Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:3][OH:4].[Li+].[Br-].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[CH3:24][O:25][CH2:26]OC>>[CH3:1][C:2]([N+:6]([O-:8])=[O:7])([CH3:5])[CH2:3][O:4][CH2:24][O:25][CH3:26]
Reactant: CC(C)(CO)[N+](=O)[O-]
Reactant: COCOC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Product: COCOCC(C)(C)[N+](=O)[O-]
Reaction time: 24 h
Yield: 76 %

Procedure:
To a solution of 2-methyl-2-nitro-1-propanol (366.8 mg, 3.08 mmol) and LiBr (60.8 mg, 0.700 mmol) in dimethoxymethane (5 ml) was added p-toluenesulfonic acid hydrate (56.3 mg, 0.296 mmol) and stirred for 24 hours. The mixture was added to water and extracted three times with ethyl acetate and dried over MgSO4. The mixture was concentrated and purified by silica gel chromatography (hexane/ether=4/1) to give the title compound (382.7 mg; 76%).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH:9]2[CH2:10][CH2:11][CH:5]1[CH2:6][NH:7][CH2:8]2.Cl[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)C(N1CC2N(C)C(CC2)C1)=O)C>>[C:13]([N:7]1[CH2:6][CH:5]2[N:4]([CH3:3])[CH:9]([CH2:10][CH2:11]2)[CH2:8]1)([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CN1C2CCC1CNC2
Reactant: CCOC(=O)Cl
Agent: CCN(CC)C(=O)N1CC2CCC(C1)N2C
Agent: Cl
Product: CCOC(=O)N1CC2CCC(C1)N2C
Yield: 73 %

Procedure:
8-Methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (2.5 g, 0.0126 mole), prepared as described in Example 1, was reacted with 1.51 ml (0.0189 mole) ethyl chloroformate according to the procedure described above for 3-(N,N-diethylcarbamyl)-8-methyl-3,8-diazabicyclo[3.2.1]octane in Example 1. A white monohydrochloride, melting point 200°-205° C, was obtained in 73% yield: 2.16 g.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18]([C:20]2[N:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)=[O:19])[CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[N:12]1[CH2:13][CH2:14][N:15]([C:18]([C:20]2[N:25]=[CH:24][C:23]([O:26][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:22][CH:21]=2)=[O:19])[CH2:16][CH2:17]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(Cl)ccc1N1CCN(C(=O)c2ccc(O)cn2)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(C(=O)N2CCN(c3ccc(Cl)cc3C(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A mixture of 6-{[4-(2-tert-butyl-4-chlorophenyl)piperazin-1-yl]carbonyl}pyridin-3-ol (Example 208, 0.26 g, 0.69 mmol), methyl bromoacetate (0.13 g, 0.82 mmol) and potassium carbonate (0.19 g, 1.38 mmol) in N,N-dimethylformamide (5 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was filtered through NH-silica gel pad to give the title compound (0.27 g, 89%) as a white powder.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[H-].[Na+].[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.O>CN(C)C=O>[Br:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][O:1][CH:2]2[CH2:7][CH2:6][O:5][CH2:4][CH2:3]2)=[CH:13][CH:12]=1
Reactant: OC1CCOCC1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc(COC2CCOCC2)cc1
Reaction time: 24 h

