Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[CH:19][CH:18]=3)[CH:8]=2)[CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)(O)[C:48]#[N:49].N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[C:48]([CH:2]1[CH2:6][CH2:5][CH:4]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][C:10]3=[C:9]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][C:24]([NH2:26])=[O:25])=[CH:21][CH:22]=3)[CH:8]=2)[CH2:3]1)#[N:49]
Reactant: CC(C)(O)C#N
Reactant: NC(=O)Cc1ccc(Nc2cc(C3CCC(O)C3)nc3c2CCC3)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#CC1CCC(c2cc(Nc3ccc(CC(N)=O)cc3)c3c(n2)CCC3)C1
Reaction time: 24 h

Procedure:
A 25-mL round bottom flask was charged with 2-(4-((2-(3-hydroxycyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide (Diastereomer B, 0.030 g, 0.085 mmol) and triphenylphosphine (0.112 g, 0.43 mmol) and acetone cyanohydrin (0.039 mL, 0.43 mmol) in THF. To this stirred solution at 0° C. was added di-tert-butyl azodicarboxylate (0.098 g, 0.43 mmol). After stirring for 24 h, the reaction mixture was absorbed onto silica (2 g) and was purified by chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as the eluent to afford 2-(4-((2-(3-cyanocyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide (Diastereomer A: 0.021 g, 68%) as a colorless oil. MW=360.45. 1H NMR (CD3OD, 300 MHz) δ 7.34-7.28 (m, 2H), 7.20-7.14 (m, 2H), 6.69 (s, 1H), 3.50 (s, 2H), 3.28-3.10 (m, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.81 (t, J=7.5 Hz, 2H), 2.23-2.08 (m, 6H), 2.00-1.86 (m, 1H), 1.83-1.67 (m, 1H); ESI MS m/z 361 [M+H]+. Treatment with 1.25M HCl in methanol (0.093 mL, 0.115 mmol) afforded the title compound (Diastereomer A: 0.020 g, 89%) as a white solid. MW=396.91. M.p. 215-217° C. decomp. 1H NMR (DMSO-d6, 500 MHz) δ 13.74 (br s, 1H), 9.47 (br s, 1H), 7.50 (s, 1H), 7.37-7.31 (m, 2H), 7.27-7.20 (m, 2H), 6.90 (s, 1H), 6.72 (s, 1H), 3.40 (s, 2H), 3.03 (br s, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.32-2.05 (m, 7H), 1.89-1.80 (m, 1H), 1.77-1.65 (m, 1H); APCI MS m/z 361 [M+H]+.
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[C:11]2[CH2:19][N:20]([CH2:31][C:32]2[CH:48]=[CH:47][C:35]([CH2:36][NH:37][S:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)(=[O:40])=[O:39])=[CH:34][CH:33]=2)[CH:21]2[C:30]3[N:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.C(OCC)C>Br.CC(O)=O>[NH:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[CH2:19][N:20]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH2:36][NH:37][S:38]([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)(=[O:40])=[O:39])=[CH:47][CH:48]=1)[CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1
Reactant: O=S(=O)(NCc1ccc(CN(Cc2nc3ccccc3n2S(=O)(=O)c2ccccc2)C2CCCc3cccnc32)cc1)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=S(=O)(NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1)c1ccccc1

Procedure:
A solution of N-(4-{[(1-benzenesulfonyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-benzyl)-benzenesulfonamide (AMD9830) (161 mg, 0.234 mmol) in saturated HBr/AcOH (3 mL) was stirred at room temperature for 3.5 h, then diethyl ether (20 mL) was added to give a colourless precipitate. The supernatant was decanted, and the residue was partitioned between CH2Cl2 (10 mL) and saturated NaHCO3(aq) (15 mL). The basic aqueous phase was extracted with CH2Cl2 (10 mL), and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude material by column chromatography on silica gel (500:5:1 CH2Cl2/MeOH/NH4OH) gave AMD9845 (59 mg, 44%) as a yellow foam. 1H NMR (CDCl3) δ 1.68 (m, 1H), 1.99 (m, 2H), 2.24 (m, 1H), 2.67-2.91 (m, 2H), 3.68 (s, 2H), 3.86 (d, 1H, J=17 Hz), 4.05 (m, 3H), 4.14 (d, 1H, J=17 Hz), 4.87 (m, 1H), 7.01 (d, 2H, J=7.8 Hz), 7.18 (m, 3H), 7.28 (m, 2H), 7.37-7.60 (m, 6H), 7.80 (m, 2H), 8.68 (m, 1H); 13C NMR (CDCl3) δ 22.08, 24.18, 29.90, 47.66, 49.21, 54.47, 61.26, 122.30, 123.03, 127.75, 128.54, 129.65, 129.73, 133.29, 135.47, 135.74, 138.01, 139.87, 140.65, 147.63, 156.87, 158.03. ES-MS m/z 538 (M+H). Anal. Calcd. for C31H31N5SO2.0.46CH2Cl2: C, 65.52; H, 5.58; N, 12.14. Found: C, 65.56; H, 5.60; N, 12.09.
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:31])=[C:19]([C@@:21]2([CH3:30])[NH:26][C:25](=O)[CH2:24][O:23][C:22]2([CH3:29])[CH3:28])[CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:41])=CC=1.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:31])=[C:19]([C@@:21]2([CH3:30])[NH:26][C:25](=[S:41])[CH2:24][O:23][C:22]2([CH3:29])[CH3:28])[CH:20]=1
Reactant: CC1(C)OCC(=O)N[C@]1(C)c1cc(N=C(c2ccccc2)c2ccccc2)ccc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC1(C)OCC(=S)N[C@]1(C)c1cc(N)ccc1F
Temperature: 80 °C
Reaction time: 2 h
Yield: 289.8 %

