Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:7][N:6](S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:5][C:4]2[CH:20]=[C:21]([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[S:22][C:3]1=2.C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1>C(#N)C>[CH3:1][C:2]1([CH3:33])[CH2:7][NH:6][CH2:5][C:4]2[CH:20]=[C:21]([C:23]([NH:25][O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[O:24])[S:22][C:3]1=2
Reactant: CC1(C)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cc(C(=O)NOC3CCCCO3)sc21
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)CNCc2cc(C(=O)NOC3CCCCO3)sc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.2 %

Procedure:
To a mixture of 7,7-dimethyl-5-(2-nitrophenylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxamide (15.4 g, 31 mmol) and cesium carbonate (20.2 g, 62 mmol) in acetonitrile (800 mL) was added a solution of thiophenol (6.85 g, 62 mmol) in acetonitrile (70 mL). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue applied to silica gel chromatography (0-20% DCM/MeOH) to afford the title compound (8.2 g, 85%). LCMS (FA) ES+ 311; 1H NMR (400 MHz, DMSO) δ 11.49 (s, 1H), 7.30 (s, 1H), 4.91 (s, 1H), 4.01 (dd, J=15.6, 8.0 Hz, 1H), 3.71 (s, 2H), 3.55-3.44 (m, 1H), 2.71 (s, 2H), 1.69 (s, 3H), 1.53 (s, 3H), 1.25 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]Br)=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.C1C(=O)N(Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([CH3:7])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1
Reactant: COc1ccc(-c2nc(CBr)sc2Br)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2nc(C)sc2Br)cc1
Temperature: 100 °C
Yield: 57.9 %

Procedure:
To the solution of 5-Bromo-2-bromomethyl-4-(4-methoxy-phenyl)-thiazole (5.0 g, 24.3 mmol) in the 20 ml of CCl4 was added NBS (4.32 g, 24.3 mmol) and AIBN (0.4 g, 2.43 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using 1% ethyl acetate/hexane eluent to give the desired product (4.0 g, 58%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:26]2[CH2:31][CH2:30][CH:29]([CH:32]([CH3:38])[C:33]([O:35]CC)=[O:34])[CH2:28][CH2:27]2)=[N:4][CH:5]=[C:6]([NH:8][C:9]([C:11]2[O:12][C:13]([NH:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=3[F:25])=[N:14][N:15]=2)=[O:10])[CH:7]=1.C[Si](C)(C)[O-].[K+].O.Cl>C1COCC1>[CH3:1][C:2]1[C:3]([N:26]2[CH2:27][CH2:28][CH:29]([CH:32]([CH3:38])[C:33]([OH:35])=[O:34])[CH2:30][CH2:31]2)=[N:4][CH:5]=[C:6]([NH:8][C:9]([C:11]2[O:12][C:13]([NH:16][C:17]3[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=3[F:25])=[N:14][N:15]=2)=[O:10])[CH:7]=1
Reactant: CCOC(=O)C(C)C1CCN(c2ncc(NC(=O)c3nnc(Nc4cc(F)c(F)cc4F)o3)cc2C)CC1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(NC(=O)c2nnc(Nc3cc(F)c(F)cc3F)o2)cnc1N1CCC(C(C)C(=O)O)CC1
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 68.6 %

