Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].S(Cl)([Cl:19])=O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([Cl:19])=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Product: COc1cc(CC(=O)Cl)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
3,4,5-trimethoxy phenyl acetic acid (9.5 g, 0.042 mol) was added slowly to the thionyl chloride (15 g, 0.126 mol) cooled to 0° C., and warmed to room temperature, then stirred for 3 hours. Residual thionyl chloride was distilled out to obtain 3,4,5-trimethoxy phenyl acetic acid chloride (10.3 g, 0.042 mol). Thymol (6.3 g, 0.042 mol) and triethylamine (6.4 g, 0.063 mol) were dissolved in 200 ml of dichloromethane and stirred, and then the above 3,4,5-trimethoxy phenyl acetic acid chloride (10.3 g) dissolved in 50 ml of dichloromethane was added thereto drop by drop. After the reaction was completed, reaction solution was condensed, and 500 ml of ethyl acetate was added to dissolve the reaction mixture. The resultant was washed with distilled water twice, dried with anhydrous sodium sulfate, then filtered and condensed, and finally proceeded to column chromatography to obtain 9.0 g (Yield=60%) of white solid state of the object product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:13])[C:10](O)=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC)=O.[N-:27]=[N+:28]=[N-:29].[Na+]>CC(C)=O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[C:9]([CH3:13])[C:10]([N:27]=[N+:28]=[N-:29])=[O:11])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=Cc1ccc(Cl)cc1)C(=O)O
Agent: CCOC(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CC(=Cc1ccc(Cl)cc1)C(=O)N=[N+]=[N-]
Reaction time: 2 h
Yield: 87.7 %

Procedure:
To a solution of 3-(4-chlorophenyl)-2-methyl-acrylic acid (11.2 g, 57 mmol) in 500 mL of acetone at 0° C. is added triethyl amine (9.6 mL, 68 mmol) followed by ethyl chloroformate (6.2 mL, 63 mmol). The solution is allowed to warm to ambient temperatures. After 2 h, sodium azide (5.6 g, 86 mmol) in 35 mL of H2O is added. After addition, the solution is stirred for 2 hours. The solution is diluted with H2O (100 mL). The resulting solid is collected by filtration giving the title compound as a white solid (11.1 g, 50 mmol). 1H NMR (CDCl3, 300 MHz) δ7.67 (s, 1H), 3.38 (m, 4H), 2.10 9s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:7]=12.[CH3:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[ClH:1].[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:8]2[C:7]3=[C:2]([NH:27][CH2:26][C:25]4[CH:28]=[CH:29][C:22]([CH3:21])=[CH:23][CH:24]=4)[N:3]=[CH:4][CH:5]=[C:6]3[C:10]([CH3:11])=[C:9]2[CH3:12])=[CH:15][CH:16]=1
Reactant: Cc1ccc(CN)cc1
Reactant: Cc1c(C)n(Cc2ccc(F)cc2)c2c(Cl)nccc12
Product: Cc1ccc(CNc2nccc3c(C)c(C)n(Cc4ccc(F)cc4)c23)cc1
Product: Cl
Yield: 45 %

Procedure:
In accordance with the same procedures as in Step 3 of Example 198, except for using 7-chloro-1-(4-fluorobenzyl)-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-methylbenzylamine, the titled compound was obtained as a white solid. (Yield: 45%)
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:6][CH:5]=1)([OH:3])=[O:2].[CH2:21](Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:21]([O:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:8][CH:9]=1)=[O:3])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)O)cc2)cc1
Reactant: ClCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(C(=O)OCc3ccccc3)cc2)cc1

Procedure:
