Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]=[CH:5][C:4]=2[C:3]=1[C:11]([NH2:13])=O.C1COCC1>>[F:1][C:2]1[C:3]([CH2:11][NH2:13])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: NC(=O)c1c(F)ccc2[nH]ccc12
Solvent: C1CCOC1
Product: NCc1c(F)ccc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.7 %

Procedure:
A mixture of 5-fluoro-1H-indole-4-carboxamide (240 mg, 1.35 mmol) and a solution of BH3 in THF (1.0 M, 16 mL, 16 mmol) was stirred at RT for 18 hours. The reaction was quenched with a solution of HCl (1.0 M, 20 mL) followed by stirring at RT for 1.5 h. The pH of the reaction mixture was adjusted to about ca. 10 by adding a satd. aq. Na2CO3. The mixture was extracted with EtOAc (50 mL×3). The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with DCM/MeOH/TEA (10:1:0.1) to afford (5-fluoro-1H-indol-4-yl)methanamine (107) as a yellow solid (190 mg, 86.4%). MS (ESI): m/z=148.1 [M−16]+.
Reaction SMILES: C(OC([C:6]1[S:10][N:9]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([Br:17])[CH:12]=2)[N:7]=1)=O)C.[OH-].[Na+]>>[Br:17][C:13]1[CH:12]=[C:11]([C:8]2[N:7]=[CH:6][S:10][N:9]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1nc(-c2cccc(Br)c2)ns1
Agent: [Na+]
Agent: [OH-]
Product: Brc1cccc(-c2ncsn2)c1
Temperature: 100 °C

Procedure:
A mixture of 3-[3-bromo-phenyl]-[1,2,4]thiadiazole-5-carboxylic acid ethyl ester (16.8 g, 53.5 mmol), sodium hydroxide (2.4 g, 58.8 mmol), distilled water (120 mL), and ethanol (20 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to room temperature. Concentrated hydrochloric acid (5.1 mL) was added, and the reaction mixture re-heated to 100° C. for 3 hours. The solution was cooled to room temperature and extracted with diethyl ether (3×150 mL). The combined organic layers were washed with distilled water (3×100 mL), and dried over MgSO4. After the solvent was removed, 3-[3-bromo-phenyl]-[1,2,4]thiadiazole was obtained as white needles (12.7 g, 99%): mp 69-71° C.; 1H-NMR (CDCl3) δ9.89 (s, 1H), 8.52 (t, 1H, J=1.8 Hz), 8.28 (dt, 1H, J=5.2, 1.3 Hz), 7.61 (dq, 1H, J=4.9, 1.1 Hz), 7.35 (t, 1H, J=7.9 Hz); MS ((+)APCI) [M+H]+ @ m/z 241/243. Anal. Calc. For C8H5BrN2S: C, 39.85, H, 2.09, N, 11.62. Found: C, 39.82, H, 2.43, N, 11.33.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([N:13]([CH2:31][CH:32]([CH3:34])[CH3:33])[C@@H:14]3[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17][C@H:16]([C:27]([O:29]C)=[O:28])[CH2:15]3)=[O:12])[N:7]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1CO>[C:23]([O:22][C:20]([N:18]1[CH2:19][C@@H:14]([N:13]([C:11]([C:8]2[N:7]([CH2:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[C:10]=3[N:9]=2)=[O:12])[CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:15][C@@H:16]([C:27]([OH:29])=[O:28])[CH2:17]1)=[O:21])([CH3:25])([CH3:26])[CH3:24]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C2)nc2c(F)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2c(F)cccc21
Temperature: 45 °C
Reaction time: 4 h
Yield: 94.7 %

Procedure:
1-tert-Butyl 3-methyl (3R,55)-5-{{{4-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1,3-dicarboxylate (195 mg) was dissolved in tetrahydrofuran-methanol (1:2, 15 ml), 2M aqueous sodium hydroxide solution (1 ml) was added, and the mixture was stirred at 45° C. for 4 hr. The reaction mixture was concentrated under reduced pressure, neutralized with saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, concentration under reduced pressure to give the object product (180 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4](=[O:6])[CH3:5].[N+:10]([C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1)([O-:12])=[O:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:4]([C:3]1([CH3:7])[CH2:8][O:9][CH:17]([C:16]2[CH:19]=[CH:20][C:13]([N+:10]([O-:12])=[O:11])=[CH:14][CH:15]=2)[O:1][CH2:2]1)(=[O:6])[CH3:5]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)C(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)C1(C)COC(c2ccc([N+](=O)[O-])cc2)OC1

