Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].O=C1[CH2:13][C@H:12]2[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H]([CH2:10][CH2:11]2)C1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:5]=[C:4]1[CH2:13][CH:12]2[N:14]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH:2]([CH2:10][CH2:11]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (2.38 g, 6.6 mmol) in dry THF at 0° C. was added n-BuLi (2.7 mL, 2.5 M) dropwise. After stirring at 0° C. for 30 min, (1R,5S)-tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.2 mmol) was added and the mixture was stirred at 0° C. for additional 16 hrs. The reaction was quenched by sat. NH4Cl and extracted with EtOAc (50 mL×3) and purified by SGC (eluting with petroleum ether/ethyl acetate=20/1) to give target compound (130 mg, 27%). 1H NMR (500 MHz, CDCl3) δ4.77 (t, J=4.0 Hz, 2H), 4.21 (br s, 1H), 4.11 (br s, 1H), 2.43-2.33 (m, 2H), 2.01 (s, 1H), 1.98 (s, 1H), 1.79 (d, J=3.0 Hz, 2H), 1.53-1.49 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][N:4]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:18][O:17][N:16]([CH3:15])[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[N:4][CH:5]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Reactant: CNOC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1
Temperature: 7 °C

Procedure:
To a 1 L 3-neck flask equipped with an overhead stirrer, Claisen adaptor, nitrogen bubbler, 125 mL addition funnel, and thermocouple was added 6-(trifluoromethyl)nicotinoyl chloride (49.3 g, 235 mmol, Intermediate 4: step a), dichloromethane (493 mL), and N,O-dimethylhydroxylamine hydrochloride (25.63 g, 258.8 mmol). After the mixture was cooled to 7° C., diisopropylethylamine (90.26 mL, 517.6 mmol) was added such that the addition temperature did not exceed 16° C. After the addition, the reaction was allowed to warm to room temperature. The reaction was then transferred to a reparatory funnel and the organic layer was washed with saturated aqueous NaHCO3 (2×100 mL) followed by water (100 mL) and then dried over sodium sulfate and filtered. Removal of solvent afforded a brown oil as the title compound.
Reaction SMILES: CS(O[CH2:6][CH:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][O:9][CH2:10][CH3:11])(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>CN(C=O)C.O>[N:20]([CH2:6][CH:7]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:8][O:9][CH2:10][CH3:11])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOCC(COS(C)(=O)=O)NC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCC(CN=[N+]=[N-])NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 24 h

Procedure:
To a solution of 2-[(tert-butoxycarbonyl)amino]-3-ethoxypropyl methanesulfonate (1.6 g, 5.4 mmol) in DMF (20 mL) was added sodium azide (1.10 g, 16.2 mmol) and then the reaction mixture was heated to 50° C. After 24 hours, the reaction mixture was diluted with water and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated under reduced pressure and the resulting residue was purified via silica chromatography to give tert-butyl (1-azido-3-ethoxypropan-2-yl)carbamate. MS ESI calc'd. for C10H21N4O3 [M+H]+ 245. found 245.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39]([CH2:41][C:42]5[N:46]([CH2:47][CH2:48][CH3:49])[CH:45]=[N:44][CH:43]=5)=[O:40])=[CH:35][CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[C:51]([OH:56])(=[O:55])[C:52]([OH:54])=[O:53]>C(OCC)(=O)C.C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:34]=[CH:35][C:36]([S:39]([CH2:41][C:42]5[N:46]([CH2:47][CH2:48][CH3:49])[CH:45]=[N:44][CH:43]=5)=[O:40])=[CH:37][CH:38]=4)=[O:31])=[CH:20][C:19]=3[CH:50]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[C:51]([O-:56])(=[O:55])[C:52]([O-:54])=[O:53]
Reactant: O=C(O)C(=O)O
Agent: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCC)cc2)CCCN3CC(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C([O-])C(=O)[O-]
Reaction time: 8 h

