Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].CC(O)C.[N:7]1([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([OH:39])=[C:18]([CH:38]=2)[C:19]([NH:21][C:22]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[CH:28][C:23]=2[C:24]([O:26]C)=[O:25])=[O:20])[CH2:10][CH2:9][CH2:8]1.[ClH:40]>O>[ClH:40].[N:7]1([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([OH:39])=[C:18]([CH:38]=2)[C:19]([NH:21][C:22]2[CH:31]=[C:30]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:29]=[CH:28][C:23]=2[C:24]([OH:26])=[O:25])=[O:20])[CH2:10][CH2:9][CH2:8]1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCC2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(Nc1cc(-c2ccccc2)ccc1C(=O)O)c1cc(OCCN2CCC2)ccc1O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (0.11 mL) was added to a 2-propanol (1.0 mL) suspension of the obtained methyl 2-(5-(2-(azetidin-1-yl)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoate (0.032 g), followed by stirring at 50° C. for 1 hour. The reaction mixture was cooled to room temperature, and water was added thereto. After adjusting the pH to 6.0 with 1.0 mol/L hydrochloric acid, the solid substance was collected by filtration. Ethyl acetate (1.5 mL) and a 4.0 mol/L hydrogen chloride-dioxane solution (0.10 mL) were added to the obtained solid substance, followed by stirring at room temperature for 1 hour and 30 minutes. The solid substance was collected from the reaction mixture by filtration to obtain 0.021 g of 2-(5-(2-(azetidin-1-yl)ethoxy)-2-hydroxybenzamido)-4-phenylbenzoic acid hydrochloride as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[C:8]([Cl:11])[CH:9]=2)[CH2:4][CH:3]1[CH2:17][CH3:18].[Br:19]Br>Br.C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[C:8]([Cl:11])[CH:9]=2)[CH2:4][C:3]1([Br:19])[CH2:17][CH3:18]
Reactant: CCC1Cc2cc(OCC(=O)O)c(Cl)cc2C1=O
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: CCC1(Br)Cc2cc(OCC(=O)O)c(Cl)cc2C1=O

Procedure:
(1-Oxo-2-bromo-2-ethyl-6-chloro-5-indanyloxy)acetic acid is prepared by following substantially the same procedure as described in Example 1, Step B, using the following reagents: (1-oxo-2-ethyl-6-chloro-5-indanyloxy)acetic acid (13.44 g., 0.05 mole), bromine (8.79 g., 0.055 mole), acetic acid (135 ml.) and 48% hydrobromic acid (2 drops). The crude yield of the product is 17.38 g. (100%), m.p. 157°-159° C. Recrystallization from benzene gives (1-oxo-2-bromo-2-ethyl-6-chloro-5-indanyloxy)acetic acid as white needles, m.p. 159.5°-160.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[NH:6][C:5]2=[O:23].[CH3:24][C:25](OC(C)=O)=[O:26]>N1C=CC=CC=1>[C:25]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=1)[NH:6][C:5]2=[O:23])(=[O:26])[CH3:24]
Reactant: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c2cc1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: COc1cc2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c2cc1OC(C)=O
Temperature: 105 °C
Reaction time: 2 h

