Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4](C(C([O-])=O)O)O)([O-])=[O:2].[CH:11]1([CH2:14][N:15]2[CH2:33][CH2:32][C@:22]34[C:23]5[C:24]6[O:31][C@H:21]3[C@H:20]([N:34]([CH3:45])[C:35](=[O:44])[CH:36]=[CH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:19][CH2:18][C@@:17]4([OH:46])[C@H:16]2[CH2:29][C:28]=5[CH:27]=[CH:26][C:25]=6[OH:30])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][N:15]2[CH2:33][CH2:32][C@:22]34[C:23]5[C:24]6[O:31][C@H:21]3[C@H:20]([N:34]([CH3:45])[C:35](=[O:44])[CH:36]=[CH:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:19][CH2:18][C@@:17]4([O:46][C:1](=[O:2])[CH3:4])[C@H:16]2[CH2:29][C:28]=5[CH:27]=[CH:26][C:25]=6[OH:30])[CH2:12][CH2:13]1
Reactant: CN(C(=O)C=Cc1ccccc1)[C@@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Product: CC(=O)O[C@@]12CC[C@@H](N(C)C(=O)C=Cc3ccccc3)[C@@H]3Oc4c(O)ccc5c4[C@@]31CCN(CC1CC1)[C@@H]2C5

Procedure:
tartrate 144 (yield: 48%) was obtained by following the procedure of example 133 but using 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(N-methylcinnamamido)morphinan (free base of 99) instead of 17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxy-6α-(N-methyl-3,4-dichlorophenylacetamido) morphinan (free base of 1).
Reaction SMILES: O[C@H:2]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O-:5])=[O:4].[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=1)([O-:16])=[O:15].[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:27]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[N+:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([C@H:2]([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:26][CH3:27])=[O:4])=[O:23])=[CH:24][CH:25]=1)([O-:16])=[O:15]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C([O-])[C@H](O)CCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H](CCc1ccccc1)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 4.5 °C

Procedure:
To a cold (ice bath) solution of commercially available (R)-2-hydroxy4-phenyl-butyrate, ethyl ester (1.86mL, 9.60 mmole), p-nitrobenzoic acid (6.42 g, 38.4mmole, 4 eq) and triphenylphosphine (10.07 g, 38.4 mmole, 4 eq.) in anhydrous tetrahydrofuran (110 mL) was added diethyl azodicarboxylate (6.05 mL, 38.4 mmole, 4 eq) dropwise over a period of 40 minutes keeping the internal temperature between 4 and 5° C. After stirring for one additional hour at 4-5° C., the ice bath was removed and the solution was allowed to stir at ambient temperature for 5 days. The solvents were removed and the residue was redissolved in a mixture of ether and ethyl acetate (600 mL). Silica gel (200 mL) was added and the solvents removed. The adsorbate was flash chromatographed (gradient (80/20-70/30 petroleum ether/ethyl acetate) to give the title compound as a yellow oil (4.03 g): NMR (CDCl3); δ8.30 (d, J=9 Hz, 2H), 8.18 (d, J=9 Hz, 2H), 7.38-7.18(m, 5H), 5.28 (t, J=2 Hz, 1H), 4.23(q, J=7 Hz, 2H), 2.85 (t, J=8 Hz, 2H), 2.40-2.33 (m, 2H), 1.29 (t, J=7H, 3H); MS [(+) FAB]: [M+H] m/z=358.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:53]1[CH2:57][CH2:56][CH2:55][C@@H:54]1[C:58](O)=[O:59]>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:58]([C@H:54]2[CH2:55][CH2:56][CH2:57][O:53]2)=[O:59])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: O=C(O)[C@H]1CCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)[C@H]1CCCO1
Reaction time: 1 h
Yield: 28.3 %