Procedure:
To a solution of (−)-8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propyl-1H-imidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (100 mg) in ethyl acetate (4 ml) was added a solution of oxalic acid (6.46 mg) in ethanol (2 ml), after which the solvent was distilled off under reduced pressure. Ethyl acetate (5 ml) was added, and the solvent was again distilled off under reduced pressure, after which ethyl acetate (4 ml) was added, and the mixture was allowed to stand overnight under light shielding. The precipitated crystals were filtered, and further washed with ethyl acetate (5 ml), after which the resultant was dried under reduced pressure to give (−)-8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-propyl-1H-imidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide/oxalate (50 mg) as yellow crystals (Compound 13).
Reaction SMILES: [C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7]([N+]([O-])=O)=[CH:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]1=2)#[N:2].C([O:23]CCO)C>Cl.[Fe]>[C:1]([N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:23])[CH2:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]1=2)#[N:2]
Reactant: CCOCCO
Reactant: N#CN1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Agent: [Fe]
Agent: Cl
Product: N#CN1c2ccccc2CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
26.3 g (0.1 mole) of 5-cyano-10-nitro-5H-dibenz[b,f]azepine are suspended in a mixture of 265 ml of ethylene glycol monoethyl ether and 75 ml of concentrated hydrochloric acid. 40 g of iron powder are added in small portions at 40° in the course of 40 minutes and the temperature is maintained at 40° by external cooling. The mixture is stirred for a further 2 hours at room temperature, is then heated to 80°, the precipitated product dissolving again, and is filtered through a heated suction filter, which is subsequently washed with ethylene glycol monoethyl ether. The crystallisation which commences in the filtrate is completed by adding 200 of ml of water. After cooling for one hour in an ice-bath, filtration is carried out followed by washing with a mixture of ethylene glycol monoethyl ether and water in a ratio of 1:1. 5-cyano-10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine is obtained which is identified, by comparing the IR spectra, with material from Example 27.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[C:13]1([S:19]([CH2:22][CH2:23][S:24][C:25]2[N:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27]([OH:29])=O)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:34]1([CH2:40][NH2:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>C(Cl)Cl>[CH:34]1([CH2:40][NH:41][C:27](=[O:29])[C:26]2[CH:30]=[CH:31][CH:32]=[N:33][C:25]=2[S:24][CH2:23][CH2:22][S:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)(=[O:20])=[O:21])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NCC1CCCCC1
Reactant: O=C(O)c1cccnc1SCCS(=O)(=O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C(NCC1CCCCC1)c1cccnc1SCCS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
264 mg (1.62 mmol) of CDI were added to a solution of 500 mg (1.55 mmol) of 2-(2-(phenylsulfonyl)ethylthio)nicotinic acid in DCM (12 ml), and the mixture was stirred for 1 h at RT. A solution of 200 μl (1.55 mmol) of cyclohexanemethylamine in DCM (12 ml) was then added, and stirring was continued for a further 16 h at RT. The reaction solution was then washed in each case three times with sat. aq. ammonium chloride solution and saturated aqueous NaHCO3 solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. 624 mg (1.49 mmol, 96%) of N-(cyclohexylmethyl)-2-(2-(phenylsulfonyl)ethylthio)nicotinamide were obtained as residue.
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12](#[N:14])[CH3:13].[C:15]1([C:25](OCC)=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>O1CCCC1>[C:15]1([C:25]([CH2:13][C:12]#[N:14])=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CC#N
Reactant: CCOC(=O)c1cccc2ccccc12
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCC(=O)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
To a solution of 2.50 M of n-butyllithium in hexane (49.9 mL, 125 mmol) in tetrahydrofuran (49.9 mL) cooled to −78° C. is added acetonitrile (6.52 mL, 125 mmol) drop-wise. The resulting cloudy mixture is stirred for 30 min. Ethyl α-napthoate (8.87 mL, 49.9 mmol) is added drop-wise and the reaction mixture is stirred at −78° C. for 2 hr. The reaction is warmed to room temperature, quenched with acetic acid (50 ml) and partitioned between ethyl acetate and water. The organic layer is dried over Na2SO4, filtered and concentrated in vacuo. The crude material is purified by column chromatography (eluent: 5-15% CH2Cl2/methanol) to provide 1-naphthoylacetonitrile (6.99 g, yield 72%). 1H NMR (400 MHz, CDCl3) δ 8.82 (d, J=8.7 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 7.90 (t, J=8.1 Hz, 2H), 7.71-7.64 (m, 1H), 7.57 (dt, J=15.5, 7.2 Hz, 2H), 4.21 (s, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]([C@@H:10]([OH:16])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>CCCCC.CN(C=O)C>[CH2:18]([O:16][C@H:10]([C@@H:4]([O:3][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6])[C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CN(C)C(=O)[C@H](O)[C@@H](O)C(=O)N(C)C
Reactant: CCCCCCCCCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCO[C@@H](C(=O)N(C)C)[C@@H](OCCCCCCCCCCCC)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24.4 %

