Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:11]([CH:12]([CH3:14])[CH3:13])[CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:15])[C:4](=[CH2:16])[CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH:12]([CH:11]1[CH2:10][C:9]2[CH:5]([CH2:6][CH2:7][C:8]=2[CH3:15])[C:4](=[CH2:16])[CH2:3][C:2]1=[O:1])([CH3:14])[CH3:13]
Reactant: C=C1CC(O)C(C(C)C)CC2=C(C)CCC12
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: C=C1CC(=O)C(C(C)C)CC2=C(C)CCC12
Yield: 90.8 %

Procedure:
A solution, cooled to -10°, of 1.10 g of 6-hydroxy-7-isopropyl-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene (isomer A) in 50 ml of acetone was treated within 10 minutes with 2 ml of Jones reagent (5.3 mM CrO3) and the reaction mixture obtained then poured on to ice-cold bicarbonate solution. Extraction with ether, washing the extracts with bicarbonate solution and water, drying with sodium sulphate, concentration and distillation under reduced pressure yielded 990 mg (yield 90%) of 7-isopropyl-1-methyl-4-methylen-6-oxo-2,3,3a,4,5,6,7,8-octahydroazulene (isomer A) in the form of a colourless oil; b.p.0.01 ca 75°; IR(film):νmax = 3100, 1708, 1642, 1460, 1440, 1390, 1370, 1255, 1205, 1140, 1090, 1062, 1005, 970, 900, 800 cm-1. The compound has a sweet, spicy, woody odour. In analogous manner there were obtained from 1.10 g of the B-isomer of 6-hydroxy-7-isopropyl-1-methyl-4-methylen-2,3,3a,4,5,6,7,8-octahydroazulene, 890 g (yield 81%) of the B-isomer of the corresponding 6-oxo-octahydroazulene; b.p.0.01 ca 75°; IR(film): νmax = 1390, 1710, 1642, 1470/60/40, 1390, 1370, 1265, 1180, 1092, 1062, 1000, 970, 900 cm- 1. The compound has a fresh woody, slightly spicy, camphorous odour.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[CH2:16][C@@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][N:13]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[O:23])(=O)=O)=CC=1.[C:35]1(=[O:45])[NH:39][C:38](=[O:40])[C:37]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]12.[K]>CN(C)C=O>[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:24][C:22]([N:13]2[CH2:14][C@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:16][C@H:12]2[CH2:11][N:39]2[C:38](=[O:40])[C:37]3=[CH:41][CH:42]=[CH:43][CH:44]=[C:36]3[C:35]2=[O:45])=[O:23])=[CH:27][CH:28]=1
Reactant: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2COS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)N2C[C@H](OS(C)(=O)=O)C[C@H]2CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 70 °C
Reaction time: 4 h
Yield: 77.6 %

Procedure:
To a solution of (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (6.35 g: 12.27 mmole) in dimethylformamide (60 ml), potassium phthalimide (2.7 g) is added. The mixture is stirred at 70° C. for 4 hours. The reaction mixture is poured into ice water and extracted with ethyl acetate. The extract is successively washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is purified by silica gel column chromatography (toluene: ethyl acetate=2:1) to give (2S,4R)-1-p-methoxybenzyloxycarbonyl-4-methanesulfonyloxy-2-phthalimidomethylpyrrolidine (4.65 g). Yield: 77.5%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:18]([C:17]1[CH:21]=[C:22]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:23]=[CH:24][C:16]=1[O:15][CH:12]([CH3:14])[CH3:13])=[O:19])[CH2:7]2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: Clc1cccc2c1CCNC2
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2c(Cl)cccc2C1

Procedure:
Prepared in analogy to example 1.1 from 5-chloro-1,2,3,4-tetrahydro-isoquinoline (CA [73075-43-1]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [CH2:1]([N:4]([C:16](=[O:21])[CH2:17][CH2:18][CH:19]=[CH2:20])[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[CH3:15])C=C>C(=C1CCCC(P(Cl)(Cl)(C2CCCCC2)C2CCCCC2)C1=C1N(C2C(C)=CC(C)=CC=2C)CCN1C1C(C)=CC(C)=CC=1C)C1C=CC=CC=1.[Ru]>[N:4]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=2[CH3:15])[CH2:1][CH2:20][CH:19]=[CH:18][CH2:17][C:16]1=[O:21]
Reactant: C=CCCC(=O)N(CC=C)c1ccc(C(=O)OC)cc1C
Agent: [Ru]
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=C2C(=Cc3ccccc3)CCCC2P(Cl)(Cl)(C2CCCCC2)C2CCCCC2)c(C)c1
Product: COC(=O)c1ccc(N2CCC=CCC2=O)c(C)c1

