Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][C:23](OCC)=[O:24])=[CH:17][CH:16]=1>C(OCC)(=O)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[NH:7][C:5]3[N:4]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:3]=[C:2]([CH3:1])[C:6]=3[C:23](=[O:24])[CH:22]=2)=[CH:19][CH:20]=1
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Reactant: CCOC(=O)CC(=O)c1ccc(Br)cc1
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccccc2)c2[nH]c(-c3ccc(Br)cc3)cc(=O)c12
Temperature: 130 °C
Reaction time: 8 h

Procedure:
Into a 250 mL round-bottom flask, was placed a solution of 3-methyl-1-phenyl-1H-pyrazol-5-amine (20 g, 115.61 mmol, 1.00 equiv) in polyphosphoric acid (100 mL), ethyl 3-(4-bromophenyl)-3-oxopropanoate (31.21 g, 115.59 mmol, 1.00 equiv). The resulting solution was stirred overnight at 130° C. in an oil bath, then cooled to room temperature. The resulting solution was diluted with ice water:ethyl acetate (500 mL/500 mL). The resulting solution was extracted with ethyl acetate (5×500 mL), the organic layers combined and dried over anhydrous magnesium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The resulting residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:20) to yield 6-(4-bromophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridin-4(7H)-one as a white solid. 1HNMR (300 MHz, CDCl3, ppm): δ 1.46-1.48 (3H, m), 6.87 (1H, s), 7.28-8.26 (9H, m).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12]>C(Cl)Cl>[Br:1][C:15]1[CH:14]=[CH:13][C:11]([NH2:12])=[C:10]([F:9])[CH:16]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ccccc1F
Solvent: ClCCl
Product: Nc1ccc(Br)cc1F
Reaction time: 0.33 h

Procedure:
160 Parts of solid N-bromosuccinimide were added in portions over a 2-hour period to a solution of 100 parts of 2-fluoroaniline in 400 parts of methylene chloride cooled to 0°. After stirring for 20 minutes, the dark red mixture was washed four times; 200 parts of cold water were used for each washing. The red organic phase was dried with anhydrous sodium sulfate and evaporated under 300 mm.Hg to 164 parts of brown, oily 4-bromo-2-fluoroaniline, nD25 : 1.5885.
Reaction SMILES: [C:1]1([Mg]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:9]=[C:10]1[CH2:26][C@H:14]2[O:15][C:16]3[CH:21]=[C:20]([CH2:22][CH:23]=[CH2:24])[C:19]([OH:25])=[CH:18][C:17]=3[C@@H:13]2[CH2:12][CH2:11]1>>[OH:9][C:10]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:26][C@H:14]2[O:15][C:16]3[CH:21]=[C:20]([CH2:22][CH:23]=[CH2:24])[C:19]([OH:25])=[CH:18][C:17]=3[C@@H:13]2[CH2:12][CH2:11]1
Reactant: C=CCc1cc2c(cc1O)[C@@H]1CCC(=O)C[C@H]1O2
Reactant: Cl[Mg]c1ccccc1
Product: C=CCc1cc2c(cc1O)[C@@H]1CCC(O)(c3ccccc3)C[C@H]1O2

Procedure:
The addition of phenyl magnesium chloride to the product of Example 12 can be accomplished following the procedure of Example 9.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[NH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17].CC([O-])(C)C.[K+]>CS(C)=O>[CH2:2]([N:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCBr
Reactant: O=C1CCCN1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCCCCCCCN1CCCC1=O

Procedure:
22.1 g 1-Bromodecane (0.1 mol), 8.5 g (0.1 mol) of 2-pyrrolidone and 11.2 g (0.1 mol) of potassium tert-butylate were stirred in 100 ml of absolute DMSO for one hour. The DMSO was removed under reduced pressure, the residue taken up with diethyl ether, and washed with water (2 times). After drying with anhydrous MgSo4 and evaporating, the residue was distilled in vacuo. A first fraction, boiling between 140° and 147° C./1.2 mm Hg was discarded. The second fraction 17.4 g of pure product, b.p. 148° C./1.2 mm Hg.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:14]3[C:25](=[O:29])[NH:26][C:27](=[O:28])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]1=2.[Li].[Li][S:33][CH3:34]>O1CCOCC1.O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:15]1[C:14]2[C:25](=[O:29])[NH:26][C:27](=[O:28])[C:13]=2[C:12]2[C:11]3[CH:10]=[C:9]([OH:30])[CH:8]=[CH:7][C:6]=3[N:5]([CH2:4][CH2:3][CH2:2][S:33][CH3:34])[C:17]=2[CH:16]=1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1Cl)cc1c2c2cc(O)ccc2n1CCCBr
Reactant: [Li]SC
Agent: [Li]
Solvent: O
Solvent: C1COCCO1
Product: CSCCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4Cl)cc21)C(=O)NC3=O
Reaction time: 9 h