Procedure:
Sodium hydride (3.60 g, 60%, 90.0 mmol) was washed with pentane (3×) before DMF (150 ml) and (+)-(2R,3R)-2,3-dihydroxy-N,N,N′,N′-tetramethylsuccinamide (9.2 g, 45.0 mmol, origin: Aldrich) were added. The reaction mixture was left stirring at room temperature for 90 min, then a solution of 1-iodododecane (28.0 g, 94.5 mmol) in DMF (50 ml) was added. The reaction was left stirring for another 2 h at room temperature and then heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was extracted with ether (4×), washed with water (2×), dried (Na2SO4), and concentrated. Column chromatography (SiO2, dichloromethane/acetone 3:1) gave 5.93 g (28%) of a pale-yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:32][CH2:33][CH3:34])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:27][C:28](O)=[O:29])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[O:17])[C:7]1=[O:31])[CH3:2].Cl.C(N=C=NCCCN(C)C)C.[NH2:47][C:48]1[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=1>ClCCl.C(OCC)(=O)C>[CH2:33]([O:32][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:27][C:28]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([CH3:54])=[CH:50][CH:49]=2)=[O:29])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)=[O:17])[C:7]1=[O:31])[CH3:34]
Reactant: Cc1ccc(N)cc1
Reactant: CCOC(CN1C(=O)C(CC(=O)O)(NC(=O)Nc2cccc(OC)c2)c2ccccc21)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2cccc(OC)c2)c2ccccc21)OCC
Reaction time: 9 h
Yield: 77.4 %

Procedure:
In 30 ml of dichloromethane was dissolved 0.50 g of (-)-1-(2,2-diethoxyethyl)-3-hydroxycarbonylmethyl-3-(N'-(3-methoxyphenyl)ureido)indolin-2-one, and 0.22 g of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride and 0.20 g of p-toluidine were successively added thereto. After stirring the mixture for 9 hours, the reaction mixture was diluted with ethyl acetate and washed successively with dilute hydrochloric acid and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 0.46 g of the title compound as a white powder. Because the compound is an enantiomer of the compound of Example 188, the NMR data are the same as those of the latter compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4](P(=O)(OC)OC)[O:3]1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28].C(N(CC)CC)C>O1CCCC1>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:2](=[O:1])[O:3]2)=[CH:21][C:20]=1[N+:27]([O-:29])=[O:28]
Reactant: COP(=O)(OC)C1OC(=O)c2ccccc21
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C=C2OC(=O)c3ccccc32)cc1[N+](=O)[O-]
Temperature: 15 °C
Reaction time: 4 h

Procedure:
A stirred solution of dimethyl 3-oxo-1,3,-dihydroisobenzofuran-1-ylphosphonate (2.42 g, 0.01 mol; prepared in a manner similar to that described in Example 23) and 4-methoxy-3-nitrobenzaldehyde (1.81 g, 0.01 mol) in tetrahydrofuran (15 ml) was cooled to 15° C. and a solution of triethylamine (1.01 g, 0.01 mol) in tetrahydrofuran (1.5 ml) was added dropwise at <25° C. The mixture was stirred at ambient temperature for 4 hours, allowed to stand at this temperature for a further 16 hours and the resulting mixture was concentrated in vacuo. The residue was triturated with water (50 ml) and stirred at ambient temperature for 2 hours before the resulting solid was collected by filtration and dried in vacuo for 24 hours to give crude 3-(4-methoxy-3-nitrobenzylidene)-3H-isobenzofuran-1-one (2.53 g) as a yellow solid, m.pt. 173–181° C., which was used directly in the next stage.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([CH:8]=O)[CH2:3]1.O.[NH2:11][NH2:12]>CCCCO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]2[NH:11][N:12]=[CH:8][CH:4]2[CH2:3]1
Reactant: NN
Reactant: CN1CCC=C(C=O)C1
Solvent: CCCCO
Solvent: O
Product: CN1CCC2NN=CC2C1

