Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C=C(C)C(C(N2CCC(N3CCCC3)CC2)=O)=C(C)C=1.[CH3:23][C:24]1[C:29]([C:30]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH2:34][CH2:33]2)=[O:31])=[C:28]([CH3:43])[CH:27]=[C:26]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][C:51]([F:54])([F:53])[F:52])[CH:45]=2)[N:25]=1.N1CCC(N2CCC[C@H]2[CH2:66][O:67][C:68](=[O:75])[C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)CC1>>[CH3:23][C:24]1[C:29]([C:30]([N:32]2[CH2:37][CH2:36][CH:35]([N:38]3[CH2:39][CH2:40][CH2:41][C@H:42]3[CH2:66][O:67][C:68](=[O:75])[C:69]3[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=3)[CH2:34][CH2:33]2)=[O:31])=[C:28]([CH3:43])[CH:27]=[C:26]([C:44]2[CH:49]=[CH:48][CH:47]=[C:46]([O:50][C:51]([F:53])([F:54])[F:52])[CH:45]=2)[N:25]=1
Reactant: Cc1cc(-c2cccc(OC(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: O=C(OC[C@@H]1CCCN1C1CCNCC1)c1ccccc1
Agent: Cc1cc(Br)cc(C)c1C(=O)N1CCC(N2CCCC2)CC1
Product: Cc1cc(-c2cccc(OC(F)(F)F)c2)nc(C)c1C(=O)N1CCC(N2CCC[C@H]2COC(=O)c2ccccc2)CC1

Procedure:
In analogy to the procedures described for intermediate 1 and for intermediate 4B,2,4-dimethyl-6-(3-trifluoromethoxy-phenyl)-nicotinic acid (example 28) was converted into its acid chloride and reacted with benzoic acid (S)-1-piperidin-4-yl-pyrrolidin-2-ylmethyl ester (intermediate 3) to give benzoic acid (S)-1-{1-[2,4-dimethyl-6-(3-trifluoromethoxy-phenyl)-pyridine-3-carbonyl]-piperidin-4-yl}-pyrrolidin-2-ylmethyl ester, which was subsequently saponified to give the title compound as colorless amorphous solid. MS: 478.2 (MH+).
Reaction SMILES: [NH2:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:13].[C:14]12([CH2:24][C:25](Cl)=[O:26])[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2>>[C:14]12([CH2:24][C:25]([NH:1][N:2]3[C:11](=[O:12])[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[NH:4][C:3]3=[O:13])=[O:26])[CH2:21][CH:20]3[CH2:19][CH:18]([CH2:17][CH:16]([CH2:22]3)[CH2:15]1)[CH2:23]2
Reactant: Nn1c(=O)[nH]c2ccccc2c1=O
Reactant: O=C(Cl)CC12CC3CC(CC(C3)C1)C2
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1c(=O)[nH]c2ccccc2c1=O

Procedure:
3-Amino-1H-quinazoline-2,4-dione and 1-adamantaneacetyl chloride were reacted as describe in Example 5 to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.58-1.68 (m, 12H), 1.92-1.98 (m, 3H), 1.98-2.07 (m, 2H), 7.21-7.27 (m, 2H), 7.68-7.74 (m, 1H), 7.93-7.96 (m, 1H), 10.34 (s, 1H), 11.51 (s, 1H) ppm; MS (DCI/NH3) m/z 354 (M+H)+; Elemental Analysis: Calculated for 1.58-1.68 (m, 12H), 1.92-1.98 (m, 3H), 1.98-2.07 (m, 2H), 7.21-7.27 (m, 2H), 7.68-7.74 (m, 1H), 7.93-7.96 (m, 1H), 10.34 (s, 1H), 11.51 (s, 1H).
Reaction SMILES: C[O-].[Na+:3].CCO.CN1[CH:15]=[CH:14][C:12](=[O:13])N(C)C1=O.[C:17]([CH2:19][C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[S:21])#[N:18]>CO>[C:17]([C:19]1[CH:15]=[CH:14][C:12](=[O:13])[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]=1[S-:21])#[N:18].[Na+:3]
Reactant: N#CCC(=S)Nc1ccccc1
Reactant: Cn1ccc(=O)n(C)c1=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: N#Cc1ccc(=O)n(-c2ccccc2)c1[S-]
Temperature: 25 °C

