Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[CH3:6])[CH3:2].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][CH:34]=1)[CH:30]=[O:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C>C1COCC1.[NH4+].[Cl-]>[CH2:1]([O:3][C:4](=[O:18])[C:5]([CH3:6])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:16])([F:15])[F:17])=[CH:10][CH:9]=1)[CH:30]([C:29]1[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:28]=1)[OH:31])[CH3:2]
Reactant: O=Cc1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)C(C)Oc1ccc(C(F)(F)F)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(Oc1ccc(C(F)(F)F)cc1)C(O)c1cccc(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 48.3 %

Procedure:
A −78° C. solution of 2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester (10.0 g, 38.1 mmol) in THF (80 mL) was transferred via cannula to a −78° C. solution of 1.5 M LDA-THF complex (45.8 mL, 68.7 mmol) in THF (80 mL). The resultant mixture was stirred for 5 minutes at −78° C. and then 3-benzyloxybenzaldehyde (7.3 g, 34.4 mmol) was added in one portion and the reaction mixture stirred at −78° C. for 5 minutes and was then was quenched with a −78° C. THF solution of acetic acid (6.82 g, 113.5 mmol). The reaction mixture was diluted with aqueous saturated NH4Cl and extracted with Et2O. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford 19.84 g of crude product that was purified by flash chromatography using 8:1 then 4:1 hexanes:acetone to afford 7.88 g (44%) 3-(3-benzyloxy-phenyl)-3-hydroxy-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester as a mixture of diasteriomers. Rf=0.55 (1:1 hexanes:acetone). 1NMR.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C([O-])(O)=O.[Na+]>C(Cl)CCl>[CH3:27][S:28]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:13][CH2:12]1)(=[O:30])=[O:29]
Reactant: Nc1ccccc1N1CCN(Cc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1N1CCN(Cc2ccccc2)CC1
Yield: 95.7 %

Procedure:
To a round-bottomed flask equipped with magnetic stirring was added 2-[4-benzylpiperazinyl]phenylamine (34 g, 127 mmol) in ClCH2CH2Cl (100 mL) and pyridine (12 mL, 140 mmol). The reaction mixture was stirred for 5 min. To the reaction was added methanesulfonyl chloride (Aldrich) (11 mL, 139 mmol), and the reaction mixture was heated at reflux for 18 h. After cooling to RT a satd soln of NaHCO3 (50 mL) was added. The organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (2×50 mL). All organic fractions were combined, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford the sulfonamide as yellow oil (42 g). MS (ESI, pos. Ion) m/z: 346 (M+H); MS (ESI, neg. Ion) m/z: 344 (M−H). Calc'd for C18H23N3O2S: 345.15.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][CH:3]=1.CO.[OH-].[Na+].[I:16]I>O>[I:16][C:11]#[C:10][CH2:9][O:8][C:5]1[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: C#CCOc1ccc(C)nc1
Reactant: II
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ccc(OCC#CI)cn1
Reaction time: 0.5 h
Yield: 83.2 %

Procedure:
A solution of 160 g (1.10 moles) 6-methyl-3-(2-propynyloxy) pyridine and 2000 ml methanol was cooled to 0° C. and 750 g 25% sodium hydroxide solution was slowly added. Iodine (362 g. 1.4 moles) was added portionwise and the resulting suspension stirred at 0°-10° C. for an additional 30 min. The reaction mixture was then poured into 4000 ml water and the solids filtered to give 250 g 3-(3-iodo-2-propynyloxy)-6-methylpyridine. Yield=90% Recrystallization from methanol gave analytically pure material, mp 155°-157° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]#[N:15])=[C:12]([Cl:16])[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N:17]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[CH:21]=1)=[C:18]=[O:19]>C(Cl)Cl.C1COCC1>[Cl:16][C:12]1[C:13]([C:14]#[N:15])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:18]([NH:17][C:20]3[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=3)=[O:19])=[CH:7][CH:6]=2)[CH:9]=[CH:10][N:11]=1
Reactant: N#Cc1c(-c2ccc(N)cc2)ccnc1Cl
Reactant: Cc1cccc(N=C=O)c1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc(NC(=O)Nc2ccc(-c3ccnc(Cl)c3C#N)cc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.1 %

