Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3=[N:21][CH:22]=[CH:23][C:24]([CH3:25])=[C:19]3[N:18]=[C:17]2[CH2:26][CH2:27][CH3:28])=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3=[N:21][CH:22]=[CH:23][C:24]([CH3:25])=[C:19]3[N:18]=[C:17]2[CH2:26][CH2:27][CH3:28])=[CH:11][CH:10]=1
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(O)cc1
Reaction time: 7 h
Yield: 81.6 %

Procedure:
To a solution of the product of Step C (0.60 g, 1.62 mmol) in 10 mL of MeOH was added 60 mg of a 10% Pd/C catalyst and was stirred under a H2 atmosphere (1 atm) for 7 hours. The reaction mixture was then filtered through magnesium sulfate and the filtrate was concentrated in vacuo to yield 0.372 g (82%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([NH:12][C@@H:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C@H:14]3[N:22]([C:24](=[O:27])[CH2:25]Cl)[CH3:23])=[O:11])[NH:5][C:4]=2[C:3]=1[Cl:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(Cl)Cl>[Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([NH:12][C@H:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C@@H:14]3[N:22]([CH3:23])[C:24](=[O:27])[CH2:25][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:11])[NH:5][C:4]=2[C:3]=1[Cl:28]
Reactant: CN(C(=O)CCl)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: C1COCCN1
Solvent: ClCCl
Product: CN(C(=O)CN1CCOCC1)[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 0.9 %

Procedure:
2,3-Dichloro-N-{(1R,2R)-1-[(chloroacetyl)(methyl)amino]-2,3-dihydro-1H-inden-2-yl}4H-thieno[3,2-b]pyrrole-5-carboxamide (Method 10, 100 mg, 0.22 mol) and morpholine (100 mg, 12.6 mmol) were dissolved in DCM, stirred at ambient temperature for 20 hours and the volatiles removed by evaporation under reduced pressure. EtOAc (10 mL) was added and the mixture washed with water (2×5 mL), brine (5 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure to give the title compound (60 mg, 54%) as a buff coloured powder.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=O.[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[NH:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([C@H:18]1[CH2:22][O:21][C:20](=[O:23])[N:19]1[C:6](=[O:8])[CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:10])[F:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1N[C@@H](Cc2ccccc2)CO1
Reactant: O=C(O)CCCC(F)(F)F
Product: O=C(CCCC(F)(F)F)N1C(=O)OC[C@@H]1Cc1ccccc1

Procedure:
Intermediate S-1G was prepared from 5,5,5-trifluoropentanoic acid (3.35 g, 21.46 mmol) and (4S)-4-benzyl-1,3-oxazolidin-2-one (3.80 g, 21.46 mmol) by the general method shown for Intermediate S-1B. Intermediate S-1G (5.67 g, 84%) was obtained as a colorless viscous oil: 1H NMR (400 MHz, CDCl3) δ ppm 7.32-7.39 (2H, m), 7.30 (1H, d, J=7.05 Hz), 7.18-7.25 (2H, m), 4.64-4.74 (1H, m), 4.17-4.27 (2H, m), 3.31 (1H, dd, J=13.35, 3.27 Hz), 3.00-3.11 (2H, m), 2.79 (1H, dd, J=13.35, 9.57 Hz), 2.16-2.28 (2H, m), 1.93-2.04 (2H, m).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12])#[N:2].[CH2:13]([N:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[NH:19][CH2:18][CH2:17][CH2:16]1)[CH3:14]>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:19]2[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([CH2:13][CH3:14])[CH2:16][CH2:17][CH2:18]2)=[O:9])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: CCN1CCCNc2ccccc21
Reactant: Cc1cc(C(=O)O)ccc1C#N
Product: CCN1CCCN(C(=O)c2ccc(C#N)c(C)c2)c2ccccc21

