Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:19][C:20]1[C:24](B(O)O)=[C:23]([CH3:28])[O:22][N:21]=1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>O.CO.ClCCl.C(#N)C>[CH3:19][C:20]1[C:24]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[O:17][CH3:18])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)=[C:23]([CH3:28])[O:22][N:21]=1
Reactant: Cc1noc(C)c1B(O)O
Reactant: COc1ccccc1-c1c[nH]c2ncc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1-c1c[nH]c2ncc(-c3c(C)noc3C)cc12
Yield: 72 %

Procedure:
To 5-bromo-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (40 mg, 0.087 mmol), 3,5-dimethyl-isoxazole-4-boronic acid (16 mg, 0.114 mmol) and [1,1′-bis(diphenylphosphine)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (4 mg, 0.0044 mmol) in a Smith process vial was added 0.6 mL of a 1:1 mixture of acetonitrile, and a 2 M solution of sodium carbonate in water, the reaction was run in a Personal Chemistry® microwave reactor at 165° C. for 1200 s. The reaction mixture was diluted with 1:1 methanol/dichloromethane, filtered, and the filtrate was adsorbed on silica gel. Purification on silica gel with a gradient of MeOH/CH2Cl2 afforded 5-(3,5-dimethyl-isoxazol-4-yl)-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine as beige crystals (20 mg, 71% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.41 (s, 3H), 3.81 (s, 3H), 7.01 (dt, J=1.0, 7.0 Hz, 1H), 7.11 (dd, J=1.0, 8.0 Hz, 1H), 7.28 (dt, J=1.5, 7.0 Hz, 1H), 7.51 (dd, J=2.0, 8.0 Hz, 1H), 7.73 (d, J=3.0 Hz, 1H), 7.90 (d, J=1.5 Hz, 1H), 8.22 (d, J=2.0 Hz, 1H), 1.1.9 (s, t H). MS: m/z 320 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11].S(Cl)(Cl)=O.[CH3:17]O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:17])=[O:11]
Reactant: CO
Reactant: O=C(O)c1cc2ccccc2[nH]1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc2ccccc2[nH]1
Yield: 99.2 %

Procedure:
To 300 ml of a methanol solution of 30.0 g (186.2 mmol) of 2-indolecarboxylic acid was dropwise added 44.3 g (372.3 mmol) of thionyl chloride at 0° C. The reaction mixture was refluxed for 2 hours and the solvent was then distilled off under reduced pressure. Ice water was poured onto the resulting residue. The mixture was made basic by the addition of concentrated ammonium hydroxide. The mixture was extracted three times with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure to give 32.34 g (99.2%) of methyl 2-indolecarboxylate.
Reaction SMILES: B.O1CCCC1.[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)=[O:9]>C1(C)C=CC=CC=1.O1CCCC1>[Cl:16][C:12]1[CH:11]=[C:10]([C@H:8]([OH:9])[CH3:7])[CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1cccc(Cl)c1
Agent: B
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C[C@@H](O)c1cccc(Cl)c1
Reaction time: 0.17 h
Yield: 77.4 %

Procedure:
To a solution of borane-tetrahydrofuran (0.647 mL, 0.647 mmol, Aldrich, 1 M solution in THF) and (S)-MeCBS (0.647 mL, 0.647 mmol, Aldrich, 1M solution in toluene) was added simultaneously a solution of 3-chloroacetophenone (1.00 g, 6.47 mmol) in anhydrous tetrahydrofuran (2.42 mL) and a solution of borane-tetrahydrofuran (3.24 mL, 3.24 mmol, Aldrich, 1 M solution in THF) over 30 min at ambient temperature. After complete addition, the reaction mixture was stirred for 10 min, quenched slowly at 0° C. with methanol (0.94 mL) and then saturated HCl in ether (0.12 mL). After stirring at 0° C. for 5 min and ambient temperature for 30 min, the solution was concentrated in vacuo to an oil. The oil was twice diluted with benzene and concentrated in vacuo, diluted with ether, and concentrated in vacuo to an oil. The oil was purified by flash chromatography (silica gel, 20% EA in hexane) to give (R)-1-(3-chlorophenyl)ethanol as a clear colorless oil (0.784 g, 78%). Optical rotation in CHCl3 at 20° C. at concentration 0.220 was +40.90 (Literature, Bull. Chem. Soc. Jpn. 1996, 69(4), 1079-1085, optical rotation in CHCl3 at 21° C. at concentration 0.220 was +44°).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH3:30])[CH:18]=3)=[O:16])[CH2:6][C:5]=12.C(N(CC)CC)C.[Cl:38][C:39]([Cl:44])([Cl:43])[C:40](Cl)=[O:41]>ClCCl>[Cl:38][C:39]([Cl:44])([Cl:43])[C:40]([C:3]1[N:4]2[C:5]([CH2:6][N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[CH3:29])=[C:19]([CH3:30])[CH:18]=3)=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10]2)=[CH:1][CH:2]=1)=[O:41]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Temperature: 25 °C