Procedure:
A mixture of Example 35C (0.1 g, 0.43 mmol), 1-isocyanato-3-methylbenzene (0.06 mL, 0.43 mmol) in CH2Cl2 (3 mL) and THF (3 mL) was stirred at room temperature overnight, then treated with an additional 0.02 mL of 1-isocyanato-3-methylbenzene, stirred for 5 more hours at room temperature then for 2.5 h at 50° C. The resulting precipitate was collected via filtration to give 0.1 g of the title compound. MS (ESI(+)) m/e 363 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH2:11][CH:12]1[C:18](=[O:19])[N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:16]2[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:15]=2[N:14]2[C:31]([CH3:34])=[N:32][N:33]=[C:13]12)C)C1C=CC=CC=1.[H][H]>C(O)C.[Ni]>[CH3:1][NH:8][CH2:10][CH2:11][CH:12]1[C:18](=[O:19])[N:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:16]2[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:15]=2[N:14]2[C:31]([CH3:34])=[N:32][N:33]=[C:13]12
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1N(c1ccccc1)C(=O)C2CCN(C)Cc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CNCCC1C(=O)N(c2ccccc2)c2cc(Cl)ccc2-n2c(C)nnc21

Procedure:
4 g of 4-[2-(N-benzyl-N-methylamino)ethyl]-1-methyl-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,5]benzodiazepin-5-one in 100 ml of ethanol containing 0.4 of Raney nickel is hydrogenated at 50 p.s.i. hydrogen pressure until 0.0085 moles of hydrogen is absorbed. The suspension is filtered and the filtrate is evaporated. The residue is triturated with a small amount of cold ether and the title compound is filtered off and dried.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[C:12]1([CH2:18][OH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.O>[CH2:18]([O:19][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: FC(F)(F)c1cncc(Cl)c1
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1cncc(OCc2ccccc2)c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of 3-chloro-5-(trifluoromethyl)pyridine (10.0 g, 55.1 mmol) in N,N-dimethylformamide (DMF) (150 mL) was added dropwise phenylmethanol (5.96 g, 55.1 mmol) under nitrogen at rt. The reaction mixture was stirred at 40° C. for 2 h, diluted with water (300 mL) and extracted with ethyl acetate (300 mL×3). Combined organic parts were washed with brine, dried over anhydrous Na2SO4 and concentrated. The crude product (100 g) was used into next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)[NH:8][C:7]2=[O:21].COC1C(N)=C(C=CC=1)C(N)=O.[H][H]>CO.[C].[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)[NH:8][C:7]2=[O:21]
Reactant: O=c1[nH]c(-c2ccc([N+](=O)[O-])cc2)nc2c(O)cccc12
Reactant: [H][H]
Agent: [Pd]
Agent: COc1cccc(C(N)=O)c1N
Solvent: CO
Product: Nc1ccc(-c2nc3c(O)cccc3c(=O)[nH]2)cc1

Procedure:
8-Hydroxy-2-(4'-nitrophenyl)quinazolin-4-[3 H]-one, prepared from 3-methoxy-2-aminobenzamide as in Example 5, (50 mg, 0.18 mmol) was suspended in methanol (20 ml) with palladium-carbon catalyst (20 mg) and the reaction vessel was placed under the atmosphere of hydrogen at ambient temperature and pressure. The reaction mixture changed from a yellow suspension to a clear, colourless solution, whereupon the catalyst was removed by filtration through Celite™. The solvent was removed under vacuum to leave a cream pale brown solid, which was recystallised from aq. methanol (25.7 mg, 0.1 mmol, 57%), m.p. >230° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:12]([S-:14])#[N:13].[K+].BrBr.O>C(O)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]=[C:12]([NH2:13])[S:14][C:10]=2[CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#C[S-]
Reactant: CCCCc1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step-1: To a mixture of 4-butylaniline 67 mmol) and KSCN (26 g, 268 mmol) in acetic acid was added Br2 in acetic acid (70 mL) dropwise over 6 min at RT. The mixture was stirred at RT overnight and poured into water (2 L). The precipitate was collected, washed with water and dried to afford 6-butylbenzo[d]thiazol-2-amine. MS (ESI+) m/z 207.20 [M+H]+
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1.[O:17]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH2:19][CH:18]1[CH2:27][NH2:28]>>[O:17]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH2:19][CH:18]1[CH2:27][NH:28][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:5]([F:16])=[CH:4][N:3]=1
Reactant: NCC1COc2ccccc2O1
Reactant: Oc1cccc(Nc2nc(Cl)ncc2F)c1
Product: Oc1cccc(Nc2nc(NCC3COc4ccccc4O3)ncc2F)c1

