Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6].[H-].[Na+].[Na].[CH2:17]([SH:19])[CH3:18]>CN(C)C=O>[CH2:17]([S:19][CH2:2][CH2:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([OH:7])=[O:6])[CH3:18]
Reactant: CCS
Reactant: O=C(O)C(CCBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: CCSCCC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
(RS)-4-Bromo-2-phenylbutanoic acid (prepared as described in Farmaco (pavia) Ed. Sci. 355 21(5) 1966) (2.43 g) in dimethylformamide (5 ml) was added to a stirred suspension of sodium hydride (0.33 g, as an 80% dispersion in oil) and ethanethiol sodium salt (1.26 g) in dimethylformamide (15 ml) at 0° C. The mixture was warmed to room temperature, stirred for 2 hours and evaporated. The residue was partitioned between water and ethylacetate, the aqueous layer acidified with concentrated hydrochloric acid and extracted with ethylacetate. The organic layer was dried over sodium sulphate and evaporated to give the title compound (2 g, 89%) as an oil.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][N:3]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]2)=[O:7])[CH2:2]1.O[N:28]=[C:29]([NH2:31])[CH3:30]>>[CH3:30][C:29]1[N:31]=[C:24]([CH:10]2[CH2:11][CH:12]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[CH2:13][N:8]([C:6]([N:3]3[CH2:4][CH2:5][S:1][CH2:2]3)=[O:7])[CH2:9]2)[O:25][N:28]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCSC2)C1
Reactant: CC(N)=NO
Product: Cc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCSC3)C2)n1
Yield: 14.9 %

Procedure:
250 mg (0.644 mmol) of 1-(1,3-thiazolidin-3-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 102A) and 52.5 mg (0.708 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 1. Enantiomer separation of the racemate according to Method 16D gave 38.0 mg of the title compound from Example 315 and 41.0 mg of the title compound from Example 316 (29% of theory).
Reaction SMILES: [CH3:1][C@H:2]([C@H:39]1[O:41][C@@H:40]1[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C@H:3]1[O:22][C:20](=[O:21])[C@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[O:18][C:16](=[O:17])[C:15]([CH3:28])([CH3:27])[CH2:14][NH:13][C:11](=[O:12])[C@@H:10]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([O:37][CH3:38])=[C:34]([Cl:36])[CH:35]=2)[NH:9][C:7](=[O:8])[CH:6]=[CH:5][CH2:4]1.[ClH:48].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][C@H:2]([C@@H:39]([OH:41])[C@@H:40]([Cl:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C@H:3]1[O:22][C:20](=[O:21])[C@H:19]([CH2:23][CH:24]([CH3:25])[CH3:26])[O:18][C:16](=[O:17])[C:15]([CH3:28])([CH3:27])[CH2:14][NH:13][C:11](=[O:12])[C@@H:10]([CH2:29][C:30]2[CH:31]=[CH:32][C:33]([O:37][CH3:38])=[C:34]([Cl:36])[CH:35]=2)[NH:9][C:7](=[O:8])[CH:6]=[CH:5][CH2:4]1
Reactant: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)[C@H]3O[C@@H]3c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)C(C)(C)CNC2=O)cc1Cl
Reactant: Cl
Agent: COc1ccc(C[C@H]2NC(=O)/C=C/C[C@@H]([C@H](C)[C@@H](O)[C@@H](Cl)c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)C(C)(C)CNC2=O)cc1Cl
Agent: COc1ccc(C[C@H]2NC(=O)/C=C/C[C@@H]([C@H](C)[C@H]3O[C@@H]3c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)C(C)(C)CNC2=O)cc1Cl
Agent: O=C([O-])[O-]
Product: COc1ccc(C[C@H]2NC(=O)C=CC[C@@H]([C@H](C)[C@@H](O)[C@@H](Cl)c3ccccc3)OC(=O)[C@H](CC(C)C)OC(=O)C(C)(C)CNC2=O)cc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of Cryptophycin 52 (6 mg, 0.009 mol, Example 22 or 22A) in 0.6 mL of 2:1 1,2-dimethoxymethane/water was added 2 μL of 12 N HCl. The solution was allowed to stir at room temperature for 20 h, neutralized with potassium carbonate, filtered through a 5μ filter, and evaporated. The acetonitrile-soluble material was purified by reverse-phase HPLC on C18 (250×10 mm column) using 4:1 MeOH/H2O to obtain 3.0 mg of Cryptophycin 55 (48%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH:8]=1>C(O)C.C(O)(=O)C.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccccn2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(c2ccccn2)CC1
Yield: 100 %