Procedure:
A solution of sodium methoxide in MeOH (30 wt %, 202.2 g) was added to absolute EtOH (360 mL) followed by 1,3-dimethyluracil (75 g) and 2-cyano-N-phenyl-thioacetamide (Adhikari et al, Australian J. Chem., 1999, 52, 63-67) (90 g). The resulting mixture was heated at reflux for 8 h and then allowed to cool to ambient temperature overnight. The reaction mixture was then cooled to +5° and maintained at this temperature for at least an hour when the product was recovered by filtration. The filter cake was washed with cold (+5°) absolute ethanol (450 mL) and then dried to constant weight under vacuum at 45° to give the title compound as a pale pink solid (130.0 g). The product thus obtained contains residual EtOH and MeOH, estimated at 12.2 wt % by 1H nmr, corresponding to a corrected yield of 114.1 g. δH (DMSO-d6) 7.32 (2H, m), 7.27-7.18 (1H, m), 7.16 (1H, d, J 9.1 Hz), 6.92 (2H, m), 5.63 (1H, d, J 9.1 Hz). LCMS (Conditions B) (ES+) RT 2.43 minutes, 229 (M+H)+.
Reaction SMILES: C(O)(=O)C.[BH3-]C#N.[Na+].[Cl:9][C:10]1[C:11]([CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:12]([CH:16]=O)[CH:13]=[N:14][CH:15]=1.[CH3:26][C:27]1([CH3:34])[O:31][CH:30]([CH2:32][NH2:33])[CH2:29][O:28]1>CO>[Cl:9][C:10]1[C:11]([CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[C:12]([CH2:16][NH:33][CH2:32][CH:30]2[CH2:29][O:28][C:27]([CH3:34])([CH3:26])[O:31]2)[CH:13]=[N:14][CH:15]=1
Reactant: O=Cc1cncc(Cl)c1COC1CCCCO1
Reactant: CC1(C)OCC(CN)O1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC1(C)OCC(CNCc2cncc(Cl)c2COC2CCCCO2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Acetic acid (133 μL) and NaBH3CN (14.8 mg, 0.235 mmol) were added to a stirred solution of 5-chloro-4-(tetrahydro-pyran-2-yloxymethyl)-pyridine-3-carbaldehyde (40 mg, 0.157 mmol) and 2,2-dimethyl-1,3-dioxolane-4-methanamine (203 μL, 1.57 mmol) in MeOH (1 mL). After stirring for 2 h at room temperature the solvent was removed in vacuo and the residue was partitioned between DCM (10 mL) and saturated NaHCO3 solution (10 mL). After extraction of the aqueous layer with DCM (2×10 mL) the combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting title compound was used for the next reaction without purification. MS (m/z): 370.9 [M+H+].
Reaction SMILES: [OH2:1].[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[OH2:13]>ClC1C=CC=CC=1Cl>[CH3:3][C:2]([CH3:7])=[CH:12][C:2]1[CH:7]=[CH:6][C:5]([CH:5]([CH3:6])[C:4]([OH:13])=[O:1])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Solvent: Clc1ccccc1Cl
Product: CC(C)=Cc1ccc(C(C)C(=O)O)cc1
Temperature: 25 °C

Procedure:
A solution of p-toluenesulphonic acid monohydrate (8.4 g) in o-dichlorobenzene (60 ml) was heated at 110° to 120° and treated dropwise with a previously prepared solution of 2-[4-(1-hydroxy-2-dimethylethyl)phenyl]propionic acid (9 g) in o-dichlorobenzene (40 ml) over a period of 20 minutes at the same temperature. The reaction mixture was rapidly cooled to room temperature, poured into water and extracted several times with ether. The combined ethereal extracts were washed with water and then treated with a 5% solution of NaOH. The separated aqueous phase was acidified with a 10% solution of hydrochloric acid and extracted again with ether and the organic phase was separated.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([OH:14])=[O:13].Cl.[Cl:17][C:18]1[CH:19]=[C:20]([NH:24]N)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20]2[C:21]([C:3]([S:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[CH2:11][C:12]([OH:14])=[O:13])=[C:2]([CH3:15])[NH:24]2)=[CH:22][CH:23]=1
Reactant: CC(=O)CSc1ccccc1CC(=O)O
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: Cc1[nH]c2cc(Cl)ccc2c1Sc1ccccc1CC(=O)O

