Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]C)=[O:31])=[CH:25][CH:24]=2)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6].[OH-].[Li+].Cl>C(O)C.O1CCCC1.O>[CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([C:21]#[C:22][C:23]2[CH:24]=[CH:25][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:27][CH:28]=2)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:17])([CH3:18])[CH2:13][C:12]2([CH3:19])[CH3:20])=[O:6]
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(=O)OCC(C)(C)C)c3c(c2)C(C)(C)CC(C)(C)O3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)COC(=O)c1cc(C#Cc2ccc(CC(=O)O)cc2)cc2c1OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
A solution of 6-(4-methoxycarbonylmethyl-phenylethynyl)-2,2,4,4-tetramethyl-chroman-8-carboxylic acid 2,2-dimethylpropyl ester (Intermediate 49, 0.198 g, 0.42 mmol) in ethanol (1 mL), tetrahydrofuran (1 mL) and water (1 mL) was treated with 1N lithium hydroxide (1.5 mL, 1.5 mmol) and the resulting reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was neutralized with 2N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water and brine, and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a greenish-yellow solid (0.16 g, 84%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([OH:10])=O)[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1.C(N(CC)CC)C.[N+:22]([C:25]1[CH:26]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:28]=[CH:29][CH:30]=1)([O-:24])=[O:23]>CN(C=O)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:34]2[CH2:35][CH2:36][N:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([N+:22]([O-:24])=[O:23])[CH:26]=3)[CH2:32][CH2:33]2)=[O:10])[N:5]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:3]=1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.1 %

Procedure:
To a solution of (5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid (1.1 g, 5.28 mmol) in DMF (10 mL) is added triethylamine (1.47 mL, 10.57 mmol), followed by 1-hydroxy-7-benzotriazole (0.755 g, 5.55 mmol) and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (1.06 g, 5.55 mmol). After stirring 15 min at RT, 1-(3-nitro-phenyl)-piperazine (1.09 g, 5.28 mmol) is added to the reaction mixture. After stirring overnight at RT, solvent is evaporated and the resulting yellow oil is dissolved in ethylacetate (20 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL), and brine (50 mL). The organic layer is dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude mixture is purified by column chromatography on silica gel (cyclohexane/ethylacetate 0-80%) to give 2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-1-[4-(3-nitro-phenyl)-piperazin-1-yl]-ethanone (1.24 g, 59%). 1H-NMR (400 MHz, MeOD): δ=2.31 (s, 3H), 3.31-3.40 (m, 2H), 3.41-3.49 (m, 2H), 3.77-3.85 (m, 4H), 5.25 (s, 2H), 6.43 (s, 1H), 7.38-7.42 (m, 1H), 7.44-7.51 (m, 1H), 7.69-7.72 (m, 1H), 7.80-7.81 (s, 1H). MS: m/z=398 (M+1).
Reaction SMILES: [P:1]([OH:5])([O-:4])([O-:3])=[O:2].[Ca+2].S([O-])([O-])(=O)=O.[K+:12].[K+]>>[OH:3][P:1]([O-:5])([OH:4])=[O:2].[K+:12].[OH:3][P:1]([OH:5])([OH:4])=[O:2]
Reactant: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Agent: [K+]
Product: O=P(O)(O)O
Product: O=P([O-])(O)O

Procedure:
In an alternative reaction, the solid monocalcium phosphate is reacted with potassium sulfate to yield primarily KH2PO4 with little or no H3PO4 coproduct. Conversely, if a portion of the (uncrystallized) MCP/H3PO4 liquor is reacted with potassium sulfate the resulting KH2PO4 /H3PO4 solution will have a plant food value of 0-24-6. A portion of any of the K2O products may be recycled back to the acidulation vessel to provide makeup for the K2O lost in the hydrolysis sector.
Reaction SMILES: [F-].[K+].[C:3]1([NH:9][S:10]([C:13]2[CH:14]=[C:15](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])[CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:24](#N)[CH3:25]>>[C:3]1([NH:9][S:10]([C:13]2[CH:14]=[C:15](/[CH:19]=[CH:20]/[C:21]([OH:23])=[O:22])[CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[CH2:24]([O:22][C:21](=[O:23])/[CH:20]=[CH:19]/[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([S:10](=[O:12])(=[O:11])[NH:9][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:14]=1)[CH3:25]
Reactant: CC#N
Agent: O=C(O)/C=C/c1cccc(S(=O)(=O)Nc2ccccc2)c1
Agent: [F-]
Agent: [K+]
Product: CCOC(=O)/C=C/c1cccc(S(=O)(=O)Nc2ccccc2)c1
Temperature: 80 °C

