Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)(=O)[CH3:2].[C:5](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH2:19][C:20]1[CH:45]=[CH:44][C:23]([CH2:24][N:25]2[C:33]3[C:28](=[CH:29][C:30]([Cl:34])=[CH:31][CH:32]=3)[C:27]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:42])([CH3:35])[C:26]2=[O:43])=[C:22]([O:46][CH3:47])[CH:21]=1.C(=O)([O-])O.[Na+]>ClCCCl.CC(C)=O>[Cl:34][C:30]1[CH:29]=[C:28]2[C:33](=[CH:32][CH:31]=1)[N:25]([CH2:24][C:23]1[CH:44]=[CH:45][C:20]([NH:19][CH:1]([CH3:2])[CH3:5])=[CH:21][C:22]=1[O:46][CH3:47])[C:26](=[O:43])[C:27]2([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Cl:42])[CH3:35]
Reactant: CC(=O)O
Reactant: COc1cc(N)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(C)=O
Product: COc1cc(NC(C)C)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.26 ml of acetic acid, 0.14 ml of acetone and then 0.56 g of sodium triacetoxyborohydride are added to 0.40 g of the compound of Example 48 in 10 ml of 1,2-dichloroethane at room temperature. After stirring for 2 hours at room temperature, the reaction mixture is hydrolysed with an aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic phase is washed with water and dried over anhydrous sodium sulphate and the solvents are evaporated under reduced pressure. The expected product is obtained by filtration of the crystallized evaporation residue taken up in n-pentane;
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:25][C:26]1[O:30][C:29]([C:31]2([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)=[N:28][C:27]=1[CH2:38][CH2:39]OS(C1C=CC(C)=CC=1)(=O)=O>>[F:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[F:22])[O:15][C:5]([CH3:14])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:39][CH2:38][C:27]2[N:28]=[C:29]([C:31]3([CH3:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[O:30][C:26]=2[CH3:25])=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)c(F)c1
Product: Cc1oc(C2(C)CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)c(F)c2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(3,4-difluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-[5-methyl-2-(1-methylcyclohexyl)oxazol-4-yl)-ethyl ester using the method of Example 56. 1H NMR (400 MHz, CDCl3) δ 7.15 (d, 2H, J=8.60 Hz), 7.00 (q, 1H, J=8.99 Hz), 6.79 (d, 2H, J=8.60 Hz), 6.77-6.74 (m, 1H), 6.63-6.61 (m, 1H), 4.12 (t, 2H, J=6.25 Hz), 3.19 (d, 1H, J=14.08 Hz), 3.09 (d, 1H, J=14.08 Hz), 2.97 (t, 2H, J=6.25 Hz), 2.31 (s, 3H), 2.16-2.08 (m, 2H), 1.61-1.35 (m, 8H), 1.39 (s, 3H), 1.29 (s, 3H); MS (ES+) calcd for C29H34NO5F2: Found m/e 514.3 (M+1, 100%).
Reaction SMILES: [N+](=[C:3]([C:17](=[O:29])[CH2:18][C@@H:19]1[C@H:22]([C:23]([O:26][CH3:27])([CH3:25])[CH3:24])[C:21](=[O:28])[NH:20]1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>C1C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[O:29]=[C:17]1[CH2:18][C@H:19]2[N:20]([C:21](=[O:28])[C@H:22]2[C:23]([O:26][CH3:27])([CH3:24])[CH3:25])[C@H:3]1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)=[O:5]
Reactant: COC(C)(C)[C@@H]1C(=O)N[C@@H]1CC(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Product: COC(C)(C)[C@@H]1C(=O)N2[C@@H](C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)C[C@H]12
Temperature: 25 °C
Yield: 103.3 %