Procedure:
To a solution of 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.070 g, 0.189 mmol) in dry THF:DMF (4:1 mL) was added TBTU (0.182 g, 0.567 mmol) and TEA (3 mL) and stirred for 1 h under nitrogen atmosphere. To the reaction mixture (R)-(+)tetrahydro-2-furoic acid (0.032 g, 0.283 mmol) was added and stirred for 18 h at room temperature. The reaction mass was quenched in water, extracted with ethyl acetate and concentrated to afford crude product which was purified by column chromatography eluting with MeOH:DCM to afford 0.025 g of the desired title product. 1H NMR (400 MHz, DMSO d6): δ 1.23 (s, 2H), 1.74-1.92 (m, 3H), 2.09-2.24, (m, 1H), 3.75-3.80 (m, 1H), 3.89-3.94 (m, 1H), 4.26-4.37 (m, 3H), 7.43-7.45 (d, J=8.4 Hz, 1H), 7.61-7.63 (d, J=8.4 Hz, 2H), 7.85-7.87 (d, J=8.8 Hz, 2H), 8.19-8.21 (d, J=8.8 Hz, 2H), 8.50-8.53 (m, 1H), 12.71 (br s, 1H); MS (m/z): 465.55 (M−H−).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[I:22][CH3:23]>>[I-:22].[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][N+:19]([CH3:23])([CH3:21])[CH3:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CI
Reactant: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CN(C)C)c1
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2C[N+](C)(C)C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of [2-(3,5-dimethylphenyl)-1H-indol-3-ylmethyl]dimethylamine (350 mg in 4 mL diethyl ether) was added 0.5 mL iodomethane and the mixture stirred at room temperature. After 3 hours, the mixture was filtered and the solids dried in vacuo to provide the crude title compound. (414 mg).
Reaction SMILES: [OH:1][C@@H:2]([CH3:38])[C@H:3]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[N:12](COCC[Si](C)(C)C)[CH:11]=1)=[O:9])[CH2:4][O:5][CH3:6].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[OH:1][C@@H:2]([CH3:38])[C@H:3]([NH:7][C:8]([C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[N:21]([CH3:29])[N:20]=3)[N:17]=2)[NH:12][CH:11]=1)=[O:9])[CH2:4][O:5][CH3:6]
Reactant: COC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H](C)O
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: COC[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H](C)O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.9 %

Procedure:
In a 10 mL round-bottom flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2S)-2-hydroxy-1-methoxymethyl-propyl)-amide (44 mg, 0.081 mmol) and TFA (0.3 ml, 3.9 mmol) were combined with dichloromethane (1 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (1 mL) and ethylenediamine (0.15 ml, 2.2 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (hot dichloromethane/heptane) to afford 15 mg (46%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2S)-2-hydroxy-1-methoxymethyl-propyl)-amide as an off-white solid. MS: [M+H]+=413; 1H NMR (300 MHz, DMSO-d6) δ: 12.83 (br. s., 1H), 9.14 (s, 1H), 8.62 (dd, J=8.8, 5.3 Hz, 1H), 8.44 (s, 1H), 8.30 (d, J=9.6 Hz, 1H), 7.68 (dd, J=9.6, 1.8 Hz, 1H), 7.13 (td, J=9.1, 2.0 Hz, 1H), 4.94 (d, J=5.6 Hz, 1H), 4.17-4.23 (m, 1H), 4.15 (s, 3H), 3.85-3.96 (m, 1H), 3.75 (dd, J=9.6, 5.6 Hz, 1H), 3.57 (dd, J=9.6, 3.5 Hz, 1H), 3.25 (s, 3H), 1.17 (d, J=6.1 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=O)=[CH:4][CH:3]=1.[C:16]1([C:22]2[O:26][C:25]([NH2:27])=[N:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH2:14][NH:27][C:25]2[O:26][C:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:23][N:24]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: Nc1nnc(-c2ccccc2)o1
Product: Cc1noc(-c2ccc(Br)cc2)c1CNc1nnc(-c2ccccc2)o1