Procedure:
A mixture of the bromide (58) (60.0 mg, 0.124 mmol) prepared as described in example 172 and lithium thiomercaptide (13 mg, 0.2481 mmol) in p-dioxane (5 mL) was refluxed for 16 h. A further 10 mg of LiSMe was added and refluxing was continued for a further 9 h. The mixture was diluted with water, extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to drynessto give the sulfide (130 directly (47.1 mg, 84%) which crystallised from ethyl acetate/petroleum ether as an orange powder, mp 218–220° C. 1H NMR δ [(CD3)2SO] 11.07 (br s, 1H), 9.39 (br s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.80 (s, 1H), 7.61–7.56 (m, 2H), 7.53–7.43 (m, 3H), 7.15 (dd, J=8.8, 2.4 Hz, 1H), 4.52 (t, J=6.9 Hz, 2H), 2.45 (t, J=7.0 Hz, 2H), 2.01 (m, 2H), 2.00 (s, 3H). FABMS found [M+H]+: 453.0840, 451.0859. C24H20ClN2O3S requires 453.0854, 451.0883.
Reaction SMILES: C([O:5][C:6](=[O:21])[CH2:7][CH2:8][C@H:9]([NH:13]C(OC(C)(C)C)=O)[C:10](O)=[O:11])(C)(C)C.CCN=C=NCCCN(C)C.[ClH:33].[CH2:34]([N:38]1[CH:42]=[C:41]([NH:43][C:44]([NH:46][C:47]2[CH:52]=[CH:51][C:50]([O:53][C:54]([F:57])([F:56])[F:55])=[CH:49][CH:48]=2)=[O:45])[N:40]=[C:39]1[C:58]([NH:60][CH2:61][CH2:62][OH:63])=[O:59])[CH2:35][CH2:36][CH3:37]>CN(C=O)C.CN(C1C=CN=CC=1)C>[ClH:33].[NH2:13][C@H:9]([C:10]([O:63][CH2:62][CH2:61][NH:60][C:58]([C:39]1[N:38]([CH2:34][CH2:35][CH2:36][CH3:37])[CH:42]=[C:41]([NH:43][C:44]([NH:46][C:47]2[CH:48]=[CH:49][C:50]([O:53][C:54]([F:55])([F:56])[F:57])=[CH:51][CH:52]=2)=[O:45])[N:40]=1)=[O:59])=[O:11])[CH2:8][CH2:7][C:6]([OH:21])=[O:5]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCCCn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)NCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCn1cc(NC(=O)Nc2ccc(OC(F)(F)F)cc2)nc1C(=O)NCCOC(=O)[C@@H](N)CCC(=O)O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
91 mg (0.30 mmol) of (2S)-5-tert-butoxy-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid are dissolved in 5 ml of DMF and, after addition of 58 mg (0.3 mmol) of EDCI×HCl and 37 mg (0.30 mmol) of DMAP, stirred at room temperature for 10 minutes. Then 70 mg (0.15 mmol) of 1-butyl-N-(2-hydroxyethyl)-4-[({[4-(trifluoromethoxy)phenyl]amino}-carbonyl)amino]-1H-imidazole-2-carboxamide (Example 81) are added, and the mixture is stirred at room temperature overnight. The reaction mixture is purified by preparative HPLC. The product-containing fractions are evaporated in vacuo.
Reaction SMILES: [OH:1][C:2]([OH:23])(O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](O)=O.[N+]([O-])(O)=[O:25].N([O-])=O.[Na+]>O.C([O-])(=O)CCCCCCC/C=C\C[C@@H](CCCCCC)O.[Zn+2].C([O-])(=O)CCCCCCC/C=C\C[C@@H](CCCCCC)O>[C:2]([OH:23])(=[O:1])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[CH2:12][C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[OH:25]
Reactant: O=C(O)CCCCCCCCCCCCCCCCC(O)(O)O
Reactant: O=[N+]([O-])O
Agent: CCCCCC[C@@H](O)C/C=C\CCCCCCCC(=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCC[C@@H](O)C/C=C/CCCCCCCC(=O)O
Reaction time: 0.17 h