Procedure:
A mixture of 2.90 mL of 4-hydroxy-tetrahydropyran in 30 mL of dry N,N-dimethylformamide was added dropwise to a stirred suspension of 0.84 g of sodium hydride (95%, dispersion in mineral oil) in 30 mL of dry N,N-dimethylformamide at 5° C. The resulting clear solution was allowed to come to room temperature and stirring was continued for 24 hours, followed by dropwise addition of 9.40 g of 4-bromo-benzylbromide in 50 mL of dry N,N-dimethylformamide at 5° C. and stirring at room temperature for 24 hours. The mixture was poured into water and extracted with ethyl acetate. The combined extracts were washed with water and brine, dried (sodium sulfate), and concentrated. The residue was purified by silica chromatography (isohexane/ethyl acetate=9/1, 8/2, 7/3, 6/4 v/v) yielding 5.40 g of 4-(4-bromo-benzyloxy)-tetrahydropyran as an oil. EI-MS: 270 (M+).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.C[Al](C)C.CCCCCCC.[C:30]([Si:34]([CH3:55])([CH3:54])[O:35][CH2:36][C:37]1[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])[CH:39]=[C:40]([C:42](OC)=[O:43])[N:41]=1)([CH3:33])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1.O>[Si:34]([O:35][CH2:36][C:37]1[N:38]([CH2:46][O:47][CH2:48][CH2:49][Si:50]([CH3:51])([CH3:52])[CH3:53])[CH:39]=[C:40]([C:42]([NH:1][C@@H:2]([CH3:18])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=3)=[N:5]2)=[O:43])[N:41]=1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:55])[CH3:54]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(CO[Si](C)(C)C(C)(C)C)n1
Agent: C[Al](C)C
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Into a flask containing a solution of (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.4 g, 17.5 mmol) in toluene (20 ml), 2 M solution of trimethyl aluminium in heptane (2.62 ml, 52.6 mmol) was added at 0° C. The resulting mixture was stirred at 0° C. for 10 min and a solution of methyl 2-((tert-butyldimethyl-silyloxy)methyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylate (0.7 g, 17.5 mmol) in toluene (20 ml) was added at 0° C. The reaction mixture was heated at 110° C. for 4 h and diluted with water. The mixture was filtered through a celite bed and the filtrate was extracted with EtOAc. The organic layer was concentrated under reduced pressure. The product was purified by flash column chromatography. Yield 400 mg. 1H-NMR (400 MHz; DMSO-d6): δ −0.05 (s, 9H), 0.05 (s, 6H), 0.82-0.84 (s, 11H), 1.14 (d, 3H), 3.47 (t, 2H), 4.26-4.40 (m, 3H), 4.74 (s, 2H), 5.38 (s, 2H), 6.94 (d, 1H), 7.73 (s, 1H), 7.83 (d, 1H), 7.99 (d, 2H), 8.10 (d, 2H). LC-MS: [M+1]=629.38.
Reaction SMILES: [CH3:1][S:2]([N:5]=[CH:6]OCC)(=[O:4])=[O:3].[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1>C(OCC)C>[CH3:1][S:2]([N:5]=[CH:6][NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)(=[O:3])=[O:4]
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CCOC=NS(C)(=O)=O
Solvent: CCOCC
Product: CS(=O)(=O)N=CNC1CCN(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 39.3 %

Procedure:
Into a solution of 760 mg of ethyl N-methanesulfonyl-formimidate in diethyl ether (20 ml) was dropped 0.95 g of 4-amino-1-benzylpiperidine at room temperature. After stirring for 2 hours, the crystals thus precipitated were filtered and washed with diethyl ether to thereby give 580 mg of N2-methanesulfonyl-N1-(1-benzylpiperidin-4-yl)formamidine as colorless needles. These crystals were dissolved in 30 ml of methanol and 500 mg of 10% palladium-carbon was added thereto. Then the resulting mixture was stirred in a hydrogen atmosphere under atmospheric pressure for 1 hour followed by filtration through celite. After distilling off the solvent under reduced pressure, the residue was recrystallized from acetone/ethyl acetate to thereby give 310 mg of the title compound as colorless needles.
Reaction SMILES: Br[C:2]1[N:3]([CH3:17])[C:4](=[O:16])[C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:7]=[N:8][C:9]=2[N:10]=1.ClC1N(C)C(=O)C2N(C3CCCC3)C=NC=2N=1.[NH2:35][C@@H:36]1[CH2:40][CH2:39][CH2:38][C@H:37]1[OH:41].C(N(CC)CC)C>CC#N>[OH:41][C@@H:37]1[CH2:38][CH2:39][CH2:40][C@H:36]1[NH:35][C:2]1[N:3]([CH3:17])[C:4](=[O:16])[C:5]2[N:6]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: Cn1c(Br)nc2ncn(C3CCCC3)c2c1=O
Reactant: N[C@@H]1CCC[C@H]1O
Agent: Cn1c(Cl)nc2ncn(C3CCCC3)c2c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cn1c(N[C@@H]2CCC[C@H]2O)nc2ncn(C3CCCC3)c2c1=O

