Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:19][CH:18]=[CH:17][N:5]2[C:6](=[O:16])[C:7]=1[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=1.[O-]CC.[Na+]>C(O)C>[O:16]=[C:6]1[N:5]2[CH:17]=[CH:18][S:19][C:4]2=[N:3][C:2](/[CH:1]=[CH:20]/[C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:7]1[C:8]1[CH:9]=[CH:10][C:11]([C:12]#[N:13])=[CH:14][CH:15]=1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Reactant: O=Cc1cccnc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1ccc(-c2c(/C=C/c3cccnc3)nc3sccn3c2=O)cc1
Yield: 57 %

Procedure:
The title compound was prepared by condensation of Intermediate 4 (350 mg, 1.309 mmol) with nicotinaldehyde (196 mg, 1.833 mmol) in presence of sodium ethoxide (178 mg, 2.618 mmol) in ethanol (15 ml) according to the procedure outlined in Example 9 to give 266 mg of the desired product as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 6.88 (d, J=15.6 Hz, 1H), 7.30-7.38 (m, 1H), 7.50-7.58 (m, 3H), 7.84-7.93 (m, 4H), 8.02 (d, J=4.8 Hz, 1H), 8.47 (d, J=3.9 Hz, 1H), 8.70 (s, 1H); ESI-MS (m/z) 357.32 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]([OH:8])=O)[CH2:3]1.Cl.[CH3:10][O:11][NH:12][CH3:13].ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl.O>[CH3:10][O:11][N:12]([CH3:13])[C:6]([CH:4]1[CH2:3][C:2](=[O:1])[CH2:5]1)=[O:8]
Reactant: CNOC
Reactant: O=C1CC(C(=O)O)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)C1CC(=O)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
A mixture of 3-oxo-cyclobutanecarboxylic acid (2.28 g, 20.0 mmol), O,N-dimethyl-hydroxylamine hydrochloride (1.94 g, 20.0 mmol), 1-hydroxybenzotriazole (2.99 g, 22.0 mmol), (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride (4.22 g, 22.0 mmol) and triethylamine (4.04 g, 40.0 mmol) in dichloromethane (50 mL) was stirred at room temperature for 24 hours. The mixture was diluted with water (30 mL), and extracted with dichloromethane (2×30 mL). The combined organic extracts were washed with water (20 mL) and brine (20 mL), and dried over sodium sulfate. The filtrate was evaporated in vacuo and the residue was purified by silica chromatography to provide N-methoxy-N-methyl-3-oxocyclobutanecarboxamide (2.68 g, 17.0 mmol, yield: 85%).
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([CH2:22][OH:23])[CH:16]=[CH:15]4)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[CH2:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[CH:18]=[C:17]([CH:22]=[O:23])[CH:16]=[CH:15]4)[CH2:7][CH2:6]2)[CH2:1][CH2:2][CH2:3]1
Reactant: OCc1ccc2cc(OC3CCC4(CCCC4)CC3)ccc2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=Cc1ccc2cc(OC3CCC4(CCCC4)CC3)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.2 %

Procedure:
[6-(Spiro[4.5]dec-8-yloxy)-naphthalen-2-yl]-methanol (257.2 mg, 0.8285 mmol) in methylene chloride (9 mL, 100 mmol) was added Dess-Martin periodinane (0.492 g, 1.16 mmol) and was stirred at room temperature for 1 hour. After pass through si gel plug, the solvent was concentrated down to give product as a solid (256 mg, 100%). LCMS Rt=2.44 min/m/z=309.56 ([M+1], 100%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][N:15](C(OCC)=O)[CH2:14][C@@H:13]1[O:23][CH2:24][CH2:25][CH3:26])=[O:10].[OH-].[K+].O.NN.O>C(O)CO>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@@H:13]1[O:23][CH2:24][CH2:25][CH3:26])=[O:10]
Reactant: CCCO[C@H]1CN(C(=O)OCC)CC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: CCCO[C@H]1CNCC[C@H]1NC(=O)c1[nH]c(C)c(Cl)c1Cl
Temperature: 25 °C
Yield: 0.1 %

