Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2NC=CC=2C(N2CCC[C@@H](NC(=O)C(NC3C=C(Cl)C=C(Cl)C=3)C3COC3)C2)=N[CH:2]=1.[NH2:33][CH:34]([CH:38]1[CH2:41][O:40][CH2:39]1)[C:35]([OH:37])=[O:36].N1C2NC=CC=2C(N2CCC[C@@H](N)C2)=NC=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH2:33][CH:34]([CH:38]1[CH2:41][O:40][CH2:39]1)[C:35]([O:37][CH3:2])=[O:36]
Reactant: NC(C(=O)O)C1COC1
Reactant: O=C(N[C@@H]1CCCN(c2ncnc3[nH]ccc23)C1)C(Nc1cc(Cl)cc(Cl)c1)C1COC1
Agent: CCN=C=NCCCN(C)C
Agent: N[C@@H]1CCCN(c2ncnc3[nH]ccc23)C1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(N)C1COC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(N—((R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl)-2-(3,5-dichlorophenylamino)-2-(oxetan-3-yl)acetamide). To a solution of 2-amino-2-(oxetan-3-yl)acetic acid (0.3 mmol) and (R)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-amine (0.3 mmol) in DMF (2 mL) was added DIEA (0.9 mmol), EDCI (0.33 mmol), and HOBt (0.33 mmol). The resulting solution was then stirred at rt for 1 h. The solvent was removed in vacuo to afford a residue, which was purified by reverse phase chromatography C18 column and 10% acetonitrile/water containing 0.1% TFA to afford the title compound. 1H NMR (400 MHz, MeOD) δ 8.08 (s, 1H), 7.03 (d, J=3.51 Hz, 1H), 6.55 (d, J=3.51 Hz, 1H), 6.41 (t, J=1.76 Hz, 1H), 6.37 (d, J=1.76 Hz, 1H), 4.64-4.69 (m, 1H), 4.54-4.60 (m, 1H), 4.42 (t, J=6.27 Hz, 1H), 4.07 (d, J=9.29 Hz, 1H), 3.71-3.97 (m, 3H), 1.83-1.93 (m, 1H), 1.76 (br. s., 1H), 1.62 (br. s., 1H). EIMS (m/z): calcd. for C22H24Cl2N6O2(M+1H) 475. found 475.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1[N:14]=[C:15]([NH:18][CH:19]=[O:20])[S:16][CH:17]=1)[C:10]([OH:12])=O.[CH3:21][CH:22]1[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[N:25]2[C:31](=[O:34])[CH:32]([NH2:33])[C@H:24]2[S:23]1.C[Si](CC(N)=O)(C)C.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.CN(C)C=O>[CH3:21][CH:22]1[CH:27]=[C:26]([C:28]([OH:30])=[O:29])[N:25]2[C:31](=[O:34])[CH:32]([NH:33][C:10](=[O:12])[C:9](=[N:8][O:7][CH3:6])[C:13]3[N:14]=[C:15]([NH:18][CH:19]=[O:20])[S:16][CH:17]=3)[C@H:24]2[S:23]1
Reactant: CC1C=C(C(=O)O)N2C(=O)C(N)[C@H]2S1
Reactant: CON=C(C(=O)O)c1csc(NC=O)n1
Agent: CON=C(C(=O)O)c1csc(=NC=O)[nH]1
Agent: C[Si](C)(C)CC(N)=O
Agent: O=C([O-])O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CC(C)S[C@H]12)c1csc(NC=O)n1
Temperature: 3 °C