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: [2-(2-oxo-propylsulfanyl)-phenyl]-acetic acid and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:19])=[C:9]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1.O[N:26]1[C:30](=[O:31])[CH2:29][CH2:28][C:27]1=[O:32].Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[OH:1][C:2]1[C:7]2[C:8]([CH3:19])=[C:9]([CH2:14][CH2:15][C:16](=[O:18])[O:17][N:26]3[C:30](=[O:31])[CH2:29][CH2:28][C:27]3=[O:32])[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:3]=1
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCC(=O)O)=C2C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)C(CCC(=O)ON1C(=O)CCC1=O)=C2C
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.7 %

Procedure:
To a solution of 6 mg (0.018 mmol) of the acid 5-Hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-propanoic acid in anhy. methylene chloride under argon was added 10.3 mg (5 eq.) of N-hydroxysuccinimide (NHS) (Aldrich) followed by 8.6 mg (2.5 eq.) of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCl) (Sigma). After stirring at RT under argon for 4 hr TLC indicated only traces of starting material were left. The reaction mixture was directly subjected to chromatography on silica gel plates, eluting with 50% EtOAc-hexane. The product band was isolated, washed with a little EtOAc, the washings stripped of solvent under reduced pressure and the residue dried under high vacuum to give 5 mg (65%) of 1-[3-(5-Hydroxy-2,2,4-trimethyl-7-pentyl-2H-1-benzopyran-3-yl)-1-oxopropoxy]-2,5-pyrrolidinedione as a foam. HR (+) FAB MS: Calc (M+H), 430.2230; Observed, 430.2266.
Reaction SMILES: [N+:1]([C:4]1[C:5](=[O:18])[N:6]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>[Pd].CO>[C:14]([O:13][C:11](=[O:12])[CH2:10][N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([NH2:1])[C:5]1=[O:18])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)Cn1cccc([N+](=O)[O-])c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Cn1cccc(N)c1=O
Yield: 98.6 %

Procedure:
The compound of Example 137 (54 g, 0.213 mole) and 880 ml of methanol and 5 g of 10% palladium on carbon were stirred under 1 Atm of hydrogen for 24 hours. The reaction mixture was filtered and the carbon was washed with 200 mL of dichloromethane. The organic layer was evaporated to yield 47.08 g (98.5 %) of the title compound as a brown solid.
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:45]3[CH2:46][CH2:47][N:42]([CH2:41][CH2:40][O:39][CH3:38])[CH2:43][CH2:44]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCN1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCOC)CC1