Procedure:
To the 30 gallon (˜136 L) reactor was charged the (E)-3-(3-phenylsulfamoyl-phenyl)-acrylic acid ethyl ester (5) (4.48 kg; 331.39 g/mol; 13.5 mol) along with 2 M aqueous sodium hydroxide (17.76 L; ˜35 mol). The mixture was heated to 40-50° C. and held at this temperature for 2 hours before sampling, at which point the reaction was deemed to be complete with no compound (5) being detected by HPLC. The batch was adjusted to pH 2.2 using 1 M aqueous hydrochloric acid while maintaining the batch temperature between 40-50° C. The product had precipitated and the batch was cooled to 20-30° C. and held at this temperature for 1 hour before filtering and washing the cake with water (8.9 L). The filtrate was discarded. The batch was allowed to condition on the filter overnight before being charged back into the reactor and slurried in water (44.4 L) at 40-50° C. for 2 hours. The batch was cooled to 15-20° C., held for 1 hour, and then filtered and the residue washed with water (8.9 L). The filtrate was discarded. The crude title compound (6) was transferred to an oven for drying at 45-55° C. under vacuum with a slight nitrogen bleed for 5 days (this was done for convenience) to give a white solid (3.93 kg, 97% yield). The moisture content of the crude material was measured using Karl Fischer (KF) titration and found to be <0.1% (w/w). To the 30 gallon (˜136 L) reactor was charged the crude compound (6) along with acetonitrile (47.2 L). The batch was heated to reflux (about 80° C.) and held at reflux for 2 hours before cooling to 0-10° C. and holding at this temperature overnight in order to precipitate the product. The batch was filtered and the residue was washed with cold acetonitrile (7.9 L). The filtrate was discarded and the residue was dried under vacuum at 45-55° C. for 21.5 hours. The title compound (6) was obtained as a fluffy white solid (3.37 kg, 84% yield with respect to compound (5)) with a purity of 99.89% (AUC) by HPLC.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH:7]1[O:14][CH:6]21)#[N:2].[N-:15]=[N+:16]=[N-:17].[Na+].[Cl-].[NH4+]>CN(C)C=O.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C@@H:7]([OH:14])[C@@H:6]2[N:15]=[N+:16]=[N-:17])#[N:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)c2ccc(C#N)cc2C2OC21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)c2ccc(C#N)cc2[C@@H](N=[N+]=[N-])[C@@H]1O
Temperature: 60 °C
Yield: 56.3 %

Procedure:
A mixture of 5-cyano-1,1-dimethyl-2,3-epoxyindane (1.34g), sodium azide (0.533g), and ammonium chloride (0.44g) in dry N,N-dimethylformamide (20 ml) was stirred and heated at 60° C., under nitrogen, for 3h. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with water, brine, and then dried (Na2SO4). Removal of solvents in vacuo, followed by chromatography of the residue (Si gel, eluted with 30% EtOAc in pentane) gave the title compound as a gum (0.93g).
Reaction SMILES: CON=[CH:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[O:8][C@@H:7]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:6]1.CC=[O:34]>CO>[CH:4]([C@@H:5]1[C@@H:9]([CH2:10][O:11][N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[O:8][C@@H:7]([N:23]2[CH:31]=[C:29]([CH3:30])[C:27](=[O:28])[NH:26][C:24]2=[O:25])[CH2:6]1)=[O:34]
Reactant: CC=O
Reactant: CON=C[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CON1C(=O)c2ccccc2C1=O
Solvent: CO
Product: Cc1cn([C@H]2C[C@H](C=O)[C@@H](CON3C(=O)c4ccccc4C3=O)O2)c(=O)[nH]c1=O