Procedure:
A mixture of 6-hydroxy-7-methoxy-2-(3-nitrophenyl)quinazolin-4(3H)-one (2.3 g, 7.34 mmol), Ac2O (40 mL) and pyridine (4 mL) were heated at 105° C. for 3.5 h. The reaction mixture was allowed to cool and poured into ice-water (ca. 300 mL) and the resulting slurry was stirred for 2 h. The solid was collected by filtration and washed with water, EtOH and Et2O and dried under high vacuum to give 7-methoxy-2-(3-nitrophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl acetate. (2.6 g, 7.31 mmol, 99%). HPLC retention time 6.24 min.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([CH2:27][CH2:28][CH2:29]Cl)[O:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][O:20]2)=[CH:15][CH:14]=1.O>CN(C)C=O>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2([CH2:27][CH2:28][CH2:29][O:3][C:4]3[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=3)[C:7]#[N:8])[O:20][CH2:21][C:22]([CH3:25])([CH3:26])[CH2:23][O:24]2)=[CH:17][CH:18]=1
Reactant: N#Cc1cccc(O)c1
Reactant: CC1(C)COC(CCCCl)(c2ccc(Br)cc2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)COC(CCCOc2cccc(C#N)c2)(c2ccc(Br)cc2)OC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
236 mg (5.9 mmol) of sodium hydride (oily, 60%) was stirred in dimethylformamide. 691 mg (5.8 mmol) of 3-hydroxybenzonitrile was added thereto under cooling with ice. After stirring at room temperature for 30 minutes, a solution of 2 g (5.75 mmol) of 2-(4-bromophenyl)-2-(3-chloropropyl)-5,5-dimethyl-1,3-dioxane in dimethylformamide was added to the reaction mixture, and they were stirred at 100° C. overnight. Water was added to the mixture. After the extraction with ethyl acetate, the organic layer was washed with 1 N aqueous sodium hydroxide solution and saturated aqueous common salt solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the crude title compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([OH:9])=O)(=[O:3])[CH3:2].CC[N:16]([CH:20]([CH3:22])C)[CH:17]([CH3:19])C.N1CCCC1>CN(C=O)C>[OH:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([N:16]2[CH2:17][CH2:19][CH2:22][CH2:20]2)=[O:9])=[CH:5][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(C(=O)O)ccc1O
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCNC1
Product: CC(=O)c1cc(C(=O)N2CCCC2)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
To a solution of 500 mg (2.8 mmol) of 3-acetyl-4-hydroxy-benzoic acid in 5 mL of DMF, 721.6 μL (4.2 mmol) of TFA-OPfp and 731.5 μL (4.2 mmol) of DIEA were added. The clear solution was stirred at room temperature for 15 minutes, then 467.5 μL (5.6 mmol) of pyrrolidine was added. The mixture was stirred for another hour and was then evaporated to dryness. The oily residue was taken up in 50 mL water-50 mL ethyl acetate mixture, the EtOAc phase was separated, washed twice with 1 M HCl, water, saturated NaHCO3, brine and was dried with Na2SO4. The EtOAc was evaporated; the oil was purified on an open silica gel column using a toluene/ethyl acetate gradient containing 5% acetic acid to yield 410 mg (51%) Compound 18.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][OH:13])[CH:3]=1.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH2:21]([O:20][C:14](=[O:19])[CH2:15][C:16]1([CH3:18])[C:3]2=[C:2]([CH3:1])[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]2[CH2:11][CH2:12][O:13]1)[CH3:22]
Reactant: Cc1cn(CCO)c2ccccc12
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)CC1(C)OCCn2c1c(C)c1ccccc12

Procedure:
A mixture of the intermediate of formula III, 3-methylindole-1-ethanol(26.5 g., 0.15 mole), described in Example 1, in toluene (600 ml.), ethyl acetoacetate (36 g., 0.20 mole) and p-toluenesulfonic acid (2.0 g.) is heated at reflux for 6 hr. using a water separator. The toluene solution is washed with water, 5% bicarbonate solution, and again with water. The solution is then dried over sodium sulfate and the solvent evaporated under reduced pressure to give an oil. The oil was subjected to chromatography on silica gel. Elution with 10% ethyl acetate in benzene and concentration of the eluate affords the ester, 3,4-dihydro-1,10-dimethyl-1H-1,4-oxazino[4,3-a]indole-1-acetic acid ethyl ester, as an oil, γmaxfilm 1725 cm-1.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:6][C:7]1[O:8][CH2+:9]([C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)[C:10]2[CH:16]=[C:15]([O:17]C)[C:14]([O:19]C)=[CH:13][C:11]=2[CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-].C(OCC)(=O)C>[N+](C)([O-])=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[OH:19][C:14]1[C:15]([OH:17])=[CH:16][C:10]2[CH2+:9]([C:21]3[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=3)[O:8][C:7]([CH3:6])=[CH:12][C:11]=2[CH:13]=1
Reactant: COc1cc2c(cc1OC)[CH2+](c1ccc([N+](=O)[O-])cc1)OC(C)=C2
Agent: [Al+3]
Agent: [Cl-]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C[N+](=O)[O-]
Product: CC1=Cc2cc(O)c(O)cc2[CH2+](c2ccc([N+](=O)[O-])cc2)O1
Reaction time: 4 h
Yield: 73 %