Procedure:
The carboxylic acid from Example C (0.53 g, 3.29 mmol) was reacted with 1-ethyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine from Example 23B (0.514 g, 2.92 mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 60:40); yield 0.55 g (59%).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].[CH3:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][C:10](=[O:18])[NH:9]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[Br:1][CH:2]([CH3:6])[C:3]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:18])[NH:9][CH:8]2[CH3:7])=[O:4]
Reactant: CC1NC(=O)Nc2ccccc21
Reactant: CC(Br)C(=O)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(Br)C(=O)c1ccc2c(c1)C(C)NC(=O)N2

Procedure:
2-Bromopropionyl bromide (16 g) is added dropwise to a mixture of 3,4-dihydro-4-methyl-2(1H)-quinazolinone (6.1 g) and anhydrous aluminum chloride (12.5 g) in carbon disulfide (110 ml). The reaction mixture is refluxed overnight under nitrogen, the carbon disulfide is decanted and the residue treated with hydrochloric acid (6N). The acidic residue is treated with ethyl acetate and the layers separated. The aqueous layer is extracted with ethyl acetate and the combined organic extracts washed with sat'd. aqueous sodium bicarbonate and water and dried. The organic layer is filtered and the filtrate stripped in vacuo, affording an oil which crystallizes in vacuo, M.P. 153°-156° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]1[C:16]([O:18]CC)=O.CC(C)([O-])C.[K+]>CS(C)=O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:16](=[O:18])[C:11]3=[CH:12][C:13]([CH3:15])=[CH:14][N:10]3[CH2:9][C:3]=2[CH:4]=1
Reactant: CCOC(=O)c1cc(C)cn1Cc1cc(Cl)ccc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc2n(c1)Cc1cc(Cl)ccc1NC2=O
Temperature: 80 °C
Yield: 74.6 %

Procedure:
To a solution of ethyl 1-[(2-amino-5-chloro-phenyl)methyl]-4-methyl-pyrrole-2-carboxylate (35 g, 119.55 mmoles) in dimethyl sulfoxide (120 mL) add potassium t-butoxide (14.76 g, 131.5 mmoles) over 10 minutes. Heat at 80° C. (oil-bath temperature) for 1 h. Allow to cool then pour onto water (400 mL). Collect the resulting brown powdery solid by filtration, washing well with water. Suck as dry as possible on the sinter then transfer to a dish and dry in a vacuum oven at 55° C. over phosphorus pentoxide overnight, to give 7-chloro-2-methyl-5,10-dihydro-11H-pyrrolo[2,1-c][1,4]benzodiazepin-11-one (22 g, 91%). MS (m/z): 247.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:8])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1)=[O:18].CN(C=O)C>C(OCC)(=O)C>[NH2:8][C:3]1[C:2]([Br:1])=[C:6]([CH3:7])[N:5]([CH2:16][C:17]([N:19]2[CH2:20][CH2:21][N:22]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:23][CH2:24]2)=[O:18])[N:4]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Cc1[nH]nc(N)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Br)c(N)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Bromo-5-methyl-1H-pyrazol-3-ylamine, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography ethyl acetate afforded the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3): 6.94-7.02 (m, 2H), 6.82-6.88 (t, 2H), 4.84 (s, 2H), 4.1 (s, 2H), 3.72-3.78 (m, 4H), 3.04-3.08 (m, 4H), 2.16 (s, 3H). MS (ES) M+H expected 317.37, found 318.1. MS (ES) M+H expected 396.27, found 396.
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.[CH3:26][C:27]1[NH:31][N:30]=[C:29]([NH2:32])[CH:28]=1.NC1C=CNN=1>O1CCCC1>[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[NH:5][C:4](=[O:13])[C:3]2=[CH:2][NH:32][C:29]1[CH:28]=[C:27]([CH3:26])[NH:31][N:30]=1
Reactant: O=C1Nc2ccc(F)cc2/C1=C/O
Reactant: Cc1cc(N)n[nH]1
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: Cc1cc(NC=C2C(=O)Nc3ccc(F)cc32)n[nH]1

