Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:13]2[CH:5]([C:6]3[C:11]([NH:12]2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:4][CH2:3][CH2:2]1.[Cl:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>CC(C)=O>[Cl:14][CH2:15][CH2:16][C:17]([N:12]1[CH:13]2[CH:5]([CH2:4][CH2:3][CH2:2][CH2:1]2)[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:18]
Reactant: O=C(Cl)CCCl
Reactant: c1ccc2c(c1)NC1CCCCC21
Solvent: CC(C)=O
Product: O=C(CCCl)N1c2ccccc2C2CCCCC21
Yield: 111.7 %

Procedure:
To a solution of 10 g 1,2,3,4,4a,9a-hexahydrocarbazole in 30 ml acetone was added a solution of 8.3 g 3-chloropropionyl chloride in 30 ml acetone dropwise at ambient temperature and the mixture was refluxed for 1 hour. The solvent was then distilled off under reduced pressure and the residue was dissolved in 100 ml of dichloromethane and washed with 10% hydrochloric acid twice. The solution was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to provide about 17 g of 9-(3-chloropropionyl)-1,2,3,4,4a,9a-hexahydrocarbazole as a viscous oil. This oil was not purified but submitted directly to the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].Br[CH2:11][CH:12]1[CH2:14][CH2:13]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][CH2:11][CH:12]1[CH2:14][CH2:13]1
Reactant: Oc1cc(F)ccc1Br
Reactant: BrCC1CC1
Product: Fc1ccc(Br)c(OCC2CC2)c1

Procedure:
Starting from commercially available 2-bromo-5-fluoro-phenol and bromomethyl-cyclopropane the title compound is prepared as colorless oil
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:19](=[O:24])N(OC)C)[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[I:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1>>[C:1]([O:5][C:6](=[O:25])[NH:7][CH:8]([C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:13][CH:14]=1)[C:19]([C:30]1[CH:31]=[CH:32][C:27]([I:26])=[CH:28][CH:29]=1)=[O:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: Ic1ccc(I)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)cc1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared from rac-[(methoxy-methyl-carbamoyl)-(4-trifluoromethyl-phenyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 10) and 1,4-di-iodobenzene in analogy to Example 1a): MS (ISN): 504.0 (M−H)−.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.CCCCCC.C([Li])CCC.CN(C)[CH:23]=[O:24]>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:23]=[O:24]
Reactant: c1ccc2occc2c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cc2ccccc2o1
Temperature: -50 °C
Reaction time: 0.08 h
Yield: 63 %

Procedure:
2.18 g of benzofuran was dissolved in 40 ml of anhydrous tetrahydrofuran. Thereto was dropwise added 12.3 ml of 1.5 M n-butyllithium hexane solution, in 5 minutes with stirring at -50° C. The mixture was stirred at 0° C. for 30 minutes and then cooled to -60° C. Thereto was added 1.61 g of N,N-dimethylformamide, and the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed by distillation under reduced pressure. The residue was mixed with 50 ml of ethyl acetate and 20 ml of water to dissolve the residue. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: n-hexane/ethyl acetate =20/1 to 10/1) to obtain 1.70 g (yield: 63%) of 2-benzofurancarbaldehyde as a colorless oily material.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:5]([OH:14])[C:4]1=[O:15])[CH3:2].[N:16]1([CH2:22][CH2:23]Cl)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>C(OCC)(=O)C>[CH2:1]([N:3]1[CH2:7][C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([O:14][CH2:23][CH2:22][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:4]1=[O:15])[CH3:2]
Reactant: ClCCN1CCCCC1
Reactant: CCN1CC(c2ccccc2)=C(O)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCN1CC(c2ccccc2)=C(OCCN2CCCCC2)C1=O

Procedure:
In a manner analogous to that described in Example 1, 30.5 g. 1-ethyl-3-hydroxy-4-phenyl-3-pyrrolin-2-one is reacted with 21.5 g. β-piperidinoethyl chloride. The base obtained is converted into the crystalline hydrochloride in ethyl acetate by means of gaseous hydrogen chloride. There is obtained 22.5 g. (42% of theory) 1-ethyl-3-(β-piperidinoethoxy)-4-phenyl-3-pyrrolidin-2-one hydrochloride; m.p. 120° C., (decomp.), after recrystallization from methyl ethyl ketone.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([CH2:18][N:19]([CH3:32])[CH:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)[C:21]([O-])=[O:22])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].Cl.Cl.[N:36]1([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)[CH2:40][CH2:39][CH2:38][CH2:37]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:17]([CH2:18][N:19]([CH:20]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)[C:21](=[O:22])[N:51]2[CH2:50][CH2:49][N:48]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=3[CH2:41][N:36]3[CH2:37][CH2:38][CH2:39][CH2:40]3)[CH2:53][CH2:52]2)[CH3:32])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CC1Cc2ccccc2CN1C(=O)OC(C)(C)C)C(Cc1ccc(Cl)cc1)C(=O)[O-]
Reactant: c1ccc(N2CCNCC2)c(CN2CCCC2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(CC1Cc2ccccc2CN1C(=O)OC(C)(C)C)C(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ccccc2CN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.1 %