Procedure:
To dimethylformamide (6.42 g.) was added dropwise phosphorus oxychloride (12.5 g.) over 20 minutes with stirring under cooling to 5° to 10° C., and the mixture was stirred for 30 minutes at 40° C., and then ethyl acetate (200 ml.) was added thereto with vigorous stirring. After the mixture was cooled to 3° C., 2-methoxyimino-2-(2-formylaminothiazol-4-yl)acetic acid (syn isomer), which can be represented as 2-methoxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetic acid (syn isomer), (18.34 g.) was added thereto, and then the mixture was stirred for 40 minutes at 3° to 5° C. Thus obtained solution was added to a solution, which was prepared by stirring a mixture of 2-methyl-7-amino-3-cephem-4-carboxylic acid (17.1 g.) and trimethylsilylacetamide (84 g.) in ethyl acetate (300 ml.) for 1 hour at room temperature, with vigorous stirring under cooling to -25° C. The mixture was stirred for 1 hour at -20° to -15° C. and for 30 minutes at -10° to -5° C. To the mixture was added water (200 ml.) at room temperature, and the mixture was further stirred for 20 minutes at the same temperature. After a saturated aqueous sodium bicarbonate solution was added to the mixture in order to dissolve the precipitates, the aqueous layer was separated. To the aqueous layer was added ethyl acetate, and the mixture was adjusted to pH 2 with 2N hydrochloric acid, and then the ethyl acetate layer was separated. The remaining aqueous layer was further extracted with ethyl acetate. The ethyl acetate layers were combined together, washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, treated with an activated charcoal and then concentrated. Thus obtained crystalline residue was pulverized in diethyl ether, collected by filtration and then dried to give white crystals of 2-methyl-7-[2-methoxyimino-2-(2-formylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), which can be represented as 2-methyl-7-[2-methoxyimino-2-(2-formylimino-2,3-dihydrothiazol-4-yl)acetamido]-3-cephem-4-carboxylic acid (syn isomer), (32.2 g.). This compound was recrystallized from methanol to give white crystals of the pure object compound, mp 174° to 204° C. (dec.).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.I.[S:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](SC)=[NH:25].C([O-])(O)=O.[Na+]>C(O)C>[N:1]1([CH2:6][CH2:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:24]([C:20]4[S:19][CH:23]=[CH:22][CH:21]=4)=[NH:25])[CH:15]=3)[NH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2[nH]cc(CCN3CCCC3)c2c1
Reactant: CSC(=N)c1cccs1
Agent: I
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N=C(Nc1ccc2[nH]cc(CCN3CCCC3)c2c1)c1cccs1
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A solution of 3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-5-amine (0.59 g, 2.57 mmol) in dry ethanol (10 mL) was treated with methyl thiophene-2-carbimidothioate hydroiodide (1.467 g, 5.15 mmol) at room temperature and the resulting mixture was stirred overnight. The reaction was basified with saturated NaHCO3 solution (50 mL) and product was extracted into CH2Cl2 (2×25 mL). The combined organic layer was washed with brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (2 M NH3 in MeOH:CH2Cl2, 1:9) to obtain N-(3-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-5-yl)thiophene-2-carboximidamide (0.39 g, 1.152 mmol, 44.8% yield) as a solid. 1H NMR (DMSO-d6) δ 10.59 (s, 1H), 7.70 (d, 1H, J=2.7 Hz), 7.58 (d, 1H, J=3.9 Hz), 7.26 (d, 1H, J=6.3 Hz), 7.10-7.08 (m, 2H), 6.92 (s, 1H), 6.62 (d, 1H, J=6.3 Hz), 6.23 (s, 2H), 2.80 (t, 2H, J=6.0 Hz), 2.65 (t, 2H, J=5.4 Hz), 2.52-2.48 (m, 4H, merged with DMSO peak), 1.68 (s, 4H); ESI-MS (m/z, %): 339 (MH+, 100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH:24]1[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH2:25][CH:24]1[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Reactant: CC(C)CC1CNCCN1C(=O)OC(C)(C)C
Product: CC(C)CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OC(C)(C)C

Procedure:
Intermediate 1 was coupled with 2-Isobutyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 445.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]3[CH:18]=[C:17]([C:19]([O-:21])=O)[NH:16][C:13]3=[N:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].F[B-](F)(F)F.[N:28]1(OC(N(C)C)=[N+](C)C)[C:32]2C=[CH:34][CH:35]=[CH:36][C:31]=2N=N1.N1CCCCC1.C(N(CC)C(C)C)(C)C>>[N:28]1([C:19]([C:17]2[NH:16][C:13]3=[N:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)[CH:11]=[C:12]3[CH:18]=2)=[O:21])[CH2:34][CH2:35][CH2:36][CH2:31][CH2:32]1
Reactant: O=C([O-])c1cc2cc(OCCCN3CCCC3)cnc2[nH]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Li+]
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2cc(OCCCN3CCCC3)cnc2[nH]1)N1CCCCC1
Yield: 32 %

