Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[NH:15]1[CH2:19][CH2:18][C:17]2([CH2:28][C:27](=[O:29])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[O:20]2)[CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:13][C:10]1[N:9]=[C:8]([C:5]2[N:4]=[N:3][C:2]([N:15]3[CH2:19][CH2:18][C:17]4([CH2:28][C:27](=[O:29])[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[O:20]4)[CH2:16]3)=[CH:7][CH:6]=2)[O:12][N:11]=1
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Reactant: O=C1CC2(CCNC2)Oc2ccccc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC(=O)c5ccccc5O4)C3)nn2)n1

Procedure:
The object product (148 mg, 62%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (130 mg) obtained in Example 43(2), spiro[chromene-2,3′-pyrrolidin]-4(3H)-one hydrochloride (160 mg) obtained in Example 21(2) and potassium carbonate (110 mg).
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[CH:5]=[N:4][C:3]=1[C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=1.[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[F:16][C:17]1[CH:22]=[C:21]([C:2]2[N:6]([CH3:7])[CH:5]=[N:4][C:3]=2[C:8]2[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][N:9]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cn1cnc(-c2cc(C#N)ccn2)c1Br
Reactant: OB(O)c1cccc(F)c1
Product: Cn1cnc(-c2cc(C#N)ccn2)c1-c1cccc(F)c1

Procedure:
The title compound was prepared from 2-(5-bromo-1-methyl-1H-imidazol-4-yl)pyridine-4-carbonitrile and 3-fluorophenylboronic acid according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H11FN4, 279. Found, 279.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>CO.O>[OH:20][CH:18]([CH3:19])[CH2:17][NH:16][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: CC(O)CN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: CO
Solvent: O
Product: CC(O)CNC(c1ccccc1)C(O)c1ccccc1
Temperature: 125 °C
Reaction time: 18 h
Yield: 28.1 %

Procedure:
A mixture of trans-stilbene oxide (3.93 g, 0.20 mole) and 1-amino-2-propanol (4.51 g, 0.060 mole) was heated in an oil bath at 125° C. for 1 hour. After standing at ambient temperature for 18 hours, the viscous oil was dissolved in 20 ml of methanol and diluted with water causing a white solid to precipitate. The solid was collected, washed with water, and dried under ambient conditions to give 4.57 g (84%) of the product which was recrystallized from toluene to give 3.65 g solids; m.p. 116°-118° C.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1>C1COCC1.C(OCC)C>[CH:1]1([C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH3:6])=[CH:8][CH:9]=2)([OH:15])[CH3:14])[CH2:3][CH2:2]1
Reactant: Br[Mg]C1CC1
Reactant: CC(=O)c1ccc(C)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C(C)(O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
27 ml (26.8 mmol) of 1N cyclopropylmagnesium bromide solution in THF were added to 3.00 g (22.4 mmol) of 1-(4-methylphenyl)ethanone in 60 ml of diethyl ether at RT, and the mixture was stirred at RT overnight. Then a further 11 ml (11.2 mmol) of 1N cyclopropylmagnesium bromide solution in THF were added, and the mixture was stirred at RT overnight. The reaction mixture was added to ice-water, the phases were separated, the aqueous phase was extracted with dichloromethane, and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient with addition of 0.1% triethylamine) to result in 491 mg (13% of theory) of the title compound.
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]1.Cl.[NH2:16][CH:17]([CH2:23][SH:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[CH:8]1([C:12]([NH:16][CH:17]([CH2:23][SH:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:14])[CH2:9][CH2:10][CH2:11]1
Reactant: O=C(O)C1CCC1
Reactant: CCOC(=O)C(N)CS
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C(CS)NC(=O)C1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (15 mL) was added to a suspension of cyclobutanecarboxylic acid (2.57 mL) and ethyl 2-amino-3-mercaptopropanoate hydrochloride (5 g) in DMF (40 mL). The resulting mixture was cooled in an ice bath and a solution of T3P (1.57M in THF, 20.6 mL) was added dropwise. The resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and the layers separated. The aqueous phase was extracted with DCM (2×100 mL). The combined organic solutions were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The resulting white solid was purified by silica gel chromatography eluting with 4:1 to 1:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 3.20 g.
Reaction SMILES: [CH2:1]([C:5]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)([CH2:8][N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)[C:6]#[N:7])[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)[OH:22]>[OH-].[NH4+]>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:5]([CH2:8][N:9]2[CH:13]=[N:12][CH:11]=[N:10]2)([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([NH2:7])=[O:22])=[CH:19][CH:18]=1
Reactant: O=S(=O)(O)O
Reactant: CCCCC(C#N)(Cn1cncn1)c1ccc(Cl)cc1
Agent: [NH4+]
Agent: [OH-]
Product: CCCCC(Cn1cncn1)(C(N)=O)c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 168 h
Yield: 56.5 %

