CH3:45])[C:12]([O:43][CH3:44])=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccc(F)cc3)nc2c1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCCl
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccc(F)cc3)nc2c1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.7 %

Procedure:
A solution of the acid (153) (92 mg, 0.15 mmol) and EDC (38 mg, 0.2 mmol) in dry DCM (2 ml) was stirred at room temperature overnight. Cyclopropylsulfonamide (48 mg, 0.4 mmol) and DBU (76 mg, 0.5 mmol) was added and the mixture was stirred at room temperature for 6 hours. 5% Citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with 5% citric acid and brine, dried with sodium sulphate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with ether-methanol which gave the title compound (70 mg, 65%), MS (M+H) 720.
Reaction SMILES: [C:1](Cl)(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH2:17])=[N:13][NH:14]2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[Cl:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([NH:17][C:1](=[O:5])[CH:2]=[CH:3][CH3:4])=[N:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: C/C=C/C(=O)Cl
Reactant: Nc1n[nH]c2cc(Cl)ccc12
Solvent: c1ccncc1
Product: CC=CC(=O)Nc1n[nH]c2cc(Cl)ccc12
Temperature: 6 °C
Reaction time: 0.17 h

Procedure:
0.67 cm3 of distilled crotonyl chloride is added to 50 mg of 6-chloro-1H-indazole-3-amine dissolved in 5 cm3 of pyridine and cooled to about 6° C. The mixture is stirred for 10 minutes and the temperature is then allowed to rise to about 19° C. over 22 hours. The reaction medium is then concentrated to dryness under reduced pressure (2 kPa; 40° C.) and the residue is then taken up in 50 cm3 of tetrahydrofuran and 25 cm3 of ethyl acetate. The organic phase is washed with 2×50 cm3 of distilled water and then with 50 cm3 of saturated aqueous sodium chloride solution. The resulting solution is dried over magnesium sulphate, filtered through a sinter funnel and then evaporated under the conditions described previously. The residue obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4.5 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume) and collecting 20 cm3 fractions. The fractions containing the expected product are combined and then evaporated under the conditions already described. After drying (90 Pa; 45° C.), 100 mg of N-(6-chloro-1H-indazol-3-yl)-2-butenamide, E form, are obtained in the form of a white solid melting at 226° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:9]=1)[CH:5]=[O:6].S(Cl)([Cl:18])(=O)=O>ClCCl>[Cl:18][C:3]1[C:2]([OH:1])=[CH:9][C:8]([CH2:10][CH2:11][CH2:12][O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COCCCc1cc(O)cc(C=O)c1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COCCCc1cc(O)c(Cl)c(C=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-hydroxy-5-(3-methoxypropyl)benzaldehyde from the previous step (I eq.) in dichloromethane (0.2 M) was added sulfuryl chloride (1 eq.). The resulting reaction mixture was then stirred at RT for 18 h. The volatiles were removed in vacuo and purification of the crude product thus obtained by way of column chromatography (SiO2, Hex→3:2 (v/v) Hex:EtOAc) afforded the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[NH:10][N:9]=[N:8][C:5]2=[N:6][CH:7]=1.[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([Sn](C)(C)C)[CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1>O1CCOCC1>[N:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:2]4[CH:3]=[C:4]5[NH:10][N:9]=[N:8][C:5]5=[N:6][CH:7]=4)[CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: Brc1cnc2nn[nH]c2c1
Reactant: C[Sn](C)(C)c1ccc2nccc(-c3ccncc3)c2c1
Solvent: C1COCCO1
Product: c1cc(-c2ccnc3ccc(-c4cnc5nn[nH]c5c4)cc23)ccn1
Temperature: 100 °C
Yield: 13.6 %