Procedure:
The title compound was synthesized in analogy to example 1 from lithium 5-(3-pyrrolidin-1-yl-propoxy)-1H-pyrrolo[2,3-b]pyridine-2-carboxylate, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, piperidine and N,N-diisopropylethylamine to give the desired product as a light brown solid (32% G).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[C:16]1([CH3:25])[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][CH:17]=1>C1COCC1>[CH:3]1([N:2]([CH3:1])[C:22](=[O:23])[C:19]2[CH:20]=[CH:21][C:16]([CH3:25])=[CH:17][CH:18]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CNC1CCCCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 89 %

Procedure:
To an ice cold stirred solution of N-methylcylohexylamine (20 ml, 0.15 mol) and triethylamine (22 ml) in dry THF (100 ml) under argon was slowly added p-toluoyl chloride (20 ml, 0. 15 mol) . A white precipitate formed. The ice bath was removed and the mixture stirred at ambient temperature for 24 h. Ice cold 2M, hydrochloric acid (100 ml) was added and the organic layer separated. The aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organics were washed with brine (3×100 ml), dried over anhydrous sodium sulphate, filtered and evaporated to give the crude amide, which was crystalised from hexane to give N-cyclohexyl-N-methyl 4-methylbenzamide (30.9 g, 87%) as a white crystalline solid.
Reaction SMILES: [C:1]([Mg]Cl)([CH3:4])([CH3:3])[CH3:2].[CH:7]1[C:19]2[C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]=2[CH:10]=[CH:9][CH:8]=1>>[C:1]([C:18]1([OH:20])[C:19]2[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=2[C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Mg]Cl
Reactant: O=C1c2ccccc2-c2ccccc21
Product: CC(C)(C)C1(O)c2ccccc2-c2ccccc21

Procedure:
from t-butylmagnesium chloride and 9-fluorenone;
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>ClCCl>[CH3:24][S:21]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Temperature: 23 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
A solution of tert-butyl 2-hydroxyethylcarbamate (25 mL, 161.6 mmol) in dichloromethane (60 mL) was cooled to 0° C. and stirred while first diisopropylethylamine (33.8 mL, 193.9 mmol) was added and then mesyl chloride (13.7 mL, 177.8 mmol) then was added dropwise. The mixture was allowed to warm to 23° C., stirred for 18 hours, poured into dichloromethane (200 mL) and washed with aqueous hydrochloric acid (3M, 3×25 mL) and saturated aqueous sodium hydrogencarbonate (2×25 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo to provide tert-butyl 2-methylsulfonyloxyethylcarbamate (37.39 g, 97% yield) as a brown oil; MS (PB-PCI) C8H17NO5S m/e calc 239.08; found 240 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[NH2:36]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:36][C:30]3[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:29]=3[F:28])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: Nc1ccc(F)cc1F
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Nc3ccc(F)cc3F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and 2,4-difluorophenylamine according to procedure A followed by deprotection yielded the title compound as a white solid. MS (ESI): m/z=391.2 [M+H]+.
Reaction SMILES: C([O:9][C@H:10]1[C@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]1=[O:36])(=O)C1C=CC=CC=1.C[O-].[Na+]>CO>[C@H:11]1([N:34]2[CH:42]=[C:40]([CH3:41])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[O:12][C@H:13]([CH2:24][OH:25])[C@@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: Cc1cn([C@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)c(=O)[nH]c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cn([C@H]2O[C@H](CO)[C@@H](O)[C@@H]2O)c(=O)[nH]c1=O
Reaction time: 8 h