Procedure:
In like manner to the preparation of N4-(3-aminophenyl)-N2-[2-(methoxycarbonyl)benzofurane-5-yl]-5-fluoro-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N4-(3-hydroxyphenyl)-4-pyrimidineamine and 2,3-dihydro-1,4-benzodioxin-2-ylmethylamine were reacted to give N2-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-5-fluoro-N4-(3-hydroxyphenyl)-2,4-pyrimidinediamine. LCMS: ret. time: 19.26 min.; purity: 96.2%; MS (m/e): 369.08 (MH+).
Reaction SMILES: CN(C)C=O.[CH3:6][S:7]([OH:10])(=[O:9])=[O:8].[NH:11]([CH2:15][C:16]1[O:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][CH:17]=1)[C:12]([NH2:14])=[NH:13].[CH3:24][S:25]([O:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:41])[NH2:40])[CH:35]=2)[CH:30]=1)(=[O:27])=[O:26].C1CCC(N=C=NC2CCCCC2)CC1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:6][S:7]([OH:10])(=[O:9])=[O:8].[CH3:24][S:25]([OH:28])(=[O:27])=[O:26].[NH:11]([CH2:15][C:16]1[O:20][C:19]([C:21]([O:23][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:39](=[NH:40])[NH2:41])[CH:35]=3)[CH:30]=2)=[O:22])=[CH:18][CH:17]=1)[C:12]([NH2:14])=[NH:13]
Reactant: N=C(N)NCc1ccc(C(=O)O)o1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N=C(N)NCc1ccc(C(=O)Oc2ccc3cc(C(=N)N)ccc3c2)o1
Reaction time: 0.5 h

