Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]([CH:7]1[CH:12]([CH3:13])[CH2:11][CH:10]([CH3:14])[CH2:9][CH2:8]1)[OH:6])[CH2:2][CH2:3][CH3:4].S(=O)(=O)(O)O.C(O)(C)C>O.C1(C)C=CC=CC=1>[CH2:1]([CH:5]1[CH:7]2[CH2:8][CH2:9][C:10]([CH3:14])([CH2:11][CH:12]2[CH3:13])[O:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(O)C1CCC(C)CC1C
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CC(C)O
Solvent: O
Product: CCCCC1OC2(C)CCC1C(C)C2
Yield: 70.9 %

Procedure:
A solution of 500 grams of alpha-n-butyl-4,6-dimethyl-3-cyclohexane methanol, 600 grams of sulfuric acid, 1400 grams of water and 500 grams of isopropyl alcohol is heated at reflux for 14 hours. The reaction mass is cooled, diluted with 1500 ml of H2O and 200 ml of toluene. The aqueous layer is discarded and the organic layer is washed twice with water, neutralizing with aqueous sodium hydroxide on the second wash. Distillation through a 1.5"×12" Goodloe column affords 351 grams of 3-n-butyl-1,5-dimethyl-2-oxabicyclo[2.2.2]octane (b.p. 90° C., 3 mm Hg pressure).
Reaction SMILES: [Li][C:2](C)(C)[CH3:3].[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(I)C>C1COCC1>[C:6]1([S:12]([N:15]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:2][CH3:3])(=[O:14])=[O:13])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: [Li]C(C)(C)C
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Cl)ccc21
Solvent: C1CCOC1
Solvent: CCI
Product: CCc1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
t-BuLi (3.7 mL of 1.7 M solution in pentane) was added dropwise to a solution of N-(benzensulfonyl)-5-chloroindole (1) (J. Org. Chem. 1981, 46, 3859) (1.5 g, 5.14 mmol) in THF (35 mL) at −70° C., under a nitrogen atmosphere. The mixture was stirred for 15 min, allowed to warm to room temperature over 20 min, cooled to −70° C., and treated with a solution of ethyl iodide (0.84 mL, 10.5 mmol) in dry THF (5 mL). The mixture was stirred at −78° C. for 1 h, allowed to warm to room temperature, stirred for 2 h, poured into ice (15 g), and a saturated aqueous NH4Cl solution and then extracted with ether (3×20 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo to give a residue which was purified by flash chromatography (silica gel, cyclohexane/ethyl acetate, 8:2) and crystallization from ethylacetate/cyclohexane.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]2[C:8](=[CH:9][C:10]=1Br)[CH2:7][CH:6]([C:12]([OH:14])=[O:13])[CH2:5]2.[C:18](O)(=[O:22])[C:19](O)=[O:20]>C(O)C.O1CCCC1.Cl.[Pd]>[O:20]=[C:19]1[NH:15][C:3]2[C:4]3[CH2:5][CH:6]([C:12]([OH:14])=[O:13])[CH2:7][C:8]=3[CH:9]=[CH:10][C:2]=2[NH:1][C:18]1=[O:22]
Reactant: Nc1c(Br)cc2c(c1[N+](=O)[O-])CC(C(=O)O)C2
Reactant: O=C(O)C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)C1Cc2ccc3[nH]c(=O)c(=O)[nH]c3c2C1
Temperature: 90 °C
Reaction time: 30 h

Procedure:
A mixture of 5-amino-6-bromo-4-nitroindane-2-carboxylic acid (5.5 g, 18 mmol) and 20% Pd/C (0.5 g) in 95% ethanol (250 mL) and tetrahydrofuran (250 mL) was shaken on a Parr hydrogenation apparatus under a hydrogen atmosphere (51 psi) for 30 h. After removing the catalyst, the solvent was evaporated to give a solid. The solid was dissolved in 2N HCl (150 mL) and treated with oxalic acid (4.6 g), and then the mixture was heated at 90° C. for 5 h. After cooling to room temperature, the precipitate was collected by filtration and dried in vacuo (4.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([F:12])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:15])=[O:14].[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1C=CC=CC=1>[C:17]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[C:5]([F:12])=[CH:4][C:3]=1[S:13]([NH2:16])(=[O:14])=[O:15])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc(C(F)(F)F)c(F)cc1S(N)(=O)=O
Solvent: c1ccccc1
Product: NS(=O)(=O)c1cc(F)c(C(F)(F)F)cc1NC(=O)c1ccccc1
Reaction time: 8 h
Yield: 91 %