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-5-fluoro-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and 5-methyl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-5-fluoro-1,3-dihydro-indol-2-one (0.050 gms.) is reacted with 0.055 gms. of 5-methyl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (1.5 mL).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([O:26]CC3C=CC(OC)=CC=3)[CH:21]=2)=[O:19])[S:9][C:10]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.C1(OC)C=CC=CC=1.C(=O)([O-])O.[Na+]>FC(F)(F)C(O)=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][NH:23][C:22](=[O:26])[CH:21]=2)=[O:19])[S:9][C:10]=1[C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1
Reactant: COc1ccc(COc2cc(C(=O)Nc3nc(-c4ccco4)c(-c4ccncc4)s3)ccn2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccncc2)s1)c1cc[nH]c(=O)c1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
Compound 106 (2.10 g, 4.33 mmol) and anisole (4.72 mL, 43.4 mmol) were suspended in trifluoroacetic acid (7 mL), followed by stirring at 65° C. for 30 minutes. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture to adjust the pH to 8, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (chloroform:methanol=4:1) to afford the entitled Compound 112 (1.07 g, 68%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][CH2:27][CH2:28][O:29][CH3:30])[N:20]=2)[C:15](F)=[N:16][CH:17]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[N:24]=[C:23]([CH3:25])[N:22]=[C:21]([NH:26][CH2:27][CH2:28][O:29][CH3:30])[N:20]=2)[C:15]([NH:10][C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)=[N:16][CH:17]=1
Reactant: COCCNc1nc(C)nc(-c2cc(Cl)cnc2F)n1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCNc1nc(C)nc(-c2cc(Cl)cnc2Nc2cnc(OC)c(F)c2)n1
Reaction time: 0.08 h
Yield: 62.7 %

Procedure:
A mixture of 5-fluoro-6-methoxypyridin-3-amine (Anichem, N.J., USA, 100 mg, 0.704 mmol) and 4-(5-chloro-2-fluoropyridin-3-yl)-N-(2-methoxyethyl)-6-methyl-1,3,5-triazin-2-amine (130 mg, 0.437 mmol) in THF (5 mL) was cooled in an ice bath and LiHMDS (1.0 M, 1500 μL, 1.500 mmol) was added under nitrogen. After 5 min, the cooling bath was removed. After 10 min, the mixture was neutralized with HCl (5N, 0.3 mL) and then partitioned between EtOAc (20 mL) and water (10 mL). The organic layer was washed with water (5 mL). The combined aqueous layers were extracted with EtOAc (2×5 mL). The combined organic layers were dried over Na2SO4 and concentrated. The resulting solid was triturated with EtOAc (5 mL) and filtered. The yellow solid was rinsed with ether (2×3 mL) to give the desired product as a yellow powder (115 mg). LCMS (ES, pos.): calcd for C18H19ClFN7O2: 419.1. found: 420.2 (M+H)+. 1H NMR (400 MHz, d6-DMSO) mixture of rotamers δ 11.89, 11.67 (s, 1H); 8.73 (dd, J=6.75, 2.64 Hz, 1H); 8.14-8.58 (m, 4H); 3.94 (2s, 3H); 3.46-3.65 (m, 4H); 3.23, 3.29 (s, 3H); 2.46, 2.47 (s, 3H). 19F NMR (377 MHz, d6-DMSO) δ −139.65 (S); 139.26 (S).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:45])[C@@H:10]([NH:37]C(OC(C)(C)C)=O)[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:28][O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][CH3:33])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][C:9](=[O:45])[C@@H:10]([NH2:37])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:28][O:29][C:30](=[O:36])[C:31]([CH3:35])([CH3:34])[CH2:32][CH3:33])=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(C)(C)C(=O)OCc1cccc(C)c1OCCOc1ccc([C@H](NC(=O)OC(C)(C)C)C(=O)OCc2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(C)C(=O)OCc1cccc(C)c1OCCOc1ccc([C@H](N)C(=O)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 90.7 %

