Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][N:11]=[CH:10]3)[CH2:3][CH2:2]1.CN(C)C=O.[CH:21]1([C:25]2[C:33]([C:34](=[O:37])[NH:35][CH3:36])=[CH:32][C:28]([C:29](O)=[O:30])=[C:27]([CH3:38])[CH:26]=2)[CH2:24][CH2:23][CH2:22]1>CN(C)C1C=CN=CC=1.O>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([CH:4]3[CH2:3][CH2:2][N:1]([C:29]([C:28]4[C:27]([CH3:38])=[CH:26][C:25]([CH:21]5[CH2:24][CH2:23][CH2:22]5)=[C:33]([CH:32]=4)[C:34]([NH:35][CH3:36])=[O:37])=[O:30])[CH2:6][CH2:5]3)=[CH:15][CH:14]=2)[CH:10]=[N:11]1
Reactant: c1cc2[nH]ncc2cc1C1CCNCC1
Reactant: CNC(=O)c1cc(C(=O)O)c(C)cc1C1CCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1cc(C(=O)N2CCC(c3ccc4[nH]ncc4c3)CC2)c(C)cc1C1CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.7 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 5-(piperidin-4-yl)-1H-indazole (compound 62.5, 100 mg, 0.50 mmol) in N,N-dimethylformamide (3 mL) EDC.HCl (192 mg, 1.00 mmol), 4-dimethylaminopyridine (122 mg, 1.00 mmol) and 4-cyclobutyl-2-methyl-5-(methylcarbamoyl)benzoic acid (compound 62.3, 122 mg, 0.49 mmol) were added and the resulting solution was stirred for 4 h at room temperature. The reaction was diluted with water (20 mL) and extracted with of ethyl acetate (2×25 mL). The combined organic layers were washed with brine (2×15 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate as the eluent, followed by additional purification by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.05% TFA and CH3CN (30% CH3CN up to 47% in 7 min, up to 100% in 3 min, down to 30% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield the title compound as a white solid (71.2 mg, 33%). m/z (ES+) 431 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13]O)[CH:11]=[CH:12][C:4]=2[O:3]1.C(N(CC)CC)C.CS([Cl:26])(=O)=O>C(Cl)Cl>[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][Cl:26])[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1Oc2ccc(CO)cc2NC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1Oc2ccc(CCl)cc2NC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4.59 g (23.8 mmol) of (±)-2-methyl-3-oxo-6-hydroxymethyl-3,4-dihydro-2H-1,4-benzoxazine is mixed with 5.53 g (54.6 mmol) of triethylamine after being dissolved in 900 ml of methylene chloride. At 0° C., 4.08 g (35.6 mmol) of methanesulfonic acid chloride is added in drops, and the batch is then stirred at room temperature for 5 hours. Another 3.8 ml of triethylamine and 1.4 ml of methanesulfonic acid chloride are added and stirred again for 20 hours at room temperature. A portion of methylene chloride (600 ml) is spun off. After dilution with 1 l of diethyl ether, the organic phase is washed twice with 50 ml of water each, once with 50 ml of saturated sodium bicarbonate solution and again with 50 ml of water. The organic phase is spun in after drying, and the residue is chromatographed on silica gel (mobile solvent: methylene chloride/ethanol). 2.95 g (58.7%) of the desired product in addition to 1.1 g (16.6%) of the corresponding mesylate are obtained, melting point 162-169° C.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=O)=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].C1COCC1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>CO>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[O:18][C:6]([C:5]3[CH:19]=[CH:20][C:2]([NH2:1])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=3)=[N:8][N:9]=2)=[CH:12][CH:13]=1
Reactant: Nc1ccc(C(=O)NNC(=O)c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(-c2nnc(-c3ccc(Cl)cc3)o2)cc1[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
To a 20 mL microwave vial was added 1.00 g (2.99 mmol) of 4-Chloro -benzoic acid N′-(4-amino-3-nitro-benzoyl)-hydrazide, 12 mL of THF, and 1.9934 g (8.36 mmol) of burgess reagent. The suspension was placed in the microwave at 150° C. for 30 min. To the orange/yellow suspension was added 5 mL of MeOH and the resulting precipitates were collected by filtration and dried to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.31 (d, J=8.97 Hz, 1H) 7.80 (d, J=8.59 Hz, 2H) 8.12-8.19 (m, 2.7 H) 8.25 (d, J=8.59 Hz, 2 H) 8.77 (d, J=2.02 Hz, 1 H). MS (m/z) 317.0 M (+1), tR=1.33, Meth 10
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH2:34][C@H:35]([CH3:43])[CH2:36][CH2:37][NH:38][CH2:39][CH:40]([CH3:42])[CH3:41].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:5]3[C:3](=[O:2])[N:34]4[C@H:35]([CH3:43])[CH2:36][CH2:37][N:38]([CH2:39][CH:40]([CH3:42])[CH3:41])[C@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: CC(C)CNCC[C@@H](C)N