Procedure:
Tert-butyl 4-(pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.150 g, 0.576 mmol) was dissolved in ethanol (2 mL) and acetic acid (0.2 mL). The reaction mixture was hydrogenated with Pd/C (10%) in an H-cubemapparatus at about 60° C. for about 3 minutes. The solvent was removed in vacuo to give tert-butyl 4-(pyridin-2-yl)piperidine-1-carboxylate (0.151 g, 0.576 mmol) as white solid which was used in subsequent reactions without further purification. RP-HPLC (Table 1, Method b) Rt 1.97 min; m/z: (M+H)+ 263.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH:8]=[C:7]1[O:17]C)(=[O:3])[CH3:2].I[Si](C)(C)C>C(#N)C>[C:1]([O:4][CH2:5][C:6]1([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][C:7]1=[O:17])(=[O:3])[CH3:2]
Reactant: COC1=CC(=O)c2ccccc2C1(CCC(C)C)COC(C)=O
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC(=O)OCC1(CCC(C)C)C(=O)CC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of Example 179C (0.12 g, 0.38 mmol) in acetonitrile (3.5 mL) was added iodotrimethylsilane (TMSI) (81 μL, 0.57 mmol). The reaction solution was stirred at room temperature for 3 h. After which, additional 1.5 equivalents of TMSI (81 μL) were added and stirring was continued for 2 h. The solution was quenched with water (3 mL) and extracted with ethyl acetate (2× 5 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (70% ethyl acetate/hexane) afforded product as a white solid (91%). 1H NMR (300 MHz, CDCl3) δ ppm 0.55 (s, 1H), 0.77 (m, 12H), 0.93 (m, 2H), 1.36 (m, 3H), 1.79 (m, 8H), 2.19 (m, 3H), 3.77 (m, 2H), 4.42 (d, J=11.03 Hz, 1H), 4.57 (m, 3H), 6.15 (s, 1H), 7.46 (m, 4H), 7.59 (m, 1H), 7.69 (m, 1H), 8.12 (m, 2H); MS m/z 303.0.
Reaction SMILES: O.Cl.Cl.[O:4]=[C:5]1[N:14]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:13][CH2:12][C:11]2[N:10]=[C:9]([CH2:21][CH2:22][CH3:23])[C:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][C:6]1=2.[CH:29]1([C:32]2[CH:37]=[C:36]([CH:38]=O)[C:35]([O:40][CH2:41][CH3:42])=[CH:34][C:33]=2[C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=2[F:50])[CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1.O.C(O)(=O)C.C(N(CC)CC)C>[CH:29]1([C:32]2[CH:37]=[C:36]([CH2:38][N:18]3[CH2:17][CH2:16][CH:15]([N:14]4[CH2:13][CH2:12][C:11]5[N:10]=[C:9]([CH2:21][CH2:22][CH3:23])[C:8]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][C:6]=5[C:5]4=[O:4])[CH2:20][CH2:19]3)[C:35]([O:40][CH2:41][CH3:42])=[CH:34][C:33]=2[C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=2[F:50])[CH2:31][CH2:30]1
Reactant: CCCc1nc2c(cc1C(=O)OCC)C(=O)N(C1CCNCC1)CC2
Reactant: CCOc1cc(-c2ccc(F)cc2F)c(C2CC2)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCc1nc2c(cc1C(=O)OCC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4F)cc3OCC)CC1)CC2
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a suspension of Ethyl 5-oxo-6-(piperidin-4-yl)-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate dihydrochloride monohydrate (10.1 g) in THF (203 mL) was added triethylamine (6.49 mL). The mixture was stirred for 30 minutes. 2-Cyclopropyl-5-ethoxy-2′,4′-difluorobiphenyl-4-carbaldehyde (7.73 g) was added to the mixture. The mixture was stirred for 30 minutes. Then Sodium triacetoxyborohydride (7.39 g) and acetic acid (1.33 mL) was added to the reaction mixture. The mixture was stirred at room temperature for overnight. The mixture was added to aqueous saturated sodium hydrogen carbonate solution (135 mL) and water (135 mL) at room temperature. The mixture was extracted with ethyl acetate (1.35 L). The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate) to give the title compound (13.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[CH:24]=[N:23]2)[CH:5]=[CH:6][C:7]=1[C:8](Cl)([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[NH4+:30].[OH-].Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:22]2[C:27](=[O:28])[NH:26][C:25](=[O:29])[CH:24]=[N:23]2)[CH:5]=[CH:6][C:7]=1[C:8]([NH2:30])([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]1[S:10][CH:11]=[CH:12][N:13]=1
Reactant: [NH4+]
Reactant: O=c1cnn(-c2ccc(C(Cl)(c3ccc(Cl)cc3)c3nccs3)c(Cl)c2)c(=O)[nH]1
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(c1ccc(Cl)cc1)(c1nccs1)c1ccc(-n2ncc(=O)[nH]c2=O)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of compound (36) (0.00425 mol) in THF (20 ml) was added dropwise at 5° C. to NH4OH (20 ml) and the mixture was stirred at RT for 2 hours, then poured out on ice, neutralized with HCl 6N and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 97/3). The pure fractions were collected and the solvent was evaporated. The residue was repurified by column chromatography over Kromasil C18 (eluent: CH3OH/H2O/HOAc 70/30/1). The pure fractions were collected and the solvent was evaporated. The residue was taken up in H2O and NH4OH (pH=8) was added. The precipitate was filtered off, washed with H2O and diethyl ether, and dried, yielding 0.3 g (±)-2-[3-chloro-4-[amino-(4-chlorophenyl)-2-thiazolylmethyl]phenyl]-1,2,4-triazine-3,5(2H,4H)-dione (compound 35).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[O:24])[CH:12]=[CH:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1.[C:25]([O:33][CH2:34][CH3:35])(=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[CH:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[CH:13]([CH:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:25]([O:33][CH2:34][CH3:35])=[O:32])[CH2:12][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[O:24]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(C=Cc1ccc2ccccc2c1)c1ccc2ccccc2c1
Product: CCOC(=O)C(C(=O)OCC)C(CC(=O)c1ccc2ccccc2c1)c1ccc2ccccc2c1