Procedure:
A mixture of 4-nitrobenzyl 2-diazo-4-[(2R,3R)-3-(1-methoxy-1-methylethyl)-4-oxoazetidin-2-yl]-3-oxobutanoate (707 mg) and rhodium (II) acetate (ca. 5 mg) in benzene (20 ml) was refluxed for 30 minutes. After cooling to ambient temperature, the mixture was filtered through cellulose powder. The filtrate was evaporated to give 4-nitrobenzyl (2R,5R,6R)-3,7-dioxo-6-(1-methoxy-1-methylethyl)-1-azabicyclo[3.2.0]heptane-2-carboxylate (680 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][Br:11])=[CH:4][CH:3]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.P(Cl)(Cl)(Cl)=O>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][Br:11])=[CH:4][CH:3]=1
Reactant: Oc1ccc(CCCBr)cc1
Reactant: C1=COCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: BrCCCc1ccc(OC2CCCCO2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(4′-hydroxyphenyl)-3-bromopropane 3B (3.56 g) in dichloromethane (11 mL) is added dihydropyran (2.3 mL). The reaction mixture is cooled to 0° C., and three drops of phosphorus oxychloride are added. The reaction mixture is stirred in the ice bath for a further two hours, then gradually allowed to warm to room temperature, where it is allowed to stir overnight. To the reaction mixture is then added potassium carbonate (3 g), and the reaction mixture is stirred an additional hour. The solid is then filtered out, and the solvents and residual DHP is removed in vacuo.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]([CH3:11])[N:9]=[CH:10][C:5]2=[C:4]([NH:12][CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[N:3]=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](B2OC(C)(C)C(C)(C)O2)=[N:22]1>>[NH:21]1[C:29]2[C:24](=[C:25]([C:2]3[N:7]=[C:6]4[N:8]([CH3:11])[N:9]=[CH:10][C:5]4=[C:4]([NH:12][CH2:13][CH2:14][C:15]4[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=4)[N:3]=3)[CH:26]=[CH:27][CH:28]=2)[CH:23]=[N:22]1
Reactant: Cn1ncc2c(NCCc3cccnc3)nc(Cl)nc21
Reactant: CC1(C)OB(c2n[nH]c3ccccc23)OC1(C)C
Product: Cn1ncc2c(NCCc3cccnc3)nc(-c3cccc4[nH]ncc34)nc21

Procedure:
(6-Chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(2-pyridin-3-yl-ethyl)-amine was reacted with indazole boronic acid pinacol ester in General Procedure A. Purification by preparative HPLC yielded 144. NMR (CDCl3) 3.08 (t, H, CH2, J=7.06 Hz), 4.01 (m, 2H, CH2), 4.09 (s, 3H, CH3), 5.4 (sbr, H, NH), 7.20 (m, H, ArH), 7.46 (m, H, ArH), 7.55 (m, 2H, 2×ArH), 7.84 (s, H, ArH), 8.35 (d, H, ArH, J=7.21 Hz), 8.45 (m, H, ArH), 8.50 (s, H, ArH), 10.13 (sbr, H, NH). MS: (ESI+) MH+=371.15
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]([CH2:8][N:9]2[N:13]=[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]3=[N:10]2)=[CH:6][CH:5]=1)([O-])=O>[C].[Pd].C(O)C>[N:10]1[N:9]([CH2:8][C:7]2[CH:18]=[CH:19][C:4]([NH2:1])=[CH:5][CH:6]=2)[N:13]=[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=12
Reactant: O=[N+]([O-])c1ccc(Cn2nc3ccccc3n2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Cn2nc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.5 %

Procedure:
A mixture of 2-(4-nitrobenzyl)-2H-1,2,3-benzotriazole (1.0 g), 10% palladium carbon (100 mg) and ethanol (20 ml) was stirred under a hydrogen atmosphere at room temperature for 4 hrs. Palladium carbon was removed from the reaction mixture by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 4-(2H-1,2,3-benzotriazol-2-ylmethyl)aniline (313 mg, 35%) as crystals from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 229-230° C.
Reaction SMILES: Cl[C:2]1[CH:19]=[CH:18][CH:17]=[C:16](Cl)[C:3]=1[C:4]([C:6]1[CH:11]=[C:10](O)[C:9](OC)=[CH:8][C:7]=1C)=[O:5].[CH3:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-:26].[K+].[K+]>C(O)C>[CH2:23]([O:26][C:16]1[CH:17]=[CH:18][CH:19]=[CH:2][C:3]=1[C:4]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])[CH2:22][CH3:21]
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)cc1O
Reactant: O=C([O-])[O-]
Reactant: CCCBr
Agent: [K+]
Solvent: CCO
Product: CCCOc1ccccc1C(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A mixture of 2,6-Dichloro-5'-hydroxy-4'-methoxy-2'-methylbenzophenone (Compound 5g, 1.0 g 3.2 mmol), n-propyl bromide (0.5 g, 4 mmol), potassium carbonate (2.8 g, 20 mmol) and ethanol (10 ml) is stirred for 6 h at 80° C., filtered and the filtrate is evaporated in vacuo. The residue is applied onto a flash chromatography column (silica gel, 30 g). Elution with toluene (750 ml) yields Compound 6 as a brown oil, 800 mg, (70.7% y) which slowly crystallizes (mp 73-75° C.)
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].Cl/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9].O.[CH3:12]O>S(=O)(=O)(O)O>[S:1](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:12])=[O:9])[C:2]#[N:3]
Reactant: N#C[S-]
Reactant: CO
Reactant: O=C(O)/C=C/Cl
Agent: O=S(=O)(O)O
Agent: [NH4+]
Solvent: O
Product: COC(=O)/C=C/SC#N