Procedure:
Prepared according to the procedure described in Example 2, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 5-phenyl-[1,3,4]oxadiazol-2-ylamine.
Reaction SMILES: N1C=C(C(OCC)=[O:7])C=N1.BrCC1C=CC=C(C(F)(F)F)C=1.C(=O)([O-])[O-].[K+:27].[K+].[F:29][C:30]([F:49])([F:48])[C:31]1[CH:32]=[C:33]([CH2:37][N:38]2[CH:42]=[C:41]([C:43]([O:45]CC)=[O:44])[CH:40]=[N:39]2)[CH:34]=[CH:35][CH:36]=1>CC(C)=O.CO>[OH-:7].[K+:27].[F:49][C:30]([F:29])([F:48])[C:31]1[CH:32]=[C:33]([CH2:37][N:38]2[CH:42]=[C:41]([C:43]([OH:45])=[O:44])[CH:40]=[N:39]2)[CH:34]=[CH:35][CH:36]=1
Reactant: CCOC(=O)c1cnn(Cc2cccc(C(F)(F)F)c2)c1
Reactant: CCOC(=O)c1cn[nH]c1
Agent: FC(F)(F)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: O=C(O)c1cnn(Cc2cccc(C(F)(F)F)c2)c1
Product: [OH-]

Procedure:
Ethyl pyrazole-4-carboxylate is reacted with 1-(bromomethyl)-3-(trifluoromethyl)benzene in acetone in the presence of potassium carbonate. The product, ethyl 1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-carboxylate, is then hydrolyzed with potassium hydroxide in methanol, to provide 1-{[3-(trifluoromethyl)phenyl]methyl}pyrazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][C:13](=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17])[C:5]([O:7][CH3:8])=[O:6].[K].[CH3:20][C:21](C)([O-])[CH3:22].C(Br)C=C.O>CN(C=O)C>[CH2:22]([N:12]([C:13](=[O:18])[CH2:14][CH2:15][CH:16]=[CH2:17])[C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[CH3:1])[CH:21]=[CH2:20]
Reactant: C=CCCC(=O)Nc1ccc(C(=O)OC)cc1C
Reactant: CC(C)(C)[O-]
Agent: [K]
Solvent: CN(C)C=O
Solvent: C=CCBr
Solvent: O
Product: C=CCCC(=O)N(CC=C)c1ccc(C(=O)OC)cc1C
Temperature: 70 °C

Procedure:
1.00 g (4.04 mmol) methyl 3-methyl-4-(pent-4-en-1-oyl-amino)-benzoate dissolved in 5 ml DMF are combined with 500 mg (4.37 mmol) potassium-tert.-butoxide and at 40° C. 350 μl (489 mg, 4.04 mmol) allylbromide are slowly added with stirring. Then the mixture is heated to 70° C. for 3 hours. Then the reaction mixture is poured into water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate, evaporated down i. vac., the residue is applied to silica gel and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 9:1).
Reaction SMILES: [F:1][C:2]1[C:7]([NH:8][C:9]([NH2:11])=[S:10])=[CH:6][CH:5]=[CH:4][N:3]=1.Br.Br[CH2:14][C:15]([C:17]1[S:21][C:20]([NH:22][C:23](=[O:25])[CH3:24])=[N:19][C:18]=1[CH3:26])=O.O>CCO>[F:1][C:2]1[C:7]([NH:8][C:9]2[S:10][CH:14]=[C:15]([C:17]3[S:21][C:20]([NH:22][C:23](=[O:25])[CH3:24])=[N:19][C:18]=3[CH3:26])[N:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NC(=S)Nc1cccnc1F
Reactant: CC(=O)Nc1nc(C)c(C(=O)CBr)s1
Agent: Br
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1nc(C)c(-c2csc(Nc3cccnc3F)n2)s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
According to the general procedure 1, N-(2-fluoropyridin-3-yl)thiourea (prepared from 3-amino-2-fluoropyridine (Asymchem), following procedure D) is added to a solution of N-[5-(bromoacetyl)-4-methyl-1,3-thiazol-2-yl]acetamide, hydrobromide salt (Intermediate 1) and TEA (3 eq) in EtOH. The mixture is stirred for 2 h at RT. After addition of water, the desired product is filtrated off and washed with water. N-{2-[(2-fluoropyridin-3-yl)amino]-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl}acetamide is isolated as a pale yellow solid (57%). The hydrochloride salt of a batch of N-{2-[(2-fluoropyridin-3-yl)amino]-4′-methyl-4,5′-bi-1,3-thiazol-2′-yl}acetamide (200.00 mg; 0.57 mmol; 1.00 eq.) is prepared. It is suspended in MeOH (10.00 ml) and hydrogen chloride (2.29 ml; 1.25 M; 2.86 mmol; 5.00 eq.) in methanol is added. The mixture is stirred during 20 minutes at RT and filtered. The yellow powder obtained is washed with diethyl ether and dried under vacuo, affording compound (43) in 79% yield. 1H NMR (DMSO-d6, 300 MHz) δ 2.13 (s, 3H), 2.47 (s, 3H), 3.15 (s, 2H), 7.01 (s, 1H), 7.36 (m, 1H), 7.77 (m, 1H), 8.94 (m, 1H), 10.39 (s, 1H), 12.07 (s, 1H). M− (ESI): 347.8; M+ (ESI): 349.8. HPLC, Rt: 3.0 min (purity: 100%).
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2.C([Br:25])(=O)C>C1C=CC=CC=1>[Br:25][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:16][C:3]1=2
Reactant: CC(=O)Br
Reactant: COC(=O)Cc1ccc2c(c1)C(O)c1ccccc1CO2
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc2c(c1)C(Br)c1ccccc1CO2