Procedure:
3,3-bis(Hydroxymethyl)-2-butanone (39.7 parts) and 4-nitrobenzaldehyde (30.2 parts) are combined in toluene (300 parts) containing p-toluenesulfonic acid, (p-TSA), (1.0 part) and the mixture held under reflux until a theoretical amount of water is removed by a Dean-Stark moisture trap. The solution is concentrated in vacuo and the residue washed once with dilute sodium bicarbonate solution. The product is recrystallized from ethyl acetate-heptane mixed solvent to give colorless needles, m.p. 101-102.5° C. Proton NMR and combustion analysis are consistent with those values predicted for the desired product. Combustion Analysis for C13H15NO5 --Calculated: C, 58.9%; H, 5.7%; N, 5.3%. Found: C, 59.0%; H, 5.8%; N, 5.4%.
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[CH:14]=[C:13]([N:15]3[CH2:21][CH:20]4[O:22][CH:17]([CH2:18][CH2:19]4)[CH2:16]3)[N:12]=[C:11](O)[N:10]=1)[CH2:2]2.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:11]1[N:10]=[C:9]([N:3]2[CH2:4][CH:5]3[O:8][CH:1]([CH2:7][CH2:6]3)[CH2:2]2)[CH:14]=[C:13]([N:15]2[CH2:21][CH:20]3[O:22][CH:17]([CH2:18][CH2:19]3)[CH2:16]2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(N2CC3CCC(C2)O3)cc(N2CC3CCC(C2)O3)n1
Product: Clc1nc(N2CC3CCC(C2)O3)cc(N2CC3CCC(C2)O3)n1
Temperature: 100 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
In a 25 mL round-bottomed flask was placed 4,6-di(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrimidin-2-ol (27), 12 mg, 0.038 mmol) in POCl3 (3 ml) to give a yellow solution. The mixture was stirred at 100° C. for 4 h. The mixture was cool to room temperature, poured on ice, and extracted with dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated to give the title compound as a white crystalline solid (12 mg, 93%).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)[CH2:5][C:6]1[C:7]([NH:19][CH2:20][CH:21]2[CH2:23][CH2:22]2)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[CH:21]1([CH2:20][N:19]2[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:10]=[CH:11][C:6]=3[CH2:5][CH:4]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[C:3]2=[O:2])[CH2:23][CH2:22]1
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1NCC1CC1)c1ccc(OC)cc1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1ccc(C2Cc3cnc(Nc4ccccc4)nc3N(CC3CC3)C2=O)cc1
Temperature: 85 °C

Procedure:
To a solution of crude 3-(2-phenylamino-4-cyclopropylmethylamino-pyrimidin-5-yl)-2-(4-methoxy-phenyl)-propionic acid methyl ester (51.3 mg) (from Example 14a supra) in glacial acetic acid (1 mL) was added concentrated sulfuric acid (0.1 mL) in one portion. The reaction mixture was heated at 85° C. for 3 hours. The reaction mixture was cooled, diluted with ethyl acetate (50 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by preparative thin layer chromatography to give 8-cyclopropylmethyl-6-(4-methoxy-phenyl)-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidine-7-one as a light yellow amorphous solid. (Yield 6.7 mg, 14.8%, 2 steps).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[CH:5]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:14]1[C:9]([C:8]2[N:4]([CH3:3])[CH:5]=[N:6][CH:7]=2)=[N:10][C:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:20][CH:21]=2)=[N:12][CH:13]=1
Reactant: Cn1cncc1-c1ccnc(Nc2ccc(S(N)(=O)=O)cc2)n1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1cncc1-c1nc(Nc2ccc(S(N)(=O)=O)cc2)ncc1Br
Reaction time: 1 h
Yield: 52.9 %

Procedure:
Bromine (75.5 mg, 0.47 mmol) was added to a solution of 4-(1-methylimidazol-5-yl)-2-(4-sulphamoylanilino)pyrimidine (Example 15; 0.14 g, 0.42 mmol) and sodium acetate (41.7 mg, 0.51 mmol) in acetic acid (4 ml) and the mixture stirred for 1 hour. The volatiles were evaporated and the residue partitioned between EtOAc and saturated aqueous potassium hydrogen carbonate solution. The organic phase was separated and dried. The residue was pre-absorbed on to silica gel and purified by column chromatography on silica gel eluting with DCM/2% methanolic ammonia (9:1) to give the title compound (91 mg, 52%). NMR 10.14 (s, 1H), 8.75 (s, 1H), 7.90-7.69 (m, 4H), 7.17 (s, 2H), 3.84 (s, 3H); m/z 409.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH:16]2[CH2:17][CH2:18]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:45])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC2CC2)c(C(F)(F)F)cc1N
Product: CC(C)(C)OC(=O)Nc1cc(OCC2CC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1