Procedure:
In a manner analogous to the method described in examples 8, (4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 51) was coupled with 1-(2-methoxy-ethyl)-piperazine (Oakwood) to give the title compound. HR-MS (ES, m/z) calculated for C36H46Cl2N5O3 [(M+H)+] 666.2972, observed 666.2971.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:24])[C:8]1[C:13]([C:14]2([Cl:23])[CH2:18][C:17]([F:19])=[C:16]([N:20]=[C:21]=[S:22])[S:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([CH2:5][O:6][C:7](=[O:24])[C:8]1[C:13]([C:14]2([Cl:23])[CH2:18][C:17]([F:19])=[C:16]([NH:20][C:21]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]3)=[S:22])[S:15]2)=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: C1CCNNC1
Reactant: COC(=O)COC(=O)c1ccccc1C1(Cl)CC(F)=C(N=C=S)S1
Solvent: Cc1ccccc1
Product: COC(=O)COC(=O)c1ccccc1C1(Cl)CC(F)=C(NC(=S)N2CCCCN2)S1
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution of 4.8 g of 2-chloro-4-fluoro-5-isothiocyanato-thiolbenzoic acid (methoxycarbonylmethyl) ester obtained in accordance with Example P3 in 50 ml of toluene is added dropwise, with stirring, at 20°-25° C. to a solution of 1.4 g of hexahydropyridazine in 20 ml of toluene. Stirring is continued for a further 8 hours at room temperature. Concentration by evaporation in vacuo yields 4.4 g of 2-chloro-4-fluoro-5-(1-hexahydropyridazinyl-thiocarbonylamino)-thiolbenzoic acid (methoxycarbonylmethyl) ester in resinous form.
Reaction SMILES: [Br-:1].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:22]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][C:35]3[C:42]([C:43]([F:46])([F:45])[F:44])=[CH:41][C:38]([CH2:39]O)=[CH:37][C:36]=3[C:47]([F:50])([F:49])[F:48])[CH:32]=2)[NH:27][CH:26]=1)([CH3:24])[CH3:23].N1C=CC=CC=1>C(#N)C>[CH:22]([C:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([O:34][C:35]3[C:42]([C:43]([F:46])([F:45])[F:44])=[CH:41][C:38]([CH2:39][Br:1])=[CH:37][C:36]=3[C:47]([F:50])([F:49])[F:48])[CH:32]=2)[NH:27][CH:26]=1)([CH3:24])[CH3:23]
Reactant: [Br-]
Reactant: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CO)cc3C(F)(F)F)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: c1ccncc1
Product: CC(C)c1c[nH]c2ccc(Oc3c(C(F)(F)F)cc(CBr)cc3C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.273 g (3.02 mmol) of triphenylphosphine dibromide are added under argon in portions at 0° C. to a solution of 0.97 g (2.32 mmol) of benzyl alcohol derivative from Example VI in 15 ml of acetonitrile and 0.3 ml (3.72 mmol) of pyridine. After 15 minutes the cooling bath is removed and the mixture is stirred for 2 hours at room temperature. The reaction solution is concentrated in vacuo, and the residue is dissolved in a little toluene and purified by chromatography on silica gel 60 by means of toluene.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[NH:7][C:8]=1[CH3:9].CCN(CC)CC.OS([O-])=O.[Na+]>C(Cl)Cl>[Br:1][C:5]1[C:4]([Cl:3])=[C:8]([CH3:9])[NH:7][C:6]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1cc(Cl)c(C)[nH]1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 106.2 %

Procedure:
Bromine (0.56 ml, 11 mmol) was added to a solution of 1 g (5.3 mmol) of ethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate (WO2006087543) and 0.8 ml (5.7 mmol) Et3N in CH2Cl2. After stirring at room temperature for 2 h, aqueous NaHSO3 was added and the CH2Cl2 was removed and the aqueous residue was partitioned between water and EtOAc. The EtOAc layer was separated and washed with brine. The EtOAc layer was dried over anhydrous MgSO4, and the solvent was removed to give 1.5 g of the product as a solid. MS (ES) (MH+): 240 for C8H9BrClNO2; NMR (d6-DMSO): 1.3 (t, 3H), 2.2 (s, 3H), 4.2 (q, 2H), 12.3 (s, 1H).
Reaction SMILES: C(OC(=O)C)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:19]1[CH2:23][CH2:22][O:21][CH2:20]1.C([N:27](C(=O)C)[C:28]1[NH:29][C:30](=[O:37])[C:31]2[NH:32][CH:33]=[N:34][C:35]=2[N:36]=1)(=O)C>C1(C)C=CC=CC=1>[OH:19][CH2:23][CH2:22][O:21][CH2:20][N:34]1[CH:33]=[N:32][C:31]2[C:30](=[O:37])[NH:29][C:28]([NH2:27])=[N:36][C:35]1=2
Reactant: CC(=O)N(C(C)=O)c1nc2nc[nH]c2c(=O)[nH]1
Reactant: C1COCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: Nc1nc2c(ncn2COCCO)c(=O)[nH]1
Temperature: 25 °C
Yield: 21.6 %

Procedure:
To a mixture of acetic anhydride (1.2 ml) and p-toluenesulfonic acid (0.09 g) was added with stirring dioxolane (1.02 g) --caution, exothermic. The solution was allowed to cool for several minutes. Diacetylguanine (1.45 g) and dry toluene (9 ml) were added and the reaction mixture was stirred at reflux for 18 hr. and then allowed to cool to room temperature. The toluene was decanted off and the residue triturated several times with benzene. Methanol (10 ml) was added to the residue and evaporated under reduced pressure. To the residue was added 40% aqueous methylamine (10 ml) and the mixture heated on a steam bath for 20 min. The water and methylamine were removed under reduced pressure, ethanol (10 ml) was added and evaporated. The residue was thoroughly extracted with boiling methanol (700 ml total) and the combined extracts evaporated. The resulting solid was triturated with cold ethanol and then recrystallized from methanol to give 9-(2-hydroxyethoxymethyl)guanine (0.3 g).
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])(=O)=O)(C)C.[C:33]1(=[O:39])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[OH:39][C:33]1([C:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:26])[C:38]2[C:37](=[CH:27][CH:21]=[CH:22][CH:23]=2)[CH2:36][CH2:35][CH2:34]1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN(C)C)c2ccccc2)c(C(C)C)c1
Reactant: O=C1CCCCC1
Product: CN(C)CC=C(c1ccccc1)C1(O)CCCc2ccccc21