Procedure:
A mixture of 6-bromo-1H-[1,2,3]triazolo[4,5-b]pyridine (100 mg, 0.5 mmol), 4-(4-pyridinyl)-6-(trimethylstannanyl)quinoline (204 mg, 0.55 mmol), and tetrakistriphenylphosphine palladium(0) (29 mg, 0.025 mmol) in 1,4-dioxane (3.0 mL) was heated at 100° C. for 18 h. The reaction was filtered to collect the precipitate. The solid was triturated in hot ethanol to give an off-white solid, which still contained some minor impurities. The off-white solid was triturated in hot ethanol to give the title product as a beige solid (22 mg, 14%). MS(ES)+ m/e 325.1 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]2[C:12]3[CH:11]=[C:10]([N:13]=C(C4C=CC=CC=4)C4C=CC=CC=4)[N:9]=[CH:8][C:7]=3[C:6]([CH3:28])([CH3:27])[C:5]2=[O:29])[CH2:3][CH2:2]1.C([O-])(=O)C.[Na+].Cl.NO>CO>[NH2:13][C:10]1[N:9]=[CH:8][C:7]2[C:6]([CH3:28])([CH3:27])[C:5](=[O:29])[N:4]([CH:1]3[CH2:2][CH2:3]3)[C:12]=2[CH:11]=1
Reactant: CC1(C)C(=O)N(C2CC2)c2cc(N=C(c3ccccc3)c3ccccc3)ncc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: CC1(C)C(=O)N(C2CC2)c2cc(N)ncc21
Temperature: 50 °C

Procedure:
A suspension of 1-cyclopropyl-6-(diphenylmethyleneamino)-3,3-dimethyl-1H-pyrrolo[3,2-c]pyridin-2(3H)-one (2.31 g, 6.06 mmol), sodium acetate (1.49 g, 18.2 mmol) and hydroxylamine hydrochloride (926 mg, 13.3 mmol) in methanol (60 ml) was heated to 50° C. for 3 hours. The reaction mixture was diluted with methanol, silica gel was added and the solvent was evaporated. The crude material was purified by flash chromatography on silica gel using dichloromethane/methanol as eluent. The title compound was obtained as off-white crystals (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH2:17]([NH:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35])[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>C(Cl)Cl>[CH2:17]([NH:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:35])[CH2:18][CH2:19][CH:20]=[CH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCC=CCCCNc1ccccc1C(=O)Cl
Reactant: Oc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCC=CCCCNc1ccccc1C(=O)Oc1ccc(Cl)cc1