Procedure:
3.2 g 1-Methyl-1,2,5,6-tetrahydro-pyridine-3-carbaldehyde was dissolved in 10 mL n-BuOH. Added were 2 equiv. of hydrazine hydrate, the mixture was refluxed for 24 hours and subsequently concentrated in vacuo. The residue was taken up in DCM and extracted with 2M NaOH, and the organic phase was dried over Na2SO4, filtrated and concentrated in vacuo to yield 1.78 g of a brown oil which was used without further purification in the subsequent step.
Reaction SMILES: C([O:8][C:9](=[O:23])[C@H:10]([CH:20]([CH3:22])[CH3:21])[NH:11][C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[O:17]1[CH2:18][CH2:19][N:14]([C:12]([NH:11][C@H:10]([C:9]([OH:23])=[O:8])[CH:20]([CH3:22])[CH3:21])=[O:13])[CH2:15][CH2:16]1
Reactant: [H][H]
Reactant: CC(C)[C@H](NC(=O)N1CCOCC1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)N1CCOCC1)C(=O)O

Procedure:
2.7 g (8.4 mmol) of N-morpholinocarbonyl-(L)-valine-benzyl ester are dissolved in 75 ml of ethyl acetate and the solution is hydrogenated for 3 h in the presence of 500 mg of 10% palladium on carbon at 1 atm hydrogen pressure and RT. The catalyst is filtered off and, after concentrating the solvent by evaporation, the title compound is obtained in the form of a colourless oil. 1H-NMR (300 MHz, CD3OD): 4.15 (m, 1H), 3.65 (m, 4H), 3.40 (m, 4H), 2.12 (m, 1H), 0.95 (2d, 6H).
Reaction SMILES: CON(C)[C:4]([CH:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7])=[O:5].[C:17]1([Mg]Br)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[O:5]=[C:4]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH3:7]
Reactant: CON(C)C(=O)C(C)NC(=O)OC(C)(C)C
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CC(NC(=O)OC(C)(C)C)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
tert-butyl 1-(N-methoxy-N-methylcarbamoyl)ethylcarbamate (39) (2.3 g, 10.0 mmol, 1.0 equiv.) was added to a 250 mL RBF followed by THF (100 mL). The mixture was cooled to 0° C. via an ice bath and a 1.0 M solution of PhMgBr in THF (30.0 mL, 30.0 mmol, 3.0 equiv.) was added over 8 min. The reaction stirred for 1.0 h at 0° C. and the ice bath was removed. The reaction stirred for an additional 1.0 h at rt. and was again cooled to 0° C. via an ice bath. Next, the reaction was quenched by addition of 1.0 M HCl (60 mL). The solution was transferred to a separatory funnel with additional 1.0 M HCl (40 mL) and extracted with EtOAc (3×75 mL). The organic layers were combined, washed with sat. NaCl (1×50 mL), and dried over Na2SO4. The solution was then concentrated on a rotary evaporator and dried under vacuum to give 3.1 g of crude material. The residue was purified by flash column chromatography (15% EtOAc/Hexanes) to give 2.2 g (86%) of 40 as a colorless oil.10 Rf=0.25 (15% EtOAc/Hexanes); IR (film) 3356, 2977, 1680, 1164 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.96 (d, J=7.5 Hz, 2H, Ph-H), 7.59 (t, J=7.5 Hz, 1H, Ph-H), 7.48 (t, J=7.5 Hz, 2H, Ph-H), 5.62 (br d, J=6.5 Hz, 1H, carbamate-NH), 5.30 (t, 1H, Boc-NH—CH), 3.78 (s, 3H, N—OCH3), 3.19 (s, 3H, N—CH3), 1.46 (s, 9H, Boc-t-butyl-CH3), 1.40 (d, J=7.0 Hz, 3H, CH—CH3); 13C NMR (125 MHz, CDCl3) δ 199.6, 155.5, 134.3, 133.9, 129.0, 128.8, 80.0, 51.3, 28.6, 20.1; LRMS (ESI-MS m/z): Mass calcd for C14H19NO3 [2M]+, 498.62. Found 499. Spectroscopic data were consistent with the literature data for this compound.
Reaction SMILES: [CH2:1]([NH:15][C:16](=[O:22])[C:17]([O:19]CC)=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:14])[C:9]([O:11]CC)=O.[CH2:23]([NH2:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)(Cl)Cl>[CH2:6]([NH:7][C:8](=[O:14])[C:9]([NH:35][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][NH:15][C:16](=[O:22])[C:17]([NH:35][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:19]
Reactant: CCOC(=O)C(=O)NCCCCCCNC(=O)C(=O)OCC
Reactant: CCCCCCCCCCCCN
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCNC(=O)C(=O)NCCCCCCNC(=O)C(=O)NCCCCCCCCCCCC