Procedure:
3'-Deoxy-3'-C-[(methoxyimino)methyl]-5'-O-phthalimidothymidine upon treated with CH3CHO in MeOH regenerated the 3'-C-formyl group. The product on purification by silica gel column chromatography furnished the title compound as homogeneous material in 81% overall yield for 3 steps, 1H NMR (CDCl3) δ9.95 (s, 1, CH=O); 8.62 (br s, 1, NH); 7.71-7.90 (m, 5, aromatic H, H-6); 6.06 (t, 1, H-1' J1'2' =6.61 Hz, J1'2' =6.6 Hz); 4.36-4.73 (m, 3, H-4', H-5',5"); 3.78 (m, 1, H-3'); 2.20-2.90 (m, 2, H-2",2"); 1.98 (s, 3, C5CH3).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:26])[S:17]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)(=[O:19])=[O:18])[CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][N:7]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.O.C(OCC)(=O)C.O>[ClH:1].[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[C:3]([N:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]([CH3:26])[S:17]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)(=[O:19])=[O:18])[CH2:10][CH2:9]3)=[N:4][CH:5]=[CH:6][N:7]=2)=[CH:30][CH:29]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CN(CCN1CCN(c2nccnc2Cl)CC1)S(=O)(=O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(CCN1CCN(c2nccnc2-c2ccc(F)cc2)CC1)S(=O)(=O)c1cccnc1
Product: Cl
Temperature: 110 °C
Reaction time: 18 h
Yield: 54.7 %

Procedure:
Dissolve pyridine-3-sulfonic acid [2-(3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl)-ethyl]-methyl-amide (0.200 g, 0.504 mmol) in DMA-H2O (4 mL; 3:1 v/v, previously degassed with nitrogen). Add 4-fluorophenyl boronic acid (0.084 g, 0.605 mmol), potassium carbonate (0.167 g, 1.209 mmol) and tetrakis(triphenyl-phosphine)palladium (0.029 g, 0.025 mmol). Stir the reaction mixture at 110° C. for 18 hr. Cool and dilute with ethyl acetate and water. Extract the aqueous layer with ethyl acetate and combine the organic layers. Dry the organics over sodium sulfate, filter, and concentrate. Purify by SCX chromatography, eluting with dichloromethane, dichloromethane:methanol, methanol, and 1N ammonia in methanol. Purify by silica gel chromatography eluting with hexanes:acetone 1:1 to afford the free base of the title compound (0.136 g, 59% yield).
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:5]=[C:6]([C:10]2[C:11]([CH3:34])=[N:12][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH:24][C:25](=[O:33])OC4C=CC=CC=4)=[CH:18][CH:17]=3)[C:14]=2[CH3:15])[CH:7]=[CH:8][CH:9]=1)=[O:3].[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[S:43]([NH2:46])(=[O:45])=[O:44]>>[F:35][C:36]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:37]=1[S:43]([NH:46][C:25]([NH:24][CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([N:13]2[C:14]([CH3:15])=[C:10]([C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:2]([NH2:1])=[O:3])[C:11]([CH3:34])=[N:12]2)=[CH:21][CH:20]=1)=[O:33])(=[O:44])=[O:45]
Reactant: NS(=O)(=O)c1ccc(F)cc1F
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1cccc(C(N)=O)c1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3ccc(F)cc3F)cc2)c(C)c1-c1cccc(C(N)=O)c1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-(4-{4-[3-(aminocarbonyl)phenyl]-3,5-dimethyl-1H-pyrazol-1-yl}phenyl)ethylcarbamate (step 6 of example 72) and 2,4-difluorobenzensulfonamide: MS (ESI) m/z 554 [M+H]+, 552 [M−H]−, 1H-NMR (CDCl3) δ 8.00-7.98 (1H, m), 7.83-7.73 (3H, m), 7.56-7.44 (2H, m), 7.22 (4H, s), 7.05-6.94 (1H, m), 6.20 (1H, br.s), 5.66 (1H, br.s), 3.47 (2H, t, J=6.2 Hz), 2.85 (2H, t, J=6.2 Hz), 2.21 (3H, s), 2.20 (3H, s).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:11]=[C:10]([C:19]([F:22])([F:21])[F:20])[C:9]=1[CH:23]=[O:24].C(OCC)(=O)C.O>C1COCC1>[Cl:7][C:8]1[N:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:11]=[C:10]([C:19]([F:21])([F:20])[F:22])[C:9]=1[CH2:23][OH:24]
Reactant: O=Cc1c(C(F)(F)F)nn(-c2ccccc2)c1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: OCc1c(C(F)(F)F)nn(-c2ccccc2)c1Cl
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A solution of 0.21 g (5.5 mmoles) of lithium aluminum hydride dissolved in 70 ml of THF was cooled to −30° C. Thereto was gradually added a solution of 3 g (10.9 mmoles) of 5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carboaldehyde dissolved in 30 ml of tetrahydrofuran. The resulting mixture was stirred at −30° C. for 30 minutes to give rise to a reaction. After the completion of the reaction, ethyl acetate was added, followed by stirring. Then, water was added, followed by stirring for a while. The reaction mixture was filtered under vacuum. The filtrate was extracted with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 3.0 g (yield: 99.9%) of (5-chloro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol as white crystals.
Reaction SMILES: [C:1]1([N:7]2[C:13](=[O:14])[CH2:12][C:11](=[O:15])[NH:10][C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:23][C:24]([N:26]([CH:34]([CH3:36])[CH3:35])[C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=1)=[O:25]>CN(C=O)C>[O:15]=[C:11]1[N:10]([CH2:23][C:24]([N:26]([CH:34]([CH3:36])[CH3:35])[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[O:25])[C:9]2[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=2[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:13](=[O:14])[CH2:12]1
Reactant: O=C1CC(=O)N(c2ccccc2)c2ccccc2N1
Reactant: Cc1ccc(N(C(=O)CBr)C(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.5 h
Yield: 45 %