Procedure:
A mixture of 5.7 g. of methyl 6,11-dihydro-11-hydroxydibenz[b,e]oxepin-2-acetate, 5 ml. of acetyl bromide and 60 ml. of dry benzene is refluxed for two hours. Evaporation in vacuo provides methyl 6,11-dihydro-11-bromodibenz[b,e]oxepin-2-acetate as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.Cl[C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C>[C:1]1([C:7]2[N:11]=[CH:10][N:9]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cnc[nH]2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1ccc(-c2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
A solution of 5-phenyl-1H-imidazole (504 mg, 3.5 mmol) in DMF (10 mL) was cooled to 0° C., and then NEt3 (530 mg, 5.25 mmol) was added, followed by the addition of (chloromethanetriyl)tribenzene (1.17 g, 4.2 mmol) in small portions. The resulting slurry was stirred at room temperature for 2 hours. The mixture was poured into ice-water (50 mL) and stirred until the ice melted. The resulting precipitate was collected and dissolved in DCM (100 mL). The solution was dried over sodium sulfate, filtered, concentrated and then purified by column chromatography to obtain 4-phenyl-1-trityl-1H-imidazole as a white solid (1.0 g). MS (ESI): m/z 387 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.CCN(C(C)C)C(C)C.[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)([CH3:33])[CH3:32])=[CH:27][CH:26]=1>CN(C=O)C>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([N:34]2[CH2:35][CH2:36][N:37]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:38][CH2:39]2)([CH3:33])[CH3:32])=[CH:27][CH:26]=1
Reactant: CC(C)(c1ccc(F)cc1)N1CCNCC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(c1ccc(F)cc1)N1CCN(c2ccc3nnc(C(F)(F)F)n3n2)CC1
Temperature: 80 °C
Yield: 70.3 %