Procedure:
6.5 g 2-amino-4-trifluoromethyl-5-fluoro-benzene sulfonamide are suspended in 150 ml dry benzene. 2.6 g benzoyl chloride are added to the vigorously stirred suspension, after which the reaction mixture is gently refluxed during 4 hours. The reaction mixture is then left aside overnight. The resulting white solid is then suction filtered and recrystallized from aqueous ethanol, to give 6.1 g 2-benzoylamino-4-trifluoromethyl-5-fluoro-benzene sulfonamide, m.p.= 223° C.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][CH:9]([CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH2:10][CH:11]([OH:17])[CH:12]([N+:14]([O-:16])=[O:15])[CH3:13].CCOCC>OS(O)(=O)=O.O>[C:1]([O:17][CH:11]([CH2:10][CH:9]([CH3:8])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])[CH:12]([N+:14]([O-:16])=[O:15])[CH3:13])(=[O:3])[CH3:2]
Reactant: CC(C)=CCCC(C)CC(O)C(C)[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CCOCC
Product: CC(=O)OC(CC(C)CCC=C(C)C)C(C)[N+](=O)[O-]
Temperature: -10 °C
Reaction time: 0.21 h
Yield: 87 %

Procedure:
A flask containing 1.3 g of acetic anhydride was cooled to −10° C. with a salt-ice bath, and 2.34 g of 6 was added with magnetic stirring under an N2 atmosphere. After 10-15 min, 2-5 drops of concentrated H2SO4 were added. The reaction mixture was allowed to stir for an additional 10 min, after which it was treated with 40 mL of ether and 10 mL of H2O. The mixture was extracted three times with 15 mL of saturated aqueous sodium bicarbonate and once with 10 mL of saturated aqueous NaCl. The ether layer was dried over anhydrous MgSO4, and the solvent was removed by rotary evaporation to yield 2.41 g (88%) of a mixture of stereoisomers of the nitro acetate 7. 1H NMR δ (ppm) 5.4 (broad m, CH2CH(OAc)), 5.2 (t, C═CH), 4.65 (m, CH3CHNO2), 2.1 (s, CH3CO2), 2.0 (br m, ═CHCH2), 1.60 and 1.65 (both s, CH3C(CH3)═), 1.5 (d, CH3CHNO2), 1.2-1.5 (m, CH2CH(CH3)CH2), 0.95 (d, CH2CH(CH3)CH2).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23][CH:24]5[CH2:29][CH2:28][N:27]([C:30]([CH3:35])([CH3:34])[C:31]([NH2:33])=[O:32])[CH2:26][CH2:25]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:37].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[C:20]([S:23]([CH:24]5[CH2:29][CH2:28][N:27]([C:30]([CH3:35])([CH3:34])[C:31]([NH2:33])=[O:32])[CH2:26][CH2:25]5)=[O:37])[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)C(N)=O)CC3)ccc1OCC2
Reactant: O=C(O)C(F)(F)F
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)C3CCN(C(C)(C)C(N)=O)CC3)ccc1OCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of 2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}isobutyramide from Example 192 (233 mg, 0.470 mmol) in DCM (20 mL) was added TFA (109 μL, 1.41 mmol) followed by a solution of m-CPBA (89 mg, 0.512 mmol) in DCM (2 mL). The resulting mixture was stirred for 30 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 10-40% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3 in MeOH affording 193 as a colorless foam (116 mg, 48%). LCMS: RT 2.42 min [M+H]+ 512.1. 1H NMR (DMSO, 400 MHz): δ 8.61 (1H, d, J=2.26 Hz), 7.98 (1H, s), 7.93 (1H, s), 7.55 (1H, dd, J=8.53, 2.28 Hz), 7.26 (1H, d, J=8.53 Hz), 7.09 (1H, d, J=3.29 Hz), 6.87 (1H, d, J=3.29 Hz), 5.78-5.67 (1H, m), 4.61-4.54 (4H, m), 2.80 (2H, bd, J=10.79 Hz), 2.74-2.64 (1H, m), 2.13-2.00 (2H, m), 1.78 (1H, bd, J=12.05 Hz), 1.69-1.55 (3H, m), 1.49 (3H, d, J=6.6 Hz), 1.47 (3H, d, J=6.6 Hz), 1.02 (6H, s)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:13])[N:11]=2)[CH:8]=1)#[CH:2].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+]>CN(C)C=O>[C:15]1([NH:14][C:12]([C:10]2[N:11]=[C:6]3[CH:5]=[CH:4][C:3]([C:1]4[N:21]=[N:22][NH:23][CH:2]=4)=[CH:8][N:7]3[CH:9]=2)=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#Cc1ccc2nc(C(=O)Nc3ccccc3)cn2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cn2cc(-c3c[nH]nn3)ccc2n1
Reaction time: 0.5 h
Yield: 25.1 %