Procedure:
To a stirred solution of 700 mg (2.78 mmol) 1-Phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-2,4-dione in 15 mL DMF is added 144 mg (3.61 mmol, 1.3 equiv) 60 wt % NaH at ambient temperature and stirred 0.5 h. To this solution is added 750 mg (2.78 mmol, 1.0 equiv) 2-Bromo-N-isopropyl-N-p-tolyl-acetamide, prepared as in Part B, in 1 mL DMF and stirred 18 h at ambient temperature. The solvent is removed in vacuo and the residue taken into 50 mL EtOAc and washed successively with H2O (30 mL), 1N HCl (30 mL), satd. NaHCO3 (30 mL), and brine (30 mL), dried (MgSO4), filtered and concentrated in vacuo to a yellow oil. The crude product is purified by flash chromatography on 27 g silica gel eluted successively with EtOAc/Hexanes (2:3, 500 mL), (1:1, 100 mL). Appropriate fractions were combined and concentrated in vacuo to give 554 mg (1.25 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5,-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-p-tolyl-acetamide as a white foam: 1H NMR (CDCl3, 300 MHz) δ7.43-7.07 (m, 12H), 6.90 (d, 1H, J=8.3), 5.03 (m, 1H), 4.37 (d, 1H, J=16.6), 4.04 (d, 1H, J=16.6), 3.58 (d, 1H, J=11.9), 3.49 (d, 1H, J=11.7), 2.41 (s, 3H), 1.10 (d, 6H, J=6.6); TLC Rf =0.27 (EtOAc/Hexanes, 1:1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=[O:11])=[CH:9][C:4]=2[N:3]=[N:2]1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>C(OCC)(=O)C>[CH2:18]([O:11][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][N:2]=[N:3][C:4]=2[CH:9]=1)=[O:12])[CH3:19]
Reactant: O=C(O)c1ccc2[nH]nnc2c1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2[nH]nnc2c1
Yield: 86 %