Procedure:
Ethyl 2-(1-{3-methyl-5-[({5-[(2,4,5-trifluorophenyl)amino]-1,3,4-oxadiazol-2-yl}carbonyl)amino]pyridine-2-yl}piperidin-4-yl)propanoate (Example 692) (70 mg; 0.13 mmol) was dissolved in dry THF (2.0 mL), treated with potassium trimethylsilanolate (167 mg; 1.30 mmol) and placed in a Biotage ‘Initiator’ microwave. The reaction was heated at 90° C. for 35 mins., monitoring by LCMS, as a yellow precipitate formed. The reaction was incomplete (˜9% ester remained). A further portion of potassium trimethylsilanolate (17 mg) was added and the reaction was returned to the microwave for 15 mins. Very little more reaction was seen (ie ˜5% of starting ester remained). The resulting yellow suspension was treated with water (3 mL) and acidified, to about pH 2, with dropwise addition of aq. 1M HCl. With vigorous stirring for ˜15 mins, a white precipitate formed which was filtered, washed with water and dried under vacuum at 60° C. to give the title compound (45 mg; 79% yield).
Reaction SMILES: [Na].[C:2]([NH:4][C:5]([NH:10][CH3:11])=[N:6][CH2:7][CH2:8][SH:9])#[N:3].Cl.[CH3:13][C:14]1[NH:18][CH:17]=[N:16][C:15]=1[CH2:19]Cl>C(O)C>[C:2]([NH:4][C:5]([NH:10][CH3:11])=[N:6][CH2:7][CH2:8][S:9][CH2:19][C:15]1[N:16]=[CH:17][NH:18][C:14]=1[CH3:13])#[N:3]
Reactant: CNC(=NCCS)NC#N
Reactant: Cc1[nH]cnc1CCl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CNC(=NCCSCc1nc[nH]c1C)NC#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium (1.43 g) was added, with stirring under nitrogen, to dry ethanol (100 ml). After the sodium had dissolved a solution of N-cyano-N'-methyl-N"-(2-mercaptoethyl)guanidine (4.90 g) in dry ethanol (50 ml) was added and the mixture was stirred at room temperature for 1 hour. 5-Methyl-4-chloromethylimidazole hydrochloride (5.18 g) was added in batches over a period of one hour at room temperature. The mixture was then stirred at room temperature, for a further hour and heated at reflux temperature for 1/2 hour. After cooling the mixture was filtered and the filtrate was evaporated to a glassy solid (8.8 g). This crude product was chromatographed on silica gel with acetonitrile as eluant and the solid product obtained (3.60 g) was recrystallised from acetonitrile to give N-cyano-N'-methyl-N"-[2-(5-methyl-4-imidazolylmethylthio)ethyl]guanidine, m.p. = 140°-142° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH:12]1([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[N:22]2[C:26]([CH3:27])=[C:25]([C:28]([OH:30])=O)[N:24]=[N:23]2)[CH2:14][CH2:13]1.[NH2:31][C:32]1[C:33](=[O:45])[N:34]([CH:39]2[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]2)[N:35]([CH3:38])[C:36]=1[CH3:37].C(N(CC)CC)C>C(Cl)Cl>[CH:39]1([N:34]2[C:33](=[O:45])[C:32]([NH:31][C:28]([C:25]3[N:24]=[N:23][N:22]([C:16]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=4[CH:12]4[CH2:13][CH2:14]4)[C:26]=3[CH3:27])=[O:30])=[C:36]([CH3:37])[N:35]2[CH3:38])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Reactant: Cc1c(C(=O)O)nnn1-c1ccc(F)cc1C1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2c(C)n(C)n(C3CCCCC3)c2=O)nnn1-c1ccc(F)cc1C1CC1
Reaction time: 1 h

Procedure:
To a solution of oxalyl chloride (0.055 ml, 0.632 mmol) in DCM (5 ml) was added DMF (0.065 ml, 0.842 mmol) dropwise and the mixture was stirred for 1 hr. The resulting mixture was treated with 1-(2-cyclopropyl-4-fluorophenyl)-5-methyl-1H-1,2,3-triazole-4-carboxylic acid (110 mg, 0.421 mmol) and stirring continued at RT for 30 mins. To the reaction mixture was added 4-amino-2-cyclohexyl-1,5-dimethyl-1H-pyrazol-3(2H)-one (Intermediate A) (97 mg, 0.463 mmol) followed by triethylamine (0.176 ml, 1.263 mmol) and stirring continued at RT for 30 mins. The resulting mixture was diluted with DCM, washed with water and eluted though a phase separating cartridge. The organic eluent was collected and concentrated under reduced pressure to give a brown oil. The was absorbed onto silica and purified by chromatography eluting with 0-10% MeOH in TBME. The product fractions were combined, concentrated and dried under reduced pressure to give a pale brown glassy solid. The solid was dissolved in DCM, washed with water, brine and eluted through a phase separating cartridge. The organic eluent was concentrated under reduced pressure to give the title compound as a glassy solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:35]([O:37][CH2:38][C:39]([Cl:42])([Cl:41])[Cl:40])=[O:36].O>ClCCl>[Cl:40][C:39]([Cl:42])([Cl:41])[CH2:38][O:37][C:35](=[O:36])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:24])[C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Sc2ccc(NC(=O)c3ccc(F)cc3)cc2[N+](=O)[O-])cc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccc(Sc2ccc(NC(=O)c3ccc(F)cc3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 238c (0.85 g, 2.2 mmol) in dichloromethane (40 mL) was added pyridine (0.35 g, 4.4 mmol) and 2,2,2-trichloroethyl chloroformate (0.58 g, 2.7 mmol). The mixture was stirred at room temperature for 16 h. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate (2×). The combined organic phases were washed with water, 5% HCl, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound. The residue was purified by silica gel chromatography eluting with chloroform/methanol (90:10) to give the desired product (0.90 g, 75%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[C:14]([N+:19]([O-])=O)[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt].C(#N)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])=[C:14]([NH2:19])[CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCNc1c([N+](=O)[O-])cnc2cc(OCc3ccccc3)ccc12
Agent: [Pt]
Solvent: CC#N
Product: CC(C)(C)[Si](C)(C)OCCNc1c(N)cnc2cc(OCc3ccccc3)ccc12
Reaction time: 8 h
Yield: 99.7 %

