Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[CH:6]2.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C=O)C>[N:18]([CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[CH:6]2)=[N+:19]=[N-:20]
Reactant: BrCc1ccc2c(cnn2C2CCCCO2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=NCc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 90 °C
Yield: 99.5 %

Procedure:
To a solution of 5-(bromomethyl)-1-(2-tetrahydropyranyl)indazole (compound 93, 3.0 g, 10.2 mmol) in DMF (30 mL), was added with sodium azide (Aldrich, 2.64 g, 40.6 mmol) in one portion. The suspension was heated at 90° C. for 30 minutes and a yellow solution formed. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with ether (2×150 mL). Combined organic layers were washed with brine, then dried (MgSO4). Evaporation of solvent gave the product (94) as a yellow oil (2.61 g, 99%). TLC Rf 0.63 (60:40 hexane-ethyl acetate); MS (electrospray) 258 (M+1); 1H NMR (CDCl3) δ2.03-2.15 (m, 2H), 2.55 (m, 1H), 3.72 (m, 1H), 4.02 (m, 1H), 4.52 (s, 1H), 5.71 (d, 1H, J=9.4 Hz), 7.32 (d, 1H, J=8.8 Hz), 7.56 (d, 1H, J=8.8 Hz), 7.63 (s, 1H), 8.00 (s, 1H).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]#[N:9])=[CH:4][N:3]=[CH:2]1.C([O-])([O-])=[O:15].[K+].[K+].OO>CS(C)=O>[NH:3]1[CH:4]=[C:5]([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]([NH2:9])=[O:15])[N:1]=[CH:2]1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccccc1-c1cnc[nH]1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1ccccc1-c1c[nH]cn1
Reaction time: 16 h
Yield: 74.5 %

Procedure:
To a solution of 2-(1H-imidazol-5-yl)benzonitrile (85 mg, 0.502 mmol) in DMSO (3 mL) at room temperature was added K2CO3 (69 mg, 0.502 mmol) followed by H2O2 (30%, 1.1 mL, 10.04 mmol). After stirring for 16 h, the reaction was concentrated and the crude product was purified by flash column chromatography (silica gel, 10% MeOH/DCM followed by 10% MeOH/EtOAc) to yield the desired amide as a white solid (70 mg, 0.374 mmol, 75%). 1H NMR (DMSO-d6): 7.20-7.35 (m, 5H), 7.66 (s, 1H), 7.75 (s, 1H), 7.83 (s, 1H), 12.01 (br s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([OH:25])=[O:24])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH3:20])[N:19]=[C:15]4[N:14]=[C:13]([CH2:21][OH:22])[CH:12]=3)[CH2:7][S:8][C@H:3]12.CO.[C:30]1([C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N+]=[N-])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(=NN)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)Cl.CCOCC.CCCCCC>[NH2:1][CH:2]1[C:26](=[O:27])[N:4]2[C:5]([C:23]([O:25][CH:36]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[O:24])=[C:6]([CH2:9][S:10][C:11]3[N:16]4[N:17]=[C:18]([CH3:20])[N:19]=[C:15]4[N:14]=[C:13]([CH2:21][OH:22])[CH:12]=3)[CH2:7][S:8][C@H:3]12
Reactant: Cc1nc2nc(CO)cc(SCC3=C(C(=O)O)N4C(=O)C(N)[C@H]4SC3)n2n1
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Agent: NN=C(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1nc2nc(CO)cc(SCC3=C(C(=O)OC(c4ccccc4)c4ccccc4)N4C(=O)C(N)[C@H]4SC3)n2n1