Procedure:
A suspension of 1H-benzotriazole-5-carboxylic acid in ethanol (50 ml, excess) was gently refluxed overnight in the presence of conc. sulphuric acid (0.5 ml), by which time TLC (A) indicated complete reaction. Ethanol was removed in vacuo to afford an aqueous residue that was dissolved in ethyl acetate (30 ml) and extracted with sodium chloride solution (4×20 ml). The organic layer was dried over sodium sulphate and removal of solvent in vacuo afforded the pure ester [24] in 86% yield. Rf (A) 0.75; δH(400 MHz; DMSO-d6) 1.36 (3H, t, CH3) 4.36 (2H, q, CH2) 7.94 (2H, br s, BT) 8.59 (1H, br s, BT) 16.03 (1H, s, NH); m/z (EI−HR) 191.07023 [(M) calc. for C9H9N3O2 191.06948].
Reaction SMILES: Cl[C:2]1[N:3]([CH3:12])[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[O:13]([CH2:20][CH:21]([OH:29])[CH2:22][N:23]([CH2:25][CH2:26][NH:27][CH3:28])[CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl>[O:13]([CH2:20][CH:21]([OH:29])[CH2:22][N:23]([CH2:25][CH2:26][N:27]([C:2]1[N:3]([CH3:12])[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8])[CH3:28])[CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1c(Cl)n(C)c(=O)n(C)c1=O
Reactant: CNCCN(C)CC(O)COc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(N(C)CCN(C)CC(O)COc2ccccc2)n(C)c(=O)n(C)c1=O

Procedure:
4.7 g. 4-Chloro-1,3,5-trimethylpyrimidine-2,6(1H,3H)-dione and 6.0 g. 1-phenoxy-3-(2-methylaminoethyl-N-methylamino)-propan-2-ol (b.p. 138°-142° C./0.01 mm.Hg; obtained from phenyl glycidyl ether and N,N'-dimethylethylenediamine) are stirred for 72 hours at 80° C. in 10 ml. pyridine. The reaction mixture is then dissolved in methylene chloride, washed with water, dried and chromatographed on silica gel using, as elution agent, methylene chloride-methanol (20:1 v/v). By evaporation of the pure fractions, there are obtained 3.0 g. (31% of theory) of the desired product in the form of an almost colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[CH3:29][N:30]1[CH:34]([CH2:35][CH2:36]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:33][N:32]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([C:55]([F:58])([F:57])[F:56])=[CH:51][CH:50]=2)[C:31]1=[O:59].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[C:1]([O:5][C:6](=[O:28])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:36][CH2:35][CH:34]2[CH2:33][N:32]([CH2:48][C:49]3[CH:54]=[CH:53][C:52]([C:55]([F:57])([F:58])[F:56])=[CH:51][CH:50]=3)[C:31](=[O:59])[N:30]2[CH3:29])=[CH:11][C:10]=1[CH2:16][N:17]1[C:18](=[O:27])[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25]1=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1CN1C(=O)c2ccccc2C1=O
Reactant: Cc1ccc(S(=O)(=O)OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CCC(=O)OC(C)(C)C)c(CN2C(=O)c3ccccc3C2=O)c1
Temperature: 60 °C
Yield: 72.1 %