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)CN1CC[C@@H](C)N2C(=O)c3c(OCc4ccccc4)c(=O)c(C(=O)NCc4ccc(F)cc4)cn3C[C@H]12
Yield: 58.9 %

Procedure:
(4R,12aR)—N-[(4-Fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide. The title compound was made in two steps using a similar process to that described in example Z-2. 16 (40 mg, 0.09 mmol) and [(3R)-3-aminobutyl](2-methylpropyl)amine (65 mg, 0.45 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4R,12aR)—N-[(4-fluorophenyl)methyl]-4-methyl-1-(2 methylpropyl)-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (29 mg, 60%). This material was hydrogenated in a second step as described in example Z-2 to give (4R,12aR)—N-[(4-fluorophenyl)methyl]-7-hydroxy-4-methyl-1-(2-methylpropyl)-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide (18 mg, 75%) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 0.77 (d, J=6.4 Hz, 3H), 0.84 (d, J=6.4 Hz, 3H), 1.32 (d, J=7.2 Hz), 1.45-1.49 (m, 1H), 1.57-1.67 (m, 1H), 2.03-2.12 (m, 2H), 2.21-2.27 (m, 1H), 2.73-2.79 (m, 1H), 2.87-2.92 (m, 1H), 4.16-4.24 (m, 2H), 4.45 (s, 1H), 4.54-4.64 (m, 2H), 4.96-4.99 (m, 1H), 6.96-7.00 (m, 2H), 7.20-7.32 (m, 2H), 8.27 (s, 1H), 10.46 (s, 1H), 12.55 (s, 1H); ES+ MS: 456 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH2:10][CH2:11][CH3:12].Br[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:22]=[CH:21]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[N:23]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:22]=[CH:21]3)=[C:3]([CH2:10][CH2:11][CH3:12])[CH:4]=1)#[N:7]
Reactant: COC(=O)Cn1ccc2cc(OCCCBr)ccc21
Reactant: CCCc1cc(C#N)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(C#N)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 23.4 %

Procedure:
To a mixture of 4-hydroxy-3-propylbenzonitrile (Example 33, 1.33 g, 8.28 mmol) and methyl [5-(3-bromopropoxy)-1H-indol-1-yl]acetate (Example 47, 2.70 g, 8.28 mmol) in DMF (50 mL, containing 1% water), was added cesium carbonate (5.39 g, 16.55 mmol). The mixture was stirred at rt for 24 h and then the solvent was evaporated under reduced pressure. The residue was suspended in ethyl acetate and filtered. The filtrate was concentrated and purified via silica gel column chromatography (0-10% EtOAc in hexanes) to give 787 mg (23%) of the product as a solid. This was used in later steps with no further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](N)[C:7](NC)=[C:6]([Cl:13])[C:5]=1[NH2:14].Cl.[C:17]([NH2:20])(=[NH:19])[CH3:18].[CH3:21]CO>>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH2:14])=[C:6]([Cl:13])[C:7]2[N:19]([CH3:21])[C:17]([CH3:18])=[N:20][C:8]=2[CH:9]=1)=[O:15]
Reactant: CC(=N)N
Reactant: CCO
Reactant: CNc1c(N)cc(C(=O)OC)c(N)c1Cl
Agent: Cl
Product: COC(=O)c1cc2nc(C)n(C)c2c(Cl)c1N
Temperature: 80 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
To a suspension of 1 g (3.48 mmol) of 2,5-diamino-3-chloro-4-methylamino-benzoic acid methyl ester (synthesis described in example H7) in 153 mL of EtOH is added 680 mg (6.97 mmol) of acetamidine hydrochloride. The mixture is stirred 2 days at a temperature of 80° C. Then, all the solvent is evaporated and the residue is suspended in EtOAc, the formed precipitate is filtrated and after evaporation the filtrate is purified by flash chromatography on silica gel and gave 510 mg (2.01 mmol, 58%) of a brown-reddish solid. LC/MS: 254/256 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:18][CH2:17][C:11]2([CH2:15][NH:14][C:13](=[O:16])[CH2:12]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)S(O[C:25]1[CH2:26][O:27][C:28](=[O:31])[C:29]=1C)(=O)=O.CC1C(=O)OCC=1N1CCCC2(CCNCC2)C1=O>>[O:31]=[C:28]1[O:27][CH2:26][C:25]([N:14]2[C:13](=[O:16])[CH2:12][C:11]3([CH2:10][CH2:9][NH:8][CH2:18][CH2:17]3)[CH2:15]2)=[CH:29]1
Reactant: CC1=C(OS(=O)(=O)C(F)(F)F)COC1=O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNC(=O)C2
Agent: CC1=C(N2CCCC3(CCNCC3)C2=O)COC1=O
Product: O=C1C=C(N2CC3(CCNCC3)CC2=O)CO1

Procedure:
The title compound was prepared from 3-oxo-2,8-diaza-spiro[4,5]decane-8-carboxylic acid tert-butyl ester and 4-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate in two steps in an analogous fashion to that described for 2-(4-Methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,9-diazaspiro[5.5]undecan-1-one (I-19) above.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17](Cl)(=[O:19])=[O:18])[CH2:5][CH2:4]1)[CH3:2].[NH2:21][C:22]1[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]2[C:25]([CH:26]3[CH2:36][CH:27]3[CH2:28][O:29]2)=[CH:24][CH:23]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[S:17]([NH:21][C:22]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[C:30]3[C:25]([CH:26]4[CH2:36][CH:27]4[CH2:28][O:29]3)=[CH:24][CH:23]=2)(=[O:19])=[O:18])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCC(Cc2cc(F)ccc2S(=O)(=O)Cl)CC1