Procedure:
123 mg of 6-ethynyl-N-phenylimidazo[1,2-a]pyridine-2-carboxamide, 46 mg of sodium azide, 38 mg of ammonium chloride and 5 mL of N,N-dimethylformamide are placed in a microwave tube. The reaction mixture is heated for 20 minutes in a microwave machine set at 170° C. and then for a further 30 minutes under the same conditions, followed by addition of 46 mg of sodium azide and 38 mg of ammonium chloride, and finally concentrated at 50° C. under reduced pressure. The residue is taken up in 20 mL of ethyl acetate and 20 mL of water. The aqueous phase is extracted twice with 20 mL of ethyl acetate and the combined organic phases are washed with 30 mL of saturated brine and then dried over magnesium sulfate and concentrated to dryness under reduced pressure. The residue is chromatographed on a silica cartridge, eluting with a gradient of dichloromethane and methanol (from 100/0 to 90/10). The fractions containing the expected product are combined and concentrated to dryness under reduced pressure to give 36 mg of N-phenyl-6-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine-2-carboxamide in the form of an off-white solid.
Reaction SMILES: [C:1]([CH:6]=[CH:7][CH2:8][O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@:16]3([OH:34])[CH2:17][CH2:18][C@@H:19]2[C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)[CH2:11]1)(OCC)=[O:2].O>O1CCCC1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>[OH:2][CH2:1][CH2:6][CH2:7][CH2:8][O:9][C@H:10]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@H:12]([CH2:13][CH2:14][C@@H:15]3[C@@H:24]2[CH2:23][CH2:22][C@@:20]2([CH3:21])[C@:16]3([OH:34])[CH2:17][CH2:18][C@@H:19]2[C:29]2[CH:33]=[CH:32][O:31][CH:30]=2)[CH2:11]1
Reactant: CCOC(=O)C=CCO[C@H]1CC[C@@]2(C)[C@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](c4ccoc4)CC[C@]32O)C1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CC[C@H](OCCCCO)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)CC[C@]12O
Yield: 82 %

Procedure:
To a solution of 0.40 g of 3β-(3-carbethoxyprop-2-enoxy)-17β-(3-furyl)-5β-androstan-14β-ol in 30 ml of anhydrous tetrahydrofuran, 2 ml of sodium bis(2-methoxyethoxy)aluminum hydride (solution 3.4 M in toluene) were added at room temperature. The solution was kept at reflux temperature for 8 hrs, then 10 ml of water were added and the organic solution was evaporated to dryness under reduced pressure. The residue was extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. The crude product was purified by flash-chromatography using n-hexane/ethyl acetate 70/30 as eluant to give 0.30 g of 3β-(4-hydroxybutoxy)-17β-(3-furyl)-5β-androstan-14β-ol, as a white pasty solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[S:12](Cl)(=[O:14])=[O:13].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[S:12]([N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)(=[O:14])=[O:13]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)Cl
Reactant: C1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.7 %