Procedure:
By a procedure similar to that of example 1.59.2, starting from 1,3-di(2-naphthalenyl)prop-2-en-1-one and diethyl malonate, diethyl 2-(1,3-di(2-naphthalenyl)-3-oxopropyl)malonate was obtained as colourless solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH2:7][C@H:8]2[CH2:12][O:11]C(C)(C)[O:9]2)=[CH:4][CH:3]=1.Cl.CC(=O)C>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C@H:8]([OH:9])[CH2:12][OH:11])=[CH:15][CH:16]=1
Reactant: CC1(C)OC[C@H](COc2ccc(F)cc2)O1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCO
Product: OC[C@@H](O)COc1ccc(F)cc1
Reaction time: 2 h
Yield: 50.4 %

Procedure:
A mixture of 26 parts of (S)-4-[(4-fluorophenoxy)methyl]-2,2-dimethyl-1,3-dioxolane, 35 parts of a hydrochloric acid solution 2N and 80 parts of 2-propanone was stirred for 2 hours at reflux temperature. The mixture was stirred overnight at room temperature, diluted with 240 parts of ethanol and evaporated. The residue was dissolved in trichloromethane. The organic layer was washed twice with water, dried, filtered and evaporated. The residue was crystallized from tetrachloromethane. The product was filtered off and dried, yielding 11 parts (50.4%) of (-)-(R)-3-(4-fluorophenoxy)-1,2-propanediol; [α]D =-10.08° (c=0.5% in methanol) (146).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30](F)=[CH:29][CH:28]=[CH:27][C:26]=4F)[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.O1[C:39]2[CH:40]=[CH:41][C:42]([NH2:44])=[CH:43][C:38]=2OCC1>>[CH2:2]1[C:38]2[C:39](=[CH:40][CH:41]=[C:42]([NH:44][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=6)[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:43]=2)[CH2:5][CH2:4][NH:3]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Product: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3ccc4c(c3)CNCC4)n2)c1)c1ccccc1