A solution of 11.64 g (40 mmol) of N-(4-carboxyphenyl)-4-toluenesulfonamide, 5.06 g (40 mmol) of benzyl chloride and 5.20 g (44 mmol) of di-i-propylethylamine in 100 ml of dimethylformamide is heated at 140° C. f or 4 hours. After the reaction is complete, the mixture is evaporated in vacuo, the residue is taken up in propyl acetate, and the solution is washed 2× with 2N hydrochloric acid and ##STR22## 2× with saturated NaHCO3 solution, dried over sodium sulfate and evaporated. 11.8 g (78% of theory) of N-(4-benzyloxycarbonylphenyl)-4-toluenesulfonamide, which are recrystallized from methanol, are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:15])[S:7](=[O:14])(=[O:13])[CH2:8][C:9](=O)[C:10]=2[N:11]=1.[C:16]([O-:19])([O-])=O.[K+].[K+].[CH3:22]N(C=O)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH3:15])[S:7](=[O:13])(=[O:14])[C:8]([CH3:9])([CH3:22])[C:16](=[O:19])[C:10]=2[N:11]=1
Reactant: O=C([O-])[O-]
Reactant: CN1c2ccc(Br)nc2C(=O)CS1(=O)=O
Reactant: CN(C)C=O
Agent: [K+]
Product: CN1c2ccc(Br)nc2C(=O)C(C)(C)S1(=O)=O
Temperature: 60 °C

Procedure:
To a solution of 6-bromo-1-methyl-2,2-dioxo-pyrido[3,2-c]thiazin-4-one (456 mg, 1.56 mmol) in DMF (3 ml) was added K2CO3 (2.16 g, 15.6 mmol) followed by Mel (0.29 ml, 4.7 mmol) at ambient temperature. The suspension was heated to 60° C. for 1.5 h then cooled to ambient temperature, filtered, washed with ethyl acetate and concentrated under reduced pressure. Purification by flash chromatography eluting with ethyl acetate/heptane, gradient, afforded 6-bromo-1,3,3-trimethyl-2,2-dioxo-pyrido[3,2-c]thiazin-4-one.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:14]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]([OH:37])[CH3:36])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:13])[CH3:12].[Cl-].[NH4+]>ClCCl.C(N(CC)CC)C>[C:11]([N:14]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35](=[O:37])[CH3:36])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)N(Cc1ccccc1C(C)O)c1ccccc1Oc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)c1ccccc1CN(C(C)=O)c1ccccc1Oc1ccccc1
Temperature: -45 °C
Reaction time: 0.17 h
Yield: 85.9 %

Procedure:
A solution of 0.22 ml of oxalyl chloride in 13.5 ml of dichloromethane was cooled to −70° C. or below on dry-ice-acetone, and a solution of 0.24 ml of dimethyl sulfoxide in 0.9 ml of dichloromethane was added dropwise, followed by stirring for 10 minutes. To this was added dropwise a solution of 0.48 g of N-acetyl-N-[2-(1-hydroxyethyl)benzyl]-2-phenoxyaniline in 4.5 ml of dichloromethane, and the temperature of the reaction solution was gradually raised to −45° C., followed by stirring at the same temperature for an hour. To the reaction solution was added dropwise 1.34 ml of triethylamine at −40° C. or below, followed by stirring at 0° C. for 20 minutes. The reaction solution, after addition of a saturated aqueous ammonium chloride solution, was extracted with ethyl acetate, and the extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:1) and recrystallized from ethyl acetate-hexane to give 0.41 g of N-acetyl-N-(2-acetylbenzyl)-2-phenoxyaniline.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[F:32])[CH:27]=[O:28].O>C(OCC)C>[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[F:32])[CH:27]([C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:28]
Reactant: COCOc1cccnc1Br
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: CCOCC
Product: COCOc1cccnc1C(O)c1ccc(F)c(Br)c1
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of 2-bromo-3-methoxymethoxypyridine (11.8 g) in diethyl ether (250 mL) was added, at -78° C., a 1.6M n-butyl lithium hexane solution (36.0 mL). The mixture was stirred for one hour at the same temperature, to which was further added a solution of 3-bromo-4-fluorobenzaldehyde (10.0 g) in diethyl ether (50 mL), and the mixture was stirred for one hour at the same temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract was washed with a saturated aqueous saline solution, which was then dried (sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromo-4-fluoro-α-hydroxybenzyl)-3-methoxymethoxypyridine (14.0 g) (compound A-5). Physical properties and spectrum data of the product are shown in Table 1 and Table 2.