Procedure:
44.0 g of 3-methyl-6,7-dimethoxy-1-(4-nitrophenyl)-2-benzopyrylium-perchlorate (C.A. 105, 1986, 152712h) is added to a solution of 46.3 g of AlCl3 in 170 ml of nitromethane and heated to boiling for 4 hours. The solvent is removed, the residue is treated with 500 ml of cooled 50% HCl solution, and the product that is obtained is washed with cold water. 43.5 g of crude product, which is mixed with 130 ml of acetic acid, heated to boiling and mixed with 13.3 ml of 70% HClO4, is obtained. After cooling, 30.0 g of the title compound (73%) with melting point 253°-255° C. (decomposition ethyl acetate) is obtained.
Reaction SMILES: C(O[C:6](=[O:19])[NH:7][C@@H:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C@@H:9]([OH:11])[CH3:10])(C)(C)C.[H-].[Na+].Br[CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[C:37]([F:43])=[CH:36][C:35]=1[O:44][CH3:45]>>[CH2:12]([C@H:8]1[C@@H:9]([CH3:10])[O:11][C:6](=[O:19])[N:7]1[CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=[CH:26][C:25]=1[C:34]1[CH:39]=[C:38]([CH:40]([CH3:42])[CH3:41])[C:37]([F:43])=[CH:36][C:35]=1[O:44][CH3:45])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CBr
Agent: [H-]
Agent: [Na+]
Product: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](C)[C@@H]1Cc1ccccc1

Procedure:
tert-butyl[(1S,2S)-1-benzyl-2-hydroxypropyl]carbamate (Example 317, Step B, 39 mg, 0.148 mmol) was treated with sodium hydride (60% in oil, 12 mg, 0.309 mmol) and 2′-(bromomethyl)-4-fluoro-5-isopropyl-2-methoxy-4′-(trifluoromethyl)biphenyl (Intermediate 10, 50 mg, 0.123 mmol) as described in Example 305 to afford (4S,5R)-4-benzyl-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-5-methyl-1,3-oxazolidin-2-one as a clear glass. LCMS=516.4 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers) δ 7.64-759 (m, 2H), 7.33-7.30 (m, 1H), 7.28-7.21 (m, 2H), 7.16 (s, 1H), 7.00-6.91 (m, 3H), 6.67 (d, J=3 Hz, 1H), 4.70 (d, J=2.7 Hz, 1H), 4.52-4.47 (m, 1H), 3.95 (d, J=15.8 Hz, 1H), 3.70 (s, 3H), 3.68-3.62 (m, 1H), 3.24-3.18 (m, 1H), 2.72-2.53 (m, 2H), 1.28-1.21 (m, 6H), 1.19 (d, J=6.8 Hz, 3H).
Reaction SMILES: O=[C:2]([CH2:7]CC)[CH2:3]C(O)=O.[C:10]([OH:16])(=[O:15])[CH2:11][C:12]([OH:14])=[O:13].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:3][C:2]1([CH3:7])[O:16][C:10](=[O:15])[CH2:11][C:12](=[O:14])[O:13]1
Reactant: O=C(O)CC(=O)O
Reactant: CCCC(=O)CC(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: CC1(C)OC(=O)CC(=O)O1
Temperature: 50 °C
Reaction time: 3 h
Yield: 191.3 %

Procedure:
50 g of resin-bound 2-oxopentanecarboxylic acid (1) are swollen in 200 ml of acetic acid and treated with 20 g of malonic acid (2). 10 g of anhydrous ammonium acetate are added and the mixture is heated to 50° C. After stirring carefully for 3 h, the resin is freed from the solution, washed thoroughly with DMF and methylene chloride and dried. 53 g of (3) are obtained. Removal of a sample using anhydrous TFA yields the free Meldrum's. acid derivative (3, Li-P=H) (HPLC, MS).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:8](=[O:15])[C:9]2[C:10](=[CH:12][S:13][CH:14]=2)[N:11]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O1CCCC1.CN(C)C1C=CN=CC=1>[O:15]=[C:8]1[N:7]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([F:26])([F:25])[F:27])=[CH:20][CH:21]=2)[C:6]([S:5][CH2:4][CH2:3][NH:2][C:35](=[O:37])[CH3:36])=[N:11][C:10]2=[CH:12][S:13][CH:14]=[C:9]12
Reactant: CC(=O)OC(C)=O
Reactant: NCCSc1nc2cscc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCSc1nc2cscc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-[(2-Aminoethyl)sulfanyl]-3-[4-(2,2,2-trifluoroethoxy)phenyl]thieno[3,4-d]pyrimidin-4(3H)-one hydrochloride (0.33 g) was suspended in tetrahydrofuran (30 ml), triethylamine (0.31 ml), acetic anhydride (0.28 ml) and 4-dimethylaminopyridine (37 mg) were added successively thereto, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The extract was washed successively with saturated aqueous citric acid solution, water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-yellow solid was purified by silica gel column chromatography (ethyl acetate/hexane) to give a colorless solid. This solid was recrystallized from ethyl acetate/hexane to give the title compound (0.22 g) as a colorless solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:28])[NH:26][NH2:27].[CH2:29](N(CC)CC)[CH3:30].C(Cl)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]1[S:28][C:29]([CH3:30])=[N:27][N:26]=1
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=S)NN)OCO3
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: Cc1nnc(N2N=C(c3ccc([N+](=O)[O-])cc3)c3cc4c(cc3CC2C)OCO4)s1
Temperature: 0 °C
Reaction time: 16 h
Yield: 93.5 %