Procedure:
Lithium 2-[(2-tert-butoxycarbonyl-1,2,3,4-tetrahydro-isoquinolin-3-ylmethyl)-methyl-amino]-3-(4-chloro-phenyl)-propionate (0.59 gm, 1.27 mmol), the compound of Step A (0.27 gm, 0.85 mmol), EDC (0.24 gm, 1.27 mmol) and HOBt (0.17 gm, 1.27 mmol) were combined and dissolved in anhydrous DMF (5 mL). DIPEA was added (440 microliter, 2.54 mmol), and the reaction was stirred under nitrogen overnight at room temperature. The reaction was concentrated and reconstituted in CH2Cl2 and then diluted with NaHCO3. After separation of the organic phase, the aqueous layer was extracted with CH2Cl2 (2×). The combined organics were dried (Na2SO4), filtered and concentrated. Chromatography (EtOAc to 5% MeOH/EtOAc) gave about 100 mg of 3-[({1-(4-Chloro-benzyl)-2-oxo-2-[4-(2-pyrrolidin-1-ylmethyl-phenyl)-piperazin-1-yl]-ethyl}-methyl-amino)-methyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid t-butyl ester. MS (m/z, ES+): 686.4.
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:13][CH2:12]3)[O:3]1.I([O-])(=O)(=O)=O.[Na+].Cl>O1CCCC1.O>[OH:5][B:4]([OH:3])[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:13][CH2:12]2
Reactant: CC1(C)OB(c2ccc3c(c2)CCN3S(=O)(=O)c2ccc(C#N)cc2)OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(S(=O)(=O)N2CCc3cc(B(O)O)ccc32)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 133.2 %

Procedure:
2.76 g 4-[5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-indole-1-sulfonyl]-benzonitrile and 4.32 g sodium periodate were dissolved in a mixture of 45 ml tetrahydrofuran and 15 ml water. The mixture was stirred at room temperature for two hours. Then 2 ml 4M hydrochloric acid was added and the mixture stirred at room temperature for one hour. 150 ml water were added and the mixture extracted three times with portions of 50 ml ethyl acetate. The combined organic extracts were dried over MgSO4 and the solvent removed in vacuo to obtain 2.94 g of crude 4-(5-Dihydroxyboranyl-2,3-dihydro-indole-1-sulfonyl)-benzonitrile. This material was used without further purification.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=[O:11])[CH3:10])[C:3]([O:5]CC)=O.[Cl-].C[C:14](=[NH2+:16])C>C(#N)C>[C:9]([C:8]1[CH2:14][NH:16][C:3](=[O:5])[C:2]=1[OH:1])(=[O:11])[CH3:10]
Reactant: CC(C)=[NH2+]
Reactant: CCOC(=O)C(=O)CC(C)=O
Agent: [Cl-]
Solvent: CC#N
Product: CC(=O)C1=C(O)C(=O)NC1
Temperature: -40 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
A solution of ethyl 2,4-dioxovalerate (1.13 g, 7.11 mmole), dimethylmethylene ammonium chloride (0.67 g, 7.11 mmole) and acetonitrile (3 ml) was stirred at 25° C. over 45 minutes. The resulting yellow homogeneous solution was then cooled to -40° C. and ammonia gas was bubbled through the mixture over 5 minutes, during which time a yellow solid precipitated out of solution. The stirred mixture was allowed to slowly warm to 5° C. over a period of 1 hour before addition of concentrated ammonium hydroxide (4 ml). After stirring for 1 hour, the mixture was concentrated under reduced pressure, diluted with 3N HCl (6 ml) and extracted with ethyl acetate (50 ml×10). The combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 0.34 g of the title compound as a yellow amorphous solid. M.P. 178°-180° C. (dec); 1H nmr (250 MHz, DMSO-d6) δ2.42 (s, 3H), 3.78 (s, 2H), 8.87 (s, 1H); Anal. calcd. for C6H7NO3 : C, 51.07; H, 5.00; N, 9.92. Found: C, 51.18; H, 5.23; N, 9.73.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[C:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH:32]([F:34])[F:33])[CH:26]=3)(=[O:24])=[O:23])[CH:18]=[CH:17][C:16]=2[O:35][CH3:36])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:37]>ClCCl.C(OCC)C>[ClH:37].[N:11]1([C:15]2[CH:20]=[C:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH:32]([F:34])[F:33])[CH:26]=3)(=[O:24])=[O:23])[CH:18]=[CH:17][C:16]=2[O:35][CH3:36])[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCCNCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
0.64 g of 4-[5-(3-difluoromethoxy-benzenesulfonylamino)-2-methoxy-phenyl]-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.213 mmol) were dissolved in 20 mL of dichloromethane and 1.82 mL of a 2N solution of hydrochloric acid in diethyl ether was added. After stirring at room temperature for 16 h, the solvents were evaporated, the residue redissolved in water, the aqueous phase washed with dichloromethane and then lyophilized to yield the title compound.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[C:5]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:36][OH:37])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:5]([NH:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:36][O:37][CH2:3][C:2]#[CH:1])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCBr
Reactant: CCOC(=O)C(=NO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCON=C(C(=O)OCC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 1.67 h
Yield: 77 %