Procedure:
1-(2',3',5'-Tri-O-benzoyl-α-D-arabinofuranosyl)thymine (18.6 g, 32.6 mmol) was dissolved in dry methanol and adjusted to pH 11 (as indicated by moist pH test paper) with freshly prepared sodium methoxide. After being stirred overnight, the solution was treated with Dowex-50 H+ resin, filtered, and evaporated to dryness. The residue was washed with ethyl acetate and dried, giving a crude yield of 8.0 g (69%). This was used without further purification. Its identity as Compound II was established by the following:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=[O:7].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[CH2:16]([O:7][C:6]([C:2]1[NH:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1H-pyrrole-2-carboxylic acid (1.11 g, 10 mmol) in DMF (15 mL) is added potassium carbonate (2.07 g, 15 mmol) and (bromomethyl)benzene (1.80 g, 10.50 mmol). After stirring the mixture at room temperature for 18 hours, water is added and the mixture is extracted three times with ethyl acetate. The combined organic layers are washed with water and brine then is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by flash chromatography (heptane/ethyl acetate=5:1) to give 1H-pyrrole-2-carboxylic acid benzylester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[N:17]/[C:18]3[CH:30]=[CH:29][C:21]4[O:22][C:23]([CH3:28])([CH3:27])[O:24][C:25](=[O:26])[C:20]=4[CH:19]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]3[CH:30]=[CH:29][C:21]4[O:22][C:23]([CH3:28])([CH3:27])[O:24][C:25](=[O:26])[C:20]=4[CH:19]=3)=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2cc(/N=C/c3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: O
Product: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Yield: 93.4 %

Procedure:
A solution of 6-[((E)-{4-[(4-chlorophenyl)ethynyl]phenyl}methylidene)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (3.73 g, 8.97 mmol), sodium triacetoxyborohydride (5.70 g, 26.9 mmol) and acetic acid (0.77 mL, 13.5 mmol) in anhydrous DCE (120 mL) was stirred for 48 hrs at rt. Then the reaction mixture was diluted with water (150 mL) and an aqueous saturated solution of NaHCO3 (100 mL) and extracted with DCM (250 mL and 100 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The residue was crystallized from a DCM/pentane solution. The solid was filtered, washed with pentane (2×) and dried under reduced pressure to give 3.50 g (93%) of the title compound as a yellow powder. HPLC, Rt: 5.0 min (purity: 98.1%). 1H NMR (CDCl3) δ: 7.51 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.34 (m, 4H), 7.18 (d, J=2.6 Hz, 1H), 6.86 (dd, J=8.8, 2.6 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 4.35 (s, 2H), 4.21 (brs, 1H), 1.71 (s, 6H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]=[O:30]>O1CCCC1>[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][C:29]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20])=[O:30]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: O=C=Nc1ccccc1Cl
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2ccccc2Cl)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-chlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 263°-265° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([O:11][C:12]1[CH:19]=[CH:18][C:17]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:35])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH2:31][NH:30][CH2:29][CH2:28]4)[N:21]=2)=[CH:16][C:13]=1[C:14]#[N:15])[CH3:10].Br[CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:41]([O:40][C:38](=[O:39])[CH2:37][N:30]1[CH2:29][CH2:28][C:27]2[C:32](=[CH:33][CH:34]=[C:25]([C:22]3[N:21]=[C:20]([C:17]4[CH:18]=[CH:19][C:12]([O:11][CH:9]([CH3:8])[CH3:10])=[C:13]([C:14]#[N:15])[CH:16]=4)[O:24][N:23]=3)[C:26]=2[CH3:35])[CH2:31]1)[CH3:42]
Reactant: CCOC(=O)CBr
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCNC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCOC(=O)CN1CCc2c(ccc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)c2C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A mixture of 2-[(1-methylethyl)oxy]-5-[3-(5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl)-1,2,4-oxadiazol-5-yl]benzonitrile trifluoroacetic acid salt (Example 11; 100 mg, 0.20 mmol), ethyl bromoacetate (44 mg, 30 μl, 0.26 mmol) and caesium carbonate (200 mg, 0.61 mmol) in dry DMF (3 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (10 ml) and extracted with ethyl acetate (3×5 ml). The combined extracts were dried and evaporated. Purification by chromatography on silica gel, eluting with 10% ethyl acetate in cyclohexane gave the title compound as a colourless oil (85 mg). MS m/z 461 [MH]+.
Reaction SMILES: [NH2:1][CH:2]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:19]1([S:25]([NH:1][CH:2]([P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOP(=O)(OCC)C(NS(=O)(=O)c1ccccc1)P(=O)(OCC)OCC
Reaction time: 4 h