Procedure:
A solution of ethyl (3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate (Intermediate 77, 3.3 g, 8.12 mmol) potassium hydroxide (4.55 g, 81.2 mmol), and hydrazine hydrate (4.06 g, 81.2 mmol) in ethylene glycol (100 mL) was stirred for 60 h at 120° C. The reaction mixture was cooled to room temperature and poured into water (300 mL) and extracted with ethyl acetate (2×300 mL). The combined organic extracts were dried over anhydrous sodium sulphate, filtered, and concentrated under vacuum to afford 3,4-dichloro-5-methyl-N-[(3S,4R)-3-propoxypiperidin-4-yl]-1H-pyrrole-2-carboxamide 1.5 mg, (62.5%) as solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[CH2:23]([Sn](CCC)(CCC)CCC)[CH2:24][CH3:25]>CN(C)C=O.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>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([CH2:23][CH2:24][CH3:25])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCC[Sn](CCC)(CCC)CCC
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Product: CCCc1nc(C(=O)OCC)c(O)c2sc(-c3ccccc3)nc12
Temperature: 130 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (152 mg, 0.40 mmol), tetra-n-propyltin (211 μL, 0.80 mmol) and bis(triphenylphosphine)-palladium(II) dichloride (28 mg, 0.04 mmol) in dimethylformamide (2.5 mL) was stirred at 130° C. for 1 h before it was cooled to room temperature, quenched with water, filtered. The filtrate was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a white solid (79 mg): MS: (+) m/z 343.00 (M+1), MS: (−) m/z 341.00 (M−1).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]2)(=O)=O.[F:20][C:21]1[CH:26]=[CH:25][C:24]([Sn](CCCC)(CCCC)CCCC)=[CH:23][CH:22]=1.[Cl-].[Li+].[Cl-].[F-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[CH2:12][CH2:11][CH2:10]3)=[CH:23][CH:22]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(F)cc1
Reactant: O=C1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: [Cl-]
Agent: [F-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCCc2cc(-c3ccc(F)cc3)ccc21
Temperature: 120 °C
Reaction time: 4 h
Yield: 79.6 %

Procedure:
1.00 g (3.40 mmol) of 3,4-dihydro-6-trifluoromethylsulfonyloxy-1(2H)-naphthalenone was dissolved in 10 ml of N,N-dimethylformamide in an argon atmosphere, and 1.96 g (5.10 mmol) of 4-fluorophenyltributyltin, 0.43 g (11.0 mmol) of lithium chloride and 0.12 g (0.17 mmol) of bistriphenylphosphinepalladium chloride were added to the solution. The mixture was stirred at 120° C. for 4 hours. The reaction product was cooled to room temperature. Ethyl acetate and a 2M-ammonium fluoride aqueous solution were added thereto, followed by stirring the mixture at room temperature overnight. The precipitate was filtered through Celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica-gel column chromatography (eluent: a mixture of 3% ethyl acetate and hexane) to obtain 0.65 g of the above-mentioned compound (yield 80%).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6](/[CH:11]=[CH:12]\[CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:7][C:8]([OH:10])=[O:9].[C:22](O)([CH3:25])([CH3:24])[CH3:23]>>[CH3:5][C:6](/[CH:11]=[CH:12]\[CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:7][C:8]([O:10][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:9]
Reactant: CC(C)(C)O
Reactant: CC(=CC(=O)O)/C=C\CC(C)CCCC(C)C
Solvent: O=S(Cl)Cl
Product: CC(=CC(=O)OC(C)(C)C)/C=C\CC(C)CCCC(C)C