Procedure:
To a solution of (10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-yl)-(2,2′-dimethyl-biphenyl-4-yl)-methanone of Step C (8.38 mmol) and triethylamine (16.76 mmol) in dichloromethane (30 mL) at −5° C. was added, rapidly dropwise, trichloroacetyl chloride (25 mmol). The mixture was allowed to stir and warm to room temperature overnight. The mixture was washed with 0.1N hydrochloric acid and dilute brine, then dried over anhydrous sodium sulfate, and evaporated to leave a light green oil. The compound was purified by filtration over a plug of Merck silica gel-60 eluting with dichloromethane and then treated with hot ethyl acetate/hexane (3/1) to yield a light yellow crystalline solid, m.p. 212-214° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH2:19]([O:21][C:22](=[O:26])[C@@H:23]([OH:25])[CH3:24])[CH3:20].[H-].[Na+]>C1COCC1>[CH2:19]([O:21][C:22](=[O:26])[C@@H:23]([O:25][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1)[CH3:24])[CH3:20]
Reactant: CCOC(=O)[C@H](C)O
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iii) using 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (product of example 1 step ii) (0.77 g), THF (15 mL), 2-hydroxy-(2S)-propanoic acid ethyl ester (0.40 mL) and 60% sodium hydride (0.14 g) to give the subtitle compound as a clear, colourless oil. Yield: 1 g
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]([O:26][CH3:27])([O:24][CH3:25])[C:16](=[O:23])[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].Cl[CH2:29][O:30][CH3:31].[Cl-].[NH4+]>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:27][O:26][C:15]([O:24][CH3:25])([O:14][CH3:13])[C:16](=[O:23])[CH2:17][CH:18]([CH2:29][O:30][CH3:31])[C:19]([O:21][CH3:22])=[O:20]
Reactant: COCCl
Reactant: COC(=O)CCC(=O)C(OC)(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COCC(CC(=O)C(OC)(OC)OC)C(=O)OC
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To 2.85 ml of diisopropylamine dissolved in 30 ml of anhydrous tetrahydrofuran was added 12.5 ml of 1.5M n-butyl lithium (hexane solution) at -78° C. under nitrogen atmosphere. The mixture was stirred for 15 minutes. To the solution was added 3.45 g of dimethyl 2-oxoglutarate dimethyl acetal in 15 ml of anhydrous tetrahydrofuran, taking 10 minutes. The mixture was stirred for 15 minutes. To the mixture was added a solution of 1.32 ml of chloromethyl methylether and 1.36 ml of hexamethylphosphoramide in anhydrous tetrahydrofuran, taking 10 minutes. The temperature of the reaction mixture was raised up to -20° C. taking 30 minutes, followed by stirring at the same temperature for 3 hours. To the reaction solution was added a saturated aqueous solution of ammonium chloride, followed by extraction with ethyl acetate. The extract solution was washed with water and dried (MgSO4). The solvent was evaporated off. The residue was subjected to a silica gel column chromatography, followed by elution with hexaneethyl acetate (2:1) to give 2.28 g of dimethyl 4-methoxymethyl-2-oxoglutarate dimethyl acetal as a pale yellow oily product.
Reaction SMILES: Cl.N[C@@H]1CC[C@H](NC(=O)C[NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)CC1.C1(C2CCC(=O)CC2)C=CC=CC=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.C(Cl)Cl>[F:21][C:20]([F:22])([F:23])[C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:13]([NH2:12])=[O:24]
Reactant: N[C@H]1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CC(=O)O
Product: NC(=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 140.5 %