Procedure:
Diethyl 2,2′-(hexane-1,6-diylbis(azanediyl))bis(2-oxoacetate) (5.00 g, 15.8 mmol) and dodecyl amine (5.85 g, 31.64 mmol) were dissolved in 100 ml of CHCl3. Subsequently the mixture was heated at reflux temperature for 24 hours. The solvent was removed by filtering the product. The remaining solid was washed two times with CHCl3 and two times with diethyl ether and dried in vacuum. The product was obtained as a white powder.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=O)[NH:2]1.CN(C)C=O.S(Cl)([Cl:18])=O>ClC1C=CC=CC=1>[Cl:18][C:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][N:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]sc2ccccc12
Solvent: Clc1ccccc1
Solvent: CN(C)C=O
Product: Clc1nsc2ccccc12
Reaction time: 1 h
Yield: 90 %

Procedure:
A 1 L four-neck flask equipped with a stirrer, a thermometer and a condenser tube was charged with 75.6 g (0.5 mol) of 1,2-benzisothiazol-3-one, 54.8 g (0.75 mol) of N,N-dimethylformamide and 100.0 g of chlorobenzene. While stirring, 71.4 g (0.6 mol) of thionyl chloride was added dropwise thereto over 1 hour at 70° to 80° C., and the mixture was reacted at the same temperature for 8 hours. After terminating the reaction, the liquid reaction mixture was concentrated, and a crude product obtained was distillated under reduced pressure of 0.93 kPa at 128° C. to give 75.1 g (0.45 mol) of 3-chloro-1,2-benzisothiazole. The yield based on the 1,2-benzisothiazol-3-one was 90%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[S:29][CH:30]=[C:31]([C:33](O)=[O:34])[N:32]=2)[CH:23]=1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:33]([C:31]4[N:32]=[C:28]([C:24]5[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=5)[S:29][CH:30]=4)=[O:34])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1csc(-c2cccnc2)n1
Product: Cc1ccc(NC(=O)c2csc(-c3cccnc3)n2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(pyrid-3-yl)thiazole-4-carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide and 2-(pyrid-3-yl)thiazole-4-carboxylic acid using method D. NMR; δH CDCl3 9.26,(1H, b), 9.24,(1H, d), 8.73,(1H, d), 8.28,(2H, m), 7.85,(2H, d), 7.72,(1H, dd), 7.60,(1H, d), 7.47-7.44,(3H, m), 7.32,(1H, d), 6.29,(1H, t), 3.36,(2H, m), 2.26,(3H, s), 1.10,(1H, m), 0.59,(2H, m), 0.31,(2H, m). LCMS: retention time 3.36 min, MH+469.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26](=O)[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)=[O:23])C1C=CC=CC=1.O=P(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[F:34][C:31]1[CH:32]=[CH:33][C:28]([CH2:27][C:26]2[O:23][C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[OH:8])[CH2:16][CH2:15][O:14][C:13]4([CH3:21])[CH3:20])=[N:24][CH:25]=2)=[CH:29][CH:30]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCC(=O)Cc1ccc(F)cc1)c(OCc1ccccc1)c2=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CC1(C)OCCn2c1nc(-c1ncc(Cc3ccc(F)cc3)o1)c(O)c2=O

Procedure:
A mixture of 3-(benzyloxy)-N-(3-(4-fluorophenyl)-2-oxopropyl)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.16 g, 0.3337 mmol) and POCl3 (2 mL) in toluene (15 mL) was heated at reflux for 5 h, then cooled, concentrated and the resulting residue taken up in EtOAc (50 mL), washed with water (2×10 mL), brine (10 mL), dried (Na2SO4), filtered and concentrated to give a yellow residue. Purification by preparative HPLC on C18 column using water/MeOH containing 0.1% TFA provided the title as a white solid which was crystallized from MeOH/H2O to afford colorless needles. 1HNMR (500 MHz, CDCl3) δ: 11.04-10.92 (1H, br s), 7.26 (2H, dd, J=8.6, 5.5 Hz), 7.04 (2H, t, J=8.6 Hz), 6.86 (1H, s), 4.10 (2H, s), 4.07-4.02 (4H, m), 1.65 (6H, s). HRMS (M+H) calcd for C19H19N3O4F: 372.1360. found: 372.1356. Anal calcd for C19H18N3O4F: C, 61.45; H, 4.88; N, 11.31. found: C, 61.19; H, 4.74; N, 11.14.