Procedure:
To a solution of 3-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-hydroxy-phenyl]-propionic acid tert-butyl ester (57 mg, 0.15 mmol) and Toluene-4-sulfonic acid 2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethyl ester (75 mg, 0.16 mmol) in DMF (1 ml) is added Cs2CO3 (64 mg, 0.19 mmol), and the mixture heated at 60° C. for 14 hours. The mixture is cooled, diluted with water (25 ml) and extracted with ethyl acetate (2×25 ml). The combined organic extracts were washed with brine (30 ml), dried (Na2SO4), and concentrated to an oil. Purification by flash chromatography on a Biotage silica cartridge (gradient elution, 5:1 to 1:1 hexanes:acetone) produced an oil (72 mg, 73%).
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1[NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11].N[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(#N)CC#N.O.[NH2:39][NH2:40]>>[C:22]1([C:27]2[CH:32]=[C:31]([NH:7][N:8]=[C:9]3[C:10]([NH2:11])=[N:40][N:39]=[C:12]3[NH2:13])[CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:21]=1
Reactant: NN
Reactant: Nc1ccccc1-c1ccccc1
Reactant: N#CC(C#N)=NNc1ccccc1-c1ccccc1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1cccc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
4-(3-phenylphenylhydrazono)-4H-pyrazole-3,5-diamine was prepared using 123 mg (0.5 mmol) of 2-[(biphenyl-2-yl)hydrazono]malononitrile, which was derived from 2-aminobiphenyl (169 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. Precipitate formed in the reaction tube immediately after the addition of the hydrazine hydrate then the solution cleared. Very little solid remained after heating the reaction at 75° C. for 1 hr, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate and then precipitated by the addition of hexanes. The resulting solid was isolated by filtration and dried to yield 85 mg (61%) of the compound as an orange solid.
Reaction SMILES: [OH-].[K+].Cl.[NH2:4]O.[C:6]([C:10]1[N:14]([CH3:15])[N:13]=[C:12](C2C=C(C)NC=2C)[CH:11]=1)([O:8][CH3:9])=[O:7]>O.C(O)C>[C:6]([C:10]1[N:14]([CH3:15])[N:13]=[C:12]([NH2:4])[CH:11]=1)([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(-c2cc(C)[nH]c2C)nn1C
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cc(N)nn1C
Yield: 81.2 %

Procedure:
A solution of potassium hydroxide (5.08 g, 90.7 mmol) in water (76 mL) and ethanol (76 mL) was added to a slurry of hydroxylamine hydrochloride (11.44 g, 169.5 mmol) in ethanol (127 mL). Then, 5-carbomethoxy-3-(2,5-dimethylpyrrolyl)-1-methylpyrazole (8.5 g, 36.6 mmol) was added and the mixture was refluxed under a nitrogen atmosphere for 65 h. The solvents were removed at reduced pressure and the residue was triturated with ether. Sodium sulfate was added and the heterogenous mixture was filtered. The filtrate was concentrated and the residue was chromatographed on Silica Woelm®TSC (300 g, ethyl acetate-hexane gradient) to give 4.61 g, 81% of 5-carbomethoxy-3-amino-1-methylpyrazole as a white solid mp 114° to 118° C.; 1H-NMR (CDCl3) σ 6.17 (s, 1H), 4.02 (s, 3H), 3.88 (s, 1H), 3.7 (br s, 2H); IR (KBr) 1719, 1551, 1263, 1102, 756 cm-1.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[CH:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:15]1([NH:21][S:2]([C:5]2[CH:6]=[CH:7][C:8]([F:14])=[C:9]([CH:13]=2)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC1CCCCC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(O)c1cc(S(=O)(=O)NC2CCCCC2)ccc1F
Yield: 95 %

Procedure:
5-Chlorosulfonyl-2-fluoro-benzoic acid (A, 0.508 g, 0.0021 mol), Cyclohexylamine (G, 0.211 g, 0.00212 mol) and DIEA (1.1 mL, 0.00636 mol) in CH2Cl2 were stirred at room temperature overnight. The solvent was evaporated and the crude product was purified by silica gel chromatography (MeOH containing 10% AcOH)/CH2Cl2) to give 5-cyclohexylsulfamoyl-2-fluoro-benzoic acid (H, 0.6 g, 95%). After drying overnight under vacuum, H (0.22 g, 0.737 mmol) in SOC12 (5 mL) was heated at 80° C. for 2 hours after which the SOCl2 was evaporated and the residue was dried overnight. The residue was then dissolved in tetrahydrofuran (5 mL), 3,4-difluoro-phenylamine (D, 95 mg, 0.737 mmol) was added followed by DIEA (0.8 mL). The mixture was heated to 70° C. overnight. The solvent was evaporated, followed by ethyl acetate extraction. After purification by silica gel chromatography (ethyl acetate/hexane), 0.192 g (63%) of 5-cyclohexylsulfamoyl-N-(3,4-difluoro-phenyl)-2-fluoro-benzamide (DVR-45) was obtained.