Procedure:
To an ice cooled stirred mixture of 1.0 g (2.50 mmol) of the starting material XVIII, 35 ml of dichloromethane, 0.40 ml (2.75 mmol) of triethylamine and 0.22 ml (2.80 mmol) of acetyl chloride was added. The so obtained solution was left at room temperature for 16 h, then 0.6 g of p-toluenesulfonic acid was added and the mire was stirred at 40° C. for 2 h. Then the reaction mixture was washed with sodium hydrogen carbonate solution and water until neutrality, dried and concentrated. The crude product was treated with methanol, then recrystallized from ethanol to yield 0.99 g (91%) of the title compound. Mp.: 213-215° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH:34]=O)=[CH:4][N:3]=1.[NH:36]1[CH2:40][CH2:39][CH:38]([NH:41]C(=O)OC(C)(C)C)[CH2:37]1.Cl.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][N:36]2[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37]2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: COc1cc(-c2csc3c(/C=C/C=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: COc1cc(-c2csc3c(/C=C/CN4CCC(N)C4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Yield: 19.7 %

Procedure:
N-(4-{4-Amino-7-[(1E)-3-oxoprop-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (100 mg, 0.207 mmol) and tert-butyl pyrrolidin-3-ylcarbamate (115.7 mg, 0.621 mmol) were reacted according to General Procedure B. The crude product (135 mg, 0.207 mmol) was dissolved in methanol (1 mL) and treated with 6.0 M hydrochloric acid in 1,4 dioxane (0.518 mL, 2.07 mmol) and heated to 55 degrees Celsius for 4 hours. The mixture was cooled to room temperature then 1M sodium carbonate solution (5 mL) was added and product was extracted with ethyl acetate (3×10 mL). The organic layer was separated, dried over magnesium sulfate, filtered, and the solvent was removed under reduced pressure. The product was purified via flash chromatography to furnish the title compound as an ivory powder (22.5 mg, 0.0408 mmol): LCMS (Conditions a): MH−=551 RT=3.62 minutes; 1H NMR (DMSO-d6, 400 MHz) δ 9.51 (1H), 7.97 (2H), 7.72 (1H), 7.63 (2H), 7.36 (2H), 7.21 (1H), 7.15 (1H), 7.07 (1H), 6.70 (1H), 6.26 (1H), 5.65 (1H), 4.04 (3H), 3.91 (3H), 3.51 (1H), 3.29 (2H), 2.71 (2H), 2.45 (2H), 2.10 (1H), 1.53 (1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22](Cl)[C:23]3[CH:28]=[C:27]([CH3:29])[S:26][C:24]=3[N:25]=2)=[CH:16][CH:15]=1>>[CH3:11][O:12][C:13](=[O:31])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:23]3[CH:28]=[C:27]([CH3:29])[S:26][C:24]=3[N:25]=2)=[CH:18][CH:19]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3cc(C)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(Cl)c(Cl)c3)c3cc(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dichlorobenzylamine is reacted with 4-(4-chloro-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dichlorobenzylamino)-6-methyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH:8]([CH3:16])[C:9]([O:11]C(C)(C)C)=[O:10].Cl>O1CCOCC1>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH:8]([CH3:16])[C:9]([OH:11])=[O:10]
Reactant: CC(C(=O)OC(C)(C)C)n1ccccc1=O
Agent: Cl
Solvent: C1COCCO1
Product: CC(C(=O)O)n1ccccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
To a stirred suspension of 16.6 g (74.4 mmol) of tert-butyl 2-(2-oxopyridin-1(2H)-yl)propanoate from step A in 10 mL of anhydrous 1,4-dioxane under an atmosphere of nitrogen was added 150 mL of a 4.0 M hydrogen chloride solution in 1,4-dioxane. The resulting solution was stirred overnight at ambient temperature then evaporated to dryness in vacuo to afford the title compound as a white solid (12.4 g, quantitative yield). LC-MS: m/z (ES) 168 (MH)+
Reaction SMILES: [N:1]([C@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1
Reactant: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Yield: 92.7 %