Procedure:
The title compound was prepared from (2-amino-5-cyclopropylmethoxy-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J29) (260 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-3-yl-phenyl)-propionic acid tert-butyl ester (Example K1) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (311 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([NH:10][C@H:11]([C@@H:24]([OH:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].ClC1C(C)=C(N[C@H]([C@@H](O)C)C(O)=[O:40])C=CC=1C#N.OC1C=C(C=CC=1)C(NN)=O>CCOC(C)=O>[Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([NH:10][C@H:11]([C@@H:24]([OH:26])[CH3:25])[C:12]([NH:14][NH:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([OH:40])[CH:22]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccccc2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](C)O)ccc(C#N)c1Cl
Agent: NNC(=O)c1cccc(O)c1
Solvent: CCOC(C)=O
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2cccc(O)c2)[C@H](C)O)ccc(C#N)c1Cl

Procedure:
Intermediate 7a was synthesized similarly to the procedure outlined for intermediate 1b described above using (2R,3S)-2-(3-chloro-4-cyano-2-methylphenylamino)-3-hydroxybutanoic acid (intermediate 1a) (522 mg, 1.9 mmol) and 3-hydroxy-benzohydrazide (296 mg, 1.9 mmol). After column chromatography (EtOAc), the title compound was isolated as a white solid (407 mg, 52%). 1H NMR (400 MHz, acetone-d6, δ in ppm) δ 9.80 (br s, 1H), 9.52 (br s, 1H), 8.76 (br s, 1H), 7.49 (d, J=8.7 Hz, 1H), 7.40 (m, 1H), 7.29 (at, J=8.1 Hz, 1H), 7.04 (m, 1H), 6.66 (d, J=8.7 Hz, 1H), 5.55 (d, J=7.1 Hz, 1H), 4.89 (br s, 1H), 4.39 (m, 1H), 4.11 (dd, J=3.3, 7.0 Hz, 1H), 2.35 (s, 3H), 1.34 (d, J=6.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[N+:23]([C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1)([O-:25])=[O:24]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH:20][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([N+:23]([O-:25])=[O:24])[CH:27]=2)=[O:34])=[CH:4][CH:3]=1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Product: O=C(NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1)Nc1cccc([N+](=O)[O-])c1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 3-nitrophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:21])[CH2:15][CH2:14]1)([CH3:6])([CH3:5])[CH3:4].[N:30]([CH2:33][CH3:34])=[C:31]=[O:32].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>O1CCCC1>[C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N:13]1[CH2:14][CH2:15][N:16]([C:19](=[O:29])[C:20]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([C:31]([NH:30][CH2:33][CH3:34])=[O:32])[CH2:27][CH2:28]2)=[O:21])[CH2:17][CH2:18]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)NC2CCNCC2)CC1
Reactant: CCN=C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNC(=O)N1CCC(NC(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
A mixture of 2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxo-N-piperidin-4-ylacetamide dihydrochloride (0.35 g, 0.79 mmol), isocyanatoethane (72.5 mg, 1.02 mmol) and triethylamine (329 μL, 2.36 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 16 h. The reaction mixture was poured into saturated NaHCO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the title compound (0.34 g, 99%) as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@H:8]([NH:14][C@@H:15]1[C:21](=[O:22])[N:20]([CH2:23][C:24]([OH:26])=[O:25])[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[S:17][CH2:16]1)[C:9]([O:11]CC)=[O:10].[C:31]1(=O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C([BH3-])#N.[Na+]>C(O)C>[C:9]([C@@H:8]([NH:14][C@@H:15]1[C:21](=[O:22])[N:20]([CH2:23][C:24]([OH:26])=[O:25])[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[S:17][CH2:16]1)[CH2:7][CH2:6][CH2:5][CH2:4][NH:3][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)([OH:11])=[O:10]
Reactant: CCOC(=O)[C@H](CCCCN)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Product: O=C(O)CN1C(=O)[C@@H](N[C@@H](CCCCNC2CCCCC2)C(=O)O)CSc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
A mixture of 3(R)-[5-amino-1(S)-ethoxycarbonylpentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid dihydrochloride (0.2 g) obtained in Example 59, ethanol (10 ml), cyclohexanone (2 g) and sodium cyanoborohydride (0.3 g) is allowed to stand overnight at room temperature. To the residue, after evaporation of ethanol, is added 1N aqueous sodium hydroxide (4 ml). The resulting mixture is stirred at room temperature for 1 hour, diluted with water (20 ml) and extracted 3 times with ethyl acetate (20 ml each). The aqueous layer is slightly acidified with acetic acid (1 ml) and subjected to Amberlite XAD-2 column chromatography eluting with methanol-water (1:1). The eluate is concentrated under reduced pressure and lyophilized to give 3(R)-[1(S)-carboxy-5-cyclohexylaminopentyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid (0.12 g) as colorless powder.
Reaction SMILES: [F:1][C:2]([F:10])([CH2:6][C:7]([OH:9])=[O:8])[C:3](O)=[O:4].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OC(C)=O)(C)C>[CH2:24]([NH:31][C:3](=[O:4])[C:2]([F:10])([F:1])[CH2:6][C:7]([OH:9])=[O:8])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)CC(F)(F)C(=O)O
Solvent: CC(=O)OC(C)C
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: O=C(O)CC(F)(F)C(=O)NCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 56.8 %