Procedure:
In a suspension of 11.6 g of 7-amino-3-[(5-hydroxymethyl2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl)thiomethyl]-3- cephem-4-carboxylic acid, 70 ml of methanol and 200 ml of methylene chloride was added dropwise, while stirring, diphenyldiazomethane synthesized from 15.7 g of benzophenonehydrazone, 17.3 g of mercuric oxide (yellow) and 130 ml of n-hexane, in 50 ml of methylene chloride solution, and the mixture was stirred at room temperature overnight. After the reaction mixture was condensed, ether was added thereto to crystalize, and crystal was collected by filtration and dried to obtain 15.9 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12].Cl.[CH3:17][NH:18][CH3:19].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N:18]([CH3:19])[CH3:17])=[CH:6][C:5]=1[C:11]([F:14])([F:13])[F:12]
Reactant: CNC
Reactant: COC(=O)c1ccc(F)cc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a stirred solution of 4.48 g (22.5 mmol) 4-Fluoro-2-trifluoromethyl-benzoic acid methyl ester (Rarechem) and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 8 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 13a was obtained in 72% yield (4.00 g, 16.2 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:19]=2)=[CH:12][C:11]=1[NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([OH:39])[CH:34]=1>>[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:30])[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:19]=2)=[CH:12][C:11]=1[NH:31][C:32](=[O:40])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:2]2[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=2)[CH:34]=1
Reactant: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(O)c1
Reactant: Clc1cc(Cl)ncn1
Product: Cc1ccc(NC(=O)c2cccc(N3CCOCC3)c2)cc1NC(=O)c1cccc(Oc2cc(Cl)ncn2)c1
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 47, 4,6-dichloropyrimidine was reacted with N-[2-methyl-5-(3-morpholinobenzamido)phenyl]-3-hydroxybenzamide to give the title compound in 42% yield; NMR Spectrum: (DMSOd6) 2.18 (s, 3H), 3.14 (t, 4H), 3.73 (t, 4H), 7.22 (d, 1H), 7.34 (m, 2H), 7.47 (m, 3H), 7.57 (m, 1H), 7.63 (t, H), 7.81 (d, 1H), 7.93 (d, 1H), 8.66 (s, 1H), 9.96 (s, 1H), 10.14 (s, 1H); Mass Spectrum: M+H+ 544.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[H-].[Na+].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>CN(C=O)C>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][C:2]2=[O:11])=[CH:18][CH:17]=1
Reactant: O=C1CCc2ccccc2N1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
To a solution of 3,4-dihydro-1H-quinolin-2-one (27 mmol) in 250 mL of anhydrous DMF is added NaH (60% in mineral oil) (30 mmol) and the mixture is stirred at room temperature for 30 minutes. 4-Methoxybenzyl chloride (30 mmol) is then added and the reaction mixture is stirred at room temperature for 2 hours. The solvent is evaporated. The residue is dissolved in 100 mL of water and extracted with CH2Cl2 three times. The combined organic layers are dried over MgSO4, filtered, and evaporated to give the crude 1-(4-methoxy-benzyl)-3,4-dihydro-1H-quinolin-2-one, which is used in the next step without further purification. Yield: 95%.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][O:19][C:20]3[CH:21]=[C:22]([CH2:26][CH2:27][C:28]([O:30]C)=[O:29])[CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][O:19][C:20]3[CH:21]=[C:22]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:23]=[CH:24][CH:25]=3)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CCc1cccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1cccc(OCc2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Yield: 71.7 %

Procedure:
A mixture of methyl 3-[3-[(4,5-diphenyl-2-oxazolyl)-methoxy]phenyl]propanoate (6 g, 14.5 mmol), 5N sodium hydroxide solution (8.7 mL) and methanol (150 mL) was heated to reflux on a steam bath. After 20 minutes the mixture was concentrated, diluted with water (200 mL) and 2N hydrochloric acid solution to pH=1. After filtration and drying in air overnight, the solid was recrystallized from a mixture of hexanes and CH2Cl2 to give 3-[3-[(4,5-diphenyl-2-oxazolyl)methoxy]phenyl]propanoic acid (4.15 g, 71%), m.p. 118°-120° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH3:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[C:13]([C:16]1[S:20][C:19](B(O)O)=[CH:18][CH:17]=1)(=[O:15])[CH3:14].C(=O)([O-])[O-].O>CN(C=O)C>[CH2:9]([O:8][C:6]1[N:5]=[C:4]([S:11][CH3:12])[N:3]=[C:2]([C:19]2[S:20][C:16]([C:13](=[O:15])[CH3:14])=[CH:17][CH:18]=2)[CH:7]=1)[CH3:10]
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: CCOc1cc(Cl)nc(SC)n1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(-c2ccc(C(C)=O)s2)nc(SC)n1
Temperature: 80 °C
Yield: 27.9 %