Procedure:
A mixture of 2-bromo-1-methyl-7-cyclopentylpurin-6-one and 2-chloro-1-methyl-7-cyclopentylpurin-6-one (11.4 g), (±) trans-2-aminocyclopentanol (1.2 g, 11 mmol), and triethylamine (1.2 ml) in CH3CN (20 ml) is heated to reflux for 12 hr. The resultant mixture is cooled, concentrated in vacuo, and partitioned between EtOAc/THF 1:1 and brine. The organic layers are concentrated in vacuo and the residue is purified by flash chromatography using 6% EtOH in CH2Cl2 to give 2-(trans-2-hydroxycyclopentylamino)-1-methyl-7-cyclopentylpurin-6-one, a colorless solid (1.4 gm, MS FAB: M+H=318). A mixture of 2-(trans-2-hydroxycyclopentylamino)-1-methyl-7-cyclopentylpurin-6-one (1.3 gm, 4.1 mm) and triphenylphosphine dibromide (prepared from triphenylphosphine (1.2 g) and 0.2 ml bromine) in DMF (20 ml) is stirred at room temperature for 18 hr and heated to 70° C. for 6 hr. Dilute NaOH is added to the cooled reaction mixture to adjust the pH to 10, and the resultant solution is extracted with EtOAC/THF (1:1). The organic layer is concentrated in vacuo and purified by flash chromatography using 15% EtOH in CH2Cl2 and recrystallized from CH2Cl2 /hexane to give the title compound, a solid, mp 133°-134° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[O:11]1CC[CH2:13][CH2:12]1.C(Cl)Cl.C(OC(=O)C)(=O)C>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:12]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:11])[CH3:13]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: C1CCOC1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(C(=O)O)cc1

Procedure:
To 20 g. of 4-hydroxybenzoic acid in suspension in 150 ml. of tetrahydrofuran (THF) and 150 ml. methylene chloride, 35 g. of triethylamine, 35 g. of acetic anhydride and 3 g. of 4-dimethylaminopyridine are added and the mixture refluxed for 30 minutes. The solvents are thereafter evaporated under reduced pressure and 6N hydrochloric acid is added to the residue. The resulting slurry is filtered, washed with water and dried, affording 20 g. of the captioned compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:20]#[N:21])[N:12]3[C:17](Cl)=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[C:4]([CH3:22])[CH:3]=1.[CH2:23]([CH:26]([NH2:30])[CH2:27][CH2:28][CH3:29])[CH2:24][CH3:25].C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:10]=[C:11]([C:20]#[N:21])[N:12]3[C:17]([NH:30][CH:26]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:24][CH3:25])=[CH:16][C:15]([CH3:19])=[N:14][C:13]=23)=[C:4]([CH3:22])[CH:3]=1
Reactant: Cc1cc(Cl)n2c(C#N)cc(-c3c(C)cc(Br)cc3C)c2n1
Reactant: CCCC(N)CCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(CCC)Nc1cc(C)nc2c(-c3c(C)cc(Br)cc3C)cc(C#N)n12
Temperature: 25 °C
Yield: 74.4 %

Procedure:
A mixture of 8-(4-bromo-2,6-dimethyl-phenyl)-4-chloro-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (30.0 g), 1-propyl-butylamine (18.5 g), N,N-diisopropylethylamine (15.5 g) in ethanol (90 mL) was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogencarbonate, and then extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a solid. The solid was washed with diisopropylether to give 8-(4-bromo-2,6-dimethyl-phenyl)-2-methyl-4-(1-propyl-butylamino)-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (27.0 g).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:12]([OH:16])[CH2:13][C:14]#[CH:15]>C(N(CC)CC)C.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([C:15]#[C:14][CH2:13][CH2:12][OH:16])[CH:3]=1
Reactant: C#CCCO
Reactant: Brc1cnc2ccccc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: OCCC#Cc1cnc2ccccc2c1
Yield: 136.9 %