Procedure:
Propargyl bromide (4.16 g.) was added to a suspension of ethyl 2-(2-tritylaminothiazol-4-yl)-2-hydroxyiminoacetate (syn isomer, 10 g.), potassium carbonate (4.84 g.) and N,N-dimethylformamide (22 ml.) under atmosphere of nitrogen gas and stirred at room temperature for 100 minutes. The insoluble substance was filtered off and washed with a little of N,N-dimethylformamide. The filtrate and washing solution were combined together, and water (400 ml.) was added to the solution. After the suspension was extracted with ethyl acetate (400 ml.), the extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. After treating the solution with activated charcoal, the solution was concentrated in vacuo. The residue was triturated with diisopropyl ether. The precipitates were collected by filtration, and washed with diisopropyl ether to give ethyl 2-(2-tritylaminothiazol-4-yl)-2-propargyloxyiminoacetate (syn isomer, 8.34 g.).
Reaction SMILES: [CH3:1]I.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][C:25]([CH3:26])=[C:20]3[NH:19][C:18]2=[O:27])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H-].[Na+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:21]3=[N:22][CH:23]=[CH:24][C:25]([CH3:26])=[C:20]3[N:19]([CH3:1])[C:18]2=[O:27])=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1ccnc2c1[nH]c(=O)n2-c1ccc(OCc2ccccc2)cc1
Reactant: CI
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccnc2c1n(C)c(=O)n2-c1ccc(OCc2ccccc2)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
MeI (0.377 mL) was added to a solution of 3-[4-(benzyloxy)phenyl]-7-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.0 g) and NaH (0.362 g) in DMF (20 mL) at 20° C. The mixture was stirred at 20° C. under a dry atmosphere for 1 h. The mixture was diluted with sat. NaHCO3 at 20° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo to give 3-[4-(benzyloxy)phenyl]-1,7-dimethyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2.0 g). This product was subjected to the next reaction without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:17])[CH2:14][CH2:15]Cl)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4].[C:18]1([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+].CC(C)=O.[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41]>CC(C)=O.CN(C)C=O.N1C=CC=CC=1>[C:39]([OH:44])(=[O:43])[C:40]([OH:42])=[O:41].[CH3:1][N:2]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:17])[CH2:14][CH2:15][N:27]3[CH2:28][CH2:29][N:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH2:25][CH2:26]3)=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4]
Reactant: CN1C(=O)CCc2cc(C(=O)CCCl)ccc21
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CN1C(=O)CCc2cc(C(=O)CCN3CCN(c4ccccc4)CC3)ccc21
Reaction time: 7 h