Procedure:
The castor oil acids from 50 kg of castor oil, obtained according to (1) and (2), are warmed in the crude state with 20 l of 50% strength HNO3 (50°-60°). A solution of 1.2 kg of sodium nitrite in 15 l of water is run in whilst stirring well, and the mixture is kept at 50°-60° C. for a further 10 minutes and then rapidly cooled, for example by pouring it onto ice. The reaction product separated from the aqueous phase can be further processed in the crude state like castor oil acid; the pure ricinelaidic acid is obtained by extracting the reaction product with boiling ligroin and crystallizing out by cooling.
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][CH:3]=1.[CH2:7]([NH2:19])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu]I.CN(C)CCO>[CH2:7]([NH:19][C:2]1[CH:6]=[CH:5][S:4][CH:3]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCN
Reactant: Brc1ccsc1
Agent: [Cu]I
Agent: CN(C)CCO
Agent: O=P([O-])([O-])[O-]
Product: CCCCCCCCCCCCNc1ccsc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 48.7 %

Procedure:
A mixture of 3-bromothiophene (7.20 g, 44.16 mmol), dodecylamine (12.28 g, 166.24 mmol), Cu (0.14 g, 2.21 mmol), CuI (0.42 g, 2.21 mmol), K3PO4 (18.75 g, 88.32 mmol), and N,N-dimethylethanolamine (60 mL) is purged with N2. The reaction mixture is then stirred for 2 days at 90° C. under nitrogen. The reaction mixture is quenched with water and extracted with diethyl ether followed by washing with brine. The organic layer is dried over Na2SO4. The crude compound is purified by column chromatography on silica gel with 0-5% ethyl acetate in hexane as eluent to give 3-dodecylaminothiophene (6a) as a brown solid (5.75 g, 49%). 1H-NMR (400 MHz) ppm 7.11 (dd, 1H, J=3.0 Hz, J=5.2 Hz), 6.58 (dd, 1H, J=1.5 Hz, J=5.1 Hz), 5.88 (dd, 1H, J=1.5 Hz, J=3.0 Hz), 3.02 (t, 2H, J=7.1 Hz), 1.58 (m, 2H), 1.35 (m, 18H), 0.86 (t, 3H, J=6.8 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][O:22][CH3:23].[F:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][O:22][CH3:23])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:31]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)(=[O:33])=[O:32])[C:18]=2[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[N:11]=1
Reactant: COCCc1nc2c(N)nc3c(c2n1CCCCN)CCCC3
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: COCCc1nc2c(N)nc3c(c2n1CCCCNS(=O)(=O)c1ccc(F)cc1)CCCC3

Procedure:
According to the general method of Example 5, 1-(4-aminobutyl)-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine and 4-fluorobenzenesulfonyl chloride were combined. Recrystallization from 4:1 n-propyl acetate\methanol provided N1-{4-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]butyl}-4-fluoro-1-benzenesulfonamide as a white crystalline solid, m.p. 191.0-193.0° C. 1H NMR (300 MHz, DMSO-d6) δ 7.86-7.81 (m, 2H), 7.67 (broad s, 1H), 7.45-7.39 (m, 2H), 5.65 (broad s, 2H), 4.15 (m, 2H), 3.76 (t, J=6.7 Hz, 2H), 3.27 (s, 3H), 3.00 (t, J=6.7 Hz, 2H), 2.90 (broad s, 2H), 2.78 (m, 2H), 2.65 (broad s, 2H), 1.75 (broad s, 4H), 1.61 (m, 2H), 1.43 (m, 2H); MS (CI) m/e 476 (M+H). Analysis: Calculated for C23H30FN5O3S: %C, 58.09; %H, 6.36; %N, 14.73; Found: %C, 58.37; %H, 6.35; %N, 14.60.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[C:5]([O:9][CH2:10][CH3:11])=[CH:4][N:3]=1.[CH:12]1([CH:17]([OH:20])[CH:18]=[CH2:19])[CH2:16][CH2:15][CH2:14][CH2:13]1.C([O-])(=O)C.[Na+]>CC(N(C)C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:19][CH2:18][C:17]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:20])[C:5]([O:9][CH2:10][CH3:11])=[CH:4][N:3]=1
Reactant: CCOc1cnc(Cl)cc1I
Reactant: C=CC(O)C1CCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOc1cnc(Cl)cc1CCC(=O)C1CCCC1
Temperature: 90 °C
Yield: 80.4 %