Procedure:
One gram of thionyl chloride is added with stirring at room temperature to 0.5 g. of trans/cis 3,7,11-trimethyldodeca-2,4-dienoic acid and the mixture heated at about 50° for 10 minutes. Excess thionyl chloride is removed by evaporation and then t-butyl alcohol (about 2 equivalents) is added and the mixture heated at about 50° for about 5 minutes. Excess t-butyl alcohol is removed by evaporation to yield trans/cis t-butyl 3,7,11-trimethyldodeca-2,4-dienoate which is purified by chromatography.
Reaction SMILES: [O-]CC.[Na+].[C:5]([C:7]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=2[NH:20]C(=O)C(C)(C)C)=[C:10]([CH2:27][CH3:28])[N:9]([CH2:29][CH3:30])[N:8]=1)#[N:6]>C(O)C>[CH2:27]([C:10]1[N:9]([CH2:29][CH3:30])[N:8]=[C:7]2[C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:13]=1[N:20]=[C:5]2[NH2:6])[CH3:28]
Reactant: CCc1c(-c2ccc(OC)cc2NC(=O)C(C)(C)C)c(C#N)nn1CC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCc1c2c(nn1CC)c(N)nc1cc(OC)ccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60.3 %

Procedure:
A solution of sodium ethoxide in ethanol (21% by weight, 2.29 mL, 13.9 mmol) was added to a solution of N-[2-(3-cyano-1,5-diethyl-1H-pyrazol-4-yl)-5-methoxyphenyl]-2,2-dimethylpropanamide (0.5 g, 1.41 mmol) in ethanol (10 mL). The reaction mixture was stirred at room temperature for 20 minutes and then heated at reflux overnight. The reaction mixture was allowed to cool to room temperature and was concentrated under reduced pressure. The resulting residue was triturated with water to provide a solid that was isolated by filtration, washed with water, and dried. The material was purified by chromatography on a HORIZON HPFC system (silica gel, gradient elution with 0-20% CMA in chloroform) followed by crystallization from acetonitrile to yield 0.23 g of 1,2-diethyl-7-methoxy-2H-pyrazolo[3,4-c]quinolin-4-amine as beige needles, mp 210-211° C.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Cu](C#N)[C:20]#[N:21]>>[C:20]([C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])#[N:21]
Reactant: CCCCCCCCCCCCc1ccsc1Br
Reactant: N#C[Cu]C#N
Product: CCCCCCCCCCCCc1ccsc1C#N
Yield: 34 %

Procedure:
A reaction between 2-bromo-3-dodecylthiophene (Compound-1, 81.0 mmol) and excess copper cyanide (CuCN) produced 2-cyano-3-dodecylthiophene (Compound-2, 34% yield), which was heated and reacted with excess (approximately 2.5 equivalents) dithiophosphoric acid O,O′-diethylether in tetrahydrofuran (THF) solution for about 12 hours. The obtained 2-thioamino-3-dodecylthiophene (Compound-3, 45% yield) and 1.2 equivalents of bromooctanone were reacted to obtain 2-thiazole(3′-dodecyl)-3-dodecylthiophene (Compound-4, 32% yield), which was in turn reacted with N-bromosuccinimide (NBS) to obtain the thiophene-thioazol derivative (Compound-5, 82% yield). An NMR analysis result of the resultant product was as follows:
Reaction SMILES: C([O:5][C:6](=[O:73])[C@H:7]([CH2:64][CH2:65][C:66]([O:68]C(C)(C)C)=[O:67])[NH:8][C:9](=[O:63])[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:62])[CH2:19][CH2:20][S:21][CH2:22][CH:23]([O:44][C:45](=[O:61])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60])[CH:24]([O:26][C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH3:25])=[CH:12][CH:11]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:45]([O:44][CH:23]([CH:24]([O:26][C:27](=[O:43])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH3:25])[CH2:22][S:21][CH2:20][CH2:19][C:18]([NH:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([NH:8][C@H:7]([C:6]([OH:73])=[O:5])[CH2:64][CH2:65][C:66]([OH:68])=[O:67])=[O:63])=[CH:11][CH:12]=1)=[O:62])(=[O:61])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH3:60]
Reactant: CCCCCCCCCCCCCCCC(=O)OC(C)C(CSCCC(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCC(=O)OC(C)C(CSCCC(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A solution of 4-[6,7-bis(palmitoyloxy)-4-thiaoctanoylaminomethyl]benzoyl-glutamic acid di-t-butyl ester as obtained in Example 75 (574 mg) in methylene chloride (4 ml)-trifiuoroacetic acid (5 ml) was stirred at room temperature for 4 hours, after which the solvent was distilled off under reduced pressure. The residue was recrystallized from methanolwater to yield the title compound (505 mg, yield 99%) as a colorless powder.
Reaction SMILES: ClC1C=C(C=CC=1Cl)C(C1C=CC=CC=1)=O.[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=O)[CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1[Cl:24].[CH3:36][NH2:37]>[Ti](Cl)(Cl)(Cl)Cl>[Cl:17][C:18]1[CH:19]=[C:20]([CH:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[N:37][CH3:36])[CH2:27][CH2:26]2)[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: O=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Reactant: CN
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C(c1ccccc1)c1ccc(Cl)c(Cl)c1
Product: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21