Procedure:
A 3-liter stainless steel Parr vessel was charged sequentially with 5% platinum on carbon catalyst, acetonitrile (250 mL), 7-(benzyloxy)-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-nitroquinolin-4-amine (102 g, 0.225 mol), and additional acetonitrile (1250 mL). The vessel was evacuated and charged with hydrogen gas (30 psi, 2.1×105 Pa). The vessel was shaken overnight. The reaction mixture was then filtered through a layer of CELITE filter agent. The filter cake was rinsed with additional acetonitrile (2 L), and the combined filtrates were concentrated under reduced pressure to provide 95 g of 7-(benzyloxy)-N4-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)quinoline-3,4-diamine as an orange-green solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][C@@H:11]2[O:14][C:15](=[O:24])[N:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@@H:10]2[CH2:9]1.[NH2:25][C:26]1[C:27]([C:40](O)=[O:41])=[N:28][C:29]([C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])=[CH:30][CH:31]=1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1>CN(C=O)C.O>[NH2:25][C:26]1[C:27]([C:40]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[N:8]2[CH2:13][CH2:12][C@@H:11]3[O:14][C:15](=[O:24])[N:16]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C@@H:10]3[CH2:9]2)=[O:41])=[N:28][C:29]([C:32]2[C:33]([F:39])=[CH:34][CH:35]=[CH:36][C:37]=2[F:38])=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(c3ccncc3N)C[C@H]21
Reactant: Nc1ccc(-c2c(F)cccc2F)nc1C(=O)O
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1C(=O)O[C@H]2CCN(c3ccncc3NC(=O)c3nc(-c4c(F)cccc4F)ccc3N)C[C@H]21
Reaction time: 15 h
Yield: 46 %

Procedure:
To a solution of (3aR,7aS)-tert-butyl 5-(3-aminopyridin-4-yl)-2-oxohexahydrooxazolo[4,5-c]pyridine-3(2H)-carboxylate (1.0 equiv.) in DMF (0.3 M) was added 3-amino-6-(2,6-difluorophenyl)picolinic acid (1.2 equiv.), EDC (1.2 equiv.) and HOAt (1.2 equiv.). The solution was stirred for 15 h. To the mixture was added water and the precipitate was filtered. To the filtrate was added EtOAc, and the organic solution was extracted (3 times), dried with Na2SO4, and concentrated to give an orange syrup. The crude was triturated with EtOAc and hexanes mixture and the precipitate was filtered off to give pure product in 46% yield. LCMS (m/z): 567.0 (MH+), LC Rt=3.03 min.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH2:31][CH3:32])[CH2:13][C:14]([C:16]1([O:29][CH3:30])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1)=[O:15].C(N(CC)CC)C>ClCCl>[CH3:30][O:29][C:16]1([C:14](=[O:15])[CH2:13][C:12](=[O:11])[CH2:31][CH3:32])[CH2:17][CH2:18][N:19]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[CH2:20][CH2:21]1
Reactant: CCC(O)CC(=O)C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCC(=O)CC(=O)C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 56.6 %