Procedure:
As in Example 17, a solution of (S)-alpha-[[(1,1-dimethyethoxy)carbonyl]amino]-4-[2-[2-[(2,2-dimethyl-1-oxobutoxy)methyl]-6-methylphenoxy]ethoxy]benzeneacetic acid benzyl ester (2.59 g) in dichloromethane (8 mL) containing trifluoroacetic acid (8 mL) was stirred at room temperature for 45 minutes. The crude product was isolated in the previously described manner, was purified by HPLC (ethyl acetate-hexane; 1:1) to furnish 1.97 g of (S)-alpha-amino-4-[2-[2-[(2,2-dimethyl-1-oxobutoxy)methyl]-6-methylphenoxy]ethoxy]benzeneacetic acid benzyl ester as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([S:9](Cl)(=[O:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl-:15].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1>[Cl:15][C:5]1[CH:14]=[CH:13][C:8]([S:9]([C:8]2[CH:13]=[CH:14][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:11])=[O:10])=[CH:7][CH:6]=1
Reactant: [Cl-]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: CC(=O)Nc1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 41.6 %

Procedure:
A mixture of 70.1 g of N-acetylsulfanilyl chloride and 60 g of aluminum chloride in 200 ml of p-chlorobenzene was heated until the evolution of hydrogen chloride ceased and then refluxed for 2 hours. The chlorobenzene was removed by decantation and the residue diluted with ether. The resulting gummy solid was recovered by filtration and treated with dilute hydrochloric acid and ethanol. The resulting solid was collected, dissolved in hot ethanol and concentrated, giving 19.31 g of the desired product as pale gray crystals, mp 187.5°-188.5° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C([N:11]1[CH:16]2[CH2:17][CH2:18][CH:12]1[CH2:13][C:14](=[C:19]1[C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([OH:33])[C:27]=3[O:26][C:25]3[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:15]2)=O>CO>[CH:12]12[NH:11][CH:16]([CH2:17][CH2:18]1)[CH2:15][C:14](=[C:19]1[C:32]3[CH:31]=[CH:30][CH:29]=[C:28]([OH:33])[C:27]=3[O:26][C:25]3[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:13]2
Reactant: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3c(O)cccc31)C2)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Oc1cccc2c1Oc1ccccc1C2=C1CC2CCC(C1)N2
Reaction time: 8 h
Yield: 38.2 %

Procedure:
Potassium carbonate (7.21 g, 52 mmol) was added to a solution of Compound 4a (7.27 g, 18 mmol) in methanol (60 mL), and the reaction was stirred overnight. The reaction was filtered and then ion exchange resin was added (100 g, AG 50W-X210) and the reaction stirred 1 h. The resin was collected by filtration and washed sequentially with water (50 mL) and then methanol (50 mL). The resin was then treated with ammonia in methanol (2M, 500 mL) for 1 h before being collected by filtration again. The filtrate was concentrated under reduced pressure to afford Compound 2 (2.1 g). Procedure 6
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[C:12]([OH:14])=O)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][C:49]([C:59]1[CH:63]=[C:62]([NH2:64])[O:61][N:60]=1)([CH3:58])[CH2:50][O:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][O:53]1.[H-].[Na+]>CN(C=O)C>[CH3:58][C:49]([C:59]1[CH:63]=[C:62]([NH:64][C:12]([C@@H:8]2[CH2:9][CH2:10][CH2:11][N:7]2[CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[O:14])[O:61][N:60]=1)([CH3:48])[CH2:50][O:51][CH:52]1[CH2:57][CH2:56][CH2:55][CH2:54][O:53]1
Reactant: CC(C)(COC1CCCCO1)c1cc(N)on1
Reactant: O=C(O)[C@@H]1CCCN1C1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(COC1CCCCO1)c1cc(NC(=O)[C@@H]2CCCN2C2CCOCC2)on1
Temperature: 25 °C
Reaction time: 1 h
Yield: 20.1 %