Procedure:
To a mixture of 2-methoxy-4-nitrobenzenesulfonylchloride (600 mg) and THF (5 mL), a mixture of piperidine (406 mg) and THF (1 mL) was added and stirred at room temperature for 12 hours. After addition of 10% hydrochloric acid, the reaction liquid was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give 1-[(2-methoxy-4-nitrophenyl)sulfonyl]piperidine (714 mg) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH:11](O)[CH2:12][OH:13].N1C=CC=CC=1.[CH2:21]([NH:23][S:24](Cl)(=[O:26])=[O:25])[CH3:22].Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH2:12][O:13][S:24](=[O:26])(=[O:25])[NH:23][CH2:21][CH3:22]
Reactant: CCNS(=O)(=O)Cl
Reactant: COc1ccccc1OCC(O)CO
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCNS(=O)(=O)OCCCOc1ccccc1OC
Yield: 69.8 %

Procedure:
A solution of 19.8 g (0.1 mole) of glyceryl guaiacolate in 100 ml of methylene chloride and 21.6 ml (0.26 mole) of pyridine was added in a thin stream to a stirred solution of 37.3 g (0.26 mole) of ethysulfamoyl chloride (prepared using procedure of Example 2, pt. a) in 150 ml of methylene chloride, and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was treated with 150 ml of 2N hydrochloric acid solution, and the layers were separated. The organic layer was washed with 150 ml of 2N hydrochloric acid solution, twice with 150 ml portions of water, dried (magnesium sulfate), and the solvent was evaporated under reduced pressure. The residue was purified by chromatography (4.5×90 cm glass column; 500 g of silica gel; methylene chloride-acetone, 25:1). Fractions containing the product were combined, and the solvents wre evaporated under reduced pressure to give 20.2 g (49%) of the title compound as a light-yellow, viscous oil containing a trace of methylene chloride.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH3:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=1.BrC1[C:32]([O:33][CH2:34]C)=[CH:31]C=CN=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:31][CH2:32][O:33][CH3:34])[C:15]2[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC1CCN(Cc2ccccc2)CC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCOc1cccnc1Br
Product: COCCN(c1ncccc1[N+](=O)[O-])C1CCN(Cc2ccccc2)CC1

Procedure:
Following the general procedure of EXAMPLE 70, and making non-critical variations but substituting 1-benzyl-4-(2-(methoxy)ethylamino)piperidine (EXAMPLE 107) for 1-benzyl-4-(methylamino)piperidine and 2-chloro-3-nitropyridine for 2-bromo-3-ethoxypyridine and using a reaction time of 2 hrs, the title compound is obtained, C,H,N: Anal. Calcd for C20H26N4O3 : C=64.85, H=7.07, N=15.12-found: C=64.66, H=7.08, N=14.88.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:24])[C:9]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:33][C:34]#[N:35]>CC(C)=O>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH2:33][C:34]#[N:35])=[CH:21][CH:22]=3)[CH:15]=2)[N:10]([CH3:24])[C:9]=1[CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc2n1C
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(Cc2ccccc2)c2cc(-c3ccc(OCC#N)cc3)ccc2n1C