Procedure:
To a solution of oxalyl chloride (0.168 mL, 1.92 mmol) in dichloromethane (10 mL) at −78° C. was slowly added dimethyl sulfoxide (0.272 mL, 3.84 mmol). After 5 min, a solution of tert-butyl 4-(3-hydroxy-1-oxopent-1-yl)-4-methoxypiperidine-1-carboxylate (0.404 g, 1.28 mmol) from Step B in dichloromethane (5 mL) was added via syringe. The reaction mixture was stirred for 45 min at -78° C. and then triethylamine (1.1 mL, 7.68 mmol) was added. After 5 min, the reaction mixture was removed from the cooling bath, allowed to warm to room temperature for 1.5 h, poured into water, and extracted three times with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography eluting with 10% ethyl acetate/hexanes to afford the title compound (0.227 g).
Reaction SMILES: Cl.[O:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5](N)[CH2:4][CH2:3]1.[F:13][C:14]([F:26])([F:25])[C:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH:19]([CH3:24])[CH2:18]1)=[O:16].[BH4-].[Na+]>CC(O)C>[F:26][C:14]([F:13])([F:25])[C:15]([N:17]1[CH2:22][CH2:21][CH:20]2[N:5]3[CH2:4][CH2:3][O:2][C:7]4[CH:8]=[CH:9][CH:10]=[C:11]([C:6]3=4)[C:19]2([CH3:24])[CH2:18]1)=[O:16]
Reactant: NN1CCOc2ccccc21
Reactant: CC1CN(C(=O)C(F)(F)F)CCC1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC12CN(C(=O)C(F)(F)F)CCC1N1CCOc3cccc2c31
Temperature: 25 °C
Yield: 89.7 %

Procedure:
2,3-Dihydro-4H-1,4-benzoxazin-4-amine hydrochloride (0.0830 g, 0.444 mmol) and 1-trifluoroacetyl-3-methylpiperidin-4-one (0.0929 g, 0.444 mmol) were combined in 2-propanol (3.75 mL) and stirred at reflux for 3.75 hours under N2. The reaction mixture was cooled to room temperature, NaBH4 (0.0523 g, 1.38 mmol) was added and the reaction mixture was refluxed for 1 hour under N2. The cooled reaction mixture was quenched with CH3OH (2 mL) and partitioned between CH2Cl2 and H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined CH2Cl2 extracts were washed with H2O, dried over Na2SO4, filtered and concentrated to yield crude 8-trifluoroacetyl-6b-methyl-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole (0.130 g). MS (ESI+) for C16H17F3N2O2 m/z 327.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](Br)=[CH:4][CH:3]=1.[Li]CCCC.[I:18]I.OS([O-])=O.[Na+]>C1COCC1>[I:18][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: II
Reactant: Brc1ccc(Br)c2ccccc12
Agent: O=S([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Brc1ccc(I)c2ccccc12
Temperature: -70 °C
Reaction time: 1 h

Procedure:
100 g (350 mmol) of 1,4-dibromonaphthalene are initially introduced in 11 of THF, cooled to −70° C., and 235 ml of n-BuLi (1.6 M in hexane, 370 mmol) are added dropwise. After 1 h, 103 g (406 mmol) of I2 in 250 ml of THF are added dropwise, the mixture is stirred at −70° C. for a further 2 h, warmed to 0° C. and quenched by the addition of 50 ml (644 mmol) of aqueous NaHSO3 solution (w=39%). The phases are separated, and the aqueous phase is extracted once with MTB. The combined organic phases are washed with saturated sodium chloride soln., dried over sodium sulfate, filtered and evaporated in a rotary evaporator. The residue is purified by column chromatography (SiO2, heptane), and the further purification is carried out by recrystallisation from isopropanol, giving 1-iodo-4-bromonaphthalene as a yellow solid.
Reaction SMILES: I[C:2]1[C:7](=[O:8])[C:6]([N+:9]([O-:11])=[O:10])=[C:5]([CH3:12])[NH:4][C:3]=1[CH3:13].[Cu][C:15]#[N:16]>CN1CCCC1=O>[CH3:13][C:3]1[NH:4][C:5]([CH3:12])=[C:6]([N+:9]([O-:11])=[O:10])[C:7](=[O:8])[C:2]=1[C:15]#[N:16]
Reactant: Cc1[nH]c(C)c([N+](=O)[O-])c(=O)c1I
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: Cc1[nH]c(C)c([N+](=O)[O-])c(=O)c1C#N
Temperature: 125 °C
Reaction time: 0.25 h
Yield: 40.9 %