Procedure:
150 mg (0.52 mmol) methyl 4-(allyl-pent-4-en-1-oyl-amino)-3-methyl-benzoate are dissolved in 110 ml degassed dichloromethane and rinsed for 30 minutes with argon. Then 88 mg (104 μmol) benzylidene-[1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene]-dichloro-(tricyclohexylphosphine)-ruthenium (2nd generation Grubbs Catalyst) are added and the mixture is refluxed for 4.5 hours. Then it is evaporated down i. vac., the residue is applied to silica gel and purified by chromatography on silica gel (eluant: petroleum ether/ethyl acetate 3:2).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:33]=[CH:34][CH:35]=1)[CH2:11][S:12][C:13]1[S:14][C:15]2[CH:21]([CH:22](C(OCC)=O)[C:23]([O:25]CC)=[O:24])[CH2:20][CH2:19][CH2:18][C:16]=2[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>C(O)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:33]=[CH:34][CH:35]=1)[CH2:11][S:12][C:13]1[S:14][C:15]2[CH:21]([CH2:22][C:23]([OH:25])=[O:24])[CH2:20][CH2:19][CH2:18][C:16]=2[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C(=O)OCC)C1CCCc2nc(SCc3cccc(Oc4ccccc4)c3)sc21
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CC1CCCc2nc(SCc3cccc(Oc4ccccc4)c3)sc21
Temperature: 120 °C
Reaction time: 12 h
Yield: 91.6 %

Procedure:
A mixture of diethyl {2-[(3-phenoxybenzyl)thio]-4,5,6,7-tetrahydro-1,3-benzothiazol-7-yl}malonate (1.21 g, 2.36 mmol), 37% hydrochloric acid (10 mL) and acetic acid (10 mL) was heated with stirring at 120° C. for 12 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate, washed successively with 10% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the title compound (890 mg, 92%) as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(O)CC1
Yield: 100.8 %

Procedure:
1(tert-Butoxycarbonyl)-4-piperidone (5 g, 0.025 moles) was treated with sodium borohydride (1.89 g, 0.05 moles) as in the method of Example 37, Step 2 to give the title compound 5.07 g (100%); 1H NMR (CDCl3) inter alia 1.45 (9 H, s), 1.29-1.41 (2 H, m), 2.42-3.05 (2H, m), 3.75-3.99 (3H, m).
Reaction SMILES: [Cl-].[NH4+].[CH3:3][N:4]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[N:15]([S:37]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)(=[O:39])=[O:38])[C:16]([C:18]4[CH:19]=[N:20][C:21]([N:24]5[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]5)=[N:22][CH:23]=4)=[CH:17][C:10]=23)[C:6]([C:46]2[CH:51]=[CH:50][C:49]([N+:52]([O-])=O)=[CH:48][CH:47]=2)=[N:5]1>O.CO.[Fe]>[NH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:6]2[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[C:11]4[N:15]([S:37]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)(=[O:38])=[O:39])[C:16]([C:18]5[CH:23]=[N:22][C:21]([N:24]6[CH2:25][CH2:26][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:28][CH2:29]6)=[N:20][CH:19]=5)=[CH:17][C:10]=34)=[CH:8][N:4]([CH3:3])[N:5]=2)=[CH:47][CH:48]=1
Reactant: Cn1cc(-c2ccnc3c2cc(-c2cnc(N4CCN(C(=O)OC(C)(C)C)CC4)nc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Cn1cc(-c2ccnc3c2cc(-c2cnc(N4CCN(C(=O)OC(C)(C)C)CC4)nc2)n3S(=O)(=O)c2ccccc2)c(-c2ccc(N)cc2)n1
Temperature: 70 °C