Procedure:
To a stirred solution of ammonium thiocyanate (7.2 g., 0.095 mole) in 4N sulfuric acid solution (50 ml) at 40° C., a solution of trans-3-chloroacrylic acid (10.0 g., 0.095 mole) in 35 ml of methanol was added dropwise within 5 minutes. The mixture was refluxed for 18 hours, cooled and poured into water which was extracted thoroughly with ether. The ether extract was washed with saturated sodium bicarbonate solution and then with water. After drying (MgSO4), the solution was concentrated to give an oil which distilled at 70° C./0.3 mm; yield, 7.2 g.; NMR (CDCl3) 7.3 (d, 1H, J=14.4 cps); 6.35 (d, 1H, J=14.4 cps); 3.8 (s, 3H); IR(KBr) 2180, 1725 cm-1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[CH2:29][CH2:30][CH3:31])=[CH:7][CH:6]=1)[CH3:2].[BH4-].[Na+].CC(C)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[C:16]3[CH:17]=[C:18]([CH:21]([OH:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[CH2:29][CH2:30][CH3:31])=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCCc1nc2ccc(C(=O)c3ccccc3)cc2n1Cc1ccc(C(=O)OCC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Product: CCCc1nc2ccc(C(O)c3ccccc3)cc2n1Cc1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a solution of 4-(6-benzoyl-2-propyl-benzoimidazol-1-ylmethyl)-benzoic acid ethyl ester (1.5 g; 3.5 mmol) in ethanol (50 mL) was added sodium borohydride (1.0 g; 29.4 mmol). After stirring at ambient temperature for 4 hours, acetone (20 mL) was added. The solvent was evaporated. The residue was dissolved in ethyl acetate and washed with water. The organic phase was evaporated to give the title compound (0.9 g, 60% yield) as a white solid which was used without further purification in step 2.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([CH:11]=[O:12])[O:8][N:7]=1)=[O:5])C>O1CCOCC1.Cl>[CH:11]([C:9]1[O:8][N:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:10]=1)=[O:12]
Reactant: CCOC(=O)c1cc(C=O)on1
Agent: Cl
Solvent: C1COCCO1
Product: O=Cc1cc(C(=O)O)no1
Yield: 86.3 %