Procedure:
To 1.20 g (6.02 mmol) of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid in DMF (50 mL) are added 3.67 mL (21.1 mmol) diisopropyl-ethyl-amine and 3.44 g (9.03 mmol) of HATU. The solution is stirred at RT for 1 h. In a second flask to 1.45 g (6.02 mmol) of 3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-ylamine (intermediate 7a) in DMF (25 mL) are added 602 mg sodium hydride (60% dispersion in oil; 15.1 mmol) under cooling by an ice bath. Then this solution is added to the activated acid and stirring is continued for 48 h. The reaction mixture is purified by HPLC-MS to afford 0.51 g of (S)-1-(tetrahydro-pyran-4-yl)-pyrrolidine-2-carboxylic acid (3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl)-amide. Yield: 20%; ESI-MS: 422 [M+H]+; HPLC (Rt): 1.55 min (method C)
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]2[CH2:26][CH2:25][CH2:24][CH2:23][C:6]=2[C:7]=1[C:8]([NH:10][C@H:11]([C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1)[CH3:12])=[O:9].CN1CCN(C)C1=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=1>O>[Cl:49][C:46]1[CH:47]=[CH:48][C:43]([CH2:42][N:2]([CH3:1])[C:3]2[S:4][C:5]3[CH2:26][CH2:25][CH2:24][CH2:23][C:6]=3[C:7]=2[C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:44][CH:45]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CNc1sc2c(c1C(=O)N[C@@H](C)c1ccc(C(=O)OC)cc1)CCCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2c(N(C)Cc3ccc(Cl)cc3)sc3c2CCCC3)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 27.4 %

Procedure:
To methyl 4-[(1S)-1-({[2-(methylamino)-4,5,6,7-tetrahydro-1-benzothien-3-yl]carbonyl}amino)ethyl]benzoate (0.41 g) was added 1,3-dimethyl-2-imidazolidinone (4.0 mL), and potassium carbonate (0.30 g) and 1-(bromomethyl)-4-chlorobenzene (0.34 g) were added thereto under ice-cooling, followed by stirring at 50° C. overnight. The reaction mixture was cooled to room temperature, and then water (50 mL) was added thereto, followed by extraction with ethyl acetate. The obtained organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate: 15/1-4/1) to obtain methyl 4-{(1S)-1-[({2-[(4-chlorobenzyl)(methyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]ethyl}benzoate (0.15 g).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH:19](O)[CH:20]([CH2:36][CH3:37])[C:21]([N:23]2[C@@H:27]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][O:25][C:24]2=[O:35])=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])=[O:10])C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[C:9]([C:11]1[CH:12]=[C:13]([CH2:19][CH:20]([CH2:36][CH3:37])[C:21]([N:23]2[C@@H:27]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:26][O:25][C:24]2=[O:35])=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])([OH:10])=[O:8]
Reactant: CCC(C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)C(O)c1ccc(OC)c(C(=O)OCc2ccccc2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCC(Cc1ccc(OC)c(C(=O)O)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reaction time: 1 h
Yield: 124.8 %