Procedure:
N-(2-(cis-4-amino-cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide hydrochloride (60 mg, 0.158 mmol, 1 eq), 4-phenylcyclohexanone (28 mg, 0.158 mmol, 1 eq) and sodium triacetoxyborohydride (67 mg, 0.316 mmol, 2 eq) were stirred in 2% acetic acid/methylene chloride (10 mL) at room temperature for 20 hours. Worked up by adding saturated sodium bicarbonate (10 mL). Stirred 10 minutes then extracted 3 times with methylene chloride (10 mL). The organic layers were combined, dried (sodium sulfate) and stripped to give an oil. Purified over silica gel in 100% ethyl acetate to 4:1 methylene chloride/methanol to give N-(2-oxo-2-(cis-4-(cis- and trans-4-phenylcyclohexylamino)cyclohexylamino)ethyl)-3-(trifluoromethyl)benzamide (42 mg) as an off-white amorphous solid. MS found: (M+H)+=502.33.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=O)=[C:8]2Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[SH:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]>>[C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]3[CH:16]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[S:25][C:8]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1c(Cl)n(-c2ccccc2)c2ccccc12
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1cc2c3ccccc3n(-c3ccccc3)c2s1
Yield: 79.6 %

Procedure:
Prepared from 1-Phenyl-2-chloroindole-3-carbaldehyde (0.90 g), K2CO3 (1.38 g) and methyl 2-mercaptoacetate (0.55 ml) yielding (51) 0.86 g (79.6%). M.p. 147°-149° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1F)[CH3:2].[S-2:14].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[SH:14])[CH3:2]
Reactant: [S-2]
Reactant: CCOC(=O)c1cccc(F)c1F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cccc(F)c1S
Reaction time: 10 h

Procedure:
A solution of ethyl-2,3 difluorobenzoate (1.07 g, 5.75 mmol) in DMF (10 mL) was treated with sodium sulfide (896 mg, 11.5 mmol, 2.0 equiv) at 23° C. The mixture was stirred under argon for 10 h. The solution was diluted with ethyl acetate (50 mL) and water (50 mL) and 10% citric acid (5 mL). The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, decanted and concentrated under reduced pressure to give 3-Fluoro-2-mercapto-benzoic acid ethyl ester: 1H NMR (300 MHz, CDCl3) δ 7.71 (t, 1H), 7.38 (m, H), 7.12 (m, 1H), 4.41 (q, 2H), 1.40 (t, 3H); LCMS (100% area) Rt=4.53 min, (pos) [M+H]/z Calc'd 201.0, found 200.9.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:13])=[N:4][C:5]([C:9]([Cl:12])([Cl:11])[Cl:10])=[N:6][C:7]=1[CH3:8].[Cl:14][C:15]([Cl:20])([Cl:19])[C:16](Cl)=[O:17]>>[Cl:1][C:2]1[C:3]([O:13][C:16](=[O:17])[C:15]([Cl:20])([Cl:19])[Cl:14])=[N:4][C:5]([C:9]([Cl:10])([Cl:11])[Cl:12])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(C(Cl)(Cl)Cl)nc(O)c1Cl
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Product: Cc1nc(C(Cl)(Cl)Cl)nc(OC(=O)C(Cl)(Cl)Cl)c1Cl

Procedure:
The carboxylic ester compounds of the present invention may be prepared by reacting trichloroacetamidine with a selected acetoacetate to form the corresponding 4-hydroxy-2-trichloromethylpyrimidine, which is then reacted with a selected carboxylic acid chloride. These general reactions are illustrated below in equations (A) and (B). In equation (A), trichloroacetamidine is reacted with ethyl 2-chloroacetoacetate to form 5-chloro-4-hydroxy-6-methyl-2-trichloromethyl-pyrimidine. In equation (B), the 5-chloro-4-hydroxy-6-methyl-2-trichloromethylpyrimidine is reacted with trichloroacetyl chloride to form 5-chloro-6-methyl-4-trichloroacetoxy-2-trichloromethylpyrimidine. ##STR3##
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:11]#[C:12][CH2:13][OH:14])[CH:4]=[CH:3][N:2]=1>C(O)C.CO.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH2:11][CH2:12][CH2:13][OH:14])[CH:4]=[CH:3][N:2]=1
Reactant: OCC#Cc1cccc2ccncc12
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: OCCCc1cccc2ccncc12
Reaction time: 22 h
Yield: 33.3 %