Procedure:
A mixture of 3-iodo-2,6-dimethyl-5-nitropyridin-4(1H)-one (0.59 g, 2.006 mmol) and copper(I) cyanide (0.359 g, 4.01 mmol) in N-methyl-2-pyrrolidone (NMP) (10 mL) was heated at 125° C. for 2 h, at which time it was allowed to cool to ambient temperature and poured into ice/water/saturated NH4Cl (100 mL). The mixture was stirred for 15 min (pH˜6-7), then allowed to stand in an ice bath for 1 h. The solids were filtered, washed with a small amount of water, air dried for 10 min, and further dried in a vacuum oven at 37° C. for 18 h to give 2,6-dimethyl-5-nitro-4-oxo-1,4-dihydropyridine-3-carbonitrile (176 mg, 0.820 mmol, 40.9% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.30-2.38 (m, 3 H) 2.44-2.48 (m, 3 H) 12.78 (br. s., 1 H). MS(ES) [M+H]+ 193.9.
Reaction SMILES: [OH-].[K+].[CH3:3][N:4]([CH3:34])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH2:31][CH3:32])[C:23]=3[CH3:33])=[C:13](S(C)(=O)=O)[CH:14]=[CH:15][C:16]=2C)=[CH:7][CH:6]=1.[CH3:35][C:36]1[NH:37]C2[C:43]([CH:44]=1)=CC=CC=2.[OH-].[NH4+].[Cl-].[Na+]>CC(C)=O.O>[CH3:34][N:4]([CH3:3])[C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]([CH2:31][CH3:32])[C:23]=3[CH3:33])=[C:13]3[C:14](=[CH:15][CH:16]=2)[NH:37][C:36]([CH3:35])=[C:44]3[CH3:43])=[CH:9][CH:10]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: CCn1c(C)c(-c2c(S(C)(=O)=O)ccc(C)c2-c2ccc(N(C)C)cc2)c2ccccc21
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O
Product: CCn1c(C)c(-c2c(-c3ccc(N(C)C)cc3)ccc3[nH]c(C)c(C)c23)c2ccccc21
Yield: 61.7 %

Procedure:
With stirring, 2.0 g of potassium hydroxide was added slowly to a mixture of 6.7 g of [(4-dimethylaminophenyl)(1-ethyl-2-methylindol-3-yl)(4-methylphenylsulfonyl)]methane, 2.5 g of 2-methylindole and 75.0 ml of acetone. The resulting mixture was stirred approximately twenty hours at ambient temperature and slowly added with stirring to cold water. The precipitate which formed was collected by filtration and washed three times each with 50.0 ml of hexane. The hexane-wet filter cake was dissolved in toluene. The toluene solution was extracted with water and the toluene layer containing the product was stirred with decolorizing carbon for approximately thirty minutes and the carbon removed by filtration. The toluene was removed by distillation at reduced pressure to obtain a gum-like residue. The residue was dissolved in 150.0 ml of acetone and the resulting solution was added slowly to a mixture of 800.0 ml of water, 10.0 ml of concentrated ammonium hydroxide and 50.0 ml of saturated aqueous sodium chloride solution. The solid which separated was collected by filtration, washed with water and dried in vacuo to obtain 3.9 g of [(4-dimethylaminophenyl)(1-ethyl-2-methylindol-3-yl)(2-methylindol-3-yl)]methane (Formula V: R1 =R2 =R8 =R9 =R11 =H; R3 =N(CH3)2 ; R7 =R10 =CH3 ; R6 =C2H5), a pale brown-colored solid which melted over the range of 69°-80.5° C. An infrared maxima appeared at 745 (C--H;s) cm-1. A toluene solution of the product spotted on an acidic clay-coated paper or phenolic resin-coated paper slowly developed a blue-red-colored image.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:63])[CH2:21][N:19]2[CH2:20][CH:5]([CH2:6][C@:7]([C:59]([O:61][CH3:62])=[O:60])([C:22]3[CH:23]=[C:24]4[C@:32]56[C@@H:36]7[C@:37]([CH2:56][CH3:57])([C@@H:41]([O:52][C:53]([CH3:55])=[O:54])[C@@:42]8([O:48][C:46](=[O:47])[N:45]([CH2:49][CH2:50][Cl:51])[C:43]8=[O:44])[C@@H:31]5[N:30]([CH3:58])[C:25]4=[CH:26][C:27]=3[O:28][CH3:29])[CH:38]=[CH:39][CH2:40][N:35]7[CH2:34][CH2:33]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:9]=3[CH2:17][CH2:18]2)[CH2:4]1.[C:64]1([S:78]([OH:81])(=[O:80])=[O:79])[C:73]2[CH:72]=[CH:71][CH:70]=[C:69]([S:74]([OH:77])(=[O:76])=[O:75])[C:68]=2[CH:67]=[CH:66][CH:65]=1>CO>[CH3:1][CH2:2][C@@:3]1([OH:63])[CH2:21][N:19]2[CH2:20][CH:5]([CH2:6][C@:7]([C:59]([O:61][CH3:62])=[O:60])([C:22]3[CH:23]=[C:24]4[C@:32]56[C@@H:36]7[C@:37]([CH2:56][CH3:57])([C@@H:41]([O:52][C:53]([CH3:55])=[O:54])[C@@:42]8([O:48][C:46](=[O:47])[N:45]([CH2:49][CH2:50][Cl:51])[C:43]8=[O:44])[C@@H:31]5[N:30]([CH3:58])[C:25]4=[CH:26][C:27]=3[O:28][CH3:29])[CH:38]=[CH:39][CH2:40][N:35]7[CH2:34][CH2:33]6)[C:8]3[NH:16][C:15]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[C:9]=3[CH2:17][CH2:18]2)[CH2:4]1.[C:64]1([S:78]([O-:81])(=[O:80])=[O:79])[C:73]2[CH:72]=[CH:71][CH:70]=[C:69]([S:74]([O-:77])(=[O:76])=[O:75])[C:68]=2[CH:67]=[CH:66][CH:65]=1
Reactant: O=S(=O)(O)c1cccc2c(S(=O)(=O)O)cccc12
Agent: CC[C@]1(O)CC2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@]5(OC(=O)N(CCCl)C5=O)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Solvent: CO
Product: O=S(=O)([O-])c1cccc2c(S(=O)(=O)[O-])cccc12
Reaction time: 8 h