Procedure:
The crude product of Preparation 27, 4-chloro-6-ethoxy-2-methylsulfanylpyrimidine, (525 mg, 2.56 mmol) was dissolved in DMF (4 mL). To this solution was added 5-acetyl-2-thiopheneboronic acid (523 mg, 3.08 mmol), PdCl2dppf (209 mg, 0.26 mmol), potassim carbonate (1.06 g, 7.69 mmol) and water (0.4 mL). The reaction mixture was heated at 80° C. under nitrogen atmosphere for overnight. The reaction mixture was cooled and poured into 30 mL of water and was then extracted with diethyl ether (20 mL×3) three times. The ether layer was separated and dried with anhydrous MgSO4 and concentrated in vacuo. The resulting crude product was purified by flash silica column chromatography (20% ethyl acetate in hexane) to give product 1-[5-(6-ethoxy-2-methylsulfanyl-pyrimidin-4-yl)-thiophen-2-yl]-ethanone (210 mg, 28% yield over two steps). 1H-NMR (CDCl3): δ 7.67 (m, 2 H), 6.68 (s, 1 H), 4.46 (q, J=7.1 Hz, 2 H), 2.60 (s, 3 H), 2.59 (s, 3 H), 1.40 (t, J=7.1 Hz, 3 H).
Reaction SMILES: [CH3:1][CH2:2][C@@:3]12[O:15][C@@H:14]1[C@H:12]1[CH2:13][N:5]([CH2:6][CH2:7][C:8]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[NH:54][C:9]=3[C@@:10]([C:50]([O:52][CH3:53])=[O:51])([C:16]3[CH:21]=[C:20]4[C@@:22]56[C@@H:33]([N:34]([CH:35]=O)[C:19]4=[CH:18][C:17]=3[O:48][CH3:49])[C@@:32]([OH:41])([C:37]([O:39][CH3:40])=[O:38])[C@H:31]([O:42][C:43]([CH3:45])=[O:44])[C@:27]3([CH2:46][CH3:47])[CH:28]=[CH:29][CH2:30][N:25]([C@H:26]53)[CH2:24][CH2:23]6)[CH2:11]1)[CH2:4]2.N1C2C(=CC=CC=2)C=C1.N1C2C(=CC=CC=2)CC1>O1CCCC1>[CH3:1][CH2:2][C@@:3]12[O:15][C@@H:14]1[C@H:12]1[CH2:13][N:5]([CH2:6][CH2:7][C:8]3[C:60]4[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=4[NH:54][C:9]=3[C@@:10]([C:50]([O:52][CH3:53])=[O:51])([C:16]3[CH:21]=[C:20]4[C@:22]56[C@@H:26]7[C@:27]([CH2:46][CH3:47])([C@@H:31]([O:42][C:43]([CH3:45])=[O:44])[C@:32]([OH:41])([C:37]([O:39][CH3:40])=[O:38])[C@@H:33]5[N:34]([CH3:35])[C:19]4=[CH:18][C:17]=3[O:48][CH3:49])[CH:28]=[CH:29][CH2:30][N:25]7[CH2:24][CH2:23]6)[CH2:11]1)[CH2:4]2
Reactant: CC[C@]12CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(c4cc5c(cc4OC)N(C=O)[C@H]4[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]6(CC)C=CCN7CC[C@]54[C@@H]76)C[C@H](C3)[C@H]1O2
Agent: c1ccc2[nH]ccc2c1
Agent: c1ccc2c(c1)CCN2
Solvent: C1CCOC1
Product: CC[C@]12CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(c4cc5c(cc4OC)N(C)[C@H]4[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]6(CC)C=CCN7CC[C@]54[C@@H]76)C[C@H](C3)[C@H]1O2