Procedure:
A solution of ethyl-5-formylisoxazole-3-carboxylate (25 mg) in 1,4-dioxan (3 ml) and 2M hydrochloric acid (1 ml) was stirred and heated at reflux for 5 h.; cooled and the solvents removed in vacuo. The residue was triturated in diethyl ether. The solvent was removed and the residue dried to leave the title compound (18 mg) as an orange/brown solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH:13](C(OC(C)(C)C)=O)[C:14](OC(C)(C)C)=O)=[CH:8][C:7]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[CH:29]=3)=[N:6]2)[CH2:3][CH2:2]1.[H-].[Na+].C(OC(C)(C)C)(=O)CC(OC(C)(C)C)=O.BrC[C:56]1[C:57](=O)[N:58]([CH2:71][CH:72]2CC2)N=C(C2C=CC(OC)=C(F)C=2)C=1.[CH3:76][N:77](C)C=O>O>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][CH2:13][CH2:14][N:58]3[CH2:57][CH2:56][N:77]([CH3:76])[CH2:72][CH2:71]3)=[CH:8][C:7]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([F:36])[CH:29]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: COc1ccc(-c2cc(CBr)c(=O)n(CC3CC3)n2)cc1F
Reactant: COc1ccc(-c2cc(CC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(=O)n(CC3CC3)n2)cc1F
Reactant: CN(C)C=O
Agent: CC(C)(C)OC(=O)CC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2cc(CCCN3CCN(C)CC3)c(=O)n(CC3CC3)n2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
Preparation of 2-cyclopropylmethyl-4-[2,2-di(tert-butoxycarbonyl)ethyl]-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one After 55% sodium hydride (322 mg, 7.38 mmol) was added to a solution of di-tert-butyl malonate (970 mg, 4.48 mmol) in N,N-dimethylformamide (10 mL), 4-bromomethyl-2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one (1.8 g, 4.90 mmol) was added under ice-cold stirring. The reaction mixture was stirred at room temperature for 1 hour, poured into water, and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was isolated and purified by chromatography on silica gel (hexane/ethyl acetate=3/1) to yield the title compound as a yellow powder (yield: 1.39 mg, 61.8%).
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[F:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:35][C:34](=[O:36])[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)[CH:23]=[CH:24][CH:25]=1>>[F:19][C:20]1[CH:21]=[C:22]([CH:26]2[CH2:35][CH:34]([OH:36])[C:33]3[C:28](=[CH:29][CH:30]=[C:31]([OH:37])[CH:32]=3)[O:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CC(c2cccc(F)c2)Oc2ccc(O)cc21
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: Oc1ccc2c(c1)C(O)CC(c1cccc(F)c1)O2

Procedure:
2-(3-Fluorophenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 220 mg of 2-(3-fluorophenyl)-6-hydroxychroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.85 (s, 1H), 7.45 (m, 1H), 7.30-7.25 (m, 2H), 7.15 (m, 1H), 6.88 (d, 1H, J 2.8 Hz), 6.62 (d, 1H, J 8.7 Hz), 6.55 (dd, 1H, J 8.7, 2.8 Hz), 5.44 (d, 1H, J 7.0 Hz), 5.15 (d, 1H, J 10.7 Hz), 4.86 (m, 1H), 2.29 (m, 1H), 1.86 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][C:5]([C:12]2[N:13]([C:33](Cl)=[O:34])[C:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:4]([O:36][CH2:37][CH3:38])[CH:3]=1.Cl.Cl.[CH3:41][S:42]([CH2:45][CH2:46][CH2:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)(=[O:44])=[O:43]>>[Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:6][C:5]([C:12]2[N:13]([C:33]([N:51]3[CH2:50][CH2:49][N:48]([CH2:47][CH2:46][CH2:45][S:42]([CH3:41])(=[O:43])=[O:44])[CH2:53][CH2:52]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:4]([O:36][CH2:37][CH3:38])[CH:3]=1
Reactant: CS(=O)(=O)CCCN1CCNCC1
Reactant: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(Cl)c(S(C)(=O)=O)cc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCCS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, 2-(4-chloro-2-ethoxy-5-methanesulfonylphenyl)-4,5-bis-(4-chlorophenyl)-4,5-dimethyl-4,5-dihydroimidazole-1-carbonyl chloride was reacted with 1-(3-methanesulfonyl-propyl)-piperazine dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 30% of 1:1 ethanol/acetonitrile in carbon dioxide). HR-MS (ES, m/z) calculated for C35H42N4O6S2Cl3 [(M+H)+] 783.1606, observed 783.1596
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[CH:4][C:5]([O:13][CH2:14][CH3:15])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:3]([CH2:16][Br:29])=[CH:4][C:5]([O:13][CH2:14][CH3:15])=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1cc(Br)c(C)cc1OCC
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(Br)c(CBr)cc1OCC

Procedure:
After dissolving ethyl 5-bromo-2-ethoxy-4-methylbenzoate (19.72 g) in carbon tetrachloride, azobisisobutyronitrile (1.13 g) was added and the mixture was heated to reflux for 30 minutes. N-bromosuccinimide was added and the mixture was further heated to reflux for 1 hour. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (10.54 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:4]([C:18]([OH:20])=O)[CH:3]=1.O=S(Cl)Cl>C(Cl)Cl>[Br:1][C:2]1[O:6][CH:5]2[CH2:7][N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:18](=[O:20])[CH:4]2[CH:3]=1
Reactant: COc1ccc(CNCc2oc(Br)cc2C(=O)O)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc(CN2CC3OC(Br)=CC3C2=O)cc1
Yield: 28.6 %