Procedure:
To 1% (w/v) solution of vinzolidine free base (95+% purity) in methanol is added dropwise with stirring a stoichiometric amount (1 mole per mole) of a 2% methanolic solution of 1,5-naphthalenedisulfonic acid. The resulting solution was allowed to stand at ambient temperature for about two hours, during which time period crystallization of the vinzolidine 1,5-naphthalenedisulfonate salt begins. The crystallizing solution is kept at about 0° C. overnight and is then filtered. The filter cake is washed with a small amount of methanol and then dried in vacuo overnight at ambient temperature. The salt is then allowed to stand in air for about two hours. The yield of vinzolidine 1,5-naphthalenedisulfonate is 95-97%.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([O:33][CH:34]([CH2:36][CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:35])[CH:12]=[C:13]2[C:18]=1[CH:17]([C:19](OC1C=CC([N+]([O-])=O)=CC=1)=[O:20])[CH2:16][C:15]([CH3:32])([CH3:31])[CH2:14]2)C1C=CC=CC=1.[NH2:45][C:46]([NH2:48])=[O:47].[H-].[Na+]>CS(C)=O>[OH:8][C:9]1[CH:10]=[C:11]([O:33][CH:34]([CH2:36][CH2:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH3:35])[CH:12]=[C:13]2[C:18]=1[CH:17]([C:19]([NH:45][C:46]([NH2:48])=[O:47])=[O:20])[CH2:16][C:15]([CH3:32])([CH3:31])[CH2:14]2
Reactant: CC(CCCc1ccccc1)Oc1cc2c(c(OCc3ccccc3)c1)C(C(=O)Oc1ccc([N+](=O)[O-])cc1)CC(C)(C)C2
Reactant: NC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)CC(C)(C)CC2C(=O)NC(N)=O

Procedure:
By reacting 1.2 g. (2 mmole) p-nitrophenyl 8-benzyloxy-3,3-dimethyl-6-(5-phenyl-2-pentyloxy)tetralin-1-carboxylate, 0.3 g. (5 mmole) urea and 0.248 g. (10 mmole) sodium hydride in 12 ml. dimethylsulfoxide at room temperature for one hour and isolation of product by the method of Example 89, Part B and removal of benzyl group by hydrogenolysis by the procedure of Example 89, Part C affords the pure title compound in 36% overall yield. 1H-NMR (CDCl3) ppm (delta): 0.77 (s, 3H), 1.1 (m, 8H), 1.7 (m, 4H), 2.5 (m, 4H), 3.6 (m, 1H), 4.16 (m, 1H), 5.7 (s, 1H), 6.1 (s, 2H), 7.1 (s, 5H), 8.2 (s, 2H).