Procedure:
By using a procedure similar to that described in Example 22 but starting from β-dimethylaminopropiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (20 g) and from cyclohexanone (5 cc), 1-(1-hydroxy-1-cyclohexyl)-3-dimethylamino-1-phenyl-1-propene (Z) hydrochloride (6 g) is obtained in the form of a white powder melting at 197° C. after recrystallisation from a mixture (50 cc) of isopropanol and isopropyl ether (60/40 by volume).
Reaction SMILES: [NH:1]([C:13]([CH3:15])=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:16](O)[CH3:17]>Cl>[NH:1]([C:13]([CH3:15])=[O:14])[C@H:2]([C:10]([O:12][CH2:16][CH3:17])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCO
Reactant: CC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(C)=O

Procedure:
To a solution of N-Ac-L-Phe (5.0 g, 24.1 mmol) in 120 ml of ethanol was added a few drops of concentrated HCl. The reaction mixture was refluxed overnight, then concentrated under reduced pressure. The residual solid was dissolved in ethyl acetate, washed twice with dilute NaHCO3, then once with water. The organic phase was dried over MgSO4, concentrated under reduced pressure, and dried under vacuum, to give N-Ac-Phe-OEt as a white solid.
Reaction SMILES: [O:1]([C:8]1[C:9]2[N:16]([CH2:17][CH:18]([O:22]CC)[O:19]CC)[CH:15]=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[O:1]([C:8]1[C:9]2[N:16]([CH2:17][CH:18]([OH:22])[OH:19])[CH:15]=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(Cn1ccc2ncnc(Oc3ccccc3)c21)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC(O)Cn1ccc2ncnc(Oc3ccccc3)c21
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
4-Phenoxy-5-(2,2-diethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (1.1 g) was dissolved in dichloromethane (4.53 mL)/trifluoroacetic acid (4.53 mL), and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (100 mL). The mixture washed with saturated aqueous sodium hydrogen carbonate (80 mL), and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the title compound (826 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[S:10][C:11]([CH3:16])=[CH:12][C:13]=2[C:14]#[N:15])=[C:4]([N+:17]([O-])=O)[CH:3]=1.[Sn](Cl)Cl.Cl.O>C(O)C.O>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[S:10][C:11]([CH3:16])=[CH:12][C:13]=3[C:14]([NH2:15])=[N:17][C:4]=2[CH:3]=1
Reactant: Cc1cc(C#N)c(Nc2ccc(Cl)cc2[N+](=O)[O-])s1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1cc2c(s1)Nc1ccc(Cl)cc1N=C2N
Yield: 221.2 %

Procedure:
Suspend 2-(4-chloro-2-nitro-phenylamino)-5-methyl-thiophene-3-carbonitrile (2.92 g) in ethanol (40 ml), add anhydrous tin(II)chloride(5 g,) in 1:1 concentrated hydrochloric acid/water (32 ml) and heat the mixture under reflux for 2 hours. Dilute the mixture with water and allow to cool. Collect the precipitate formed by filtration and dry under high vacuum to give 7-chloro-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride as a yellow solid (3.3 g, 90%): mass Spectrum (FIA) 264/266 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][CH3:20])(=[O:18])=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:30](S(Cl)(=O)=O)[CH2:31][CH2:32]CC.C(N)C(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:22]2[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=2[Cl:29])[C@H:12]([CH3:21])[CH2:13][CH2:14][CH2:15][S:16]([NH:19][CH2:20][CH:31]([CH3:32])[CH3:30])(=[O:17])=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reactant: CCCCCS(=O)(=O)Cl
Solvent: CC(C)CN
Product: CC(C)CNS(=O)(=O)CCC[C@@H](C)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Yield: 66 %