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CCC(Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)CC1
Yield: 77.1 %

Procedure:
2-(1-Ethylpiperidine-4-ylmethyl)-4-fluorobenzenesulfonyl chloride (Intermediate 178, 0.165 g) was added to a solution of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (Intermediate 42, 0.290 g) in DCM (5 mL) and pyridine (1 mL) and the resultant mixture was stirred at room temperature for 21 hours. The mixture was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of 2M NH3 in methanol and DCM with a gradient of 0-20% to give methyl (1aRS,7bSR)-5-[2-(1-ethyl-piperidin-4-ylmethyl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.200 g) as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[K+].[Br-].Br[CH2:24][C:25]1[CH:34]=[CH:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=1>C(#N)C>[Br-:10].[CH2:11]([C:33]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]([CH3:24])[C:34]=1[N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[NH:5][CH:4]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCCCCCCCCCBr
Reactant: Clc1nc[nH]c1Cl
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCCCCCCCCCc1c(-[n+]2c[nH]c(Cl)c2Cl)c(C)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) will be dissolved into acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) will be added and the mixture will be allowed to stir for 0.5 h. 1-bromodecane (9 mmol) will be added and the solution will be allowed to reflux overnight. The solution will be filtered hot to remove a white precipitate (presumed to be KBr) and 2-bromomethylnaphthalene (1.98 g, 9 mmol) will be added and the mixture will be returned to reflux overnight. The mixture will be allowed to cool to room temperature, resulting in a yellow/white precipitate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.Cl.[NH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[F:31])=[CH:20][CH:19]=1)=O.[OH2:32]>>[NH2:14][C:15]1[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=3[F:31])=[CH:20][CH:19]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:11])=[O:32])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: NCC(=O)c1ccc(-c2ccc(F)cc2F)cc1
Reactant: O
Agent: Cl
Product: Nc1c(-c2ccc(-c3ccc(F)cc3F)cc2)nc2ccc(Cl)cc2c1C(=O)O

Procedure:
A basic aqueous solution of 4.3 g of 5-chloroisatin in water was reacted with 9.4 g of 2-amino-1-(2',4'-difluoro[1,1'-biphenyl]-4-yl)ethanone hydrochloride by the procedure described in example 20, giving 6.1 g of the desired compound as a yellow solid, mp 253°-254° C.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:16]([OH:18])[CH3:17].[Cl:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][NH:25][C:26]([C:28]2[C:29](=[O:40])[C:30]3[CH:37]=[C:36]([CH2:38]Cl)[O:35][C:31]=3[N:32]([CH3:34])[CH:33]=2)=[O:27])=[CH:22][CH:21]=1.O>CN(C=O)C>[Cl:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][NH:25][C:26]([C:28]2[C:29](=[O:40])[C:30]3[CH:37]=[C:36]([CH2:38][N:4]([CH2:17][CH:16]([OH:18])[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][N:10]=4)[CH3:1])[O:35][C:31]=3[N:32]([CH3:34])[CH:33]=2)=[O:27])=[CH:22][CH:21]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(O)c1ccccn1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Solvent: O
Solvent: CN(C)C=O
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1ccccn1
Temperature: 90 °C

Procedure:
N,N-Diisopropylethylamine (0.11 mL) and rac-2-methylamino)-1-pyridin-2-ylethanol (Preparation 36, 0.094 g) were added to a suspension of N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]-pyridine-5-carboxamide (Example 2, 0.150 g) in DMF (10 mL). The reaction mixture was heated to 90° C. for 1 h. The mixture was allowed to cool to room temperature, poured into water (25 mL), and was extracted with CH2Cl2 (4×25 mL). The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The resulting solid was purified by column chromatography (CH2Cl2/methanol; 99/1, 98/2, 97/3, 95/5) followed by recrystallization from ethyl acetate to yield 0.082 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 130-132° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.65, 8.54, 8.43-8.42, 7.76-7.73, 7.47-7.45, 7.41-7.32, 7.24-7.21, 6.83, 5.31, 4.79-4.74, 4.55, 3.89, 3.74, 2.79-2.74, 2.66-2.61, 2.33; MS (ESI+) m/z 481 (M+H)+. Anal. Found: C, 62.08; H, 5.25; N, 11.57; Cl, 7.39.
