Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[CH3:18][O:19][C:20](=[O:35])[C@H:21]([CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[CH3:18][O:19][C:20](=[O:35])[C@H:21]([CH2:30][CH2:31][CH2:32][CH2:33][NH2:34])[N:22]([C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1)[C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24]
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@H](CCCCN)NC(=O)OC(C)(C)C
Product: COC(=O)[C@H](CCCCN)N(C(=O)OC(C)(C)C)C(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and NE-(tert-butoxycarbonyl)-L-lysine methyl ester (Bachem), the title compound was prepared as an oil. The reaction was monitored by tlc (Rf=0.40 in 50% EtOAc/hexanes) and the product was purified by flash chromotography using 50% EtOAc/hexanes as the eluent.
Reaction SMILES: [CH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][C:2]=1[OH:11].BrC1C=C(O)C=CC=1.[C:20]1([CH:26]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29](=[O:36])[C:28]2=[O:37])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.FC(F)(F)C1OC(CN2C3C(=CC=CC=3)C(=O)C2=O)=CC=1>>[C:38]1([CH:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29]([OH:36])([C:3]3[C:2]([OH:11])=[CH:1][C:10]4[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=4[CH:4]=3)[C:28]2=[O:37])[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1ccc2c(c1)CCCC2
Agent: O=C1C(=O)N(Cc2ccc(C(F)(F)F)o2)c2ccccc21
Agent: Oc1cccc(Br)c1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1cc2c(cc1O)CCCC2

Procedure:
Following the procedure as described in PREPARATION 2A and making non-critical variations using 5,6,7,8-tetrahydro-2-naphthol to replace 3-bromophenol, and 1-(diphenylmethyl)-1H-indole-2,3-dione to replace 1-((5-(trifluoromethyl)furan-2-yl)methyl)indoline-2,3-dione, 1-(diphenylmethyl)-3-hydroxy-3-(3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dihydro-2H-indol-2-one was obtained (76%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 8.73 (s, 1H), 7.52-7.49 (m, 1H), 7.32-7.28 (m, 10H), 7.09 (dd, J=5.6, 3.2 Hz, 2H), 6.95 (s, 1H), 6.75 (s, 1H), 6.51-6.48 (m, 2H), 4.31 (s, 1H), 2.70 (br s, 2H), 2.52 (br s, 2H), 1.72 (br s, 4H); MS (ES+) m/z 444.1 (M−17).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: Cc1c2n(c3c(-c4ccc(F)cc4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (70 mg, 88%), MS (ISP) m/z=320.5 [(M+H)+], mp 292° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10](CC([O-])=O)CC([O-])=O)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+]>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C([O-])CC(CC(=O)[O-])c1ccc([N+](=O)[O-])cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc([N+](=O)[O-])cn1
Temperature: 0 °C
Yield: 92 %

Procedure:
A suspension of 102.0 g (0.361 mol) of 2-(5-nitro-2-pyridyl)-1,3-propanedicarboxylate, from Step 1, in 600 mL of 20% aqueous sulfuric acid solution was heated at 95° C. for 24 hours. The resultant solution was poured onto 1 kg of ice and the aqueous mixture was adjusted to a pH within the range pH 10-12 with 50% aqueous sodium hydroxide solution. The precipitate was filtered and dissolved in ethyl acetate. The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated to a solid residue. The residue was washed with hexane. The hexane was removed by filtration and the solid was dried to afford 45.86 g (92% yield) of the title compound; 1H NMR (CDCl3) d 2.71 (s, 3H), 7.36 (d, 1H, J=9.0 Hz), 8.37 (dd, 1H, J=3.0 Hz, 9.0 Hz), 9.33 (d, 1H, J=3.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:14][C:8]2[N:9]=[CH:10][N:11]=[C:12](Cl)[C:7]=2[C:6]=1[CH3:15])=[O:4].[NH2:16][C:17]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:18]=1[O:19][CH:20]([CH3:26])[CH2:21][C:22]([CH3:25])([OH:24])[CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[F:31][C:28]1[CH:29]=[CH:30][C:17]([NH:16][C:12]2[C:7]3[C:6]([CH3:15])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[S:14][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:18]([O:19][CH:20]([CH2:21][C:22]([OH:24])([CH3:25])[CH3:23])[CH3:26])[CH:27]=1
Reactant: COC(=O)c1sc2ncnc(Cl)c2c1C
Reactant: CC(CC(C)(C)O)Oc1cc(F)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC(C)CC(C)(C)O)c2c1C
Temperature: 25 °C