Procedure:
A solution of 3-bromoquinoline (13.57 mL, 0.10 mol) and 3-butyn-1-ol (9.0 mL, 0.12 mol) in 40 mL of triethylamine and 75 mL of dichloromethane is degassed by bubbling dry nitrogen through it for 15 minutes, and 0.7 g (0.001 mol) of bis(triphenylphosphine)palladium dichloride and 0.013 g of cuprous iodide are added. The flask is flushed with nitrogen and the mixture heated to reflux for 5 hours. The cooled mixture is diluted with dichloromethane and washed with water, dried (sodium sulfate), and concentrated to give 27 g of a gold oil. The oil was triturated with diethyl ether to give 18.2 g of the title compound as a tan solid; mp 95.7°-96.7° C.
Reaction SMILES: CO[C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH2:29])[CH:22]=[CH:23][C:24]=1[O:25][CH3:26].C[O-].[Na+].CO>C1(C)C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][NH:29][C:3](=[O:16])[CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:10][CH:11]=2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1ccc(CCN)cc1OC
Reactant: COC(=O)CCc1ccc(C(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COc1ccc(CCNC(=O)CCc2ccc(C(F)(F)F)cc2)cc1OC

Procedure:
3-(4-trifluoromethyl-phenyl)-propionic acid methyl ester is dissolved in toluene, 1.05 equivalents 2-(3,4-dimethoxy-phenyl)-ethylamine (commercially available) and 1.1 equivalents sodium methoxide (30% in methanol) are added. At normal pressure the reaction mixture is heated to a maximum of 110° C. and methanol distilled until full conversion is reached. The reaction mixture is washed with water and sulfuric acid. During cooling of the organic phase, the compound 3 crystallises and is filtered, washed with cold toluene and dried in vacuo at 50° C.
Reaction SMILES: [NH2:1][C:2]1([C:10]#[N:11])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4][CH2:3]1.ClC(Cl)C.Cl.[F:17][C:18]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:19]=1[CH2:20][O:21][C:22]1[C:23]2[N:24]([C:28]([C:32](Cl)=[O:33])=[C:29]([CH3:31])[N:30]=2)[CH:25]=[CH:26][CH:27]=1>C(N(CC)CC)C>[C:10]([C:2]1([NH:1][C:32]([C:28]2[N:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH2:20][C:19]4[C:18]([F:17])=[CH:38][CH:37]=[CH:36][C:35]=4[F:39])[C:23]3=[N:30][C:29]=2[CH3:31])=[O:33])[CH2:7][O:6][C:5]([CH3:8])([CH3:9])[O:4][CH2:3]1)#[N:11]
Reactant: CC1(C)OCC(N)(C#N)CO1
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC1(C#N)COC(C)(C)OC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
Under an argon gas flow, to a mixture of 10.4 g of 5-amino-2,2-dimethyl-1,3-dioxane-5-carbonitrile, 27.8 ml of triethylamine, and 280 ml of dichloroethane were added 27.2 g of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carbonyl chloride hydrochloride and 12 ml of dichloroethane at room temperature, followed by stirring at 70° C. for 2 hours. After leaving to be cooled to room temperature, the insoluble materials were separated by filtration and washed with dichloroethane. The filtrate was washed with a 10% aqueous citric acid solution three times, and the aqueous layer was extracted with chloroform. The organic layer was combined, washed with water, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The obtained residue was azeotropic distilled with ethyl acetate twice. To the obtained residue was added THF, and the insoluble materials were separated by filtration and washed with THF. The filtrate was concentrated and the residue was purified by silica gel column chromatography to obtain 27.7 g of N-(5-cyano-2,2-dimethyl-1,3-dioxan-5-yl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl[S:16]([N:19]=C=O)(=[O:18])=[O:17].C1(C)C=CC=CC=1>C1C=CC=CC=1>[N+:12]([C:5]1[CH:4]=[CH:3][C:2]([O:1][S:16](=[O:18])(=[O:17])[NH2:19])=[CH:7][C:6]=1[C:8]([F:11])([F:10])[F:9])([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc(O)cc1C(F)(F)F
Reactant: O=C=NS(=O)(=O)Cl
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: NS(=O)(=O)Oc1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Yield: 77.6 %