Procedure:
To a solution of ammonium chloride (3.00 mmol) in H2O (5 ml) was added iron powder (1.66 mmol) followed by a solution of 1,1-dimethylethyl 4-{5-[4-[1-methyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-2-pyrimidinyl}-1-piperazinecarboxylate (0.333 mmol) in methanol (10 ml). The resulting mixture was heated at 70° C. for 2 hours, the hot solution filtered through a pad of celite 545 and concentrated to yield the title product as a yellow solid (quant.) which was used crude in the next step. ESMS [M+H]+: 692.2.
Reaction SMILES: O.[C:2]([C:4]1[CH:5]=[C:6]([N:10]2[C:16](=[O:17])[CH2:15][C:14](=[O:18])[NH:13][C:12]3[C:19]4[C:24]([CH:25]=[CH:26][C:11]2=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:7]=[CH:8][CH:9]=1)#[N:3].[H-].[Na+].I[CH3:30]>CS(C)=O.CCCCCC>[C:2]([C:4]1[CH:5]=[C:6]([N:10]2[C:16](=[O:17])[CH2:15][C:14](=[O:18])[N:13]([CH3:30])[C:12]3[C:19]4[C:24]([CH:25]=[CH:26][C:11]2=3)=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:7]=[CH:8][CH:9]=1)#[N:3]
Reactant: CI
Reactant: N#Cc1cccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)c1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: O
Product: CN1C(=O)CC(=O)N(c2cccc(C#N)c2)c2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 27.3 %

Procedure:
To a water-cooled solution of 5-(3-cyanophenyl)-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione (98 mg, 0.30 mmol) in DMSO (1 mL) was added 50-72% sodium hydride (12 mg). The mixture was stirred at room temperature for 1 hour, to which was added iodomethane (0.06 mL, 1 mmol). The mixture was stirred for 4 hours at room temperature, to which was added 50-72% sodium hydride (6 mg) and iodomethane (0.03 mL, 0.5 mmol). The mixture was stirred at room temperature for 18 hour, treated with cold water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was washed with ethyl acetate, then with hexane, to give 5-(3-cyanophenyl)-1-methyl-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione as a pale yellow crystal (28 mg, yield 27%). Then the solvent of washings was removed under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1), to give 5-(3-cyanophenyl)-1,3-dimethyl-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione as a pale yellow oil (9 mg, yield 8%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[CH:12]/[C:13]([OH:15])=O)[CH:9]=2)[CH:4]=[CH:3]1.C(N(CC)CC)C.C(Cl)(=O)OCC.O.O.[N:31]1([CH:37]2[C:47]3[C:42](=[N:43][CH:44]=[CH:45][CH:46]=3)[CH2:41][CH2:40][C:39]3[CH:48]=[CH:49][CH:50]=[CH:51][C:38]2=3)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>C(Cl)Cl.O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](/[CH:11]=[CH:12]/[C:13]([N:34]3[CH2:35][CH2:36][N:31]([CH:37]4[C:47]5[C:42](=[N:43][CH:44]=[CH:45][CH:46]=5)[CH2:41][CH2:40][C:39]5[CH:48]=[CH:49][CH:50]=[CH:51][C:38]4=5)[CH2:32][CH2:33]3)=[O:15])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: c1ccc2c(c1)CCc1ncccc1C2N1CCNCC1
Reactant: Cn1ccc2ccc(/C=C/C(=O)O)cc21
Agent: CCOC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1ccc2ccc(/C=C/C(=O)N3CCN(C4c5ccccc5CCc5ncccc54)CC3)cc21
Reaction time: 1 h
Yield: 74.5 %

Procedure:
1.01 g of (E)-3-(1-methyl-6-indolyl)acrylic acid was suspended in 20 ml of methylene chloride. 560 mg of triethylamine was added thereto. To the mixture was dropwise added 570 mg of ethyl chlorocarbonate at -30° to -20° C. The mixture was stirred for 1 hour at the same temperature. To the reaction mixture was added 1.73 g of 5-(piperazin-1-yl)-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine dihydrate. The mixture was stirred for 1 hour at room temperature. To the reaction mixture was added 20 ml of water. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/acetone=5/1) to obtain 1.73 g of 5-[4-{(E)-3-(1-methyl-6-indolyl)acryloyl}piperazin-1-yl]-10,11-dihydro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[NH:16][CH:17]=[C:18]([C:20](F)(F)F)[N:19]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[NH4+:25].C(O)(=O)C>CCOC(C)=O.CCCCCC>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3[NH:16][CH:17]=[C:18]([C:20]#[N:25])[N:19]=3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [NH4+]
Reactant: COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1OC1CCCC1
Agent: [OH-]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2nc(C#N)c[nH]2)cc1OC1CCCC1
Yield: 35 %