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([NH:10][C:11](=[O:33])[C@@H:12]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH:23]=[CH2:24])=[CH:16][CH:15]=1)[CH2:5][CH:6]([CH2:8]C)[CH3:7].[OH-].[Na+].CO>C1COCC1.O>[CH2:21]([O:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@H:12]([NH:25][C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C:11]([NH:10][C@@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:3]([OH:34])=[O:2])=[O:33])=[CH:19][CH:18]=1)[CH2:22][CH:23]=[CH2:24]
Reactant: C=CCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)CC)C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCCOc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl ester 20 (2.30 g, 4.97 mmol) was dissolved in THF (30 mL) and NaOH (0.298 g, 7.46 mmol) dissolved in water (10 mL) was added. Methanol (10 mL) was added to obtain a homogenous solution and this was stirred at rt for 18 h. The reaction mixture was then concentrated in vacuo and the residue was partitioned between EtOAc and 1M hydrochloric acid. The aqueous phase was extracted twice more with EtOAc and the combined organic extracts were washed with brine, dried (MgSO4), filtered and concentrated in vacuo to yield a white solid, 2.14 g, 96%. m.p. 68-70° C.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[F:11][C:12]([F:21])([F:20])[C:13]#[C:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C(N(CC)CC)C>ClCCl>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:3]1[C:13]([C:12]([F:11])([F:21])[F:20])=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:1][N:2]=1
Reactant: ON=C(Cl)c1ccccn1
Reactant: CCOC(=O)C#CC(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1onc(-c2ccccn2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 6.7 %

Procedure:
To a yellow, homogeneous mixture of N-hydroxypicolinimidoyl chloride (4.67 g, 29.8 mmol) and ethyl 4,4,4-trifluorobut-2-ynoate (4.50 g, 27.1 mmol) in dichloromethane (90 mL) at room temperature was added triethylamine (7.93 mL, 56.9 mmol) slowly over 30 min. During the addition, the reaction mixture slowly became dark in color. The reaction was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was diluted with ether (100 mL) and washed with water (100 mL). The organic layer was collected, and the aqueous layer was extracted with ether (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. By HPLC, the product mixture contained a ˜15:85 mixture of the desired isomer and its regioisomer. The mixture was purified by preparative HPLC, and the desired fractions were concentrated under reduced pressure. The residue was diluted with ethyl acetate (100 mL), washed with a saturated aqueous solution of sodium bicarbonate (100 mL), washed with brine (50 mL), and dried over anhydrous magnesium sulfate. Concentration under reduced pressure afforded ethyl 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylate (0.518 g, 1.81 mmol, 6.7% yield) as a pale yellow, viscous oil. The compound had an HPLC ret. time=2.18 min.—Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=286.9. 1H NMR (400 MHz, CDCl3) δ ppm 1.46 (t, J=7.15 Hz, 3H), 4.54 (q, J=7.03 Hz, 2H), 7.46 (ddd, J=7.53, 4.77, 1.25 Hz, 1H), 7.76-7.81 (m, 1H), 7.83-7.89 (m, 1H), and 8.78 (d, J=4.77 Hz, 1H).
Reaction SMILES: [OH:1][C@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[CH2:34][C:35](=[O:41])[NH:36]2.N1CCCCC1>C(O)C>[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1/[C:34](=[CH:14]/[C:11]1[NH:10][C:7]3[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[C:5](=[O:16])[C:6]=3[C:12]=1[CH3:13])/[C:35](=[O:41])[NH:36]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 73 %

Procedure:
(R)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde if (50 mg, 0.156 mmol), 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 3d (34.3 mg, 0.14 mmol) and piperidine (7.7 μL, 0.078 mmol) were dissolved in 0.3 mL of ethanol under stirring at room temperature. The reaction system was stirred at 80° C. in an oil bath in dark for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the oil bath was removed. The reaction system was naturally cooled down to room temperature to precipitate solids. The resulting solids were filtered to give the title compound 2-[(Z)-4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-[(R)-2-hydroxy-3-morpholin-4-yl-propyl]-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 3 (56 mg, yield 73%) as a yellow solid.