Procedure:
4-Chloro-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid methyl ester (540 mg) and 4-(2-amino-5-fluorophenoxy)-2-methylpentan-2-ol (500 mg) were dissolved in dioxane (20 ml) and p-toluenesulfonic acid monohydrate (70 mg) was added. The reaction was heated under reflux for 2 h. Then the reaction mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with water. The organic layer was separated, dried, filtered and evaporated. The residue triturated with methanol and the precipitate was filtered to give the intended product.
Reaction SMILES: I(C1C=CC=CC=1C(O)=O)(=O)=O.[F:13][C:14]([F:30])([F:29])[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][OH:28])[N:26]=2)=[CH:18][CH:17]=1.O>CS(C)=O>[F:30][C:14]([F:13])([F:29])[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[S:23][CH:24]=[C:25]([CH:27]=[O:28])[N:26]=2)=[CH:18][CH:17]=1
Reactant: OCc1csc(-c2ccc(OC(F)(F)F)cc2)n1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1csc(-c2ccc(OC(F)(F)F)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
A solution of 2-iodoxybenzoic acid (441 mg) in dimethylsulfoxide (5 mL) was added to a solution of {2-[4-(trifluoromethoxy)phenyl]-1,3-thiazol-4-yl}methanol (361 mg) in dimethylsulfoxide (10 mL) and the resulting mixture was stirred at room temperature overnight. After water was added, the mixture was filtered through Celite and then extracted with ethyl acetate. The solvent was distilled off under reduced pressure to afford the title compound (358 mg) as the residue.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].[CH:27]([C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1)=[O:28].C(O)(=O)C>O1CCCC1>[C:23]([O:22][C:19]([CH2:20][CH:27]([C:29]1[CH:38]=[CH:37][C:32]([C:33]([O:35][CH3:36])=[O:34])=[CH:31][CH:30]=1)[OH:28])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: COC(=O)c1ccc(C(O)CC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
Diisopropylamine (0.55 mL, 3.9 mmol) was dissolved in dry tetrahydrofuran (10 mL), and 2.66 M n-butyllithium in hexane (1.4 mL, 3.6 mmol) was added dropwise at 0° C. The reaction solution was stirred at 0° C. for 10 minutes and cooled to −78° C., and after dropwise addition of tert-butyl acetate (0.58 mL, 4.3 mmol), stirred at −78° C. for 30 minutes. Methyl 4-formylbenzoate (0.70 g, 4.3 mmol) in tetrahydrofuran (6 mL) was added dropwise at −78° C. over 5 minutes, and the reaction solution was stirred at −78° C. for 10 minutes and at 0° C. for 1 hour, then adjusted to pH 7 with acetic acid (0.43 mL, 7.5 mmol) and returned to room temperature over 12 hours. The solution was concentrated by evaporating tetrahydrofuran under reduced pressure, and ethyl acetate and water were added. The organic layer was separated and dried under reduced pressure to dryness to give 1.17 g of the crude desired product. The crude desired product was purified by silica gel column chromatography (Merck silica gel 60, 22 g, n-hexane-ethyl acetate 4:1) to give 0.84 g of the desired product (yield 84%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:24][CH3:25]>CC#N.C1COCC1.[Ag-]=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:24][CH3:25])[C@@H:10]([NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Reactant: CCI
Agent: O=[Ag-]
Solvent: C1CCOC1
Solvent: CC#N
Product: CCO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
29.1 A solution of 150 mg (3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (example 22.4) in 3 ml MeCN and 1 ml THF was treated with 300 mg silver(I) oxide and 0.35 ml iodoethane. The reaction mixture was stirred over night, then was again treated with 300 mg silver(I) oxide and 0.35 ml iodoethane. The reaction mixture was agitated over night at r.t., then filtrated. The filtrate was concentrated. The crude product was purified by chromatography (silica gel; gradient: cyclohexane->EtOAc) to give 90 mg (3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-ethoxy-pyrrolidine-1-carboxylic acid tert-butyl ester as light yellow oil. MS 373.1 ([M−H]−)
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].P([O-])([O-])([O-])=O.Br[CH2:11][C:12]1([CH3:38])[CH:16]([C:17]([O:19][CH2:20][C:21]([Cl:24])([Cl:23])[Cl:22])=[O:18])[N:15]2[C:25](=[O:37])[CH:26]([NH:27][C:28](=[O:36])[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:14]2[S:13]1>CC(C)=O>[C:1]([S:3][CH2:11][C:12]1([CH3:38])[CH:16]([C:17]([O:19][CH2:20][C:21]([Cl:22])([Cl:23])[Cl:24])=[O:18])[N:15]2[C:25](=[O:37])[CH:26]([NH:27][C:28](=[O:36])[CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:14]2[S:13]1)(=[O:4])[CH3:2]
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: CC(O)=S
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: CC(=O)SCC1(C)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Yield: 32.3 %