Procedure:
##STR50## In a solvent mixture of 8 ml of dry N,N-dimethylformamide (DMF) and dry pyridine, were dissolved 2.0 g of 5-guanidinomethyl-furan-2-carboxylic acid methanesulfonate and 1.8 g of 6-amidino-2-naphthol methanesulfonate. To the resulting solution, while being cooled in ice, were added 1.8 g of DCC and a catalytic amount of 4-dimethylaminopyridine. The mixture was stirred for 30 minutes with cooling in ice and then overnight at 30° C. The insolubles were removed by filtration and ethyl ether was added to the filtrate. The supernatant was removed by decantation. The residue was dissolved in a small amount of methanol and the methanol solution was added dropwise to ethyl ether. After precipitation the supernatant was removed by decantation. These procedures were repeated twice. Finally, the precipitate was collected by filtration and dried to obtain 1.2 g of a pale yellow substance of 6-amidino-2-naphthyl 5-guanidinomethyl-furan-2-carboxylate dimethanesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:10](=O)[C:11]([N:14]([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[N:6][CH:7]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([N:14]([CH3:16])[CH3:15])([CH3:13])[CH3:12])=[N:9][N:8]=2)[CH:7]=1
Reactant: CN(C)C(C)(C)C(=O)NNc1ccc(F)cn1
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(C)(C)c1nnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of Intermediate 76a (195 mg, 0.81 mmol), Ph3P (426 mg, 1.62 mmol) and Et3N (452 □L, 3.25 mmol) in THF (9.00 mL) at 0° C. was added hexachloroethane (385 mg, 1.62 mmol). The reaction was stirred at RT overnight then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was dissolved in MeOH and loaded onto an SCX-2 cartridge, which was washed with MeOH and eluted with 2M NH3 in MeOH. The reaction showed 50% conversion so was re-submitted to the reaction conditions overnight at 50° C. The workup and purification procedures were repeated to give the title compound (153 mg, 85%). 1H NMR (300 MHz, CDCl3): 1.60 (6H, s), 2.20 (6H, s), 7.16 (1H, ddd, J 9.9, 7.4, 2.4), 7.71 (1H, ddd, J 9.9, 5.0, 0.8), 8.89 (1H, ddd, J 4.4, 2.4, 0.8).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[CH3:24][N:25]([CH3:36])[S:26]([C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[CH3:24][N:25]([CH3:36])[S:26]([C:29]1[CH:34]=[CH:33][C:32]([NH:35]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:31][CH:30]=1)(=[O:27])=[O:28]
Reactant: CN(C)S(=O)(=O)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Product: CN(C)S(=O)(=O)c1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1c from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-aminobenzenesulphonic acid-dimethylamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:9](=[O:16])[NH:8][C:5]2=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:20][CH2:21][O:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][O:24]1>CN(C)C=O>[O:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]1[O:22][CH2:21][CH2:20][N:8]1[C:5]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:10]2([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[C:9]1=[O:16]
Reactant: Cc1ccc2c(c1)C1(CCNCC1)C(=O)N2
Reactant: BrCCOC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)C1(CCNCC1)C(=O)N2CCOC1CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Methyl-spiro[indoline-3,4′-piperidin]-2-one (prepared as in Org. Prep. Proced. Int. (1995), 27(6), 691-694)(0.05 g, 0.023 mmol) was dissolved in dry N,N-dimethylformamide (4.0 mL). To the reaction mixture was then added at 0° C. sodium hydride (60% in mineral oil, 10.0 mg, 0.28 mmol) under nitrogen atmosphere and the reaction mixture was stirred at 0° C. for one hour. To the reaction mixture was then added at 0° C. 2-(2-bromo-ethoxy)-tetrahydro-pyran (0.048 g, 0.023 mmol). The reaction mixture was stirred at 0° C. for 1 hour, then at room temperature under nitrogen atmosphere for 18 hours. The reaction mixture was then partitioned between water-ice and ethyl acetate. The organic layer was washed with brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield the title compound as a crude oil. The crude oil was purified via flash chromatography (3% methanol/dichloromethane) to yield the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][C:5]2[S:9][CH:10]=[CH:11][C:4]=2[S:3]1(=[O:13])=[O:12].CS(C)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]=[C:26]=[O:27])=[CH:21][CH:20]=1>C(N(CC)CC)C>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([C:6]2[C:5]3[S:9][CH:10]=[CH:11][C:4]=3[S:3](=[O:13])(=[O:12])[N:2]([CH3:1])[C:7]=2[OH:8])=[O:27])=[CH:21][CH:20]=1
Reactant: CN1C(=O)Cc2sccc2S1(=O)=O
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1C(O)=C(C(=O)Nc2ccc(Br)cc2)c2sccc2S1(=O)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3.1 G. of 3,4-dihydro-2-methyl-3-oxo-2H-thieno[ 2,3-e] 1,2-thiazine 1,1-dioxide are dissolved in 31 ml. of absolute dimethylsulfoxide under an atmosphere of nitrogen. 1.44 G. of freshly distilled triethylamine and 2.83 g. of 4-bromophenyl isocyanate are added to the solution and the mixture is then stirred for 24 hours at room temperature. This mixture is then poured into 225 ml. of 3-N hydrochloric acid and the precipitate which separates out is filtered on a sinter filter, washed three times with 20 ml. of distilled water each time and dried as much as possible. The precipitate is dissolved in 250 ml. of methylene chloride, dried over sodium sulfate, stirred with activated charcoal and filtered. The organic phase is shaken out four times with 250 ml. of saturated sodium bicarbonate solution each time and the aqueous phase is shaken again each time with a little methylene chloride. The combined aqueous phases are rendered strongly acid with concentrated hydrochloric acid. The product which separates out is extracted three times with 250 ml. of methylene chloride each time. The combined organic phases are dried over sodium sulfate, stirred with activated charcoal, filtered and the solvent is removed by distillation. The crystalline residue is dissolved in 50 ml. of chloroform. While boiling, activated charcoal is added and the mixture is filtered hot. The product is made to crystallize by scratching. The crystals are removed by filtration, digested with a little cold chloroform, and 4'-bromo-3-hydroxy-2-methyl-2N-thieno[[2,3-e] 1,2-thiazine-4-carboxanilide 1,1-dioxide, melting point 178° C. to 179° C. (decomposition), is obtained.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[Cl:24][C:25]1[CH:32]=[C:31](F)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28].CC(C)([O-])C.[K+].O>C1COCC1>[Cl:24][C:25]1[CH:32]=[C:31]([CH:30]=[CH:29][C:26]=1[C:27]#[N:28])[O:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]([NH:16][C:12]1[CH:13]=[CH:14][C:15]2[N:3]([CH2:1][CH3:2])[C:4]3[C:9]([C:10]=2[CH:11]=1)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[O:23]
Reactant: CCn1c2ccccc2c2cc(NC(=O)CCCCO)ccc21
Reactant: N#Cc1ccc(F)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCn1c2ccccc2c2cc(NC(=O)CCCCOc3ccc(C#N)c(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 37.1 %