Procedure:
A mixture of 2-chloro-5-ethoxy-4-iodo-pyridine (1.5 g, 5.3 mmol), 1-cyclopentyl-2-propen-1-ol (0.83 g, 6.61 mmol), sodium acetate (0.54 g, 6.6 mmol), palladium (II) acetate (24 mg, 0.11 mmol) in DMAC (10 mL) was heated to 90° C. under N2 for 16 hours. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layers were washed with saturated NaHCO3, brine, dried over MgSO4 and concentrated. Purification by silica gel chromatography (0% to 60% EtOAc in hexanes) gave the desired product (1.2 g, 58%). 1H NMR (300 MHz, CDCl3): δ 1.44 (t, J=7.0 Hz, 3 H), 1.55–1.87 (m, 8 H), 2.75 (m, 2 H), 2.86 (m, 3 H), 4.11 (q, J=7.0 Hz, 2 H), 7.09 (s, 1 H), 7.89 (s, 1 H).
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:6]=1.CN1C=CN=C1CC=CC1C=CC(C(OC)=O)=C(C2C=CC(F)=CC=2)C=1.[CH2:48]([N:55]1[CH:59]=[CH:58][N:57]=[CH:56]1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[CH2:48]([N:55]1[CH:59]=[CH:58][N:57]=[C:56]1[CH2:2][CH:3]=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:6]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: COC(=O)c1ccc(C=CCBr)cc1-c1ccc(F)cc1
Reactant: c1ccc(Cn2ccnc2)cc1
Agent: COC(=O)c1ccc(C=CCc2nccn2C)cc1-c1ccc(F)cc1
Product: COC(=O)c1ccc(C=CCc2nccn2Cc2ccccc2)cc1-c1ccc(F)cc1
Yield: 76 %

Procedure:
Methyl 4-[3-(1-benzylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate was prepared from methyl 4-(3-bromoprop-1-en-1-yl)-2-(4-fluorophenyl)benzoate as described for methyl 4-[3-(1-methylimidazol-2-yl)prop-1-en-1-yl]-2-(4-fluorophenyl)benzoate in Example 19, but using N-benzylimidazole. Yield: 76%
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([CH2:7][C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH3:17]O>>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([CH2:7][C:8]([O:10][CH3:17])=[O:9])=[CH:5][CH:6]=1
Reactant: Cc1ccc(CC(=O)O)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(C)cc1
Temperature: 65 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A 500-mL round bottom flask, with stirrer bar, was charged with p-tolylacetic acid (10.0 g, 66.5 mmol) and methanol (240 mL). Concentrated sulfuric acid (0.1 mL) was added at room temperature. The resulting solution was stirred at 65° C. for 18 h. After this time, the mixture was concentrated in vacuo, and the residue was diluted with ethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). The organic layer was washed with saturated sodium chloride (2×20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the title compound (11.8 g, 100%) as a colorless oil. MW=164.20. 1H NMR (CDCl3, 300 MHz) δ 7.20-7.10 (m, 4H), 3.68 (s, 3H), 3.59 (s, 2H), 2.33 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][CH2:12][C:13]([C:15]1[N:16]=[CH:17][NH:18][CH:19]=1)=O.P(=O)(O)(O)O.S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:10][O:9][C:8]1[C:3]([O:2][CH3:1])=[C:4]2[C:5]([C:13]([C:15]3[N:16]=[CH:17][NH:18][CH:19]=3)=[CH:12][CH2:11]2)=[CH:6][CH:7]=1
Reactant: COc1cccc(CCC(=O)c2c[nH]cn2)c1OC
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COc1ccc2c(c1OC)CC=C2c1c[nH]cn1
Yield: 46.1 %