Procedure:
A solution of (2S,4R)-4-azido-l-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (112 g) in methanol (870 ml) was hydrogenated under ambient pressure for 5 hours in the presence of 10% palladium on carbon (20.2 g). After removal of the catalyst by filtration, the filtrate was evaporated in vacuo to give (2S,4R)-4-amino-1-t- butoxycarbonyl-2-methoxycarbonylpyrrolidine (93.8 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][C:3]=1C.[C:25]1([CH3:34])[C:26]([N:31]=[C:32]=[O:33])=[CH:27][CH:28]=[CH:29][CH:30]=1>O1CCCC1>[CH3:34][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:22][CH:23]=1)=[O:33]
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Reactant: Cc1ccccc1N=C=O
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Yield: 56.1 %

Procedure:
A mixture of 0.93 g 10,11-dihydro-10-(4-amino-3-methylbenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine and 0.37 g of o-tolyl isocyanate in 50 ml of tetrahydrofuran is heated at reflux under argon for 24 hours. The volatiles are evaporated in vacuo to a residue which is dissolved in methylene chloride and passed through a pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.68 g of the desired product as crystals, m.p. 155°-158° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl(O)(=O)(=O)=O.C([O-])(O)=O.[Na+].CCOCC.[C:26](OC(C)=O)([CH3:29])([CH3:28])[CH3:27]>>[C:1]1([CH2:7][C:8]([O:10][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: CC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 68 %

Procedure:
A solution of 2-phenylacetic acid (12 g, 88 mmol) in t-BuOAc (250 mL) in a 1 L round-bottomed flask was treated with perchloric acid (70% redistilled, 0.212 mL, 3.53 mmol) and stirred at room temperature for 20 hours. The solution was transferred very slowly to stirred mixture of saturated aqueous NaHCO3 and Et2O. Gas evolution was observed. The resulting layers were separated and the organic layer was washed with saturated aqueous NaHCO3, dried over MgSO4, filtered, and concentrated to give Intermediate S-3D (11.6 g, 68% yield): 1H NMR (500 MHz, chloroform-d) δ 7.34-7.29 (m, 2H), 7.28-7.22 (m, 3H), 3.52 (s, 2H), 1.44 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CN=C1.[CH:14]([Si:17](Cl)([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])([CH3:16])[CH3:15]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][Si:17]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:14]([CH3:16])[CH3:15]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Oc1cccc(Br)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)[Si](Oc1cccc(Br)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 24 h
Yield: 78.8 %

Procedure:
A mixture of 3-bromophenol (1.00 g, 5.78 mmol), and imidazole (984 mg, 14.45 mmol) in 6 mL of DMF was cooled to 0° C. and triisopropylsilyl chloride (922 μL, 6.94 mmol) was added and the solution was stirred for 24 hours. The reaction mixture was quenched with 10 mL H2O and 5 mL saturated aqueous NaHCO3. The aqueous layer was extracted with ether (3×10 mL), the pooled organic extracts were washed with brine, dried (MgSO4), and concentrated. The resulting oil was flash chromatographed on silica gel with hexanes to yield 209 (1.50 g, 79%). 1H NMR (CDCl3) δ 1.09 (d, J=7.2 Hz, 18H), 1.17-1.30 (m, 3H), 6.75-6.81 (m, 1H), 7.00-7.10 (m, 3H); 13C NMR (CDCl3) 156.89, 130.26, 124.14, 123.29, 122.5, 118.47.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]([CH3:11])=[CH:5][C:4]=2[C:3]=1[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26](S(C)(=O)=O)[N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][O:23][C:24]1[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([O:1][C:2]2[CH:10]=[CH:9][C:8]3[NH:7][C:6]([CH3:11])=[CH:5][C:4]=3[C:3]=2[C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[N:25]=1
Reactant: Cc1cc2c(C(=O)OCc3ccccc3)c(O)ccc2[nH]1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2ccc3[nH]c(C)cc3c2C(=O)OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
A mixture comprising 2.2 g of benzyl 5-hydroxy-2-methylindol-4-carboxylate, 1.7 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 1.3 g of potassium carbonate in 20 ml of N,N-dimethylformamide, was heated and stirred at a temperature of from 70° to 80° C. for two hours. The mixture was returned to room temperature, then poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure, was crystallized from isopropyl ether to obtain 2.8 g (yield: 85%) of the desired product. mp: 135°-139° C.