Procedure:
Next, (4S)-3-[3-(3-benzyloxycarbonyl-4-methoxyphenyl)-2-ethyl-3-hydroxypropionyl]-4-benzyl-2-oxazolidinone (1.35 g, 2.61 mmol) and 22 ml of trifluoroacetic acid were mixed under cooling with ice and triethylsilane (3.95 ml, 26.1 mmol) was added over 5 minutes. The mixture was stirred for 1 hour under cooling with ice, followed by stirring for 4 days at room temperature. The reaction mixture was concentrated and the residue was poured into 0.5 mol/l aqueous solution of sodium hydroxide, which was washed with ethyl acetate. The aqueous layer was made acidic and extracted with methylene chloride. The extract was washed with brine, then dried over anhydrous magnesium sulfate and concentrated to obtain 1.34 g of crude (4S)-3-[3-(3-carboxy-4-methoxyphenyl)-2-ethylpropionyl]-4-benzyl-2-oxazolidinone as a yellow oil. This compound was used for next reaction without purifying further.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11]2[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[C:17]([OH:18])[C:10]=2[S:9]1=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]Br.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([N:8]1[C:12](=[O:13])[C:11]2[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[C:17]([O:18][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH3:22])[C:10]=2[S:9]1=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCCOCCBr
Reactant: COc1ccc(O)c2c1C(=O)N(Cc1ccccc1)S2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COCCOCCOc1ccc(OC)c2c1S(=O)N(Cc1ccccc1)C2=O
Yield: 63.6 %

Procedure:
Reaction of 3.03 g (0.01 mol) of 2-benzyl-7-hydroxy-4-methoxybenzisothiazol-3-one-1-oxide (Preparation 14A) with 2.01 g (0.011 mol) of 2-(2-methoxyethoxy)ethyl bromide in methyl ethyl ketone in the presence of 2 g (0.015 mol) of potassium carbonate afforded 2.58 g (64%) of 2-benzyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]benzisothia-zol-3-one-1-oxide, which, on oxidation with 1.1 g (0.0063 mol) of 3-chloroperbenzoic acid in MDC, gave 2-benzyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin. Debenzylation of 0.25 g (0.0006 mol) of the product with 0.13 g (0.0021 mol) of ammonium formate in methanol in the presence of 0.25 g of 10% palladium-on-charcoal gave 0.21 g (100%) of the ammonium salt of 4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin. Reaction of 1.4 g (0,004 mol) of the ammonium salt with 0.63 g (0,004 mol) of chloromethyl phenyl sulfide in DMF afforded 2-phenylthiomethyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin, which, on reaction with sulfuryl chloride in MDC, afforded 0.53 g (35%) of 2-chloromethyl-4-methoxy-7-[2-(2-methoxyethoxy)ethoxy]saccharin.
Reaction SMILES: [N:1](=[CH:9][CH2:10]Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]Cl.[C:12]([O:16][C:17](=[O:25])[NH:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([O:16][C:17](=[O:25])[NH:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:10][CH2:9][N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:21][CH2:20]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: ClCC=NCCCCCCCl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(CCN2CCCCCC2)CC1

Procedure:
It is synthesized analogously to ester 4 starting from 2-(hexamethyleneimino)ethyl chloride (13.8 g) and ester 3 (12.4 g).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[NH2:12][C:13]1[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=1)[C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17].CCN(C(C)C)C(C)C>C(#N)C>[CH2:19]([O:18][C:16]([C:15]1[CH:14]=[C:13]([NH:12][CH:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])[CH:24]=[CH:23][CH:22]=1)=[O:17])[CH:20]=[CH2:21]
Reactant: C=CCOC(=O)c1cccc(N)c1
Reactant: O=C(O)C(Br)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C=CCOC(=O)c1cccc(NC(C(=O)O)c2ccccc2)c1
Temperature: 100 °C
Yield: 98.4 %

Procedure:
2-Bromo-2-phenylacetic acid (1.86 g, 8.65 mmol) was added to a solution of allyl 3-aminobenzoate (2.30 g, 13.0 mmol) and DIPEA (2.27 ml, 13.0 mmol) in acetonitrile (48 ml). The reaction was heated at 100° C. for 1 hour under microwave irradiation. The solvent was removed in vacuo and the residue was purified by flash chromatography (DCM/MeOH=95/5) to obtain 2-(3-(allyloxycarbonyl)phenylamino)-2-phenylacetic acid (2.65 g, 98% yield).