Procedure:
5 g (0.0206 mole) of 3-(2,3-dimethoxyphenyl)-1-(1H-imidazol-4-yl)-1-propanone prepared in Example 2.4.a (and/or in Example 2.3.a) are stirred at room temperature for 16 hours in 100 ml of a 50:50 (v/v) mixture of 85% phosphoric acid and 95% sulphuric acid. The reaction medium is then poured onto ice, the mixture is brought to pH 7.5 by addition of an aqueous solution of sodium hydroxide cooled to a temperature of less than 10° C., and the mixture is then extracted with dichloromethane. The solvent is evaporated from the organic phase and the residue is treated by chromatography (stationary phase:silica; eluent: 95:5 (v/v) mixture of dichloromethane-methanol). 2.3 g of 4-(6,7-dimethoxy-1H-inden-3-yl)-1H-imidazole are obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32][CH:31]=3)[S:29][C:20]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([O:16][CH3:17])=[CH:11][C:10]=1[NH:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][N:22]=[C:21]2[CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[CH:32][CH:31]=3)[S:29][C:20]=12
Reactant: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(C=O)cc4)sc23)c(Cl)cc1Cl
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4ccc(CN5CCC(O)CC5)cc4)sc23)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 4 h
Yield: 50.5 %

Procedure:
4-Hydroxypiperidine (100 mg, 0.99 mmol) is added to a suspension of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-(4-formylphenyl)thieno[3,2-b]pyridine-6-carbonitrile (165 mg, 0.36 mmol) in 5 mL of dichloromethane and 2 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (0.55 g, 2.60 mmol) is added. After stirring at 0° C. for 4 hours, 3 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 1.5 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with a gradient of ethyl acetate to 5% methanol in ethyl acetate to provide 98 mg of 7-[(2,4-dichloro-5-methoxyphenyl)amino]-2-{4-[(4-hydroxypiperidin-1-yl)methyl]phenyl}thieno[3,2-b]pyridine-6-carbonitrile as yellow crystals, mp 149-150° C.; 1H NMR (DMSO-d6) δ 1.35-1.45 (m, 2H), 1.65-1.75 (m, 2H), 2.00-2.10 (m, 2H), 2.62-2.70 (m, 2H), 3.47 (s, 3H), 3.85 (s, 3H), 4.54 (d, J=4 Hz, 1H), 7.37 (s, 1H), 7.40 (d, J=8 Hz, 2H), 7.67 (d, J=8 Hz, 2H), 7.76 (s, 1H), 7.89 (s, 1H), 8.59 (s, 1H), 9.72 (s, 1H); MS 536.9 (M−H)−.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].CCN(CC)CC.[CH3:13][C:14]1([CH3:22])[O:19][CH2:18][CH:17]([CH2:20][OH:21])[CH2:16][O:15]1>C(Cl)Cl>[CH3:13][C:14]1([CH3:22])[O:19][CH2:18][CH:17]([CH2:20][O:21][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:16][O:15]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCC(CO)CO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OCC(COS(C)(=O)=O)CO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
MsCl (4.4 mL, 56 mmol) was added slowly to a solution of Et3N (9.8 mL, 71 mmol) and (2,2-dimethyl-[1,3]dioxan-5-yl)-methanol (6.87 g, 47.0 mmol) in CH2Cl2 (100 mL) at 0° C. (bath temp). The reaction mixture was stirred at rt for 2 h and then quenched with H2O (100 mL). The mixture was extracted with CH2Cl2 and the organic fractions were dried (MgSO4) and concentrated in vacuo to give the title compound as a colorless liquid: yield 10.02 g (95%).
Reaction SMILES: [OH-].[K+].[C:3]([NH:7][NH:8][C:9]([NH:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10])(=O)[CH2:4][CH3:5].Cl>O>[CH2:4]([C:3]1[N:11]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9](=[O:10])[NH:8][N:7]=1)[CH3:5]
Reactant: CCC(=O)NNC(=O)NCCOc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCc1n[nH]c(=O)n1CCOc1ccccc1
Temperature: 95 °C
Reaction time: 0.67 h
Yield: 63.5 %

Procedure:
A solution of potassium hydroxide (88.4 g., 1.576 mole) in 10 liters of water is stirred and heated to 95° C.; then 1-propionyl-4-(2-phenoxyethyl)-semicarbazide (396.1 g., 1.576 mole) added and the mixture stirred at 95°-96° C. for a 40 min. period. Insolubles are collected and the filtrate stirred in an ice bath as 145 ml. (1.74 mole) of 37% hydrochloric acid is added. Stirring is continued with cooling to provide a white solid which is collected, rinsed with water and air dried to provide 233.5 g., (63.5% yield) of 5-ethyl-4-(2-phenoxyethyl)-2H-1,2,4-triazol-3(4H)-one, m.p. 136°-139° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:2]1.[C:16](Br)([CH3:19])([CH3:18])[CH3:17]>C1CCCCC1.ClCCl.[Ag-]=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])=[CH:2]1
Reactant: COC(=O)C(O)c1csc2ccccc12
Reactant: CC(C)(C)Br
Agent: O=[Ag-]
Solvent: ClCCl
Solvent: C1CCCCC1
Product: COC(=O)C(OC(C)(C)C)c1csc2ccccc12
Reaction time: 20 h
Yield: 18.5 %