Procedure:
2.6 Grams of 1-methyl-6-(1-oxo-3-chloropropyl)-3,4-dihydrocarbostyril, 1.2 g of pyridine and 2.0 g of 4-phenylpiperizine were mixed into 30 ml of dimethylformamide and the mixture was stirred at 70°-80° C. for 7 hours. The reaction mixture was poured into 100 ml of 5%-sodium hydrogencarbonate solution and was extracted with chloroform. The chloroform layer was washed with water, dried and chloroform was removed by distillation. The residue thus obtained was dissolved with acetone and the pH of the solution was adjusted to pH 4 by adding 5%-oxalic acid acetone solution to form crystalline precipitates. The precipitates were collected by filtration and recrystallized from ethanol-water to obtain 2.8 g of 1-methyl-6-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyril monooxalate in colorless flake-like crystals.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[Cl:30][C:31]1[CH:32]=[C:33]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][C:45]([O:56][CH3:57])=[CH:46][C:47]=3[O:49][CH2:50][C@@H:51]3[CH2:55][CH2:54][CH2:53][NH:52]3)[N:42]=[CH:41][N:40]=2)[CH:34]=[CH:35][C:36]=1[F:37].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:30][C:31]1[CH:32]=[C:33]([CH:34]=[CH:35][C:36]=1[F:37])[NH:38][C:39]1[C:48]2[C:43](=[CH:44][C:45]([O:56][CH3:57])=[CH:46][C:47]=2[O:49][CH2:50][C@@H:51]2[CH2:55][CH2:54][CH2:53][N:52]2[C:1](=[O:5])[CH2:2][OH:3])[N:42]=[CH:41][N:40]=1
Reactant: COc1cc(OC[C@@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(OC[C@@H]2CCCN2C(=O)CO)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
Glycolic acid (20 mg) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 109 mg) were added sequentially, each in one portion, to a stirred solution of N-(3-chloro-4-fluorophenyl)-7-methoxy-5-[(2S)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (96 mg) and N,N-diisopropylethylamine (83 μl) in DCM (3 ml) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 16 hours 30 minutes and then diluted with DCM (10 ml) and washed with saturated aqueous sodium hydrogen carbonate and water. The organic layer was dried (MgSO4) and concentrated in vacuo to leave a yellow oil, which was purified by column chromatography using 0-10% methanol in dichloromethane as eluent to give the title compound as a white solid (55 mg, 50%); NMR Spectrum (DMSO-d6) 9.90 (s, 1H), 8.42 (s, 1H), 8.15 (dd, 1H), 7.70-7.60 (m, 1H), 7.40 (t, 1H), 6.88 (d, 1H), 6.78 (d, 1H), 4.65-4.53 (m, 2H), 4.40 (dd, 1H), 4.17 (dd, 1H), 4.03 (d, 1H), 3.90 (s, 3H), 3.45-3.35 (m, 3H), 2.10-1.82 (m, 4H); Mass spectrum MH+ 461.
Reaction SMILES: [CH:1]1[C:6]([C:7]([C:18]2[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([C:25]([OH:27])=[O:26])[CH:19]=2)=[C:8]2[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:11](=[O:12])[CH:10]=[CH:9]2)=[CH:5][C:4]([C:28]([OH:30])=[O:29])=[C:3]([OH:31])[CH:2]=1.[NH3:32].N.N.[Sn].[Tc:36]([O-])(=O)(=O)=O>>[Tc:36].[CH:9]1[C:8]([C:7]([C:6]2[CH:1]=[CH:2][C:3]([OH:31])=[C:4]([C:28]([OH:30])=[O:29])[CH:5]=2)=[C:18]2[CH:19]=[C:20]([C:25]([OH:27])=[O:26])[C:21](=[O:24])[CH:22]=[CH:23]2)=[CH:14][C:13]([C:15]([OH:17])=[O:16])=[C:11]([OH:12])[CH:10]=1.[NH3:32].[NH3:32].[NH3:32]
Reactant: O=[Tc](=O)(=O)[O-]
Agent: N
Agent: O=C(O)C1=CC(=C(c2ccc(O)c(C(=O)O)c2)c2ccc(O)c(C(=O)O)c2)C=CC1=O
Agent: [Sn]
Product: [Tc]
Reaction time: 0.25 h

Procedure:
To a vessel containing 2 mg. of aluminon and a piece of tin foil was added 1 ml. of pertechnetate solution and the pH adjusted to 5 with acid. The liquid mixture was allowed to stand for 15 minutes. Essentially all the pertechnetate was reduced to give a complex of technetium with the aluminon.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11](Cl)=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17](O)=[O:18].N1C=CC=CC=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][C:11]1[O:12][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[N:14]=1)([O-:3])=[O:2]
Reactant: Nc1ccccc1C(=O)O
Reactant: O=C(Cl)Cc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1oc(Cc2cccc([N+](=O)[O-])c2)nc2ccccc12
Temperature: 120 °C