Procedure:
This compound was prepared according to the procedure used in Example 84. A mixture of 10.4 g (0.05 mole) of 5-hydroxy-2-nitrobenzotrifluoride, 7.8 g (0.055 mole) of chlorosulfonyl isocyanate and 75 ml of toluene gave 11.1 g (78%) of tan solid, mp 95°-97° C. (benzene).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][NH:12][O:13][CH3:14].C(N(CC)CC)C.NC1C(N)=NC=CC=1>ClCCl>[CH3:14][O:13][N:12]([CH3:11])[C:8](=[O:9])[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CNOC
Agent: Nc1cccnc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-phenylacetyl chloride (commercially available, 4.7 g, 30.5 mmol) in dichloromethane (100 ml) was treated with N,O dimethylhydroxylamine (3.25 g, 33.5 mmol), followed by the addition of triethyl amine (8.5. g 61 mmol) and diaminopyridine (305 mgs). The mixture was stirred at room temperature overnight. The mixture was quenched with water (50 mL) and a saturated solution of ammonium chloride (50 mL). The residue was isolated in a typical aqueous workup and purified by MPLC with 0 to 2% MeOH:CH2Cl2 to give N-methoxy-N-methyl-2-phenylacetamide, (Intermediate 13) (3.5 g 78.7%).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].[C:6](Cl)(Cl)=[O:7].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1.C(N(CC)CC)C.[OH-].[Na+]>O.C(Cl)(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: Cc1cccc(N)n1
Reactant: CC(C)(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cccc(NC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
55.6 g (0.75 moles) of t-butanol and 450 mL of chloroform were added to a reaction system followed by blowing in 65.3 g (0.66 moles) of phosgene over the course of 2.5 hours while holding the internal temperature at −5° C. to 0° C., and then simultaneously supplying a mixed solution containing 32.4 g (0.30 moles) of 2-amino-6-picoline, 133.5 g (1.32 moles) of triethylamine and 300 mL of chloroform to the reaction system over the course of 2.5 hours using a metering pump (supply rate: 3 mL/min). After supplying the mixed solution, the solution was stirred for 1 hour at 0° C. Next, water and 28% sodium hydroxide were sequentially added while holding the internal temperature at 0° C. or lower. After separating the liquid, the aqueous phase was extracted with chloroform, and the organic phases were combined and mixed. A portion of the organic phase was sampled and subjected to quantitative analysis by HPLC. The target (6-methyl-pyridin-2-yl)-carbamic acid tert-butyl ester was obtained at yield of 98%. Only an extremely small amount of 1,3-bis-(6-methyl-pyridin-2-yl)-urea (urea compound) was present.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([O:10]CC2C=CC=CC=2)=[C:3]1[CH:18]([O:21][CH3:22])[CH2:19][CH3:20].[ClH:23]>CO.O.[Pd]>[ClH:23].[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[C:4]([OH:10])=[C:3]1[CH:18]([O:21][CH3:22])[CH2:19][CH3:20]
Reactant: CCC(OC)c1c(OCc2ccccc2)c(=O)cc(C)n1C
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Product: CCC(OC)c1c(O)c(=O)cc(C)n1C
Yield: 79.3 %

Procedure:
1,6-Dimethyl-2-(1-methoxypropyl)-3-benzyloxy-pyridin-4(1H)-one (1.65 g, 5.5 mmol) was dissolved in methanol (30 ml)/water (10 ml) and adjusted to pH 1 with concentrated hydrochloric acid prior to hydrogenolysis for 4 hours in the presence of 5% Pd/C catalyst (0.35 g). Filtration followed by rotary evaporation gave the crude product as a white solid. Recrystallization from methanol/diethyl ether gave the pure title compound (1.08 g, 79.3%) as a white crystalline solid. m.p. 225-227° C.
Reaction SMILES: [CH:1]([CH:4]1[CH:9]([C:10]#[N:11])[CH2:8][CH:7]2[CH2:12][CH:5]1[C:6]2([CH3:14])[CH3:13])([CH3:3])[CH3:2].C(C1C(CN2C(=O)C(CC3C=CN=CC=3)(CC3C=CN=CC=3)NC2=CC(C2C=CC(C#N)=CC=2)=O)CC2CC1C2(C)C)(C)C.[N-]=[C:60]=[S:61]>>[CH:1]([CH:4]1[CH:9]([CH2:10][N:11]=[C:60]=[S:61])[CH2:8][CH:7]2[CH2:12][CH:5]1[C:6]2([CH3:14])[CH3:13])([CH3:3])[CH3:2]
Reactant: CC(C)C1C(C#N)CC2CC1C2(C)C
Reactant: [N-]=C=S
Agent: CC(C)C1C(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Product: CC(C)C1C(CN=C=S)CC2CC1C2(C)C