Procedure:
To a 500 mL flask was charged 75.0 g (0.24 mole) of alpha-n-butyl-alpha-(4-chlorophenyl)-1H-1,2,4-triazole-1-propanenitrile followed by 300 mL of 95% sulfuric acid. The mixture was stirred at 90° C. for 7 days after which the mixture was cooled to room temperature, diluted with ice and neutralized with ammonium hydroxide until basic (pH 8). The product was extracted with ethylene dichloride then washed with water and dried over magnesium sulfate. The solvent was concentrated and gave 45 g (56.5% yield) of a solid melting point 197°-199° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[S:12]([O-:15])([OH:14])=[O:13].[Na+:16].C(O)C>O>[F:9][C:8]([F:11])([F:10])[C:7]1[C:2]([S:12]([O-:15])(=[O:14])=[O:13])=[N:3][CH:4]=[CH:5][CH:6]=1.[Na+:16]
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])c1ncccc1C(F)(F)F
Yield: 67.9 %

Procedure:
In a flask, 2-chloro-3-(trifluoromethyl)pyridine (20.0 g, 110 mmol) , sodium hydrogen sulfite (46 g, 442 mmol), ethanol (200 ml) and water (200 ml) were charged and heated under reflux for 138 hours. After evaporating off the solvent from the reaction mixture, conc. hydrochloric acid was added to the residue and then evaporated to dryness. This residue was extracted with methanol, and the methanol phase was filtered and evaporated to dryness to obtain sodium 3-(trifluoromethyl)pyridine-2-sulfonate (18.6 g). Yield, 68%.
Reaction SMILES: C(N(CC)CC)C.Br[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11].[SH:15][C:16]1[N:17]([C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([C:31]#[N:32])=[CH:23][CH:22]=2)[CH:18]=[CH:19][N:20]=1>ClCCl>[C:31]([C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([N:17]2[CH:18]=[CH:19][N:20]=[C:16]2[S:15][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:22][CH:23]=1)#[N:32]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(-n2ccnc2S)c2ccccc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CSc1nccn1-c1ccc(C#N)c2ccccc12
Reaction time: 3 h

Procedure:
Triethylamine (4.92 mL, 35.32 mmol), followed by ethyl bromoacetate (3.74 mL, 33.72 mmol) were added to a stirring slurry of 4-(2-mercapto-1H-imidazol-1-yl)-1-naphthonitrile (8.07 g, 32.11 mmol) in dichloromethane (60 mL) and stirring continued for 3 h. The mixture was washed with aqueous HCl solution (0.2M 100 mL), 50% saturated sodium chloride solution (50 mL), dried over sodium sulfate, filtered, and concentrated. Hexanes (100 mL) were added and the mixture concentrated to provide ethyl 2-(1-(4-cyanonaphthalen-1-yl)-1H-imidazol-2-ylthio)acetate as a light-tan solid (10.47 g, (97%).
Reaction SMILES: [OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH2:34][O:35]C(=O)C)[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=O)[CH2:4][CH2:3]1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:51]([NH2:55])[CH2:52][CH2:53][CH3:54].O>CN(C)C=O>[OH:1][C:2]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][CH2:33][CH2:34][OH:35])[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11]([NH:55][CH2:51][CH2:52][CH2:53][CH3:54])=[O:13])[CH2:4][CH2:3]1
Reactant: CCCCN
Reactant: CC(=O)OCCOc1ccccc1C1(O)CCN(CCC(C(=O)O)(c2ccccc2)c2ccccc2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNC(=O)C(CCN1CCC(O)(c2ccccc2OCCO)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
In 5 mL of anhydrous dimethylformamide was dissolved 81 mg (0.17 mmol) of 4-(4-hydroxy-4-(2-(2-acetoxyethoxy)phenyl)piperidino)-2,2-diphenylbutyric acid. The resulting solution was stirred at room temperature for 1 hour. To the reaction mixture were added 36 mg (0.22 mmol) of carbodiimidazole, and after one hour 16 mg (0.22 mmol) of n-butylamine. After stirring at 70° C. for 24 hours, stirring was conducted for further 3 hours at 130° C., whereby the reaction was completed. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with water and drying. The residue obtained by distilling off the solvent under reduced pressure was purified by chromatography on an alumina column and then chromatography on a silica gel column, whereby 35 mg (yield: 38.9%) of 4-(4-hydroxy-4-(2-(2-hydroxyethoxy)phenyl)piperidino)-N-butyl-2,2-diphenylbutaneamide (Compound No. 73) was obtained.
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([N:11]([CH3:10])[C:2]2[C:7]([CH3:8])=[C:6]([I:9])[CH:5]=[CH:4][N:3]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1c(I)ccnc1F
Reactant: CNC1CCCCC1
Product: Cc1c(I)ccnc1N(C)C1CCCCC1