Procedure:
Acetone (20 ml) and thioacetic acid (0.12 g) were added to pH 6.7 phosphate buffer (20 ml). To a mixture was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g) under stirring. After stirring for 5 hours at room temperature, the reaction mixture was post-treated in the similar manner as described in Example 6 to give oily 2,2,2-trichloroethyl 2-acetylthiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.173 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]([CH3:24])=[CH2:23])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][N:12]=1)[CH2:9][CH3:10].[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].C([NH+](CC)CC)C>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:21][C:22]([CH3:24])=[CH2:23])=[C:6]([CH:19]=1)[CH2:7][N:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:27][N:26]=[N:25][N:18]=2)=[CH:13][N:12]=1)[CH2:9][CH3:10]
Reactant: [N-]=[N+]=[N-]
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C#N)cn1
Agent: CC[NH+](CC)CC
Agent: [Cl-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(-c2nnn[nH]2)cn1
Temperature: 120 °C
Reaction time: 7 h
Yield: 30.1 %

Procedure:
2-[N-(5-Bromo-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]-5-cyanopyridine (reference example 10) (0.45 g, 1.16 mmol) in N-methylpyrrolidone (12 ml) was treated with sodium azide (228 mg, 3.5 mmol) followed by triethylammonium chloride (251 mg, 1.8 mmol) and heated with stirring at 120° C. (oil bath) for 7 hours under an argon balloon. The resultant red solution was poured into ice/water (30 ml), acidified and extracted twice with ethyl acetate (total 50 ml). The combined organic extracts were washed twice with water, dried (MgSO4) and evaporated to give a brown gum. The gum was purified by MPLC to give the title compound as an off-white foam (150 mg, 30%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:50]=[CH:49][C:43]([C:44](OCC)=[O:45])=[CH:42][CH:41]=4)=[N:18][N:19]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[F-].[Na+]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]2[CH:12]=[C:13]([C:16]3[C:17]([C:40]4[CH:50]=[CH:49][C:43]([CH2:44][OH:45])=[CH:42][CH:41]=4)=[N:18][N:19]([C:21]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:20]=3)[CH:14]=[CH:15][C:10]2=[N:9][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Agent: [Al+3]
Agent: [F-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3ncc(-c4ccccn4)n3c2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 49.9 %