Procedure:
The same procedure that was used in example 1 was followed except that 2-isopropyl-3-isothiocyanatomethyl-6,6-dimethyl-bicyclo[3.1.1]heptane was used in the place of (+)-3-pinanemethyl isothiocyanate in step D to give the titled compound as a tan solid. 2-Isopropyl-3-isothiocyanatomethyl-6,6-dimethyl-bicyclo[3.1.1]heptane was prepared by reduction of 2-isopropyl-6,6-dimethyl-bicyclo[3.1.1]heptane-3-carbonitrile to the requisite amine following the procedure in step C of example 42 and subsequent conversion to the isothiocyanate using step A of example 15: C.I. m/z 588 [M+1]; 1H NMR (CDCl3)δ 10.45 (br s, 1H), 8.42-8.46 (m, 4H), 7.82 (d, J=8.1 Hz, 2H), 7.69 (d, J=8.1 Hz, 2H), 7.13 (m, 2H), 7.07 (m, 2H), 5.22 (s, 1H), 3.32 (dd, J=11.2, 13.9 Hz, 1H), 3.24 (d, J=13.1 Hz, 2H), 3.01-3.10 (m, 2H), 2.92 (dd, J=3.1, 13.9 Hz, 1H), 1.96 (m, 1H), 1.76 (m, 1H), 1.59-1.70 (m, 3H), 1.32 (m, 1H), 1.24 (m, 1H), 1.14 (s, 3H), 1.05 (d, 10.2 Hz, 1H), 0.86 (d, J=6.6 Hz, 3H), 0.78 (d, J=6.9 Hz, 3H), 0.70 (s, 3H), 0.50 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[NH3:13].[O:14]1CC[CH2:16][CH2:15]1>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([NH:13][C:15](=[O:14])[CH3:16])[CH:11]=[CH:10]2
Reactant: N
Reactant: Oc1ccc2cc(Br)ccc2c1
Reactant: C1CCOC1
Product: CC(=O)Nc1ccc2cc(O)ccc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
Into a high pressure reaction vessel (fitted for shaking), tetrahydrofuran (200 ml) was combined with 6-bromo-2-naphthol. The reaction vessel was then charged with gaseous ammonia (800 psi, 56.2 kg/cm2) and warmed to 80° C. for 3 days. The resulting solution was removed by reduced pressure and some of the solid precipitate 6-amino-2-napthol (10 g) was placed (without further purification) into a 500 ml round bottom flask). The solid was completely dissolved into a 50:50 mixture of water:ethanol. The resulting solution was warmed to boiling and acetic anhydride (7 g) was added. After 1 hour of continuous stirring, the solution was cooled and crystals of N-(6-hydroxy-2-naphthyl)acetamide formed (8 g, 63% yield).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])[CH2:4][OH:5].CCN(CC)CC.P=PP.C1C[O:27][CH2:26]C1>>[F:13][C:7]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:6]=1[C@@H:3]1[CH2:4][O:5][C:26](=[O:27])[NH:2]1
Reactant: C1CCOC1
Reactant: N[C@@H](CO)c1ccc(F)cc1F
Agent: Cl
Agent: P=PP
Solvent: CCN(CC)CC
Product: O=C1N[C@H](c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a stirred mixture of (R)-2-amino-2-(2,4-difluorophenyl)ethanol hydrochloride (0.58 g, 2.8 mmol) in THF (18 mL) was added Et3N (1.2 mL, 8.9 mmol). The reaction mixture was cooled in an ice bath under N2. A solution of triphosphene (0.33 g, 1.1 mmol) in THF (10 mL) was added. The reaction was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by column chromatography (EtOAc/hexane, 1:1) to give (R)-4-(2,4-difluorophenyl)oxazolidin-2-one (0.50 g, 91%).