Procedure:
The title compound was prepared from N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide and 2,3-dihydro-1,4-benzodioxin-6-amine in a manner analogous to Example 64. 1H NMR (400 MHz, DMSO-d6) δ 4.20 (m, 4H), 6.45 (d, 1H, J=5.3 HZ), 6.72 (d, 1H, J=8.8 Hz), 7.10 (m, 2H), 7.22 (m, 2H), 7.28 (m, 2H), 7.35 (m, 2H), 7.46 (d, 1H, J=8.1 Hz), 7.98 (s, 1H), 8.20 (d, 1H, J=5.3 Hz), 8.83 (d, 1H, J=6.9 Hz), 9.35 (s, 1H), 10.93 (s, 1H); ESIMS (M+H)+=577.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH2:43])=[CH:40][CH:39]=1>>[Cl:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][NH:43][C:3]([C:5]2[N:14]3[C:8]([CH2:9][N:10]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[CH3:33])=[C:23]([CH3:34])[CH:22]=4)=[O:20])[C:11]4[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=4[CH2:13]3)=[CH:7][CH:6]=2)=[O:4])=[CH:40][CH:39]=1
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: NCc1ccc(Cl)cc1
Product: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4ccc(Cl)cc4)n3Cc3ccccc32)cc1C

Procedure:
The title compound was synthesized in the manner of Example 13 from 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 and 4-chlorobenzylamine, m.p. 196-197° C. MS [(+)ESI, m/z]: 558 [M+H]+
Reaction SMILES: [C:1]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(N(CC)CC)C>CS(C)=O.C[C@@H]1[C@@H]2C(=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3[C@H]2O)C(=O)C2C(O)=CC=CC1=2.OP(=O)=O.OP(=O)=O.OP(=O)=O.[O-]P(=O)=O.[Na+]>[C:1]([N:11]1[CH2:17][CH2:16][CH2:15][C@H:12]1[CH:13]=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Agent: C[C@H]1c2cccc(O)c2C(=O)C2=C(O)[C@]3(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]3[C@@H](O)[C@@H]21
Agent: O=P(=O)O
Agent: O=P(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
To a stirred solution of N-Cbz-L-prolinol (5g, 21.26 mmol, from steps 24b or 24c above) in 20 mL of anhydrous DMSO were added 8.89 mL (63.79 mmol) of triethylamine and 10.75 g (63.79 mmol) of SO3 -pyridine complex in 35 mL of DMSC). The reaction mixture was stirred at room temperature for 10 min, then poured into 200 mL of ice water. The mixture was extracted with ether, the extract was dried over Na2SO4 and concentrated to afford the title product, 3.058 g (70% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31](O)=[O:32])[C:25]=1[CH3:34])(=[O:12])=[O:11].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH:62]1[CH2:67][CH2:66][CH:65]([N:68]2[CH2:73][CH2:72][O:71][CH2:70][CH2:69]2)[CH2:64][CH2:63]1.[Li+].[Cl-]>CN(C=O)C.C(Cl)(Cl)Cl.C(O)(C)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([CH2:30][C:31]([N:62]2[CH2:67][CH2:66][CH:65]([N:68]3[CH2:73][CH2:72][O:71][CH2:70][CH2:69]3)[CH2:64][CH2:63]2)=[O:32])[C:25]=1[CH3:34])(=[O:11])=[O:12]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)O
Reactant: C1CC(N2CCOCC2)CCN1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CC(=O)N1CCC(N2CCOCC2)CC1
Reaction time: 0.25 h