Procedure:
4-chloro-N-[2,5-dichlorophenyl]-N-[4-[(2-methylpropyl amino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide was prepared analogous to 4-chloro-N-[2,5-dichlorophenyl]-N-[4 [(methylamino)sulfonyl]-1(R)-methylbutyl]benzenesulfonamide by reacting (4R)-4-[2,5-dichlorophenyl][4-chlorophenyl)sulfonyl]-amino]pentylsulfonyl chloride with iso-butylamine. Yield=66%; MS (ESI+), 541 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:19]([CH2:25][C:26]#[N:27])(=O)[C:20]([CH3:23])([CH3:22])[CH3:21]>C1(C)C=CC=CC=1>[C:20]([C:19]1[CH:25]=[C:26]([NH2:27])[N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[N:11]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: COc1ccc(NN)cc1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
Solid 4-methoxyphenylhydrazine hydrochloride (25.3 g) was suspended in toluene (100 mL) and treated with triethylamine (20.2 g). The mixture was stirred at RT for 30 min and treated with pivaloylacetonitrile (18 g). The reaction was heated to reflux and stirred overnight. The hot mixture was filtered, the solids washed with hexane and dried in vacuo to afford 3-tert-butyl-1-(4-methoxyphenyl)-1H-pyrazol-5-amine (25 g, 70%). 1H NMR (DMSO-d6): δ 7.5 (d, 2H), 7.0 (d, 1H), 6.4 (s, 1H), 6.1 (s, 2H), 3.9 (s, 3H), 1.3 (s, 9H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20][N:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1>>[F:19][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=2)=[N:7][C:2]([NH:20][N:21]2[CH:25]=[CH:24][CH:23]=[CH:22]2)=[N:3][CH:4]=1
Reactant: CC(C)Oc1ccc(Nc2nc(Cl)ncc2F)cc1
Reactant: Nn1cccc1
Product: CC(C)Oc1ccc(Nc2nc(Nn3cccc3)ncc2F)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-5-fluoro-N-(4-isopropoxyphenyl)-4-pyrimidineamine was reacted with 1-aminopyrrole to provide 5-fluoro-N4-(4-isopropoxyphenyl)-N2-(1H-pyrrol-1-yl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.93 (s, 1H), 9.21 (s, 1H), 7.97 (d, 1H, J=4.1 Hz), 7.47 (d, 2H, J=8.8 Hz), 6.70 (dd, 2H, J=2.3 and 4.7 Hz), 6.67 (d, 2H, J=8.8 Hz), 6.02 (dd, 2H, J=2.3 and 4.7 Hz), 4.48 (sept, 1H, J=5.8 Hz), 1.21 (d, 6H, J=5.8 Hz). LCMS: ret. time: 23.44 min.; purity: 90%; MS (m/e): 328 (MH+).
Reaction SMILES: [N+:1]([O-:4])([OH:3])=O.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[NH:16][C:15]([C:17]([F:20])([F:19])[F:18])=[C:14]([C:21]3[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)[CH:13]=2)=[CH:8][CH:7]=1.O>C(OC(=O)C)(=O)C>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[NH:16][C:15]([C:17]([F:19])([F:18])[F:20])=[C:14]([C:21]3[S:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=3)[C:13]=2[N+:1]([O-:4])=[O:3])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3ccc(Cl)cc3)[nH]c2C(F)(F)F)s1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1ccc(-c2c(C(F)(F)F)[nH]c(-c3ccc(Cl)cc3)c2[N+](=O)[O-])s1
Temperature: 25 °C

Procedure:
A 90% nitric acid solution (0.02 g, 0.28 mmol) is added to a solution of 5-(p-chlorophenyl)-3-(5-nitro-2-thienyl)-2-(trifluoromethyl)pyrrole (0.13 g, 0.34 mmol) in acetic anhydride. The reaction mixture is stirred at room temperature for ten minutes, treated with additional 90% nitric acid solution (0.02 g, 0.28 mmol), stirred at room temperature for 15 minutes, poured into water, stirred at room temperature overnight and extracted with ether. The combined organic extracts are dried over MgSO4 and concentrated in vacuo to obtain the title product as a tan solid which is identified by 1HNMR spectral analysis.