Procedure:
There is described in U.S. Pat. Nos. 4,536,518 and 4,556,676 to W. M. Welch, Jr. et al., as well as in the paper of W. M. Welch, Jr. et al., appearing in the Journal of Medicinal Chemistry, Vol. 27, No. 11, p. 1508 (1984), a multi-step method for synthesizing pure racemic cis-(1S) (4S)-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro -1-naphthaleneamine, starting from the readily available 3,4-dichlorobenzophenone and proceeding via the known racemic or (±)-4-(3,4-dichlorophenyl)-4-butanoic acid and then to (±) -4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenone (see also U.S. Pat. Nos. 4,777,288 and 4,839,104 to G. J. Quallich et al. for improved methods leading to these intermediates), with the latter ketone then being condensed with methylamine in the presence of titanium tetrachloride to yield N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H)-naphthalenylidene]methanamine. In the last step of the overall synthesis, the aforementioned imine is then readily reduced by means of catalytic hydrogenation or by the use of a metal hydride complex to yield N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthaleneamine, which is actually a mixture of the cis- and trans-isomers in the form of a racemate. The aforesaid isomeric mixture is then separated into its component parts by conventional means, e.g., by fractional crystallization of the hydrochloride salts or by column chromatography on silica gel of the corresponding free base. Resolution of the separated cis-racemate free base compound while in solution with an optically-active selective precipitant acid, such as D-(-)-mandelic acid, in a classical manner then ultimately affords the desired cis-(1S)(4S)-enantiomer (sertraline).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[CH3:18])[C:6]([OH:8])=O)#[N:2].O[N:20]=[C:21]([C:23]1[CH:31]=[CH:30][C:26]2[NH:27][CH:28]=[N:29][C:25]=2[CH:24]=1)[NH2:22]>>[NH:27]1[C:26]2[CH:30]=[CH:31][C:23]([C:21]3[N:20]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([N:12]5[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]5[CH3:18])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:8][N:22]=3)=[CH:24][C:25]=2[N:29]=[CH:28]1
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C#N
Product: CC1CCCCN1c1ccc(-c2nc(-c3ccc4[nH]cnc4c3)no2)cc1C#N