Procedure:
A mixture of 2-(3-cyclopentyloxy-4-methoxyphenyl)-4-trifluoromethyl-imidazole (1.04 g, 3.18 mmol) and 5% aqueous ammonium hydroxide (300 ml) was heated to reflux for 24 hours. The reaction mixture was cooled and carefully neutralised with acetic acid. The mixture was extracted with methylene chloride (3×150 ml) and the volatiles removed in vacuo to afford the crude product. Flash chromatography (SiO2 ; EtOAc:hexane (2:3)) produced the 2-(3-cyclopentyloxy-4-methoxyphenyl)-4-cyanoimidazole (320 mg, 35%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([N+:15]([O-])=O)[C:3]=1[NH2:18].Cl.O(N)C.N1C=CC=CC=1>C(O)C>[F:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]2)=[CH:6][CH:5]=[C:4]([NH2:15])[C:3]=1[NH2:18]
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2F)CC1
Agent: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CN1CCN(c2ccc(N)c(N)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 25 mL round bottom flask was charged with a suspension of 1 (600 mg, 2.2 mmol), methoxylamine HCl (202 mg, 2.42 mmol), and pyridine (0.22 mL, 2.6 mmol) in ethanol (9 mL). The resulting reaction mixture was stirred at rt overnight. The crude product was concentrated, absorbed onto silica gel, and purified by flash chromatography (97:3 CH2Cl2/MeOH) to give 2 as an orange solid. LCMS m/z 303.2 (MH+), tR=2.40 mm.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[N:20]([CH3:21])[N:19]=[CH:18][C:17]=2[NH:22][C:23]([C:25]2[N:26]=[C:27](Br)[S:28][C:29]=2[NH:30]C(=O)OC(C)(C)C)=[O:24])[CH2:12][CH2:11]1)=O)CCC.[C:39]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)#[N:40]>>[NH2:30][C:29]1[S:28][C:27]([C:44]2[CH:45]=[CH:46][C:41]([C:39]#[N:40])=[CH:42][CH:43]=2)=[N:26][C:25]=1[C:23]([NH:22][C:17]1[CH:18]=[N:19][N:20]([CH3:21])[C:16]=1[N:13]1[CH2:12][CH2:11][CH:10]([CH2:9][NH2:8])[CH2:15][CH2:14]1)=[O:24]
Reactant: CCCCOC(=O)NCC1CCN(c2c(NC(=O)c3nc(Br)sc3NC(=O)OC(C)(C)C)cnn2C)CC1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: Cn1ncc(NC(=O)c2nc(-c3ccc(C#N)cc3)sc2N)c1N1CCC(CN)CC1
Yield: 30 %

Procedure:
Following Example 278, Suzuki coupling of tert-butyl 4-(5-(4-(butyloxycarbonylaminomethyl)piperidin-1-yl)-1-methyl-1H-pyrazol-4-ylcarbamoyl)-2-bromothiazol-5-ylcarbamate and 4-cyanophenyl boronic acid gave 389 as a green solid (26 mg 30% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 9.01 (s, 1H), 8.01 (d, J=8.3 Hz, 2H), 7.90 (d, J=8.3 Hz, 2H), 7.62 (s, 2H), 7.31 (s, 1H), 3.62 (s, 3H), 3.12-2.96 (m, 4H), 2.45 (d, J=5.6 Hz, 2H), 2.20-1.80 (m, 2H), 1.74 (d, J=11.6 Hz, 2H), 1.26-1.14 (m, 3H). LCMS (ES+) m/z 437 (M+1)
Reaction SMILES: C(S)CCCCCCCCCCC.[CH3:14][N:15]([CH2:17][CH:18]([C:27]1([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:19]1[CH:20]=[CH:21][C:22]([O:25]C)=[CH:23][CH:24]=1)[CH3:16].C[O-].[Na+]>>[CH3:14][N:15]([CH2:17][CH:18]([C:27]1([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[CH3:16]
Reactant: COc1ccc(C(CN(C)C)C2(O)CCCCC2)cc1
Agent: CCCCCCCCCCCCS
Agent: C[O-]
Agent: [Na+]
Product: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Temperature: 190 °C
Reaction time: 2 h