Procedure:
A solution of 0.4 g of 3-(8-isoquinolinyl)-2-propyn-1-ol in a mixture of 10 mL of ethanol and 5 mL of methanol was hydrogenated over 0.06 g 10% Pd/C at room temperature and atmospheric pressure for 22 hours and then at 50 psi for 20 hours. After the catalyst was removed by filtration and the filtrate was concentrated, the residual oil was purified by HPLC (methanol-chloroform; 1:19) and crystallized from ethyl acetate-hexane to yield 0.136 g of 8-isoquinolinepropanol, mp 66°-69° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([C:18]4[NH:22][C:21]5[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=5[N:19]=4)=[N:14][NH:15]3)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.COC1C=C(B(O)O)C=CC=1.COC1C(O)=CC=CC=1C1C=C2C(C(C3NC4C=CC=CC=4N=3)=NN2)=CC=1>>[NH:22]1[C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[N:19]=[C:18]1[C:13]1[C:12]2[C:16](=[CH:17][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([OH:2])[CH:4]=3)=[CH:10][CH:11]=2)[NH:15][N:14]=1
Reactant: COc1cccc(-c2ccc3c(-c4nc5ccccc5[nH]4)n[nH]c3c2)c1
Agent: COc1c(O)cccc1-c1ccc2c(-c3nc4ccccc4[nH]3)n[nH]c2c1
Agent: COc1cccc(B(O)O)c1
Product: Oc1cccc(-c2ccc3c(-c4nc5ccccc5[nH]4)n[nH]c3c2)c1

Procedure:
Example 24(o) was prepared in a similar manner to that described for Example 24(f), except that 6-(3-methoxy-phenyl)-3-1H-benzoimidazol-2-yl-1H-indazole, prepared in a similar manner to that described for example 24(a) except that 3-methoxy-phenylboronic acid was used instead of 5-methoxy-2-methyl-4-[2-(trimethylsilanyl)-ethoxymethoxy]-phenylboronic acid in step (viii), was used instead of 6-(2-methoxy-hydroxyphenyl)-3-1H-benzoimidazol-2-yl-1H-indazole. 1H NMR (300 MHz, DMSO-d6) δ 13.67 (s, 1H), 13.00 (s, 1H), 9.58 (s, 1H), 8.55 (d, 1H, J=8.4 Hz), 7.71-7.75 (m, 2H), 7.49-7.57 (m, 2H), 7.30 (t, 1H, J=7.8 Hz), 7.12-7.24 (m, 4H), 6.80 (dd, 1H, J=8.1, 1.5 Hz). MS (ES) [m+H]/z calc'd 327, found 327; [m−H]/z calc'd 325, found 325.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[Br:11]Br>CCOCC.C(Cl)(Cl)(Cl)Cl>[Br:11][CH:7]1[CH2:8][CH2:9][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:10]
Reactant: BrBr
Reactant: O=C1CCCc2sccc21
Solvent: CCOCC
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1c2ccsc2CCC1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
Into a solution of 6,7-dihydrobenzo[b]thiophen-4(5H)-one (15.3 g, 100 mmol) in ether (600 mL) at −10° C. is added Br2 (16.0 g, 100 mmol) in carbon tetrachloride (CCl4) (100 mL) dropwise over 50 minutes. After an additional 15 minutes at −10° C., the cold bath is removed and the mixture is allowed to warm to ambient temperature. After 1 hour, the mixture is diluted with hexane (300 mL) and washed with water (2×500 mL), aqueous sodium chloride (150 mL) and concentrated under reduced pressure to yield the crude 5-bromo-6,7-dihydrobenzo[b]thiophen-4(5H)-one (22.7 g, 98%) to which is added DMF (˜200 mL), Li2CO3 (14.8 g, 200 mmol) and LiBr (17.4 g, 200 mmol). The mixture is heated for 5 hours at 90° C. and cooled. The crude mixture is poured into water, filtered and the filtrate extracted with EtOAc (600 mL), acidified to pH=1 with concentrated HCl and extracted with EtOAc (600 mL). The combined organic layers are concentrated under reduced pressure to yield a dark oil. The crude material is subjected to chromatography on silica gel, eluting with dichloromethane in hexanes 30-100%, to provide the title compound as an off-white solid (7.62 g, 51% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:16])=O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([Cl:16])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccc([N+](=O)[O-])cc1
Yield: 100 %