Procedure:
2-Fluoro-4-iodo-3-methylpyridine (700 mg) in N-methylcyclohexanamine (2.2 ml) was heated at 180(C in a Biotage Initiator microwave reactor for 18 hours. The reaction mixture was loaded onto a silica gel cartridge, and was eluted with 0-100% dichloromethane in hexanes to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([CH:11]=O)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:14][OH:15].[OH-].[Na+]>CCO.O>[Cl:1][C:2]1[C:3]2[C:10]([CH:11]=[N:14][OH:15])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: O=Cc1c[nH]c2ncnc(Cl)c12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: ON=Cc1c[nH]c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde (1.17 g, 6.47 mmol, 1.0 eq) and hydroxylamine hydrochloride (0.54 g, 7.77 mmol, 1.2 eq) in EtOH (25 mL), aqueous NaOH solution (0.31 g, 7.77 mmol, 1.2 eq) in H2O (4 mL) was added dropwise. The resulting mixture was stirred at RT for 30 min and then was diluted with a sufficient amount of EtOH to allow stirring for additional 30 min. The solid was collected by filtration, rinsed with H2O and dried in vacuo to afford 4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbaldehyde oxime (0.89 g, 70% yield) as a mixture of isomers. ESI-MS m/z: 194.8 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.Br[CH2:23][CH2:24][CH2:25][OH:26]>>[OH:26][CH2:25][CH2:24][CH2:23][O:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: OCCCBr
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCCCO)c1

Procedure:
Alkylation reaction of phenol 58 with 3-bromo-1-propanol gave 2-(3-(3-(3-hydroxypropoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.300 g, 25%): 1H NMR (400 MHz, CDCl3) δ 7.80-7.83 (m, 2H), 7.69-7.71 (m, 2H), 7.12-7.16 (m, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.76 (s, 1H), 6.65 (dd, J=8.0, 2.4 Hz, 1H), 4.10 (d, J=6.0 Hz, 2H), 3.84-3.89 (m, 2H), 3.73 (t, J=7.2 Hz, 2H), 2.65 (t, J=8.0 Hz, 2H), 1.98-2.05 (m, 4H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1.N([C:16]1[NH:17][CH2:18][CH2:19][N:20]=1)[N+]([O-])=O>C1(C)C(C)=CC=CC=1>[NH:20]1[CH2:19][CH2:18][N:17]=[C:16]1[NH:1][CH2:2][CH:3]([OH:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1
Reactant: Cc1cccc(C(O)CN)c1
Reactant: O=[N+]([O-])NC1=NCCN1
Solvent: Cc1ccccc1C
Product: Cc1cccc(C(O)CNC2=NCCN2)c1

Procedure:
A mixture of 8.2 parts of α-(aminomethyl)-m-methylbenzyl alcohol, 6,1 parts of 2-(nitramino)-2-imidazoline and 40 parts of xylene is stirred in an oil-bath at 150°-160°C, while almost all xylene is distilled off. The residue is diluted with a few parts of acetone and allowed to crystallize. The product is filtered off and recrystallized from 4-methyl-2-pentanone, yielding α-(2-imidazolin-2-ylaminomethyl)-m-methylbenzyl alcohol; m.p. 121°C.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][CH:3]=[N:2]1.C([CH:15]([CH:19](CC=C)[C:20]([NH2:22])=[O:21])[C:16]([NH2:18])=[O:17])C=C.CCN(C(C)C)C(C)C>CN(C=O)C>[NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH:5]=[CH:4][C:3]([CH:19]([C:20]([NH2:22])=[O:21])[CH2:15][C:16]([NH2:18])=[O:17])=[N:2]1
Reactant: C=CCC(C(N)=O)C(CC=C)C(N)=O
Reactant: C1=Cc2ccccc2NN=C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)CC(C(N)=O)C1=NNc2ccccc2C=C1