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(3-benzyl-1,2-dimethyl-1H-indol-5-yl)-phenol (0.159 g, 0.486 mmol) was reacted with K2CO3 (0.087 g, 0.631 mmol) and bromoacetonitrile (0.076 g, 0.631 mmol) in acetone (5 ml) to give the product (0.161 g, 0.439 mmol, 90%) as a white solid, mp 135-138° C. 1H NMR (DMSO-d6) δ 2.40 (s, 3H), 3.68 (s, 3H), 4.07 (s, 2H), 5.18 (s, 2H), 7.08-7.12 (m, 3H), 7.20-7.25 (m, 4H), 7.32 (dd, J=1.8, 8.6 Hz, 1H), 7.41 (d, J=8.4 Hz, 1H), 7.57-7.60 (m, 3H); [ESI(+)], m/z 367 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:4]([CH3:6])[CH3:5].C(N(CC)CC)C>CS(C)=O>[CH3:5][CH:4]([CH3:6])[CH:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:2]=[O:1]
Reactant: CC(C)C(CO)NC(=O)OC(C)(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)C(C=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
To a solution of 1.75 g of tert-butyl 1-hydroxy-3-methylbutan-2-ylcarbamate (Formula 20) in 25 mL of DMSO was added 3.6 mL of triethylamine. The solution was cooled to 0° C. and 4.1 grams of sulfur trioxide pyridine complex in 25 mL of DMSO was added. The reaction mixture was stirred at room temperature for 1 hour. Then, the mixture was poured onto ice-water and extracted with ethyl acetate. The organic layers were washed with 10% acetic acid, water, 5% sodium bicarbonate, and brine, dried over sodium sulfate and concentrated. Column chromatography (30% ethyl acetate/hexane) gave 1.25 g of tert-butyl 3-methyl-1-oxobutan-2-ylcarbamate (Formula 21) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.95 (d, J=7.32 Hz, 3H), 1.03 (d, J=6.83 Hz, 3H), 1.45 (s, 9H), 2.27-2.29 (m, 1H), 4.24-4.26 (m, 1H), 9.65 (s, 1H).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].Cl.Cl[CH2:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1.[CH3:24]N(C=O)C>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([CH2:17][CH:2]([CH:3]([C:4]([O:6][CH2:7][CH3:24])=[O:5])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:1])[CH:19]=1
Reactant: ClCc1cccnc1
Reactant: CN(C)C=O
Reactant: CCOC(=O)C(CC)C(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C(=O)OCC)C(C)Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
To a suspension of diethyl methyl malonate (1.80 g, 10.2 mmol) in DMF (25 ml) at 0° C. was added sodium hydride (1.25 g, 31.0 mmol, 60%), followed by 3-(chloromethyl)pyridine hydrochloride (2.00 g, 12.2 mmol) and stirred for 8 h at room temperature. The reaction mixture was quenched with acetic acid and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford 2.50 g (91.2%) of diethyl 2-(1-(pyridin-3-yl)propan-2-yl)malonate as pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][CH2:8][C:9](=[O:11])[N:10]=1.C(O[Na])(C)=O.[CH:21]([C:23]1[N:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[O:35][CH:36]([CH3:38])[CH3:37])=O>CC(O)=O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][NH:5][C:6]1[S:7][C:8](=[CH:21][C:23]2[N:24]=[C:25]3[C:30](=[CH:31][CH:32]=2)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]3[O:35][CH:36]([CH3:38])[CH3:37])[C:9](=[O:11])[N:10]=1
Reactant: O=C1CSC(NCc2ccccc2Cl)=N1
Reactant: CC(C)Oc1c(C#N)cnc2ccc(C=O)nc12
Agent: CC(=O)O[Na]
Solvent: CC(=O)O
Product: CC(C)Oc1c(C#N)cnc2ccc(C=C3SC(NCc4ccccc4Cl)=NC3=O)nc12
Temperature: 90 °C
Yield: 35.3 %