Procedure:
To a solution of 2,2-difluorosuccinic acid (2.15 g, 14.0 mmol) in iPrOAc (23 mL) was added trifluoroacetic anhydride (2.34 mL, 16.7 mmol) in one portion at ambient temperature. The reaction solution was stirred at 50° C. for 2 hr. The reaction solution was allowed to cool to 5° C. in an ice bath. Benzyl amine (2.29 mL, 20.9 mmol) was added dropwise while the reaction temperature was maintained below 20° C. The solution was stirred at ambient temperature for 2 hr. The reaction was quenched with water (10 mL) followed by saturated Na2CO3 to pH 8-9. The separated organic phase was discarded. The aqueous phase was acidified with 6 N HCl to pH 1 and extracted with EtOAc (2×100 mL). The combined organic phase was washed with 2 N HCl, brine (100 mL), dried over MgSO4 filtered and concentrated. The intermediate was carried forward without further purification (2.89 g, 56.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.28-7.42 (m, 5 H) 7.14-7.21 (m, 1 H) 6.77 (br. s., 1 H) 4.54 (d, J=5.87 Hz, 2 H) 3.39 (t, J=14.18 Hz, 2 H).
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:13][CH2:14][C:15]([OH:18])([CH3:17])[CH3:16])[C:7]([CH3:20])([CH3:19])[CH2:6]1)[CH:2]=[CH2:3].[CH3:21][SiH:22]([CH3:24])[CH3:23]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[OH:18][C:15]([CH3:17])([CH3:16])[CH2:14][O:13][N:8]1[C:7]([CH3:20])([CH3:19])[CH2:6][CH:5]([O:4][CH2:1][CH2:2][CH2:3][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH2:10][C:9]1([CH3:12])[CH3:11]
Reactant: C[SiH](C)C
Reactant: C=CCOC1CC(C)(C)N(OCC(C)(C)O)C(C)(C)C1
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CC(C)(O)CON1C(C)(C)CC(OCCC[Si](C)(C)C)CC1(C)C

Procedure:
The title compound is prepared by reacting the compound prepared in Example 17 with trimethylsilane and hydrogen hexachloroplatinate(IV) in isopropyl alcohol.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11](Cl)=[O:12]>ClCCl>[OH:5][CH2:4][CH2:3][N:2]([CH3:1])[C:11]([C:7]1[O:6][CH:10]=[CH:9][CH:8]=1)=[O:12]
Reactant: O=C(Cl)c1ccco1
Reactant: CNCCO
Solvent: ClCCl
Product: CN(CCO)C(=O)c1ccco1
Yield: 57.6 %

Procedure:
A one liter, three necked flask was equipped with overhead stirrer, nitrogen atmosphere and an addition funnel. The flask was charged with 115 g of 2-(methylamino)ethanol (1.53 mol.) and 500 ml of dichloromethane. The reaction flask was cooled with an ice bath. Next, 100 g of furoyl chloride (0.77 mol.) was slowly added via the addition funnel over 2.5 hours. The dichloromethane was washed with NaCl(aq.). Next, the NaCl(aq.) layer was extracted with dichloromethane and the two dichloromethane layers were combined and dried over MgSO4. The dichloromethane was removed with a rotoevaporator to yield 75 g (44%) of N-(2-hydroxyethyl)-N-methylfuranamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[NH:7][C:6](=[O:12])[C:5]2([CH3:14])[CH3:13].[C:15](O)(=O)/[CH:16]=[CH:17]/[CH3:18].N>O>[CH:16]([C:15]1[NH:11][C:10]2[CH:9]=[C:8]3[NH:7][C:6](=[O:12])[C:5]([CH3:14])([CH3:13])[C:4]3=[CH:3][C:2]=2[N:1]=1)=[CH:17][CH3:18]
Reactant: C/C=C/C(=O)O
Reactant: CC1(C)C(=O)Nc2cc(N)c(N)cc21
Agent: N
Solvent: O
Product: CC=Cc1nc2cc3c(cc2[nH]1)NC(=O)C3(C)C