Procedure:
Following the procedures described for the synthesis of 11, diallylsuccinamide intermediate 16 was prepared from 14 in reasonable yield. 14 (2.5 g, 5.9 mmol), p-chloro-BZD (2.34 g, 6.2 mmol) and DIPEA (1 ml, 5.8 mmol) in 30 ml DMF was heated to 40-50 degree overnight.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][NH:5][CH:4]2[CH2:8][CH2:9][CH2:10][CH:3]12.Cl[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].C(N(CC)CC)C>ClCCl>[O:2]1[CH2:7][CH2:6][N:5]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH:4]2[CH2:8][CH2:9][CH2:10][CH:3]12
Reactant: O=C(Cl)OCc1ccccc1
Reactant: C1CC2NCCOC2C1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCOC2CCCC21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To octahydrocyclopenta[b][1,4]oxazine hydrochloride (purchased from Enamine) (300 mg, 1.83 mmol) dissolved in dichloromethane (2.4 mL) was added benzyl chloroformate (0.44 mL, 2.57 mmol). Triethylamine (0.72 mL, 5.13 mmol) was added slowly to the reaction mixture, and the reaction was stirred for 16 hours at room temperature. The mixture was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient), and then purified by chiral supercritical fluid chromatography (Chiralpak AZ-H, 21×250 mm, 10% methanol in CO2) to afford the trans stereoisomers of benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate. (4aS,7aS)-Benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate (faster eluting enantiomer): MS ESI calc'd. for C15H19NO3 [M+H]+ 262. found 262; (4aR,7aR)-Benzyl hexahydrocyclopenta[b][1,4]oxazine-4(4aH)-carboxylate (slower eluting enantiomer): MS ESI calc'd. for C15H19NO3 [M+H]+ 262. found 262.
Reaction SMILES: Cl.[CH3:2][S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C([Al](CC)CC)C.[C:20]([C:22]1[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=1)#[N:21]>ClC(Cl)C>[CH3:28][C:23]1[C:22]([C:20](=[NH:21])[NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([CH3:2])(=[O:4])=[O:5])=[CH:7][CH:8]=2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: Cc1ncccc1C#N
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: CC[Al](CC)CC
Agent: Cl
Solvent: CC(Cl)Cl
Product: Cc1ncccc1C(=N)Nc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a suspension of 4-(methylsulfonyl)aniline hydrochloride (6.85 g, 0.040 mol) in dichloroethane (400 mL) was added triethylaluminum (1.9M solution in toluene, 32.0 mL, 60 mmol) over 15 minutes at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 hours. A solution of 3-cyano-2-methylpyridine, from step 2, in 70 mL of dichloroethane was added over 10 minutes and the mixture was stirred at 75° C. for 16 hours. The reaction mixture was cooled to room temperature and treated with 50 g of silica gel. The mixture was stirred for 30 minutes and filtered. The filtrate and washings were concentrated under reduced pressure and the residue was washed with ether to give 7.3 g of crude 2-methyl-N-[4-(methylsulfonyl)phenyl]-3-pyridinecarboximidamide (60%). To a mixture of the above crude amidine (7.0 g, 0.024 mol) and sodium bicarbonate (4;0 g, 0.048 mol) in isopropanol (350 mL) was added 3-bromo-1,1,1-trifluoroacetone (6.9 g, 0.036 mol) rapidly at room temperature. After heating the reaction mixture at 75°-80° C. for 16 hours, the solvent was removed and the residue was partitioned between water and methylene chloride. The organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (ethyl acetate/acetone, 98:2) to give 4.02 g of pure 2-methyl-3-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine as a yellow solid (25%): mp (DSC) 237°-239° C. Anal. Calc'd. for C17H16F3N3O3S: C, 51.12, H, 4.04, N, 10.52, S, 8.03. Found: C, 50.92, H, 4.12, N, 10.04, S, 7.83.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C@H:15]1[NH:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[O:12])=[CH:5]2.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:25]([CH2:24][NH:23][C@@H:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:22][C@H:14]1[NH:13][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:12])([OH:27])=[O:26]
Reactant: CC(C)(C)OC(=O)CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
tert-Butyl N-((1R,2R)-2-{[(5-chloro-1H-indol-2-yl)carbonyl]amino}-2,3-dihydro-1H-inden-1-yl)glycinate (Method 8, 230 mg, 0.52 mmol) was dissolved in DCM (10 mL). TFA (1 mL) was added and the reaction stirred at ambient temperature for 3 hours. Evaporation under reduced pressure, co-evaporation with CHCl3 (2×10 mL) and crystallization from EtOAc gave the title compound (85 mg, 36%) as a powder.
Reaction SMILES: [CH3:1][C@:2]1([N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[N+:21]([O-])=O)[N:12]=[C:11]2[CH3:24])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9]>C(OCC)(=O)C.CO.[Pd].[O-2].[O-2].[Mn+4]>[NH2:21][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[C:19](=[O:20])[N:10]([C@@:2]1([CH3:1])[CH2:7][CH2:6][C:5](=[O:8])[NH:4][C:3]1=[O:9])[C:11]([CH3:24])=[N:12]2
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)n1[C@@]1(C)CCC(=O)NC1=O
Agent: [Mn+4]
Agent: [Pd]
Agent: [O-2]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1nc2cccc(N)c2c(=O)n1[C@@]1(C)CCC(=O)NC1=O
Reaction time: 16 h
Yield: 33.3 %