Reaction SMILES: Br[C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:11][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH2:13][Mg]Cl.Cl>CCOCC>[CH3:11][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:16])[CH2:13][C:2]1[CH2:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: BrC1=Cc2ccccc2C1
Reactant: CC(C)(C[Mg]Cl)c1ccccc1
Agent: Cl
Solvent: CCOCC
Product: CC(C)(CC1=Cc2ccccc2C1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 2-bromoindene (2.0 g, 10.2 mmol) and 460 mg of Pd(AcO)2 in 60 mL of ether was treated with 21 mL of 2-methyl-2-phenyl-propanyl magnesium chloride (0.5 M in ether; 10.2 mmol). The mixture was refluxed for one hour, cooled to room temperature and treated with 30 mL of aqueous hydrochloric acid (5 percent). The reaction was worked-up and the product purified (hexanes/silica) as for 2-benzyl-indene. Yield: 1.6 g (63 percent).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.ClC1C(Cl)=CC=CC=1N1CCN([CH2:29][CH:30]([OH:44])[CH2:31][CH2:32][N:33]2[C:41](=[O:42])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]2=[O:43])CC1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:29][CH:30]([OH:44])[CH2:31][CH2:32][N:33]2[C:41](=[O:42])[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]2=[O:43])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C1c2ccccc2C(=O)N1CCC(O)CN1CCN(c2cccc(Cl)c2Cl)CC1
Product: COc1ccccc1N1CCN(CC(O)CCN2C(=O)c3ccccc3C2=O)CC1
Yield: 28 %

Procedure:
Prepared from 1-(2-methoxyphenyl)piperazine and 25 in a similar fashion as described above for 26a. Yield: 28%. Mp.: 192-194° C. 1H NMR (CDCl3): δ 1.79 (q, J 6.8, 2H), 2.41 (m, 2H), 2.61 (s, 2H), 2.85 (s, 2H), 3.07 (s, 4H), 3.77 (m, 1H), 3.85 (s, 3H), 3.91 (m, 2H), 6.86 (d, J 7.0, 1H), 6.91-6.95 (m, 2H), 7.00 (m, 1H), 7.85 (dd, J 5.5, 3.0, 2H), 7.71 (dd, J 5.4, 3.1, 2H). 13C NMR (CDCl3): δ 33.8, 35.4, 50.9, 53.6, 55.6, 64.1, 64.7, 111.3, 118.4, 121.2, 123.2, 123.4, 132.4, 134.1, 141.4, 152.4.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[OH:14].Cl[CH2:16][CH:17]([OH:20])[CH2:18][OH:19].[OH-:21].[K+]>C(O)CCC>[OH:20][CH:17]([CH2:18][OH:19])[CH2:16][O:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][C:3]=1[O:14][CH2:3][CH:2]([OH:1])[CH2:7][OH:21]
Reactant: [OH-]
Reactant: OCC(O)CCl
Reactant: O=[N+]([O-])c1cc(O)c(O)cc1[N+](=O)[O-]
Agent: [K+]
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(OCC(O)CO)c(OCC(O)CO)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
8C, FIG. 8. 1,2-Dihydroxy-4,5-dinitrobenzene 8B (5.0 g, 22 mmol) and 1-chloro-2,3-dihydroxypropane (12.1 g, 110 mmol) were refluxed for 48 hours in a solution of potassium hydroxide (4.4 g) in 1-butanol (100 mL) under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure, and the dark residue was partitioned between 100 mL of THF and 100 mL of brine/50 mL water solution in a 500 mL separatory funnel. The mixture was allowed to separate and the aqueous phase was extracted with THF (2×100 mL). The combined THF extracts were washed with brine (2×50 mL), dried over MgSO4 and concentrated to an oily residue. Here, CH2Cl2 was added very carefully to insure precipitation of the crude product. After stirring for 15 minutes, the suspension was filtered with a medium glass fritted funnel and air dried for several minutes. The orange solid was taken up in 120 mL of CHCl3 and 80 mL of diethyl ether at reflux and hot filtered to remove some impurities. The crude product was dissolved in a mixture of acetone and methanol (sonication may be required), then 6 grams of deactivated silica gel was added to