Procedure:
Title compound was prepared following general procedure 1 starting from Intermediate 12 (122 mg; 0.50 mmol) and Intermediate 1 (88 mg; 0.50 mmol). Reaction mixture was filtered over a SPE-NH2 column, washed with THF followed by evaporation of the solvent under reduced pressure. Reaction mixture was extracted with ethyl acetate and combined organic phase was washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a yellow oily residue. Purification by silica column chromatography (DCM/MeOH, 98/2 then 95/5) afforded the title compound as an off-white solid. 1H NMR (DMSO, d6): δ 12.78 (s, 1H), 8.39-8.37 (m, 2H), 8.31 (s, 1H), 8.24 (dd, J=8.8, 2.2 Hz, 1H), 7.95-7.92 (m, 1H), 7.78-7.75 (m, 1H), 7.32 (d, J=8.8 Hz, 1H), 4.23-4.22 (m, 1H), 3.38-3.35 (m, 2H), 1.82-1.57 (m, 6H), 1.17 (d, 6.6 Hz, 3H). HPLC (Method A) Rt 3.65 min (Purity: 95.1%). LC/MS (method B): 358.3 (M+H)+.
Reaction SMILES: [C:1]12(CS(O)(=O)=O)C(C)(C)C([CH2:6][CH2:7]1)[CH2:4][C:2]2=O.[CH:16](OC)([O:19][CH3:20])[O:17][CH3:18].C(N(CC)CC)C>CO>[CH3:18][O:17][CH:16]([O:19][CH3:20])[CH2:6][CH2:7][CH2:1][CH:2]=[CH2:4]
Reactant: COC(OC)OC
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCN(CC)CC
Solvent: CO
Product: C=CCCCC(OC)OC
Reaction time: 8 h
Yield: 1386.9 %

Procedure:
The crude product containing compound 5 was taken up in 30 mL of MeOH, and camphorsulfonic acid (596 mg, 2.5 mmol) and trimethyl orthoformate (5.46 mL, 50 mmol) were added. The mixture was heated at reflux for 3 h, then allowed to stand at room temperature overnight. The acid was neutralized by the addition of 0.70 mL of triethylamine, and most of the solvent was removed by distillation. The residue was partitioned between water and hexane, the hexane layer was dried over anhydrous Na2SO4, and the solution was filtered through a 3 in column of silica gel, eluting with additional hexane. The solvent was removed by distillation to leave 5.0 g of the product, compound 6, as a colorless liquid. 1H NMR (CDCl3) δ 1.39-1.49 (m, 2), 1.58-1.65 (m, 2), 2.03-2.11 (m, 2), 3.31 (s, 6, CH(OCH3)2), 4.37 (t, 1, J=5.7CH(OCH3)2), 4.93-5.05 (m, 2, CH═CH2), 5.80 (dddd, 1, J=6.6, 6.6, 10.3, 16.9, CH═CH2); 13C NMR (CDCl3) δ 23.79, 31.83, 33.42, 52.49, 104.33, 114.64, 138.38.
Reaction SMILES: [F:1][CH:2]([F:31])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:23][CH:22]([NH2:24])[CH2:21]3)[N:9]=2)[C:6]2[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:5]=2[N:4]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[F:31][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH:22]([NH:24][S:33]([CH3:32])(=[O:35])=[O:34])[CH2:23]3)[N:9]=2)[C:6]2[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:5]=2[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CC(N)C2)n1
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CC(NS(C)(=O)=O)C2)n1
Yield: 86 %