Procedure:
A process for preparing VCR and formylleurosine which comprises oxidizing a tetrahydrofuran solution of the crude dimeric indole-dihydroindole alkaloids obtainable by extraction from the leaves of Vinca rosea in which VLB and leurosine are the predominant alkaloids with an aqueous chromate-sulfuric acid oxidizing solution at a temperature in the range about -80° C. to about -50° C. until substantially all the VLB and leurosine initially present are converted to vincristine and formylleurosine respectively, optionally reformylating any 1-desformyl congeners present, and then separating vincristine and formylleurosine therefrom by chromatography.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12](COCC[Si](C)(C)C)[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.C(#N)C.[C:26](#[N:31])[CH:27]=[C:28]([CH3:30])[CH3:29].C1CCN2C(=NCCC2)CC1>>[CH3:29][C:28]([N:2]1[CH:3]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][NH:12][C:8]=3[N:9]=[CH:10][N:11]=2)[CH:5]=[N:1]1)([CH3:30])[CH2:27][C:26]#[N:31]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: CC(C)=CC#N
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(CC#N)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 60 °C

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]-pyrimidine (0.216 g, 0.684 mmol) in ACN (4 mL, 0.08 mol) was added crude senecionitrile (0.111 g, 1.37 mmol), followed by DBU (200 μL, 0.002 mol) and the resulting mixture was heated to 60° C. for 23 hours. The mixture was cooled to room temperature and the ACN was evaporated. The mixture was diluted with ethyl acetate and washed with dilute HCl and brine. The organic solution was dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (ethyl acetate/hexanes) afforded the desired product.
Reaction SMILES: N(CCO)CCO.[CH3:8][C:9]([C:22]1[CH:27]=[CH:26][C:25]([O:28]CC2OC2)=[CH:24][CH:23]=1)([C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2OC2)=[CH:13][CH:12]=1)[CH3:10]>>[OH:17][C:14]1[CH:13]=[CH:12][C:11]([C:9]([C:22]2[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=2)([CH3:10])[CH3:8])=[CH:16][CH:15]=1
Reactant: CC(C)(c1ccc(OCC2CO2)cc1)c1ccc(OCC2CO2)cc1
Solvent: OCCNCCO
Product: CC(C)(c1ccc(O)cc1)c1ccc(O)cc1
Reaction time: 12 h

Procedure:
Diethanolamine (525.70 grams, 5.00 amine hydrogen equivalents) is added to a 2 liter glass reactor equipped with a mechanical stirrer, chilled water condenser, nitrogen inlet, thermostatically controlled heating mantle, thermometer, and an inlet tube for the diglycidyl ether of bisphenol A. The diethanolamine is heated to 70° C. under a stream of nitrogen flowing at 1 liter per minute, then stirring commenced. A peristaltic pump is started to add diglycidyl ether of bisphenol A (179.95 epoxide equivalent weight (EEW)) to the reactor at a rate of 1.62 gram per minute. During the course of this addition, the temperature is maintained between 70° C. and 71° C.. After a total of 899.75 grams (5.00 epoxide equivalents) of the diglycidyl ether of bisphenol A is added to the reactor, post reaction is completed for 3 hours at 75° C., 12 hours at 90° C., then 2 hours at 150° C.. The adduct is recovered as a transparent tacky solid (at 25° C.) with a hydroxyl content of 17.2 percent.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C:7]([OH:9])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.O>CS(O)(=O)=O>[Cl:14][C:12]1[CH:13]=[C:2]([Cl:1])[C:3]2[O:4][CH2:5][CH2:6][C:7](=[O:9])[C:10]=2[CH:11]=1
Reactant: O=C(O)CCOc1ccc(Cl)cc1Cl
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: O=C1CCOc2c(Cl)cc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
3-(2,4-Dichlorophenoxy)propionic acid (52.36 g,0.223 mol) is added portion-wise to a mixture of phosphorus pentoxide (70.98 g, 0.490 mol) in methanesulfonic acid (Eaton's reagent) under nitrogen. The reaction mixture is stirred at room temperature for 4 hours, poured into water and filtered to obtain a solid. The solid is washed with water and dried in a vacuum oven to give the title product as an off-white solid (45.88 g, mp 86°-87° C.).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH2:32][CH3:33])[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])[CH3:2].[CH2:35](N(CC)C1N=C(C(O)=O)C=C(C)N=1)[CH3:36]>>[CH2:32]([N:31]([CH2:35][CH3:36])[C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:16]=[C:15]([CH3:34])[C:4]([O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:3]([CH2:1][CH3:2])[CH:18]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1)[CH3:33]
Reactant: CCN(CC)c1nc(C)cc(C(=O)O)n1
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO

Procedure:
N((S)-3-{4-[5-(2-Diethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-diethylamino-6-methyl-pyrimidine-4-carboxylic acid; LC-MS: tR=1.03 min; [M+H]+=499.23. 1H NMR (D6-DMSO): δ 1.18 (t, J=7.0 Hz, 6H), 1.22 (t, J=7.3 Hz, 3H), 2.35 (s, 3H), 2.44 (s, 3H), 2.73 (q, J=7.3 Hz, 2 H), 3.25 (m, 1H), 3.44 (m, 1H), 3.67 (q, J=7.0 Hz, 4H), 3.76 (m, 2H), 3.84 (d, J=5.8 Hz, 2H), 3.96 (m, 1H), 5.31 (d, J=5.0 Hz, 1H), 5.55 (t, J=5.5 Hz, 1H), 7.30 (s, 1H), 7.69 (t, J=5.5 Hz, 1H), 7.78 (s, 2H).
Reaction SMILES: [S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[OH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH:10]1SC.[NH2:17][NH2:18]>C(O)C.COC(C)(C)C>[S:1]([OH:5])(=[O:4])(=[O:3])[CH3:2].[OH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH:10]1[NH:17][NH2:18]
Reactant: NN
Reactant: CSC1NCCCN1CCO
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: COC(C)(C)C
Product: NNC1NCCCN1CCO
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-hydroxyethyl)-2-methylthio-3,4,5,6-tetrahydropyrimidine mesylate (87.2 g) is suspended in ethyl alcohol (150 ml) and treated with anhydrous hydrazine (22 mL). The mixture becomes clear within a few minutes. It is stirred at room temperature overnight and then diluted with t-butyl methyl ether (2 liters). The solution is kept in the freezer at -20° C. until the solid separates, filters and dries. Recrystallization from isopropyl alcohol and t-butyl methyl ether gives 68.12 g of 1-(2-hydroxyethyl)- 2-hydrazino-3,4,5,6-tetrahydropyrimidine mesylate, melting point 82.2°-84.4° C.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]([O:7][CH3:8])[O:5][CH3:6].C(N(CC)CC)C.[Cl-].[Ca+2].[Cl-].[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl.C(OCC)C>[CH3:1][N:2]([CH2:3][CH:4]([O:7][CH3:8])[O:5][CH3:6])[C:21](=[O:22])[CH2:20][Cl:19]
Reactant: O=C(Cl)CCl
Reactant: CNCC(OC)OC
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(CN(C)C(=O)CCl)OC
Temperature: -20 °C
Reaction time: 1 h