Reaction SMILES: CC(OC1C=CC(C([C:18]2[CH:23]=[CH:22][C:21](OC(C)=O)=[CH:20]C=2)=C2CCCCC2)=CC=1)=O.[CH3:28][N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][CH:32]=[N:33][C:34]=2[NH2:38].C1(N)CCCC1.CN(C)C>C(O)C>[CH:21]1([NH:38][C:34]2[N:33]=[CH:32][N:31]=[C:30]3[C:35]=2[N:36]=[CH:37][N:29]3[CH3:28])[CH2:20][CH2:18][CH2:23][CH2:22]1
Reactant: Cn1cnc2c(N)ncnc21
Reactant: CC(=O)Oc1ccc(C(=C2CCCCC2)c2ccc(OC(C)=O)cc2)cc1
Agent: CN(C)C
Agent: NC1CCCC1
Solvent: CCO
Product: Cn1cnc2c(NC3CCCC3)ncnc21
Yield: 74 %

Procedure:
To prepare N6 -cyclopenyl-9-methyl Adenine the following additional steps were taken. A mixture of 6-chloro-9-methyl Adenine (0.82 g) , cyclopentylamine (0.52 ml) , trimethylamine (0.53 ml) and ethanol. (60 ml), was refluxed for 24 hours. The solution was concentrated in vacuo to a yellow syrup. The syrup was passed through a C-18 column to give 0.78 g or 74% yield of with m.p. 108°-109° C. 1HNMR(Me2SO-d6): δ1-2 (m, 9 H); 3.7 (S, CH3); 7.6(d,NH); 8.1(S,1H); 8.2(S,1H).
Reaction SMILES: [C:1]([C:3]1([NH:8][C:9](=O)[CH2:10][CH2:11][CH2:12][CH3:13])[CH2:7][CH2:6][CH2:5][CH2:4]1)#[N:2].[ClH:15].C([OH:20])CCC>>[ClH:15].[CH2:10]([C:9]1[NH:8][C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[C:1](=[O:20])[N:2]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCC(=O)NC1(C#N)CCCC1
Reactant: CCCCO
Agent: Cl
Product: CCCCC1=NC(=O)C2(CCCC2)N1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
6.88 g (30 mmol) of N-(1-cyanocyclopentyl)pentanamide (content 84.7 percent), 16.66 g of dried butanol and 10.06 g (39 mmol) of a freshly-prepared 14.13 percent solution of hydrogen chloride in butanol were heated to the reflux point (preheated oil bath) under nitrogen, with stirring, and product precipitated out as soon as the internal temperature reached ca. 100° C. After 2.9 hours of reflux (115° C.), the mixture was cooled to 1° C. and left to stand for 1 hour at this temperature. The product which had precipitated out was filtered off, washed with 10 ml of ice-cold butanol and dried at 40° C./24 mbar. The yield of the product was 4.93 g (66 percent), content 92.7 percent (HPLC).
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:23]=2[N:24]=1>C1COCC1>[Cl:29][C:25]1[C:23]2[N:24]=[C:20]([CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3])[S:21][C:22]=2[CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)OC(C)(C)C
Reactant: Clc1nc2c(Cl)cccc2s1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cc1nc2c(Cl)cccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
A 1-Liter, 3-necked round bottomed flask fitted with a nitrogen inlet, a 500 mL addition funnel and a septum stopper was charged with t-butyl acetate (26.8 mL, 200 mmol) and anhydrous THF (50 mL). Upon cooling in a dry ice-acetone bath, to the mixture was added lithium bis(trimethylsilyl)amide (1M, THF solution) (200 mL, 200 mmol) via syringe over 15 min. After stirring at that temperature for 30 minutes, to the mixture was added a solution of 2,4-dichloro-benzothiazole (8.15 g, 40 mmol) in THF (100 mL) from the addition funnel over 15 minutes. The cooling bath was removed allowing the reaction to warm to room temperature over 1 hour. The reaction mixture was concentrated, then diluted with EtOAc and a saturated NaHCO3 solution. The organic layer was separated and the aqueous layer was extracted with EtOAc twice. The combined organic layer was dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography on silica gel eluting with a gradient mixture of EtOAc/hexanes to give 11.28 g (99%) of the title compound as a yellow solid. 1H-NMR (500 MHz, DMSO-d6) δ (ppm) 8.00 (1H, dd, J=1.0, 8.0 Hz), 7.53 (1H, dd, J=1.0, 8.0 Hz), 7.36 (1H, t, J=8.0 Hz), 4.19 (2H, s), 1.38 (9H, s).