Procedure:
2 g 6-bromo-3-(2-pyridyl)imidazo[1,2-a]pyridine (compound in Production Example 63) and 5 g mixture of methyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-3-pyrazolyl]benzoate and ethyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-trityl-1H-3-pyrazolyl]benzoate were reacted in the same manner as in Example 10, whereby 4.54 g mixture of methyl 4-[4-(3-pyridin-2-ylimidazo[1,2-a]pyridin-6-yl)-1-trityl-1H-pyrazol-3-yl]-benzoate and ethyl 4-[4-(3-pyridin-2-ylimidazo[1,2-a]-pyridin-6-yl)-1-trityl-1H-pyrazol-3-yl]benzoate was obtained as a pale yellow amorphous. 638 mg of this ester mixture was added to 10 mL suspension of 50 mg lithium aluminum hydride in tetrahydrofuran, and the mixture was stirred at 50° C. for 2 hours. The reaction solution was cooled on iced water, then 220 mg sodium fluoride and 80 μL water were added thereto, and the reaction solution was returned to room temperature and stirred for 40 minutes. Insolubles were filtered off, and the filtrate was evaporated. The residue was purified by NH silica gel column chromatography (ethyl acetate/hexane) to give 298 mg of the title compound as white crystals.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([P:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[NH2:24][O:25][K].C(O)=O.C(OCC)(=O)C>C(O)C>[OH:25][NH:24][C:3](=[O:2])[CH2:4][N:5]([P:14]([CH3:22])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)CN(CCc1ccccc1)P(C)(=O)c1ccccc1
Reactant: NO[K]
Solvent: O=CO
Solvent: CCOC(C)=O
Solvent: CCO
Product: CP(=O)(c1ccccc1)N(CCc1ccccc1)CC(=O)NO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-(Methylphenylphosphinyl)-N-(2-phenylethyl)glycine methyl ester (300 mg, 0.905 mmol) is treated with 0.77 mL of NH2OK (1.76M in methanol, solution prepared as described in Fieser and Fieser, Vol. 1, p. 478). The mixture is stirred for 3 hours at room temperature, neutralized with formic acid and concentrated. The crude product is purified by silica gel flash chromatography (85:15 ethyl acetate:ethanol) giving the product with slight impurities. Preparative TLC (90:10 ethyl acetate:ethanol) gives N-hydroxy-2-[[methyl phenylphosphinyl](2-phenylethyl)-amino]-acetamide as a colorless solid: MS-IS m/z 333 [M+H]+, 350 [M+NH4 ]+, 355 [M+Na]+, 371 [M+K]+. (R1 =phenyl ethyl, R2 =H, R3 =methyl, R4 =phenyl).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:28]=2[NH2:29])[CH2:23][CH2:22]1.Cl.O1CCOCC1>CO>[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[C:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19])[C:3]([CH3:20])=[C:2]2[NH:29][C:28]1[CH:30]=[C:31]([N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH2:35]2)[CH:32]=[CH:33][C:27]=1[N:24]1[CH2:23][CH2:22][O:21][CH2:26][CH2:25]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2ccccc2F)nc2ccc(Cl)cc2c1Cl
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2F)nc2ccc(Cl)cc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4,6-dichloro-2-(2-fluorophenyl)-3-methylquinoline (116 mg, 0.38 mmol), 2,5-dimorpholinoaniline (100 mg, 0.38 mmol) and a 4.0M solution of HCl in dioxane (0.095 mL, 0.38 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification 6-chloro-N-(2,5-di-4-morpholinylphenyl)-2-(2-fluorophenyl)-3-methyl-4-quinolinamine was obtained as a yellow film. 1H NMR (400 MHz, chloroform-d) δ ppm 8.10 (1H, d, J=9.0 Hz), 7.90 (1H, d, J=2.3 Hz), 7.58-7.67 (2H, m), 7.47 (1H, d, J=8.2 Hz), 7.31-7.37 (1H, m), 7.16-7.22 (1H, m), 7.13 (1H, d, J=8.6 Hz), 6.45 (1H, dd, J=8.6, 2.7 Hz), 6.00-6.08 (1H, m), 3.93 (4H, t, J=4.5 Hz), 3.76 (4H, dd, J=5.9, 3.9 Hz), 3.06 (4H, d, J=1.2 Hz), 2.91-3.02 (4H, m), 2.20 (3H, d, J=2.3 Hz). Mass Spectrum (ESI) m/e=533.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][N:7]([N:12]=O)[C:6]=2[CH:14]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][CH2:10][CH2:9][CH2:8][N:7]([NH2:12])[C:6]=2[CH:14]=1
Reactant: O=NN1CCCSc2ccc(F)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NN1CCCSc2ccc(F)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 112.6 %

Procedure:
7-fluoro-5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine (449 mg, 2.11 mmol) was suspended in THF (1 mL of freshly distilled) and cooled to 0° C. in an ice bath. Lithium aluminum hydride (80 mg, 2.11 mmol) was added in a portion-wise fashion. The flask was removed from the ice bath and allowed to warm to room temperature and was stirred for 2 hours. Water (0.08 mL) was added and stirred for 10 minutes. 15% sodium hydroxide (0.08 mL) was added stirred for 10 minutes. Water (0.024 mL) was added and stirred for 10 minutes. The reaction was extracted with dichloromethane (2×25 mL). The organics were concentrated to a residue, then taken up in minimal amount of dichloromethane and then hydrogen chloride in ether (1 M) was added until precipatation formed, the precipatate was filtered off to give 7-fluoro-3,4-dihydro-1,5-benzothiazepin-5(2H)-amine (471 mg, 95%). 1H NMR (CD-3OD, 300 MHz): δ 7.59 (t, 1H, J=7.5 Hz), 7.28 (d, 1H, J=9.9 Hz), 7.00 (t, 1H, J=8.2 Hz), 3.52 (t, 1H, J=7.5 Hz), 2.92–2.86 (m, 1H), 2.72–2.70 (m, 2H), 2.40–2.31 (m, 1H), 2.2–2.18 (m, 2H) ppm.
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1)([O:3]CC)=[O:2].[OH-].[Na+].Cl>O>[C:1]([CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 12.5 °C
Reaction time: 2.5 h