Procedure:
6-Chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (120 mg, 0.54 mmol), DIPEA (0.094 mL, 0.54 mmol) and 1-[2-(4-fluorophenyl)propan-2-yl]piperazine (obtained as described in J. Med. Chem. 2007, 50, 3528) (120 mg, 0.54 mmol) in DMF (1.5 mL) were stirred and heated at 80° C. for 1 hour. The resulting solution was cooled to room temperature then applied to an SCX column and eluted with MeOH followed by 2M ammonia in methanol. Fractions containing product were combined and evaporated, then purified by preparative HPLC (Waters XTerra C18 column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 6-[4-[1-(4-fluorophenyl)-1-methylethyl]piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (155 mg, 70%) as a colourless solid.
Reaction SMILES: CC(C)([O-])C.[K+].[CH:7]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([CH3:17])[CH:10]=1)=[O:8].Br[CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C=O)C>[CH:7]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([CH3:17])[CH:10]=1)=[O:8]
Reactant: CCOC(=O)CCCCBr
Reactant: Cc1cc(C=O)cc(C)c1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCOc1c(C)cc(C=O)cc1C
Temperature: 110 °C

Procedure:
Potassium tert-butoxide (2.1 g, mw 112.2, 18 mmol) was added to a solution of 4-formyl-2,6-dimethylphenol (2.5 g, mw 150.2, 17 mmol) in dry DMF (15 mL) and the resultant suspension stirred under N2 at 25° C. for 5 minutes. Ethyl 5-bromovalerate (2.8 mL, mw 209.1, ρ 1.32, 18 mmol) dissolved in dry DMF (15 mL) was added, and the reaction heated at 110° C. for 5 hours, following which DMF was removed at 60° C. and 2 mm Hg. The residue was taken up in ethyl acetate (125 mL), washed with water (25 mL), 1 N aqueous NaOH (25 mL), and brine (75 mL), dried over Na2SO4, filtered, and concentrated to yield 4.47 g (97%) of NMR and TLC (Rf 0.58, CHCl3-methanol, 99:1) pure title product as an amber oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1.[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:12]1([CH3:22])[CH:13]=[CH:14][C:15]([S:18]([OH:21])(=[O:19])=[O:20])=[CH:16][CH:17]=1.[NH2:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:10])[CH2:7][CH2:8]1
Reactant: OCc1ccccc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: NC[C@H]1CC[C@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 10.0 g (63.6 mmol) of trans4-aminomethylcyclohexane-1-carboxylic acid, 25.1 g (132 mmol) of 4-toluenesulfonic acid, 50 mL (482 mmol) of benzyl alcohol, and 75 mL of toluene was heated to reflux under a N2 atmosphere using a Dean-Stark trap to collect water formed during the reaction. During reflux, all solids dissolved to leave a colorless solution. After 3 hours at reflux, the solution began to turn yellow. Heat was removed, and the flask allowed to cool to room temperature. The solids which separated out were collected and washed with diethyl ether. There was obtained 24.5 g (58.4 mmol, 92% yield) of product as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:18])[C:16]#[CH:17].[H-].[Na+].O>CN(C)C=O>[F:14][C:10]1[CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([O:18][CH2:15][C:16]#[CH:17])[N:3]=[CH:4][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: C#CCO
Reactant: Fc1cccc(-c2cc(Cl)ncn2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCOc1cc(-c2cccc(F)c2)ncn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 75.1 %

Procedure:
In 7 ml of N,N-dimethylformamide were dissolved 207 mg of 4-chloro-6-(3-fluorophenyl)pyrimidine and 67 mg of 2-propyn-1-ol, to which 48 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 6 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 170 mg of 4-(3-fluorophenyl)-6-(2-propynyloxy)pyrimidine (the present compound (56)).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[CH3:10][O:11][C:12](=[NH:17])[CH:13]=[C:14]([NH2:16])[CH3:15].[Cl-].[CH2:19]([O:21][C:22](=[O:26])[C:23](O)=O)[CH3:20].O>ClCCl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH3:15])[N:16]=[C:23]([C:22]([O:21][CH2:19][CH3:20])=[O:26])[N:17]=1
Reactant: CCOC(=O)C(=O)O
Reactant: COC(=N)C=C(C)N
Agent: Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1nc(C)cc(OC)n1
Reaction time: 1 h