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])[CH3:22])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][C:21]3[CH:22]=[CH:11][CH:6]=[C:7]([CH3:8])[CH:23]=3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(CNn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.090 g, 0.2 mmol) in tetrahydrofuran (4 mL) and methanol (0.015 mL, 0.4 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 2% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.29 (s, 3 H) 4.15 (s, 2 H) 6.94 (s, 1 H) 7.22 (m, 4 H) 7.30 (d, J=5.15 Hz, 1 H) 7.56 (t, J=7.72 Hz, 1 H) 7.68 (d, J=8.46 Hz, 1 H) 7.79 (t, J=6.99 Hz, 1 H) 7.94 (d, J=7.72 Hz, 1 H) 8.24 (d, J=5.15 Hz, 1 H) 14.26 (s, 1 H) 14.84 (s, 1 H). MS (ESI−) m/z 465(M−H)−.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[C:6]=1[CH3:7].[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:7][C:6]1[N:5]([C:8]2[N:13]=[C:12]([C:14]([F:16])([F:15])[F:17])[CH:11]=[C:10]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:22][CH:23]=3)[N:9]=2)[CH:4]=[N:3][C:2]=1[C:32]1[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: Cc1c(I)ncn1-c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Product: Cc1c(-c2ccc(N)nc2)ncn1-c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared from 2-(4-iodo-5-methyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.67) (0.25 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.13 g, 0.6 mmol) according to the general procedure VI. Obtained as a yellow solid (0.12 g, 50%). MS (ISP) 465.1 [(M+H)+]; mp 252° C.
Reaction SMILES: [O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][O:41][C:42]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)=[O:43])=[CH:36][CH:35]=1)=[O:32])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[NH2:29])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14].[OH:50][C@:51]1([C:92](O)=[O:93])[CH2:68][C@H:67]([O:69][C@@H:70]2[O:84][C@@H:83]([CH3:85])[C@H:73]3[O:74][C@H:75]4[N:80]([C@H:72]3[CH2:71]2)[CH2:79][CH2:78][O:77][C@@H:76]4[O:81][CH3:82])[C:66]2[C:53](=[C:54]([OH:91])[C:55]3[C:56](=[O:90])[C:57]4[C:62]([C:63](=[O:87])[C:64]=3[C:65]=2[OH:86])=[C:61]([O:88][CH3:89])[CH:60]=[CH:59][CH:58]=4)[CH2:52]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[CH:6]=[CH:5][C:4](=[O:7])[N:3]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([NH:15][C@H:16]([C:20]([NH:22][C@H:23]([C:31]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][O:41][C:42]([N:44]2[CH2:45][CH2:46][N:47]([C:92]([C@@:51]3([OH:50])[CH2:68][C@H:67]([O:69][C@@H:70]4[O:84][C@@H:83]([CH3:85])[C@H:73]5[O:74][C@H:75]6[N:80]([C@H:72]5[CH2:71]4)[CH2:79][CH2:78][O:77][C@@H:76]6[O:81][CH3:82])[C:66]4[C:53](=[C:54]([OH:91])[C:55]5[C:56](=[O:90])[C:57]6[C:62]([C:63](=[O:87])[C:64]=5[C:65]=4[OH:86])=[C:61]([O:88][CH3:89])[CH:60]=[CH:59][CH:58]=6)[CH2:52]3)=[O:93])[CH2:48][CH2:49]2)=[O:43])=[CH:38][CH:39]=1)=[O:32])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:30])[NH2:29])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)O)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Reactant: CC(C)[C@H](NC(=O)CCCCCN1C(=O)C=CC1=O)C(=O)N[C@@H](CCCNC(N)=O)C(=O)Nc1ccc(COC(=O)N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)N1CCN(C(=O)OCc2ccc(NC(=O)[C@H](CCCNC(N)=O)NC(=O)[C@@H](NC(=O)CCCCCN4C(=O)C=CC4=O)C(C)C)cc2)CC1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Step 3 To the intermediate 60 (13.2 mg) a solution of crude (2S,4S)-2,5,12-trihydroxy-7-methoxy-4-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracene-2-carboxylic acid 56 (9.3 mg) in anhydrous dichloromethane (2.6 ml), TBTU (5.3 mg, 0.0165 mmol), and anhydrous triethylamine (2.8 mg, 0.0275 mg) was added. The reaction mixture was stirred at room temperature under argon atmosphere for 15 minutes, until disappearance of the starting material (HPLC-MS analysis). The solvent was then evaporated under vacuum and the crude was purified by flash column chromatography (EtOH:AcOEt=1.5:8.5) on silica gel (230-400 mesh), affording 4.8 mg (red solid, yield calculated on PNU-159682=34%) of 55. MS (ESI): 1295 [M+H]+. Retention time=5.51 min(method 1).