Procedure:
Analogously to Example 11, 0.95 g. 5,6-diamino-3,3-dimethylindolin-2-one and 0.43 g. crotonic acid are heated with 10 ml. polyphosphoric acid for 30 minutes at 170° C. (bath temperature). The cooled reaction mixture is dissolved in 40 ml. water and neutralised with concentrated aqueous ammonia solution. Insoluble material is filtered off with suction, washed with water and dissolved in 100 ml. hot ethanol. After treatment with active charcoal, the hot filtrate is evaporated in a vacuum and the evaporation residue is triturated with diethyl ether. There is thus obtained 0.7 g. of the title compound which contains 0.5 mole of water per mole of substance; m.p. 252°-254° C.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[CH:24]=[C:23]([CH3:25])[O:22][N:21]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15](=[O:17])[NH:19][C:20]1[CH:24]=[C:23]([CH3:25])[O:22][N:21]=1
Reactant: Cc1cc(N)no1
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Solvent: Cc1ccccc1C
Product: Cc1cc(NC(=O)C2=C(O)c3ccccc3S(=O)(=O)N2C)no1
Temperature: 25 °C

Procedure:
To an appropriate flask equipped for reflux and/or distillation, 900 ml xylene, 40 grams (.149 moles) methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide and 19.94 grams (.203 moles) of 3-amino-5-methylisoxazole are added. The mixture is refluxed for 13-18 hours. At one hour intervals, about 3-4% of the solvent volume is distilled off. Every 4 to 5 hours fresh xylene is added, equal in amount to that distilled during this period. At the end of the heating period, the reaction is cooled to 25° C., filtered and the cake is washed with xylene. After drying, the crude product weighed 43.8 grams (88%). This material could be recrystallized from about 40-50 volumes of dioxane with an 80-85% recovery of acceptable material. An alternate procedure for the purification of crude product is as follows:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[Br:34][C:35]1[CH:36]=[CH:37][C:38]([OH:45])=[C:39](/[C:41](=[N:43]/O)/[CH3:42])[CH:40]=1>C(Cl)Cl>[Br:34][C:35]1[CH:36]=[CH:37][C:38]2[O:45][N:43]=[C:41]([CH3:42])[C:39]=2[CH:40]=1
Reactant: C/C(=N\O)c1cc(Br)ccc1O
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1noc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.1 %

Procedure:
To a stirred solution of triphenylphosphine (6.8 g, 26.1 mmol) and 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) (3.9 g, 26.1 mmol) in CH2Cl2 (50 mL) was added (E)-1-(5-bromo-2-hydroxyphenyl)ethanone oxime (11) (5.0 g, 21.73 mmol) in small portions over a period of 15 min. The mixture was stirred for additional 10 min at room temperature and then the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (silica gel, eluting with 5% ethyl acetate and hexanes) to give the title compound (12) (3.0 g, 65%) as a brown solid. 1H NMR (CDCl3, 400 MHz) δ 7.79 (s, 1H), 7.40 (dd, J=8.4, 1.6 Hz, 1H), 7.35 (d, J=8.4 Hz, 1H), 2.64 (s, 3H); MS (ESI, M+H+) C8H7BrNO, calcd. 212.0. found 212.0, 214.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cu](C#N)[C:12]#[N:13].O.N>N1C=CC=CC=1.C1(C)C=CC=CC=1>[CH:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:12]#[N:13])([CH3:10])[CH3:9]
Reactant: CC(C)c1cccc(Br)c1
Reactant: N#C[Cu]C#N
Agent: N
Solvent: O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)c1cccc(C#N)c1

Procedure:
5.15 g (25.87 mmol) m-bromo-isopropyl-benzene and 2.69 g (30.04 mmol) copper cyanide are stirred in 2.50 ml of pyridine for 24 hours at 180° C. Then 15 ml of water, 15 ml of toluene and 15 ml conc. ammonia solution are added, then the mixture is extracted. The organic phase is dried and evaporated to dryness.