Procedure:
N-Methyl-2,2-dimethoxyethanamine (50.0 grams; 0.42 mole), methylene chloride (200 ml) and triethylamine (46.6 grams; 0.462 mole) were charged into a glass reaction vessel fitted with a mechanical stirrer, and thermometer. A calcium chloride filled drying tube was attached and the solution was cooled to about -20° C. Chloroacetyl chloride (49.7 grams; 0.44 moles) dissolved in methylene chloride (25 ml) was then added dropwise, with stirring, while holding the temperature at about -20° C. to -10° C. At the end of the addition, stirring was continued at -20° C. to 10° C. for a period of about 1 hour. The solution was allowed to warm to room temperature, then was stirred at this temperature for a period of about 16 hours. Diethyl ether (125 ml) was then added and the resulting solution filtered. The filtrate was washed with water (30 ml). The washed filtrate was dried and filtered. The solvent was distilled off under mild heat and reduced pressure to yield a residue which was fractionally distilled under reduced pressure to yield the desired product N-methyl-N-(2,2-dimethoxyethyl)-2-chloroacetamide as a fraction boiling at 112° C.-119° C. at 0.30 mm. Hg.
Reaction SMILES: [OH-].[Li+].[CH2:3]([N:5]([CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH:27]=2)[CH2:22][CH2:21]1)[C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[O:9][CH2:10][C:11]([O:13]C(C)C)=[O:12])[CH3:4]>C1COCC1>[CH2:3]([N:5]([CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=3)[CH:27]=2)[CH2:22][CH2:21]1)[C:6]1[CH:7]=[C:8]([CH:17]=[CH:18][CH:19]=1)[O:9][CH2:10][C:11]([OH:13])=[O:12])[CH3:4]
Reactant: CCN(c1cccc(OCC(=O)OC(C)C)c1)C1CCc2ccc(-c3cccc(F)c3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(c1cccc(OCC(=O)O)c1)C1CCc2ccc(-c3cccc(F)c3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
Aqueous lithium hydroxide (1 N, 1 mL, 1 mmol) was added to a solution of isopropyl 2-(3-(ethyl(6-(3-fluorophenyl)-2,3-dihydro-1H-inden-1-yl)amino)phenoxy)acetate (7 mg, 0.016 mmol) in THF (1 mL) in a scintillation vial. The vial was sealed and stirred overnight at room temperature. After 24 h, the reaction mixture was allowed to cool and the volatiles were concentrated. The residue was acidified with hydrochloric acid (1 N, 1 mL) and extracted with ethyl acetate (3×2 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by preparative TLC (1000 mm thickness, 10% methanol/dichloromethane) to afford 2 mg (32%) of the title compound.
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].C>O.[Cu].CN(C)C=O>[CH3:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: Cc1ccc(O)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2cc(Cl)ccc2C(=O)O)cc1

Procedure:
A mixture of 15 g. of 2,4-dichlorobenzoic acid, 10 g. of p-methylphenol, 0.5 g. of copper powder and 20 g. of anhydrous potassium carbonate in 200 ml. of dimethylformamide is heated to 165° C and maintained thereat with stirring and under a nitrogen atmosphere. After monitoring via tlc indicates the reaction is substantially complete, the reaction mixture is diluted with water, treated with charcoal, filtered and the clear filtrate acidified. The precipitate is isolated by suction filtration, washed neutral and dried to give 2-(p-methylphenyloxy)-4-chlorobenzoic acid.
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[CH:9][C:8]([Cl:18])=[N:7][CH:6]=1)C.O1CCOCC1.[OH-].[Na+]>O>[Cl:18][C:8]1[CH:9]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:5]([C:4]([OH:19])=[O:3])=[CH:6][N:7]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1-c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cnc(Cl)cc1-c1ccccc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 100.2 %

Procedure:
A mixture of 3.20 g (10.8 mmol) 6-chloro-4-(2-chloro-phenyl)-nicotinic acid ethyl ester, 50 ml dioxane and 50 ml of a 2 M aqueous sodium hydroxide solution was stirred at room temperature for 17 h. Dilution with water was followed by washing with two portions of tert-butyl methyl ether. The combined organic layers were extracted with 1 M aqueous sodium hydroxide solution. The combined aqueous layers were acidified to pH 2 with 2 M aqueous hydrochloric acid solution and extracted with four portions of tert-butyl methyl ether. The combined organic extracts were dried with sodium sulfate and concentrated to give 2.90 g (100%) of the title compound as an off-white solid.