Procedure:
Dodecanethiol (122 g), venlafaxine (111 g), and a methanolic solution of sodium methanolate (30%, 90 g) and PEG 400 are heated to 190° C. The methanol is distilled off and the solution is stirred for 2 hours at 190° C. Then the temperature is lowered, 2-propanol (450 g) is added and the pH is adjusted to 9.5 with aqueous HCl. The precipitate is collected by suction filtration, and the cake is washed with 2-propanol, toluene, 2-propanol and water. The wet O-desmethylvenlafaxine is dried in vacuo.
Reaction SMILES: [CH:1]([NH:4]C(C)C)(C)[CH3:2].[Li+].CCC[CH2-].C(#N)C.[F:16][C:17]([F:27])([F:26])[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>C1COCC1.O>[NH2:23]/[C:22](/[C:21]1[CH:24]=[CH:25][C:18]([C:17]([F:26])([F:27])[F:16])=[CH:19][CH:20]=1)=[CH:2]\[C:1]#[N:4]
Reactant: N#Cc1ccc(C(F)(F)F)cc1
Reactant: CC(C)NC(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: O
Solvent: CC#N
Solvent: C1CCOC1
Product: N#C/C=C(\N)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under argon, 28.1 g (278 mmol) of diisopropylamine were initially charged in 450 ml of THF at −70° C. in a three-necked flask with mechanical stirrer. 148 ml of N-butyllithium solution (1.6 M in hexane, 237 mmol) were added dropwise at such a rate that the temperature did not exceed −60° C. The mixture was stirred for 10 min, and a solution of 12.9 ml (245 mmol) of acetonitrile in 100 ml of THF was then slowly added dropwise and the suspension was stirred for 30 min. A solution of 28 g (164 mmol) of 4-(trifluoromethyl)benzonitrile in 100 ml of THF was added dropwise, and the mixture was stirred at −70° C. for 20 min. The mixture was allowed to slowly warm to RT and stirred at RT for a further 16 h. 150 ml of water were added, most of the THF was distilled off and water and dichloromethane were added. The organic phase was washed with saturated aqueous sodium chloride solution. Removal of the solvent gave crystals which were purified by trituration with diisopropyl ether (once with 40 ml, twice with 20 ml). The crystals were filtered off, washed with petroleum ether and dried. This gave 27 g (78% of theory) of the product as a solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH:9](O)[CH3:10])=[CH:7][N:6]=[C:5]([S:12][CH3:13])[N:4]=1.S(Cl)([Cl:16])=O>C(Cl)(Cl)Cl>[Cl:16][CH:9]([C:8]1[C:3]([NH:2][CH3:1])=[N:4][C:5]([S:12][CH3:13])=[N:6][CH:7]=1)[CH3:10]
Reactant: O=S(Cl)Cl
Reactant: CNc1nc(SC)ncc1C(C)O
Solvent: ClC(Cl)Cl
Product: CNc1nc(SC)ncc1C(C)Cl
Yield: 113.5 %