Procedure:
A mixture of (S)-3-methyl-3-(2-methyl-5-nitro-4-oxoquinazolin-3(4H)-yl)piperidine-2,6-dione (0.30 g, 1.0 mmol) and 10% Pd—C (0.2 g, 50% wet), in 200 mL of 3:1 ethyl acetate-methanol was shaken under 50 psi H2 for 45 minutes. The mixture was filtered through Celite, and the solvent was evaporated. The residue was redissolved in 200 mL of 4:1 dichloromethane-acetone, and manganese dioxide (0.20 g, 2.2 mmol) was added. This mixture was stirred for 16 hours. The mixture was filtered through Celite, and the filtrate was evaporated. The residue was chromatographed on silica gel using a dichloromethane-acetonitrile gradient, eluting (S)-3-(5-amino-2-methyl-4-oxoquinazolin-3(4H)-yl)-3-methylpiperidine-2,6-dione as a beige solid (0.10 g, 37% yield): HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 1.63 (99.20%); mp 297-299° C.; 1H NMR (DMSO-d6) δ 1.88 (s, 3H, CH3), 2.31-2.36 (m, 1H, CHH), 2.53-2.59 (m, 2H, 2CHH), 2.62 (s, 3H, CH3), 2.71-2.84 (m, 1H, CHH), 6.53-6.56 (m, 2H, Ar), 6.95 (br, 2H, NH2), 7.35 (t, J=8 Hz, 1H, Ar), 10.72 (s, 1H, NH); 13C NMR (DMSO-d6) δ 24.5, 26.3, 28.3, 29.0, 62.2, 104.2, 110.5, 110.8, 135.0, 147.4, 150.4, 152.9, 164.9, 171.5, 173.0; Anal. Calcd for C15H16N4O3: C, 59.99; H, 5.37; N, 18.66. Found: C, 59.61; H, 5.43; N, 18.59.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14]Br)=[CH:10][CH:9]=2)=[CH:6][C:5]2[O:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[C:3]1=[O:25].[CH3:26][NH:27][CH3:28]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:27]([CH3:28])[CH3:26])=[CH:10][CH:9]=2)=[CH:6][C:5]2[O:16][N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:4]=2[C:3]1=[O:25]
Reactant: CNC
Reactant: Cn1c(-c2ccc(CBr)cc2)cc2onc(-c3ccccc3)c2c1=O
Solvent: Cc1ccccc1
Product: CN(C)Cc1ccc(-c2cc3onc(-c4ccccc4)c3c(=O)n2C)cc1

Procedure:
A mixture of 21.2 g. of the product of Example 4, containing 62% of 5-methyl-3-phenyl-6-(p-bromomethylphenyl)-isoxazolo[4,5-c]pyridin-4(5H)-one (0.0332 mole of bromo compound) and 7.2 g. (0.160 mole) dimethylamine in 300 ml. toluene is stirred overnight at room temperature. The mixture is filtered and the solid washed with toluene and the solvent evaporated in vacuo. The resulting solid is dissolved in methylene chloride and treated with 2N hydrochloric acid, the precipitate is then filtered, washed with water and ether. The solid is then dissolved in methylene chloride and 2N sodium dioxide and the organic phases separated and washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to give 5-methyl-3-phenyl-6-(p-[dimethylaminomethyl]phenyl)-isoxazolo[4,5-c]pyridin-4(5H)-one; m.p. 159°-161° C.