Procedure:
A suspension of the 5-[4-[(carboethoxy)methoxy]benzyl]thiazolidine-2,4-dione obtained by following a procedure described in any of Examples 16-22 (135 g, 0.44 M) and water (540 ml, 4 times w/v) was taken in a round bottom flask fitted with a mechanical stirrer. Aq. sodium hydroxide solution (37 g of NaOH in 135 ml of water) was added slowly over a period of 5-10 minutes at 20-25° C. Stirring was continued at ambient temperature for a further period of 2-3 h, while monitoring the reaction by TLC. After the completion of reaction, the pH of the reaction mixture was adjusted to 2 using conc. HCl (temp. raises to ˜40-45° C.) and allowed to attain room temperature. The mass was cooled to ˜10-15° C. and the solid thus obtained was filtered and dried at 60-70° C. under 1-2 mm Hg of vacuum to afford 5-[4-[(carboxy)methoxy]benzyl]thiazolidine-2,4-dione (121 g, Y=99% P=99.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH2:17])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.[OH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](O)=[O:27].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([NH:17][C:26](=[O:27])[CH2:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[OH:18])=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccccc1O
Reactant: Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: O=C(Cc1ccccc1O)Nc1nn2cccnc2c1-c1ccc(Cl)cc1
Temperature: 35 °C
Reaction time: 18 h
Yield: 19.3 %

Procedure:
The product from Example 99A (100 mg, 0.41 mmol), 2-hydroxyphenylacetic acid (124 mg, 0.82 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (157 mg, 0.82 mmol), 1-hydroxybenzotriazole hydrate (100 mg, 0.65 mmol) were combined with pyridine (8 mL) and stirred at 35° C. for 18 hours. The reaction mixture was concentrated under vacuum and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 5-95% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford 30 mg (19%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.28-10.56 (bs, 1H), 9.09 (dd, J=6.9, 1.7 Hz, 1H), 8.62 (dd, J=4.1, 1.7 Hz, 1H), 7.70-7.73 (m, 2H), 7.30-7.34 (m, 2H), 7.11-7.16 (m, 2H), 6.72-6.81 (m, 2H), 6.65-6.72 (m, 1H), 3.57 (s, 2H); MS (ESI) m/z 379 (M+H)+; Anal. calculated for C20H15ClN4O2.0.35H2O: C, 62.37; H, 4.11; N, 14.55. Found C, 62.16; H, 3.87; N, 14.49.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[N:9]([CH2:11][C:12]([OH:14])=O)[CH3:10].C(N(C(C)C)CC)(C)C.[NH2:25][N:26]([CH:34]=[NH:35])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].O.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[C:29]([O:28][C:27](=[O:33])[N:26]([NH:25][C:12](=[O:14])[CH2:11][N:9]([C:2]1[C:1]([CH3:15])=[CH:6][C:5]([CH3:7])=[CH:4][C:3]=1[CH3:8])[CH3:10])[CH:34]=[NH:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N(N)C=N
Reactant: Cc1cc(C)c(N(C)CC(=O)O)c(C)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(N(C)CC(=O)NN(C=N)C(=O)OC(C)(C)C)c(C)c1
Temperature: 25 °C
Reaction time: 65 h
Yield: 52.2 %

Procedure:
[Mesityl(methyl)amino]acetic acid (6.67 g; 32 mmol), diisopropylethylamine (20.68 g; 160 mmol), tert-butyl amino(imino)methylcarbamate (6.11 g; 38 mmol), and 1-hydroxybenzotriazole monohydrate (5.88 g; 38 mmol) were dissolved in N,N-dimethylformamide (150 mL), 2-(1H)-benzotriazol-1-yl-1,1,3,3-tetramethyluronium hexafluorophosphate (14.56 g; 38 mmol) was added thereto, and the mixture was stirred for 65 hours at room temperature. To the reaction solution, ethyl acetate (400 mL) was added, and the mixture was washed with 10% aqueous citric acid solution, brine, and saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and then distilled under reduced pressure. The resulting crystals were dispersed in diethyl ether, collected by filtration and dried to give 5.82 g of the title compound (yield 52%).