Procedure:
To a solution of tetraethyl (aminomethylene)bis-(phosphonate) (661 mg) in pyridine (2 ml) were added benzenesulfonyl chloride (0.35 ml) and then 4-(dimethylamino)pyridine (50 mg) at ambient temperature with stirring. After stirring for 4 hours at the same temperature, the reaction mixture was diluted with ethyl acetate (20 ml). The mixture was washed with 1N hydrochloric acid four times, water and saturated aqueous hydrogen bicarbonate solution successively. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (20 g) eluted with a mixture of chloroform and methanol (20:1 V/V) to give tetraethyl (phenylsulfonylaminomethylene)bis(phosphonate) as a yellow syrup (364 mg).
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:9][C:10](=[O:12])[O-:11])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].[CH3:13][O:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19].COC(C)(C)C>FC(F)(F)C(O)=O>[CH3:13][O:14][CH2:15][CH2:16][CH2:17][C:18]([C:3]([CH2:9][C:10](=[O:11])[O-:12])([CH2:4][N+:5]([CH3:8])([CH3:6])[CH3:7])[OH:2])=[O:19]
Reactant: COCCCC(=O)Cl
Reactant: C[N+](C)(C)CC(O)CC(=O)[O-]
Agent: Cl
Solvent: COC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COCCCC(=O)C(O)(CC(=O)[O-])C[N+](C)(C)C
Temperature: 25 °C
Reaction time: 384 h
Yield: 50 %

Procedure:
4.5 g (0.02 moles) of carnitine hydrochloride were dissolved in 6 ml of trifluoroacetic acid. To this solution 4-methoxybutyryl chloride was added. The resulting mixture was kept under stirring at room temperature for 16 days. Subsequently tert-butyl methyl ether was added to the mixture. An oil precipitated which was treated with anhydrous acetonitrile in order to remove the undesired carnitine. To the acetonitrile solution tert-butyl methyl ether was added and 4-methoxybutyryl carnitine precipitated. Yield 50%.
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([CH:6]([OH:11])[CH2:7][CH2:8][CH2:9][OH:10])=[CH:2]1.[O:12]1C=CC(C=O)=C1>O1CCCC1>[O:12]1[CH:5]=[CH:4][C:3]([CH:6]([OH:11])[CH2:7][CH2:8][CH2:9][OH:10])=[CH:2]1
Reactant: OCCCC(O)c1ccsc1
Reactant: O=Cc1ccoc1
Solvent: C1CCOC1
Product: OCCCC(O)c1ccoc1

Procedure:
The Grignard reagent prepared in Example 26 step (a) (0.7M, 28 ml, 19.6 mmol) and furan-3-carboxaldehyde (1.92 g, 20 mmol) in anhydrous tetrahydrofuran (15 ml) were used to prepare the title compound, using the procedure described in Example 26 step (a). The product was a colourless oil (2.42 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][CH2:37][O:38][CH3:39].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH2:37][O:38][CH3:39])[CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:27][CH:28]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: COCOc1ccccc1Br
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: COCOc1ccccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Temperature: 100 °C
Yield: 91.1 %

Procedure:
A mixture of N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate M; 500 mg, 1.19 mmol), 1-bromo-2-(methoxymethoxy)benzene (1.2 g, 5.98 mmol), Pd2(dba)3 (109 mg, 0.119 mmol, GLR), Xantphos (138 mg, 0.23 mmol, GLR) and sodium-tert-butoxide (229 mg, 2.39 mmol) in toluene (15 mL) was degassed with nitrogen for 10 minutes. The reaction mixture was heated at 100° C. for 1 h under microwave. After completion, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combiflash column chromatography (column size: 12 g; elution: 0-20% ethyl acetate in hexane) to yield N-(4-methoxybenzyl)-4-(2-(methoxymethoxy)phenyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (600 mg, 90.7%). MS (ESI, positive ion) m/z; 554.1 (M+1).