Procedure:
To a solution of the compound obtained in Step 1 (150 mg, 0.48 mmol) and 2-chloro-4-fluorobenzonitrile (75 mg, 0.48 mmol) in THF (6 mL) was added potassium t-butoxide (136 mg, 1.21 mmol), and the mixture was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 85% ethyl acetate/hexane) to give the title compound (79 mg, 0.178 mmol, 36.8%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]([C:23]1[NH:24][CH:25]=[CH:26][N:27]=1)=[O:22])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[N+:34]([C:37]1[CH:42]=CC(O)=[CH:39][CH:38]=1)([O-:36])=[O:35].CCN(CC)CC>C(Cl)Cl>[CH2:1]([O:3][P:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]([C:23]1[NH:27][CH:26]=[CH:25][N:24]=1)=[O:22])([O:6][C:7]1[CH:39]=[CH:38][C:37]([N+:34]([O-:36])=[O:35])=[CH:42][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOP(=O)(CCCCCCCCCCCOC(=O)c1ncc[nH]1)OCC
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(CCCCCCCCCCCOC(=O)c1ncc[nH]1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 16 (1.2 g, 3.0 mmol) dissolved in 25 mL of CH2Cl2 was added oxalyl chloride (0.65 n-flL, 7.5 mmol) dropwise at 0° C. The reaction mixture was allowed to slowly warm to room temperature. After stirring for 8 h, the mixture was concentrated to remove excess oxalyl chloride. The crude residue was redissolved in 20 mL of CH2Cl2, followed by the addition of 4-nitrophenol (414 mg, 3.0 mmol) and Et3N (0.80 mL, 6.0 mmol). After stirring at room temperature for 10 h, the reaction mixture was concentrated. The residue was purified by flash chromatography (hexane/EA=1:1) to give 601 mg (41%) of pure 17. 1H NMR (CDCl3, 500 MHz) δ 8.16 (d, J=9.0 Hz, 2H), 8.10 (s, 1H), 7.37 (s, 1H), 7.32 (d, J=9.0 Hz, 2H), 7.01 (s, 1H), 4.35 (t, J=6.5 Hz, 2H), 4.11 (m, 2H), 1.87 (m, 2H), 1.72 (m, 2H), 1.62 (m, 2H), 1.38-1.17 (br m, 20H). 31P NMR (CDCl3, 500 MHz) δ 30.49.
Reaction SMILES: C([O:8]C(N1CCC[C@H]1C(NC(P(OC1C=CC=CC=1)(=O)OC1C=CC=CC=1)CC1C=CC(C#N)=CC=1)=O)=O)C1C=CC=CC=1.Br.N1(C(OCC2C=CC=CC=2)=O)CCC[C@H]1C(O)=O.[CH2:64]1[CH2:69][CH2:68][CH:67]([N:70]=[C:71]=[N:72][CH:73]2[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]2)[CH2:66][CH2:65]1>C(Cl)Cl.C(N(CC)CC)C>[C:71]([NH:70][CH:67]1[CH2:66][CH2:65][CH2:64][CH2:69][CH2:68]1)([NH:72][CH:73]1[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]1)=[O:8]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: N#Cc1ccc(CC(NC(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)P(=O)(Oc2ccccc2)Oc2ccccc2)cc1
Agent: Br
Agent: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.17 h
Yield: 52 %

Procedure:
Diphenyl 1-(N-Benzyloxycarbonyl-L-prolyl)amino-2-(4-cyanophenyl)ethanephosphonate {Cbz-Pro-(4-CN-Phe)P (OPh)2 }. To a cooled solution of the phosphonate 4-CN-PheP (OPh)2.HBr (0.41 g, 0.9 mmole) and Cbz-Pro-OH (0.25 g, 1.0 mmole) in 20 mL CH2Cl2 was added 0.14 mL triethyl amine. After stirring for 10 min, DCC (0.21 g, 1.0 mmole) was added and the mixture was stirred at 0° C. for 2 h and at r.t. for 24 h. During this period, dicyclohexylurea (DCU) formed, was removed by filtration and the filtrate was evaporated. The residue was dissolved in 50 mL ethyl acetate, filtered, the filtrate was washed with 50 mL 1N HCl, water, 6% NaHCO3, and water. The organic layer was dried, filtered, and evaporated to give crude product which was then recrystallized from ether to give white crystals, yield 52% (0.29 g); mp 131-132° C.; 1H NMR (DMSO) δ 8.75(m, 1H), 7.8-7.2(m, 19H), 5.06 (m, 2H), 4.95 (m, 1H), 4.6 (q, 1H), 4.2 (m, 1H), 3.5-3.1 (m, 3H), 2.0-1.4 (m, 4H); MS (FAB+) m/e 610 (M+1). Anal. (C34H32N3O6P) C, H, N.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14].C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([Cl:18])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14]
Reactant: Cn1c(=O)oc2ccc(C(=O)O)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1c(=O)oc2ccc(C(=O)Cl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carboxylic acid (2.50 g, obtained in Example 116, step 5) in CH2Cl2 (40 mL) were added nine drops of DMF and oxalylchloride (1.78 mL). The mixture was stirred at room temperature for 2 hours and was then concentrated to dryness. The resulting solid was dried at high vacuum over night. The title compound was obtained as a colorless solid (2.85 g, 99%). MS (EI)=211.0 [M+].