Procedure:
To a solution of 6.4 g. 4-chlorophenol and 7.6 g. triethylamine in 500 ml. methylene chloride is added 10.4 g. 2-(4-tetradecenylamino)benzoyl chloride hydrochloride in 250 ml. methylene chloride. After four hours at reflux, the solution is cooled, washed with water and dilute phosphoric acid, and dried. After passing the solution through a column of alumina, the solvent is evaporated and the residue is crystallized from diisopropyl ether.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([Br:17])[C:14]=1[O:15][CH3:16])[CH2:6][C@H:7]([C:9]([OH:11])=[O:10])[NH2:8].[CH3:18]O.Cl.N>ClCCl.C(OCC)(=O)C.C1CCCCC1.CO>[CH3:18][NH:8][C@@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]1[CH:4]=[C:3]([Br:2])[C:14]([O:15][CH3:16])=[C:13]([Br:17])[CH:12]=1
Reactant: COc1c(Br)cc(C[C@@H](N)C(=O)O)cc1Br
Reactant: CO
Agent: Cl
Agent: N
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CN[C@H](Cc1cc(Br)c(OC)c(Br)c1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 5.5 g (14.12 mmol) of 3,5-dibromo-4-methoxy-D-phenylalanine-hydrochloride and 55 ml of methanol were added 150 ml of a saturated methanolic hydrogen chloride solution and the mixture was stirred for 20 hours at room temperature. The residue remaining after evaporation of the solvent was stirred with 50 ml of water and adjusted to pH 8 with saturated sodium hydrogen carbonate solution. The precipitate was suction filtered, stirred with 10 ml of isopropanol and left to stand overnight. The insoluble matter was filtered off and the filtrate was evaporated down in vacuo. The residue was further reacted as a crude product. Yield: 1.0 g (28.7% of theory) of a colourless oil , Rf=0.55 (eluant: dichloromethane/ethyl acetate/cyclohexane/methanol/conc. ammonia=300/80/25/25/3 (v/v/v/v/v)).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:28](=[O:30])(=[O:29])[NH:27][C:26](=[O:31])[CH:25]=2)=[CH:20][CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:72]1([NH2:79])[C:73]([NH2:78])=[CH:74][CH:75]=[CH:76][CH:77]=1>CN(C)C=O>[NH2:78][C:73]1[CH:74]=[CH:75][CH:76]=[CH:77][C:72]=1[NH:79][C:14](=[O:15])[CH:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:4])[CH3:3])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[S:28](=[O:29])(=[O:30])[NH:27][C:26](=[O:31])[CH:25]=2)=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)C(=O)O
Reactant: Nc1ccccc1N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)NC(Cc1ccc(C2=CC(=O)NS2(=O)=O)cc1)C(=O)Nc1ccccc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
To a solution of (2S)-2-((2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoylamino)-3-[4-(1,1-dioxido-3-oxo-2,3-dihydroisothiazol-5-yl)phenyl]-propanoic acid (15.0 mg, 0.0276 mmol) in N,N-dimethylformamide (3 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (10.5 mg, 0.027 mmol) and N,N-diisopropylethylamine (24 μL, 0.14 mmol) and premixed for 5 minutes. To the solution was added 1,2-benzenediamine (4.2 mg, 0.04 mmol) and stirred at room temperature overnight. Preformed ester was yellow in color and upon addition of the diamine continued to darken over several minutes. Product was purified by preparative LCMS to afford the desired product (7.3 mg, 42%). LCMS found for C32H36N5O7S (M+H)+: m/z=634.2.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]=[CH:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH2:6][CH2:5][C:4]1=[O:64])[CH3:2].[H][H]>[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH2:6][CH2:5][C:4]1=[O:64])[CH3:2]
Reactant: [H][H]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Agent: [Rh]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCCc4ccccc4)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (16 mg in 2 ml ethanol) was added 2 mg of 5% rhodium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 30 minutes, the mixture was filtered over diatomacous earth, concentrated and purified by preparative TLC on silica gel (ethyl acetate: hexane (1:2)+1% methanol) to give the title compound (5.5 mg).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:38][C:39]([C:42]([NH:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[CH:40][N:41]=1>>[C:45]([NH:44][C:42]([C:39]1[S:38][C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[N:41][CH:40]=1)=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)(C)NC(=O)c1cnc(Br)s1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ncc(C(=O)NC(C)(C)C)s2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-N-tert-butylthiazole-5-carboxamide following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.351 min, m/z=558.1; 1H NMR (CDCl3) 1.13 (s, 3H), 1.16 (s, 3H), 1.49 (s, 9H), 1.51 (d, 3H), 2.15-2.32 (m, 5H), 2.41 (m, 1H), 2.89 (m, 1H), 3.72 (m, 1H), 5.70 (m, 1H), 5.78 (m, 1H), 7.02 (m, 2H), 7.34 (m, 5H), 7.70 (m, 2H), 8.08 (m, 1H)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]C(=O)C)=[CH:6][C:5]=1[OH:14])(=[O:3])[CH3:2].[C:15](OCC)(=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].[O-]CC.[Na+].Cl>C(O)C.C(Cl)Cl.O>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]2[C:1](=[O:3])[CH:2]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:14][C:5]=2[CH:6]=1
Reactant: CC(=O)Nc1ccc(C(C)=O)c(O)c1
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1cc(=O)c2ccc(N)cc2o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 58.3 %

Procedure:
A mixture of N-[4-acetyl-3-hydroxyphenyl)acetamide (24.1 g, 0.125 mol) and diethyl oxalate (47.5 g, 0.33 mol) in absolute ethanol (200 mL) was added to a solution of sodium ethoxide (14 g sodium in 300 mL absolute ethanol). The reaction was heated to reflux for 2 hours and allowed to cool to room temperature then poured into water (500 mL) and methylene chloride (1500 mL). The aqueous layer was made slightly acidic using 6N hydrochloric acid. The organic layer separated and the aqueous layer washed again using methylene chloride (500 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum. The solid material (35.8 g) was dissolved in ethanol (350 mL) and concentrated hydrochloric acid (6 mL) was added. The solution was heated to reflux for 1 day, removed from heat and allowed to stand for 2 days. The orange solid was filtered to afford 17 g of ethyl 7-amino-4-oxo-4H-1-benzopyran-2-carboxylate. The mother liquor was concentrated to afford another 4.94 g of desired product. Yield 75.6%, 1H NMR (DMSO-d6) δ 1.32 (3H, t, J=7.25 Hz, CH2CH3,), 4.34 (2H, q, J=7.03 Hz, CH2CH3), 6.50 (2H, bs, NH2), 6.53 (1H, d, J=1.98 Hz, =CH), 6.69 (1H, dd, J=8.78, 1.98 Hz, ArH), 6.71 (1H, s, ArH), 7.68 (1H, d, J=8.78 Hz, ArH); MS (EI) m/z, 233 (M+).