Procedure:
A solution of 5-bromo-2-[(4-methoxy-benzylamino)-methyl]-furan-3-carboxylic acid (618 mg, 1.82 mmol) and SOCl2 (0.136 mL) in DCM (2 mL) is stirred at 85° C. for 18 hours. The mixture is concentrated in vacuo and purified by silica gel column chromatography eluting with 7:3 petroleum ether:ethyl acetate to afford the title compound (0.169 g, 28%).
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][NH:2]1.CN(C)CCCN.[C:14]([N:22]1[C:26]2[N:27]=[CH:28][C:29]3[C:30](OC4C=CC=CC=4)=[N:31][C:32]4[N:33]([N:35]=[CH:36][N:37]=4)[C:34]=3[C:25]=2[CH:24]=[N:23]1)(=O)[C:15]1C=CC=CC=1>>[CH2:14]([N:22]1[C:26]2[N:27]=[CH:28][C:29]3[C:30]([N:1]4[CH:6]=[CH:5][CH2:4][CH2:3][NH:2]4)=[N:31][C:32]4[N:33]([N:35]=[CH:36][N:37]=4)[C:34]=3[C:25]=2[CH:24]=[N:23]1)[CH3:15]
Reactant: C1=CNNC=C1
Reactant: O=C(c1ccccc1)n1ncc2c1ncc1c(Oc3ccccc3)nc3ncnn3c12
Agent: CN(C)CCCN
Product: CCn1ncc2c1ncc1c(N3C=CCCN3)nc3ncnn3c12

Procedure:
By substituting dihydropyridazine for the 3-(dimethylamino)propylamine in the procedure of Example 1 (c), 8-ethyl-5-(dihydropyridazin-1-yl)-8H-pyrazolo[4',3':5,6]pyrido[3,4-e]-[1,2,4]triazolo[1,5-a]pyrimidine is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:43])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:38]=[CH:39][N:40]=[CH:41][CH:42]=2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccncc2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccncc3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J1) (239 mg, 0.75 mmol) and 3-oxo-3-(3-pyridin-4-yl-phenyl)-propionic acid tert-butyl ester (Example K2) (223 mg, 0.75 mmol) according to the general procedure M. Obtained as an orange solid (324 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:12]=1[C:13]#[N:14].N1C=CC=CC=1.[C:28](Cl)(=[O:30])[CH3:29]>C(Cl)Cl>[C:28]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[C:12]=1[C:13]#[N:14])(=[O:30])[CH3:29]
Reactant: CC(=O)Cl
Reactant: N#Cc1c(OCCCCCCCCO)cccc1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCCCCCCCCOc1cccc([N+](=O)[O-])c1C#N
Temperature: 0 °C
Yield: 99.7 %