Procedure:
0.25 g of the product from Example 11a, supra, were dissolved in 10 mL chloroform and 0.30 g thionyl chloride were added drop-wise. The mixture was refluxed for 2 hrs and evaporated to yield 0.31 g of the title product as the hydrochloride salt.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][C@H:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:22]1[NH2:30].CCN(C(C)C)C(C)C>>[OH:20][C@H:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:22]1[NH:30][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H]2c3ccccc3C[C@@H]2O)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (1R,2S)-(−)-2-hydroxy-indan-1-ylamine and DIEA to give 2-((1R,2S)-2-hydroxy-indan-1-ylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 388 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[S:25][C:24]4=[N:26][CH:27]=[C:28]([C:29]5[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=5)[N:23]4[N:22]=3)=[CH:17][C:16]=2[O:36][CH3:37])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:38].O1CCOCC1>C(Cl)Cl.CO>[CH3:37][O:36][C:16]1[CH:17]=[C:18]([C:21]2[S:25][C:24]3=[N:26][CH:27]=[C:28]([C:29]4[CH:34]=[N:33][C:32]([NH2:35])=[N:31][CH:30]=4)[N:23]3[N:22]=2)[CH:19]=[CH:20][C:15]=1[O:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1.[ClH:38]
Reactant: COc1cc(-c2nn3c(-c4cnc(N)nc4)cnc3s2)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc(-c2nn3c(-c4cnc(N)nc4)cnc3s2)ccc1OC1CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-{4-[5-(2-Amino-pyrimidin-5-yl)-imidazo[2,1-b][1,3,4]thiadiazol-2-yl]-2-methoxy-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester (9 mg; 0.017 mmol; 1 eq) was dissolved in anhydrous DCM (1 mL) and 4M HCl in 1,4-dioxane (0.042 ml, 0.17 mmol, 10 eq) was added. The reaction mixture was stirred at RT overnight. The solvent was evaporated and the residue was co-evaporated with DCM (×3). The residue was triturated in CH3CN and filtered. The oily-solid obtained was dissolved in MeOH and evaporated to give the desired product as HCl salt (6 mg, 77%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=3.29 min, [M+H]+ m/z 424.1; 1H NMR (300 MHz, DMSO) δ 8.93 (s, 3H), 7.77 (s, 1H), 7.55 (m, 2H), 7.29 (d, J=8.9 Hz, 1H), 4.76 (m, 1H), 3.92 (s, 3H), 3.23 (m, 2H), 3.09 (m, 2H), 2.11 (m, 2H), 1.90 (m, 2H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+].O>CN1CCCC1=O>[CH2:1]([N:15]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Nc2cccc3ccccc23)cc1
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc(CN(c2ccccc2)c2cccc3ccccc23)cc1
Reaction time: 2 h
Yield: 65 %

Procedure:
Benzyl bromide (0.15M) was added to a stirred mixture of 1-phenylaminonaphthalene (0.1M) and KOH (0.15M) in N-methyl pyrrolidone (70 cm3) at 120° C. After 2 hours further stirring the mixture was poured in to water, the precipitate filtered off, washed and re-crystallised from methanol to give 20 g (65% yield) of a white solid mp 120°-123° C.
Reaction SMILES: [N+](C1C=CC(CC([O:11][CH2:12][CH:13]2[N:18](C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:17][CH2:16][N:15]([C:32]([C@@H:34]3[CH2:38][C@H:37]([S:39][C:40]4[C@H:41]([CH3:64])[C@@H:42]5[C@@H:59]([C@H:60]([OH:62])[CH3:61])[C:58](=[O:63])[N:43]5[C:44]=4[C:45]([O:47]CC4C=CC([N+]([O-])=O)=CC=4)=[O:46])[CH2:36][N:35]3C(OCC3C=CC([N+]([O-])=O)=CC=3)=O)=[O:33])[CH2:14]2)=O)=CC=1)([O-])=O.[ClH:80]>O1CCCC1.O>[ClH:80].[OH:11][CH2:12][CH:13]1[NH:18][CH2:17][CH2:16][N:15]([C:32]([C@@H:34]2[CH2:38][C@H:37]([S:39][C:40]3[C@H:41]([CH3:64])[C@@H:42]4[C@@H:59]([C@H:60]([OH:62])[CH3:61])[C:58](=[O:63])[N:43]4[C:44]=3[C:45]([OH:47])=[O:46])[CH2:36][NH:35]2)=[O:33])[CH2:14]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C(=O)OCc5ccc([N+](=O)[O-])cc5)C(COC(=O)Cc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@@H]3CN[C@H](C(=O)N4CCNC(CO)C4)C3)[C@H](C)[C@H]12

Procedure:
140 mg of 4-nitrobenzyl (1R, 5S, 6S)-2-{(2S, 4S)-2-[3-(4-nitrobenzylcarbonyloxymethyl)-4-(4-nitrobenzyloxycarbonyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio}-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] were dissolved in 2 ml of a 1:1 by volume mixture of tetrahydrofuran and water, after which 0.13 ml of 1N aqueous hydrochloric acid was added, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 140 mg of 10% w/w palladium-on-charcoal. At the end of this time, the reaction mixture was worked up and purified by the same procedure as described in Example 7(b), to give 20 mg of the title compound, as a powder.