Procedure:
A stirred mixture of 4-nitrophenylacetic acid (25 g, 0.138 mol) in thionyl chloride (50 ml, 0.685 mol) was heated at reflux for 2 hours then concentrated to yield 4-nitrophenylacetyl chloride (27.55 g) as a tan solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:17]=[C:16]([N:18]2[CH2:22][CH2:21][C@@H:20]([NH:23]C(=O)OC(C)(C)C)[CH2:19]2)[C:15]2[C:10](=[CH:11][C:12]([CH3:31])=[CH:13][CH:14]=2)[N:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:23][C@@H:20]1[CH2:21][CH2:22][N:18]([C:16]2[C:15]3[C:10](=[CH:11][C:12]([CH3:31])=[CH:13][CH:14]=3)[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:17]=2)[CH2:19]1
Reactant: Cc1ccc2c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)nc(-c3ccccc3O)nc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(N3CC[C@@H](N)C3)nc(-c3ccccc3O)nc2c1
Reaction time: 0.83 h

Procedure:
To tert-butyl (R)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-ylcarbamate (850 mg, 2.02 mmol) was added at room temperature 4 mL of 1:1 TFA:CH2Cl2. The reaction mixture was stirred for 50 min, diluted with 20 mL of CH2Cl2, and washed with 15 mL of satd. NaHCO3 solution. The organic layer was separated and dried over Na2SO4, and the solvent was removed under reduced pressure to give (R)-2-[4-(3-amino-pyrrolidin-1-yl)-7-methyl-quinazolin-2-yl]-phenol as an oil which was used without further purification.
Reaction SMILES: [CH2:1]1[C@H:3]2[C:4](=[O:28])[CH2:5][C@H:6]3[C@:19]([CH3:20])([C@@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C@@H:13]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:12][CH2:11]2)[CH2:8][CH2:7]3.[Li]>O1CCCC1.C(OCC)C>[CH2:1]1[C@H:3]2[CH:4]([OH:28])[CH2:5][C@H:6]3[C@:19]([CH3:20])([C@@H:2]12)[C@@H:18]1[C@H:9]([C@H:10]2[C@@:14]([CH2:16][CH2:17]1)([CH3:15])[C@@H:13]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:12][CH2:11]2)[CH2:8][CH2:7]3
Reactant: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(=O)[C@@H]5C[C@@H]5[C@@]43C)[C@@H]1CC[C@@H]2OC1CCCCO1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@]12CC[C@H]3[C@@H](CC[C@H]4CC(O)[C@@H]5C[C@@H]5[C@@]43C)[C@@H]1CC[C@@H]2OC1CCCCO1
Yield: 99.5 %

Procedure:
9.0 g of 1α,2α-methylene-17β-(tetrahydropyran-2-yloxy)-5α-androstan-3-one is stirred in 90 ml of tetrahydrofuran with 10 g of lithium tri-tert-butoxyalanate for 2.5 hours at room temperature. The reaction solution is diluted with diethyl ether, washed with 2N sulfuric acid and water, dried, and evaporated, yielding as a residue 9.0 g of 1α,2α-methylene-17β-(tetrahydropyran-2-yloxy)-5α-androstan-3-ol.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:24]>C1COCC1>[CH3:24][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]([C:14]=23)=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CI
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2)c2c3c(cccc31)C(=O)NCC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of compound 12 (51.3 mg, 0.20 mmol) in THF (1 mL) and 0.1 mL 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H1)-pyrimidinone (DMPU) was cooled with an ice/water bath and treated dropwise with a suspension of NaH (0.45 mmol) in THF (0.5 mL). The yellow mixture was allowed to stir at 0° C. for 10 min., and was treated dropwise with a 1M solution of iodomethane in THF (0.22 mL, 0.22 mmol). The mixture was allowed to warm to ambient temperature and stirred for 30 min. The reaction was quenched at 0° C. with saturated aqueous NH4Cl, and extracted with EtOAc (5 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by radial chromatography (2 mm SiO2; 1-5% MeOH in CH2Cl2) to yield 18 as a white solid, 44.9 mg (81%). mp 254-256° C. (dec.); 1H NMR (DMSO-d6) δ2.88 (m, 2H), 3.40 (m, 2H), 3.74 (s, 3H), 7.34 (t, 1H, J=7.7 Hz), 7.56 (m, 5H), 7.73 (d, 1H, J=7.7 Hz), 7.80 (d, 1H, J=7.7 Hz), 8.15 (bt, 1H); Anal. (C18H16N2O.0.75 H2O) C, H, N.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([I:39])=[C:11]([C:28]([NH:30][CH2:31][CH:32]([CH2:34][CH:35]([OH:38])[CH2:36][OH:37])[OH:33])=[O:29])[C:12]([I:27])=[C:13]([C:25]=1[I:26])[C:14]([NH:16][CH2:17][CH:18]([CH2:20][CH:21]([OH:24])[CH2:22][OH:23])[OH:19])=[O:15])=[O:7])(=O)C.C([O-])(=O)C>O.S(=O)(=O)(O)O>[OH:24][CH:21]([CH2:22][OH:23])[CH2:20][CH:18]([OH:19])[CH2:17][NH:16][C:14](=[O:15])[C:13]1[C:25]([I:26])=[C:9]([NH:8][C:6](=[O:7])[CH2:5][OH:4])[C:10]([I:39])=[C:11]([C:28]([NH:30][CH2:31][CH:32]([CH2:34][CH:35]([OH:38])[CH2:36][OH:37])[OH:33])=[O:29])[C:12]=1[I:27]
Reactant: CC(=O)OCC(=O)Nc1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(C(=O)NCC(O)CC(O)CO)c1I
Agent: CC(=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(CO)Nc1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(C(=O)NCC(O)CC(O)CO)c1I
Temperature: 25 °C
Yield: 69.5 %