Procedure:
2-(8-hydroxyoctyloxy)-6-nitrobenzonitrile (804 μmol, 235 mg) (Example 274c) was dissolved in dry DCM (10 mL), cooled to 0° C., and treated successively with pyridine (3.216 mmol, 260 μL) and acetyl chloride (1.608 mmol, 114 μL). The reaction mixture was stirred and allowed to warm slowly to room temperature. When the reaction was complete, the volatiles were removed in vacuo and the crude product purified on silica gel (10% to 50% EtOAc in hexanes) to give the desired product (268 mg, 100%). MS 335 (MH+).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:15]4/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/4)=[C:9]3[N:8]=[C:7](S(C)(=O)=O)[N:6]=2)[CH2:3][CH2:2]1.C1(NC2N3N=CC(/C=C4/C(=O)NC(=O)N/4)=C3N=C(S(C)=O)N=2)CC1.[Cl:50][C:51]1[CH:52]=[C:53]([OH:57])[CH:54]=[CH:55][CH:56]=1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1.O>[Cl:50][C:51]1[CH:52]=[C:53]([CH:54]=[CH:55][CH:56]=1)[O:57][C:7]1[N:6]=[C:5]([NH:4][CH:1]2[CH2:3][CH2:2]2)[N:10]2[N:11]=[CH:12][C:13](/[CH:14]=[C:15]3/[C:16](=[O:21])[NH:17][C:18](=[O:20])[NH:19]/3)=[C:9]2[N:8]=1
Reactant: CS(=O)(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Reactant: Oc1cccc(Cl)c1
Agent: CS(=O)c1nc(NC2CC2)n2ncc(/C=C3\NC(=O)NC3=O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)nc(Oc4cccc(Cl)c4)nc23)N1
Temperature: 90 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
A (1:1) mixture of (Z)-5-((4-(cyclopropylamino)-2-(methylsulfonyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione and (Z)-5-((4-(cyclopropylamino)-2-(methylsulfinyl)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione (1.0 eq, 25 mg, 0.0704 mmol) was combined in a vial with 3-chlorophenol (5.0 eq, 45 mg, 0.35 mmol) and K2CO3 (5.0 eq, 48 mg, 0.347 mmol) in NMP (0.2 ml). The mixture was stirred at 90° C. for 1 hour. Water was added and the resulting solid was filtered and dried. Trituration in a mixture of ethyl acetate and hexanes followed by filtration provided (Z)-5-((2-(3-chlorophenoxy)-4-(cyclopropylamino)pyrazolo[1,5-a][1,3,5]triazin-8-yl)methylene)imidazolidine-2,4-dione as a tan solid (20 mg, 69%). LCMS (ES): >95% pure, m/z 412 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C@@H]1NC(=O)[C@@H](CCCN)NC(=O)[C@@H](NC([C@@H](NC([C@H](NC([C@@H](NC([C@H]2N=C([C@@H](N)[C@H](CC)C)SC2)=O)CC(C)C)=O)CCC(O)=O)=O)[C@H](CC)C)=O)CCCCNC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](CC(O)=O)NC(=O)[C@H](CC2NC=NC=2)NC(=O)[C@@H](CC2C=CC=CC=2)NC1=O)C.CC[C@H]1OC(=O)[C@H](C)[C@@H]([O:120][C@@H:121]2[O:126][C@@H:125]([CH3:127])[C@H:124](O)[C@@:123]([O:130]C)(C)[CH2:122]2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@@](O)(C)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@@]1(O)C.C[C@@H:153]1[C@H:162]([OH:163])[CH2:161][CH2:160][C@@:159]2(C)[C@H:154]1[CH2:155][CH2:156][C@:157]1(C)[C@@]3(C)C[C@H](OC(C)=O)/C(=C(\C(O)=O)/CCC=C(C)C)/[C@@H]3C[C@@H](O)[C@H:158]12>>[CH3:153][C:162]([CH2:161][CH:160]([C:122]1[C:121](=[O:120])[O:126][C:125]2[CH:127]=[CH:3][CH:2]=[CH:1][C:124]=2[C:123]=1[OH:130])[C:159]1[CH:158]=[CH:157][CH:156]=[CH:155][CH:154]=1)=[O:163]
Reactant: CC[C@H](C)[C@H](N)C1=N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(=O)O)C(=O)N[C@H](C(=O)N[C@H]2CCCCNC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](CC(=O)O)NC(=O)[C@H](Cc3cnc[nH]3)NC(=O)[C@@H](Cc3ccccc3)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](CCCN)NC2=O)[C@@H](C)CC)CS1
Reactant: CC[C@H]1OC(=O)[C@H](C)[C@@H](O[C@H]2C[C@@](C)(OC)[C@@H](O)[C@H](C)O2)[C@H](C)[C@@H](O[C@@H]2O[C@H](C)C[C@H](N(C)C)[C@H]2O)[C@](C)(O)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@]1(C)O
Reactant: CC(=O)O[C@H]1C[C@@]2(C)[C@@H](C[C@@H](O)[C@H]3[C@@]4(C)CC[C@@H](O)[C@@H](C)[C@@H]4CC[C@@]32C)/C1=C(\CCC=C(C)C)C(=O)O
Product: CC(=O)CC(c1ccccc1)c1c(O)c2ccccc2oc1=O

Procedure:
To show that non-binding compounds do not significantly influence the FT-IR spectrum of a biological macromolecule when mixed with the biological macromolecule, 3 μg of NMT was mixed with 10 μg each of Bacitracin (trace 1), Erythromycin (2), Fusidic Acid (3) and a fungal extract (4) and a differential FT-IR spectrum of each sample was obtained (FIG. 3). The non-binding compounds did not alter the spectrum of NMT. However, a nonspecific binding compound, Warfarin (60 μg), did produce a detectable peak shift for NMT.