Procedure:
{5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-acetic acid (1 eq.) and BOP (1.25 eq.) were suspended in DMF (5 mL) at rt and TEA (2.4 eq.) was added. After 15 mins, to the homogenous reaction mixture was added 4-piperidin-4-yl-morpholine (1.25 eq.) all at once. After stirring for 2 days, the reaction was added to a mixture of chloroform-isopropanol (5:1) and 5% aq. LiCl. The organic layer was separated, washed with 5% aq. LiCl (2×), 1 M aq. NaOH (3×), brine, dried and concentrated. The residue was purified to give the titled compound.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:15]=[C:14]([O:16][CH3:17])[N:13]([CH3:18])[N:12]=2)=[CH:7][C:6]=1[CH3:19])([CH3:3])[CH3:2].[Cl:20]N1C(=O)CCC1=O.C(Cl)(Cl)Cl>O>[Cl:20][C:15]1[C:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[C:6]([CH3:19])[CH:7]=2)=[N:12][N:13]([CH3:18])[C:14]=1[O:16][CH3:17]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(-c2ccc(OC(C)C)c(C)c2)nn1C
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1c(Cl)c(-c2ccc(OC(C)C)c(C)c2)nn1C
Reaction time: 14 h
Yield: 85.3 %

Procedure:
At room temperature, a mixture of 3-(4-isopropoxy-3-methyl-phenyl)-5-methoxy-1-methyl-1H-pyrazole (described in Reference Preparation example 110) 5.8 g, N-chlorosuccinimide 3.3 g and chloroform 70 ml was stirred for 14 hours. Thereto was added water 50 ml and the resulting mixture was extracted with chloroform. The organic layer was washed with water, and was dried over anhydrous magnesium sulfate and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 4-Chloro-3-(4-isopropoxy-3-methyl-phenyl)-5-methoxy-1-methyl-1H-pyrazole 5.6 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:14])[N:11]([NH2:13])[CH:12]=1.C(O)(=O)C.[CH:19](N)=[NH:20].C1(C)C=CC=CC=1>CC(O)CC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:14])[N:11]([NH:13][CH:19]=[NH:20])[CH:12]=1
Reactant: N=CN
Reactant: Cc1nc(-c2ccccc2F)cn1N
Solvent: CC(=O)O
Solvent: CCC(C)O
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccccc2F)cn1NC=N

Procedure:
Compound C3 (9.95 g, 52.0 mmol) and formamidine acetate (previously azeotroped with toluene, 13.5 g, 130 mmol) were combined in 2-butanol (160 mL) and heated at reflux for 3 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was suspended in a mixture of heptane and ethyl acetate; filtration provided the product as a pale brown powder. Yield: 8.20 g, 37.6 mmol, 72%. LCMS m/z 219.3 [M+H]+. 1H NMR (500 MHz, DMSO-d6), presumed to be a mixture of rotamers and/or tautomers; characteristic peaks: δ 7.99-8.07 (m, 1.6H), 7.51 and 7.52 (2 s [1:1 ratio], 0.6H), 7.30 (dd, J=9.8, 9.8 Hz, 0.4H), 7.16-7.21 (m, 3.4H), 2.26 and 2.18 (2 s [1.6:1 ratio], 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:18](=[O:20])[NH:17][CH:16]=[N:15][C:14]=2[N:13]([CH3:21])[C:12](=[O:22])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CC1(C)[O:34][C@@H:33]([CH2:35][O:36]N)[CH2:32][O:31]1>CC(N(C)C)=O>[OH:34][C@H:33]([CH2:35][OH:36])[CH2:32][O:31][N:17]1[C:18](=[O:20])[C:19]2[C:10]([NH:9][C:3]3[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=3[F:1])=[CH:11][C:12](=[O:22])[N:13]([CH3:21])[C:14]=2[N:15]=[CH:16]1
Reactant: CC1(C)OC[C@H](CON)O1
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(OC[C@H](O)CO)cnc21
Temperature: 80 °C
Reaction time: 1 h
Yield: 13.2 %