Procedure:
Reaction of 1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinamine and methanesulfonyl chloride as in Example 28 gave N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-3-azetidinyl}methanesulfonamide in 86% yield: mp 307-309° C.; 1H NMR (DMSO-d6) δ7.98 (d, J=8.1 Hz, 1H), 7.92 (br s, 1H), 7.73 (t, JHF=53.0 Hz, 1H), 7.40 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 4.54-4.33 (m, 3H), 4.07-3.97 (m, 2H), 3.97 (s, 3H), 3.80-3.78 (m, 4H), 3.69 (m, 4H), 2.97 (s, 3H); Anal. Calcd. for C20H24F2N8O4S.0.25H2O: C, 46.6; H, 4.8; N, 21.8. Found: C, 46.7; H, 4.8; N, 22.0%.
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].CC[N:26]([CH2:29][CH3:30])CC>CCO>[N+:21]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH:26][CH2:29][C@@H:30]1[CH2:4][CH2:5][CH2:6][O:7]1)[C:6]([N:8]([CH2:9][C:10]([F:11])([F:13])[F:12])[CH2:14][C:15]([F:16])([F:17])[F:18])=[O:7])([O-:23])=[O:22]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: CCN(CC)CC
Solvent: CCO
Product: O=C(c1ccc(NC[C@@H]2CCCO2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (78 mg, 0.224 mmol) and S-(+)-tetrahydrofurfurylamine (0.025 mL, 0.246 mmol) in 3 mL of EtOH containing Et3N (0.047 mL, 0.336 mmol). The product was purified by flash chromatography on silica gel using 1:1/hexanes:EtOAc as eluent. Yield: 95 mg (95%); 1H NMR (CDCl3) 1.72 (m, 1H), 1.99 (m, 2H), 2.13 (m, 1H), 3.99 (m, 1H), 3.53 (m, 1H), 3.85 (m, 1H), 3.97 (m, 1H), 4.25 (m, 5H), 6.99 (d, J=8.98 Hz, 1H), 7.53 (d, J=8.98 Hz, 1H), 8.30 (s, 1H), 8.51 (brs, 1H); MS (ESI) 430.28 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C@H:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][CH2:10][C@H:9]1[CH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:31]1(=[O:41])[C:35]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][CH2:33][O:32]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:20][C@H:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:12]1[CH2:11][CH2:10][C@@H:9]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:38]3[CH2:39][CH2:40][C:35]4([C:31](=[O:41])[O:32][CH2:33][CH2:34]4)[CH2:36][CH2:37]3)=[O:27])=[CH:24][CH:23]=2)[N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)O)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reactant: O=C1OCCC12CCNCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@H](Cc2ccc(C(=O)N3CCC4(CCOC4=O)CC3)cc2)CC[C@@H]1[C@H](O)c1ccccc1
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of 30 mg (0.07 mmol) 4-({(2S,5R)-1-(tert-butoxycarbonyl)-5-[(R)-hydroxy(phenyl)methyl]pyrrolidin-2-yl}methyl)benzoic acid (i-1) in 1 ml anhydrous DMF at ambient temperature was added 20 mg (0.1 mmol) 2-oxa-8-azaspiro[4.5]decan-1-one, followed by 20 mg (0.1 mmol) EDCl, 15 mg (0.10 mmol) HOBt, and 0.070 ml (0.35 mmol) diisopropylethylamine. The solution was stirred for 2 h. It was then filtered and purified by reverse-phase HPLC (TMC Pro-Pac C18; 35-100% 0.1% trifluoroacetic acid in acetonitrile/0.1% trifluoroacetic acid in water gradient). The pure fractions were lyophilized overnight to give 28 mg (70%) of the title compound as a white solid. LC/MS 549.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CC(C)=O>[CH3:8][C:7]1[C:2]([O:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([O:13][CH3:12])=[O:22])=[CH:20][CH:19]=2)=[N:3][CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ncc([N+](=O)[O-])cc2C)cc1
Temperature: 25 °C
Yield: 94.9 %

Procedure:
A mixture of commercial 2-chloro-3-methyl-5-nitro-pyridine (0.5 g, 2.88 mmol), 4-hydroxy-benzoic acid methyl ester (0.45 g, 2.96 mmol) and K2CO3 (0.398 g, 2.90 mmol) in anhydrous acetone (20 ml) was refluxed for 15 h. After cooling to room temperature, the precipitate was filtered and washed with acetone (2×10 ml). The filtrates were concentrated at reduced pressure and the residue was purified by column chromatography (eluting with DCM/hexane 5:1 then DCM) to provide methyl 4-(3-methyl-5-nitropyridin-2-yloxy)benzoate (0.788 g, 95% yield).