Procedure:
182 ml of triethylamine in 50 ml of dichloromethane are added dropwise at -30° C. to a stirred suspension of 70.2 g of methyl-3-amino-2-butenimidate dihydrochloride in 350 ml of dichloromethane. Stirring is continued for 0.5 hour at this temperature, and 42 ml of oxalic acid ethyl ester chloride are then added dropwise. Stirring is continued for 1 hour at -30° C., and the mixture is allowed to come to room temperature in the course of 12 hours. The organic phase is stirred several times with water, dried over Na2SO4 and concentrated. After filtration over silica gel (eluent: CH2Cl2), the residue is distilled in vacuo. This gives 51.5 g of ethyl 4-methoxy-6-methylpyrimidine-2-carboxylate of boiling point 105°-115° C./-0.05 mbar.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:22])[S:10]([C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[N:30]=[C:31]([NH2:34])[S:32][CH:33]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH3:22])[S:10]([C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:34][C:31]2[S:32][CH:33]=[C:29]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=3)[N:30]=2)=[O:18])=[CH:20][CH:21]=1)(=[O:11])=[O:12]
Reactant: COc1ccccc1N(C)S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1nc(-c2ccccn2)cs1
Product: COc1ccccc1N(C)S(=O)(=O)c1ccc(C(=O)Nc2nc(-c3ccccn3)cs2)cc1

Procedure:
4-(N-(2-methoxyphenyl)-N-methylsulfamoyl)benzoic acid (13) (109 mg, 0.34 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (50 mg, 0.28 mmol) using method C. The residue was purified using flash chromatography eluting with 50-100% EtOAc in hexanes. The resulting solid was triturated with diethyl ether to give 4-(N-(2-methoxyphenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as an off white solid. Yield: 46 mg (34%). 1H-NMR: 8.65-8.62 (m, 1H), 8.27 (d, J=8.5 Hz, 2H), 8.03 (d, J=7.5 Hz, 1H), 7.95-7.89 (m, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.38-7.32 (m, 2H), 7.22 (dd, J=7.5, 1.5 Hz, 1H), 7.01-6.94 (m, 2H), 3.34 (s, 3H), 3.18 (s, 3H).
Reaction SMILES: [NH:1]([CH2:3][CH2:4][CH2:5]O)[NH2:2].C(N(CC)CC)C.Cl[C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[O:24]1CCOC[CH2:25]1>>[O:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[N:1]([CH2:3][CH2:4][CH2:5][CH2:25][OH:24])[NH2:2]
Reactant: C1COCCO1
Reactant: NNCCCO
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(CC)CC
Product: NN(CCCCO)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-hydrazino-1-propanol (18.0 g.) and triethylamine (20.2 g.) in dioxane (300 ml.) was treated dropwise with a solution of 2-chlorobenzoxazole (30.8 g.) in dioxane (40 ml.) at 10° C. The reaction was then stirred at room temperature overnight. The precipitate was filtered and the filtrate concentrated in vacuo. The residue was crystallized from boiling benzene to give 4-[1-(2-benzoxazolyl)hydrazino]butanol, m.p. 87°-90° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@H:14]([CH2:15][CH:16]=[CH:17][CH2:18]1)[CH2:13][CH2:12]3)=[O:4].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[O:32]1[C@H:16]2[CH2:15][C@H:14]3[C@:19]([CH3:20])([CH2:18][C@@H:17]12)[C@@H:21]1[C@H:11]([C@H:8]2[C@@:6]([CH2:23][CH2:22]1)([CH3:7])[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH2:9]2)[CH2:12][CH2:13]3
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A solution of 17β-methoxycarbonyl-5α-androst-2-ene (7.0 g.,) and 85% m-chloroperbenzoic acid (5.0 g.) in chloroform (125 ml.) was stirred for 1.5 hr. at room temperature and then diluted with chloroform (125 ml.). This solution was washed with aqueous 10% sodium bicarbonate and water prior to drying. Filtration and evaporation afforded a solid (8.075 g.) which was recrystallised from methylene chloride/cyclohexane to afford the pure title compound; [α]D + 67°, (c, 0.8).