Procedure:
Compound 5F (1.31 g, 3.17 mmol), potassium carbonate (1.1 g, 7.92 mmol) and 1-chloro-2,4-dinitronbenzene (1.60 g, 7.92 mmol) were stirred in DMA at 80° C. for 2 hours. (R)—O-((2,2-Dimethyl-1,3-dioxolan-4-yl)methyl)hydroxylamine (4.66 g, 31.7 mmol) was added at r.t and the reaction was stirred for 1 hour at 80° C. Purification by prep-HPLC gave 210 mg (13%) of the title compound as a clear yellow solid (Deprotection occurred while concentrating the purification fractions containing 0.5% of TFA). 1H NMR (400 MHz, DMSO-d6): 6 ppm 10.18 (s, 1H) 8.93 (s, 1H) 7.81 (dd, J=10.11, 1.77 Hz, 1H) 7.62 (dd, J=7.58, 1.01 Hz, 1H) 7.37 (t, J=8.46 Hz, 1H) 5.56 (s, 1H) 4.39 (dd, J=10.74, 3.16 Hz, 1H) 4.21 (dd, J=10.61, 7.33 Hz, 1H) 3.82-3.88 (m, 1H) 3.50 (s, 3H) 3.42-3.46 (m, 2H). MS (ES) [m+H] calc'd for C17H16FIN4O5, 503. found 503.
Reaction SMILES: C1C=CC([C:7]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=2[OH:16])=[O:8])=CC=1.C(O)[C@H]1[O:23][C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O>>[OH:16][C:10]1[CH:11]=[C:12]([OH:15])[CH:13]=[CH:14][C:9]=1[C:7]([OH:8])=[O:23]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1O
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: O=C(O)c1ccc(O)cc1O

Procedure:
The same methodology as described in Example 1 was repeated with 2,4-DHB in place of 3-HB, to produce the dose response curve for 2,4-DHB (FIG. 2). From FIG. 2 it can be seen that 2,4-DHB also enhances the sweetness of the sucrose solution but there is little difference between the 400 ppm solution (SEV 6.5%) and the 1000 ppm solution (SEV 6.7%). The maximum attainable sweetness would appear to be about 6.7% SEV (based on a 5% sucrose solution).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:50])=[C:4]([S:29]([N:32](CC2C=CC(OC)=CC=2OC)[C:33]2[CH:38]=[CH:37][N:36]=[CH:35][N:34]=2)(=[O:31])=[O:30])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@@H:10]1[C:15]1[C:16]([N+:26]([O-])=O)=[N:17][N:18](C2CCCCO2)[CH:19]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[NH2:26][C:16]1[C:15]([C@H:10]2[CH2:11][CH2:12][CH2:13][CH2:14][C@@H:9]2[O:8][C:7]2[CH:6]=[CH:5][C:4]([S:29]([NH:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][N:34]=3)(=[O:31])=[O:30])=[C:3]([F:50])[C:2]=2[Cl:1])=[CH:19][NH:18][N:17]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3cn(C4CCCCO4)nc3[N+](=O)[O-])c(Cl)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Nc1n[nH]cc1[C@H]1CCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1Cl
Yield: 10 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide (198 mg, 0.341 mmol) prepared in Example 91a, triethylsilane (0.10 mL), trifluoroacetic acid (0.5 mL), dichloromethane (2.0 mL) and methanol (1.0 mL), to yield the title compound (16 mg, 9.4%) as a pale yellow solid.
Reaction SMILES: N[C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[N:5]=[C:4]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[N:3]=1.C(Br)(Br)[Br:25]>>[Br:25][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[N:5]=[C:4]([S:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[N:3]=1
Reactant: Cc1nc2c(N)nc(SCc3cccc(F)c3F)nc2[nH]c1=O
Reactant: BrC(Br)Br
Product: Cc1nc2c(Br)nc(SCc3cccc(F)c3F)nc2[nH]c1=O

Procedure:
The sub-titled compound was prepared from the product of example 35, step (a) (1.5 g) and bromoform (30 ml) using the method of Example 3, step (b).