Procedure:
To a mixture of 2-(2-chloro-benzylamino)-thiazol-4-one (48.1 mg, 0.20 mmol) (prepared as described below), AcONa (160 mg, 1.95 mmol), molecular sieves, and 6-formyl-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile (53.1 mg, 0.22 mmol, (see Example 1) in a sealed tube was added AcOH (0.3 mL). The reaction mixture was heated to 85-95° C. (oil bath) for 1.5 h. The reaction mixture was then cooled to r.t. and triturated with water. The solid was collected by filtration and washed with water. The solid was then suspended in hot MeOH (50 mL) and filtered again. The filtrate was concentrated to give a brown solid: 120.3 mg, which was purified by Biotage flash column (1%-6% MeOH in CH2Cl2) to give 6-[2-(2-chloro-benzylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-4-isopropoxy-[1,5]naphthyridine-3-carbonitrile as a yellowish solid (32.8 mg, 35.3%). HR-ES (+) m/e calcd for C23H18ClN5O2S (M+H)+ 464.0943. found 464.0943.
Reaction SMILES: [CH:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:9]C(C)([O-])C.[K+].CI>C(Cl)Cl.[Cl-].[Na+].O>[CH3:9][C:1]1([CH:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)[O-]
Reactant: O=CC1CCCCC1
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: ClCCl
Product: CC1(C=O)CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
To a solution of cyclohexanecarboxaldehyde (10.8 mL, 89.15 mmol) in DCM (500 mL) cooled to 0° C. was added potassium tert-butoxide (13.0 g, 115.9 mmol) and methyl iodide (16.65 mL, 267.5 mmol). After 30 min at this temperature, the mixture was warmed to RT and stirring was continued for an additional 5 h. The reaction was then poured into brine and extracted with DCM. The organic layer was dried over MgSO4 and the solvent was then removed carefully in vacuo to yield 9.4 g (83%) of crude 1-methylcyclohexanecarboxaldehyde which was ˜80% pure and was used directly in the next reaction.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:20]([O:24][CH2:25][CH3:26])(=[O:23])[CH:21]=[CH2:22]>>[OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[CH:9]([CH:21]([C:20]([O:24][CH2:25][CH3:26])=[O:23])[CH3:22])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCC1=NCCN1CCO
Reactant: C=CC(=O)OCC
Product: CCCCCCCCCCC(C1=NCCN1CCO)C(C)C(=O)OCC
Yield: 99.7 %

Procedure:
Fifty-three and seven tenths g (53.7 g, 0.2 mol) of 1-(2-hydroxyethyl)-2-undecyl-2-imidazoline was melted, and 60 g (0.6 mol) of ethyl acrylate was added. The mixture was reacted at a temperature of 60°-65° C. for 4 hr. in a substantially anhydrous condition. After the reaction, the excess ethyl acrylate was removed by vacuum-topping the reaction mixture at a temperature of 30°-40° C. Seventy-three and a half g (73.5 g) of 1-(2-hydroxyethyl)-2-(α-ethoxycarbonylethyl-undecyl)-2-imidazoline was obtained as a slightly yellow viscous liquid.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[NH2:39][C@H:40]([CH2:56][CH2:57][C:58]1[NH:62][N:61]=[N:60][N:59]=1)[C:41]([NH:43][C:44]1[CH:55]=[CH:54][C:47]2[CH2:48][CH2:49][N:50]([CH3:53])[CH2:51][CH2:52][C:46]=2[CH:45]=1)=[O:42].C(O)(C(F)(F)F)=O>CN(C=O)C>[NH:62]1[C:58]([CH2:57][CH2:56][C@@H:40]([NH:39][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])[C:41](=[O:42])[NH:43][C:44]2[CH:55]=[CH:54][C:47]3[CH2:48][CH2:49][N:50]([CH3:53])[CH2:51][CH2:52][C:46]=3[CH:45]=2)=[N:59][N:60]=[N:61]1
Reactant: CN1CCc2ccc(NC(=O)[C@H](N)CCc3nnn[nH]3)cc2CC1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CN1CCc2ccc(NC(=O)[C@@H](CCc3nnn[nH]3)NC(=O)c3ccc(Cl)s3)cc2CC1
Reaction time: 0.25 h

Procedure:
13 mg (0.08 mmol) 5-chloro-thiophene-2-carboxylic acid are dissolved in 0.5 ml DMF, mixed at room temperature with 26 mg (0.08 mmol) TBTU and 50 μl (0.45 mmol) NMM and stirred for 15 min. A solution of 32 mg (0.08 mmol) (R)-2-amino-N-(3-methyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-4-(1H-tetrazol-5-yl)-butyramide in 1 ml DMF is added to the reaction mixture and it is stirred overnight at room temperature. The reaction mixture is acidified with TFA, separated by chromatography through RP material (eluant: water/acetonitrile 95:5=>5:95) and then freeze-dried.