Procedure:
A mixture of methyl 2-(1-benzothiophen-3-yl)-2-hydroxyacetate (4a) (300 mg, 1.35 mmol), silver (I) oxide (938 mg, 4.05 mmol) and tertbutylbromide (910 μL, 8.1 mmol) in a mixture of cyclohexane (5 mL) and dichloromethane (1 mL) was vigorously stirred for 20 hours under a nitrogen atmosphere. The reaction mixture was then filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired ether oxide (4b) as a white solid (70 mg, 0.25 mmol, 10%).
Reaction SMILES: O=[O+][O-].C(C[O:8][C:9]1[CH:10]=[CH:11][C:12]2[CH2:13][C@H:14]3[N:26]([CH3:27])[CH2:25][CH2:24][C@:20]45[C:21]=2[C:22]=1[O:23][C@H:19]4[C@@H:18]([OH:28])[CH:17]=[CH:16][C@@H:15]35)(O)=O.ClC(OCC(C)C)=O.C([O-])(O)=O.[Na+]>CN(C=O)C.O>[CH:11]1[C:12]2[CH2:13][C@H:14]3[N:26]([CH2:25][CH2:24][C@@:20]45[C@H:15]3[CH:16]=[CH:17][C@H:18]([OH:28])[C@@H:19]4[O:23][C:22]([C:21]=25)=[C:9]([OH:8])[CH:10]=1)[CH3:27]
Reactant: CN1CC[C@]23c4c5ccc(OCC(=O)O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: CC(C)COC(=O)Cl
Agent: O=C([O-])O
Agent: O=[O+][O-]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Reaction time: 8 h

Procedure:
O3 -Carboxymethyl morphine (3.43 g) and 1.31 ml isobutyl chloroformate were combined in 30 ml DMF at 0°. The resulting clear solution was then added to a stirring solution of 2.88 g BSA and 13 g NaHCO3 in 600 ml of water at 0°. Addition was carried out by means of a syringe with its tip below the solution surface. The solution was stirred in a cold room overnight.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][S:5]1(=[O:11])=[O:10].[I-:12].[Na+]>CC(C)=O>[I:12][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][S:5]1(=[O:11])=[O:10]
Reactant: O=S1(=O)CCCCN1CCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=S1(=O)CCCCN1CCI
Temperature: 80 °C

Procedure:
To a solution of 2-(2-chloroethyl)tetrahydro-2H-1,2-thiazine 1,1-dioxide (1.3 g, 6.6 mmol) in acetone (13 mL) was added sodium iodide (4.9 g, 33 mmol). The reaction mixture was heated at 80° C. overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo. The solids were taken up in dichloromethane and filtered. The filtrate was concentrated and chromatographed (0 to 5%, methanol in dichloromethane) to provide 2-(2-iodoethyl)tetrahydro-2H-1,2-thiazine 1,1-dioxide as an orange solid. 1H NMR (400 MHz, CDCl3) δ 3.51-3.42 (m, 4 H), 3.25 (t, J=7.4 Hz, 2 H), 3.02 (t, J=6.0 Hz, 2 H), 2.20 (m, 2 H), 1.69 (m, 2 H).
Reaction SMILES: Br[CH:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([NH2:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1.O.[NH2:18][NH2:19]>CO>[N:18](=[C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([NH2:15])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1)[NH2:19]
Reactant: CC1CCC(Br)c2ncc(C(N)=O)c(=O)n21
Reactant: NN
Solvent: CO
Solvent: O
Product: CC1CCC(=NN)c2ncc(C(N)=O)c(=O)n21
Reaction time: 0.17 h
Yield: 46.5 %

Procedure:
In 150 ml. of methanol 10.0 g. (34.95 millimoles) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxamide are dissolved under heating. To the solution 20 ml. hydrazine hydrate are added dropwise under stirring carefully within 10 minutes. The reaction mixture is heated to boiling for 40 minutes whereupon the methanol is distilled off in vacuo. The crystals are filtered off, washed with water and crystallized from water. Thus 3.8 g. (46.5%) of 9-hydrazono-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidine-3-carboxamide are obtained. Mp.: 248°-250° C.