Procedure:
5-Acetoxyacetamido-N,N'-bis[(2,3-dihydroxypropyl)-2-hydroxyethyl]-2,4,6-triiodoisophthalamide (77 g, 0.086 g-mole) is dissolved in 270 ml of hot water containing 8.2 g (0.08 g-mole) sulfuric acid. The solution is stirred and heated at 95°-100° C. to hydrolyze the acetate. At the end of the reaction, the solution is cooled to room temperature and deionized using an anionic exchange resin, IRA-93 (Rohm and Haas Co.) to remove sulfuric acid. The solution is then concentrated and the crude product is purified by preparative liquid chromatography to provide the purified desired product (51 g; 0.06 g-mole, 70% yield). The 13C nmr spectra are consistent with the structure. The HPLC purity is 99.1% (C18, H2O/MeOH; 95/5). The water solubility (w/v) is 100%; the iv LD50 in mice is 5 g I/kg (based on iodine content). Osmolality: 676 mOsm/kg (32% I); viscosity: 8.2 cps (37°), 10.0 cps (25 °) (32% I).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:17])[NH:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2].[N:18]1([C:24]([C:26]2[S:27][CH:28]=[CH:29][CH:30]=2)=[O:25])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:17])[NH:8][C:9]2[C:14]([C:15]=1[N:21]1[CH2:22][CH2:23][N:18]([C:24]([C:26]3[S:27][CH:28]=[CH:29][CH:30]=3)=[O:25])[CH2:19][CH2:20]1)=[CH:13][N:12]=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: O=C(c1cccs1)N1CCNCC1
Reactant: CCOC(=O)c1c(Cl)c2cnccc2[nH]c1=O
Product: CCOC(=O)c1c(N2CCN(C(=O)c3cccs3)CC2)c2cnccc2[nH]c1=O

Procedure:
The starting materials for this synthesis was 4-aminopyridine which was protected by boc group and converted to 4-tert-butoxycarbonylamino-nicotinic acid, depicted as formula 35 in Scheme 15, by ortholithiation followed by quenching with dry ice. This intermediate was reacted with trichloromethyl chloroformate to yield 1H-pyrido[4,3-d][1,3]oxazine-2,4-dione, depicted by formula 36 in Scheme 15, which was then converted to 4-chloro-2-oxo-1,2-dihydro-[1,6]-naphthyridine-3-carboxylic acid ethyl ester, depicted by formula 37 in Scheme 15. The reaction of 4-chloro-2-oxo-1,2-dihydro-[1,6]-naphthyridine-3-carboxylic acid ethyl ester with piperazine-1-yl-thiophene-2-yl-methanone gave 2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,6]-naphthyridin-3-carboxylic acid ethyl ester, depicted by formula 38 in Scheme 15, which was reacted with corresponding alkyl halides (R—X) to yield 1-N-substituted-2-oxo-4-[4-(thiophene-2-carbonyl)-piperazin-1-yl]-1,2-dihydro-[1,6]-naphthyridine-3-carboxylic acid ethyl esters as shown in Scheme 15.