the orange solution. The slurry was concentrated to dryness and the orange solid was dried in vacuo for one hour. The orange solid was loaded on a packed deactivated silica gel column. The column was eluted starting with neat CHCl3 followed by CHCl3 with increasing concentration of methanol (0-10%). After a bright yellow impurity (monoalkylated product) was removed a colorless product began to elute (using 8-10% methanol in CHCl3 eluents). Conversely, on TLC the product will elute faster than the bright yellow monoalkylated product. The purified dialkylated tetrahydroxy product can be recrystallized from acetone/diethyl ether to yield 2.60 grams (30%) of a light yellow fluffy solid. 1H NMR (d6 -acetone): δ2.95 (bs, 4H, OH), 3.69 (d, 4H, OCH2CH(OH)CH2OH), 4.06 (p, 2H, OCH2CH(OH)CH2OH), 4.24-4.35 (m, 4H, OCH2CH(OH)CH2OH), 7.72 (s, 2H, Ar--H); 13C NMR (d6 -acetone): δ63.55, 70.89, 72.53, 109.99, 137.22, 152.77. CI MS 349.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=[O:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:22][CH2:23]Cl)=[CH:16][CH:15]=1>CN(C=O)C>[F:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[CH2:21][CH2:22][CH2:23][N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[NH:5][C:4]2=[O:12])=[CH:18][CH:19]=1
Reactant: O=c1[nH]c2ccccc2[nH]1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.72 g, 18 mmol) in DMF (15.0 mL) was added a solution of 1,3-dihydro-benzoimidazol-2-one (11) (2.6 g, 20.0 mmol, Aldrich) in DMF (10.0 mL) at room temperature. The resulting mixture was stirred at room temperature for 30 minutes and a solution of compound 2 (2.8 g, 10 mmol) in DMF (10.0 mL) was added. The resulting mixture was stirred at 60° C. for 4 hours. After this period, the mixture was cooled to room temperature and quenched with water (20 mL). The mixture was extracted with ethyl acetate (100 mL×3). The organic layer was dried with anhydrous Na2SO4 and concentrated to give a crude sample. The crude sample was purified by column chromatography using ethyl acetate/hexane gradient as an eluent to give the title compound 12. MS: m/z 379. 1H NMR (CDCl3): δ 9.41 (s, 1H), 7.10 (m, 8H), 6.92 (t, J=8 Hz, 4H), 3.93 (m, 3H), 2.07 (m, 2H), 1.73 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[C:4](=[O:17])[NH:3][C:2]1=[O:18].[CH3:19][C:20]1[O:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][NH2:32].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:19][C:20]1[O:24][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:22][C:21]=1[CH2:31][NH:32][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH:5]2[S:1][C:2](=[O:18])[NH:3][C:4]2=[O:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: O=C1NC(=O)C(Cc2ccc(S(=O)(=O)Cl)cc2)S1
Reactant: Cc1oc(-c2ccccc2)nc1CN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(-c2ccccc2)nc1CNS(=O)(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
4-[(Thiazolidine-2,4-dion-5-yl)methyl]benzenesulfonyl chloride (1.62 g, 5.31 mmol) in 25 mL of CH2Cl2 was cooled to 0° C. N-[(5-Methyl-2-phenyl-4-oxazolyl)methyl]amine (1.0 g, 5.31 mmol) in 10 mL of CH2Cl2 was added dropwise, followed by diisopropylethylamine(1.1 mL, 6.37 mmol) and the mixture stirred at 0° C. for 20 minutes,then at room temperature for 18 hours. The reaction mixture was diluted with 20 mL CH2Cl2, washed 3×25 mL 1N HCl, 1×25 mL 5% NaHCO3 and 2×25 mL brine, dried (MgSO4) and stripped to1.9 g of solids. The latter was flash chromatographed on silica gel using 3:40 ethyl acetate:hexane as eluant to yield 0.34 g of purified, present title product, mp 120°-122° C.