Procedure:
To a solution of commercially available (3-nitro-phenyl)-acetyl chloride (2.20 g, 11.05 mmol) in anhydrous DCM (9 mL) was added 2-aminobenzoic acid (0.76 g, 5.50 mmol). Pyridine (3 mL) was then added to the mixture and the reaction mixture was heated under microwave condition at 120° C. for 30 minutes, then diluted with dichloromethane and washed with NaHCO3 satured solution, then with water followed by brine. The organic phase was dried over Na2SO4, filtered and evaporated to give the 2-(3-nitro-benzyl)-benzo[d][1,3]oxazin-4-one intermediate as red oil. To a solution of 2-(3-nitro-benzyl)-benzo[d][1,3]oxazin-4-one in dry pyridine (10 mL) was added aminoguanidine hydrogencarbonate (0.90 g, 6.60 mmol) and the mixture was heated under microwave condition at 180° C. for 20 minutes. The solvent was then evaporated and the crude was purified by flash column chromatography on silica gel eluting with DCM/CH3OH 95/5 to afford the title compound as orange solid (0.35 g, 30% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[NH:16][CH:15]=1)[C:6]([O:8][CH3:9])=[O:7].Br[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][C:32]([Cl:38])=[CH:33][CH:34]=2)[N:29]=1.[H-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:23]([O-:25])=[O:24])[CH:21]=2)[N:16]([CH2:27][C:28]2[CH:37]=[CH:36][C:35]3[C:30](=[CH:31][C:32]([Cl:38])=[CH:33][CH:34]=3)[N:29]=2)[CH:15]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1ccc(Cc2c[nH]c3ccc([N+](=O)[O-])cc23)c(OC)c1
Reactant: Clc1ccc2ccc(CBr)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cc2cn(Cc3ccc4ccc(Cl)cc4n3)c3ccc([N+](=O)[O-])cc23)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a mixture of the methyl 3-methoxy-4-(5-nitroindol-3-ylmethyl)benzoate (312 mg, 0.92 mmol) (J. Med. Chem. 1990, 33, 1781-1790) and 2-bromomethyl-7-chloroquinoline (225 mg, 0.88 mmol) in DMF (3 ml) at 0° C. was added 50% NaH (48 mg, 1.04 mmol). After stirring at 0° C. for 1 hr, ice was added to the reaction mixture. When the ice had melted the resultant solid was filtered, dried and swished with Et2O to afford the title compound (311 mg).
Reaction SMILES: [CH2:1]([O:8][P:9]([O-:18])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC1C=CC=C(CC([O-])=O)C=1CC([O-])=O>CC#N>[CH2:11]([O:10][PH:9](=[O:18])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])Cc1cccc(I)c1CC(=O)[O-]
Solvent: CC#N
Product: O=[PH](OCc1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 381.3 %

Procedure:
A solution of 13 (0.80 g, 0.93 mmol) and 1H-tetrazole (98 mg, 1.39 mmol) in CH2Cl2 (15 mL) was treated with dibenzyldiisopropylphosphoramidite (0.43 mL, 1.39 mmol) and stirred at room temperature overnight. The product was partitioned between CH2Cl2 and H2O, dried with Na2SO4, filtered and concentrated. The crude product was purified by column chromatography to give the intermediate dibenzylphosphite (0.68 g, 67%). To a solution of the dibenzylphosphite (0.39 g, 0.35 mmol) in CH3CN (5 mL) was added iodobenzenediacetate (0.17 g, 0.53 mmol). The reaction mixture was stirred at room temperature for 2 h and concentrated. The residue was partitioned between EtOAc and NaHCO3. The organic layer was washed with H2O, dried with Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography on silica gel (3% 2-propanol/CH2Cl2) to give the dibenzylphosphonate (0.35 g, 88%) as a white solid.
Reaction SMILES: C[CH2:2][O-:3].[Na+].C(OCC)=O.[C:10]1([C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCO>[OH:17]/[C:16](/[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[C:18](/[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)\[CH:2]=[O:3]
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCOC=O
Solvent: CCO
Product: O=C/C(=C(\O)c1ccccc1)c1ccccc1
Temperature: 2.5 °C
Reaction time: 3 h

Procedure:
To a cooled solution of NaOEt (763 mg, 11.21 mmol) in EtOH (100 ml) was added ethyl formate (0.91 ml, 11.21 mmol) dropwise. The resulting mixture is allowed to stand for 3 hours at 0 to 5° C., and then deoxybenzoin (2 g, 10.19 mmol) was added. The mixture was stirred for 2 hours at 0 to 5° C. and then placed in the refrigerator for 4 days. After the mixture was stirred overnight at room temperature, it was poured into ice-water, and acidified, and extracted with CH2Cl2. The organic layer was washed with brine, and dried over MgSO4 anhydride, and concentrated in vacuo. The residue was purified by column chromatography (10% ethyl acetate in hexane) to give the title compound as a light yellow solid.