Procedure:
The (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-5,6,6-trimethyl-morpholin-3-one (1.13 g; 2.71 mmol) was dissolved in dioxane (80 ml) and the Lawesson's Reagent (691 mg, 1.71 mmol) was added at room temperature. The reaction mixture was stirred at 80° C. for 2 hours. Thereafter, the green solution was cooled to 23° C., then hydrochloric acid (1M, 3.42 ml) was added and the mixture was stirred for 30 minutes at room temperature. For the workup, the reaction mixture was poured into a saturated sodium hydrogen-carbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and evaporated at reduced pressure to give blue oil (1.33 g). The crude product was purified by chromatography on silica gel using a gradient of heptane and ethyl acetate=100/0 to 50/50 as the eluent. The (R)-5-(5-amino-2-fluoro-phenyl)-5,6,6-trimethyl-morpholine-3-thione was obtained as a white foam (0.63 g, 86% of theory). Mass (calculated) C13H17FN2OS [268.354]; (found) [M+H]+=269.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C:4]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([O:26][CH2:27][CH2:28][CH:29]=[C:30]([F:32])[F:31])[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1>CO>[NH2:1][C:2]1[N:6]([CH3:7])[C:5](=[O:8])[C@:4]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([O:26][CH2:27][CH2:28][CH:29]=[C:30]([F:31])[F:32])[CH:20]=2)([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([F:18])[F:17])=[CH:11][CH:10]=2)[N:3]=1
Reactant: CN1C(=O)C(c2ccc(OC(F)F)cc2)(c2ccc(F)c(OCCC=C(F)F)c2)N=C1N
Solvent: CO
Product: CN1C(=O)[C@@](c2ccc(OC(F)F)cc2)(c2ccc(F)c(OCCC=C(F)F)c2)N=C1N

Procedure:
A racemic mixture of 2-amino-5-{3-[(4,4-difluorobut-3-en-1-yl)oxy]-4-fluorophenyl}-5-[4-(difluoromethoxy)phenyl]-3-methyl-3,5-dihydro-4H-imidazol-4-one (preparation described in previous Example) was separated by chiral HPLC using column type Chiralcel AD, 5×50 cm; the mobile phase was 15% ethanol in hexane with 0.1% diethylamine at 100 mL/min to obtain the title R-isomer as a glass, identified by NMR and mass spectral analyses [mp glass; [α]D25=−14° (c=1%, MeOH); MS (ES) m/z 454.0].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH:56]1[CH2:60][CH2:59][CH2:58][C@H:57]1[CH2:61][OH:62]>CN(C=O)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:56]2[CH2:60][CH2:59][CH2:58][C@@H:57]2[CH2:61][OH:62])=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: OC[C@@H]1CCCN1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1C(=O)N1CCC[C@@H]1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-[5-(2,6-dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.2 mmol) in DMF (5 mL) was added HOBt (32 mg, 1.2 eq.), EDAC.HCl (46 mg, 1.2 eq.) and TEA (50 mg, 2.5 eq.). After stirring at rt for 30 mins, to the mixture was added (S)-(+)-2-pyrrolidine methanol (2 eq.). After stirring at rt for overnight, the reaction was concentrated and the residue was purified on a silica gel column to give 52 mg of the titled compound.
Reaction SMILES: C1(C)C=CC=CC=1.[CH3:8][C:9]1[C:20]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][C:12]2[CH2:13][CH2:14][CH2:15][C:16](=[O:18])[CH2:17][C:11]=2[CH:10]=1.S(O)(C1C=CC(C)=CC=1)(=O)=O.[CH2:36](O)[CH2:37][OH:38]>CCOC(C)=O>[CH3:8][C:9]1[C:20]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][C:12]2[CH2:13][CH2:14][CH2:15][C:16]3([CH2:17][C:11]=2[CH:10]=1)[O:38][CH2:37][CH2:36][O:18]3
Reactant: CC(=O)Nc1cc2c(cc1C)CC(=O)CCC2
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cc2c(cc1C)CC1(CCC2)OCCO1
Temperature: 25 °C
Yield: 72.6 %

Procedure:
In a 50 L mechanically stirred vessel with Dean-Stark trap, toluene (22 L) was added to N-(3-methyl-6-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)acetamide (77) (1.04 kg, 4.50 mol). TosOH (84.0 g, 442 mmol) and ethylene glycol (750 mL, 13.4 mol) were added. The resulting mixture was heated to reflux overnight, cooled to rt, diluted with EtOAc (12 L) and washed with sat. aq. NaHCO3 (12 L) and sat. aq.s NaCl (12 L). The combined aq. washes were extracted with DCM (2×8 L). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel. The product containing fractions were combined and concentrated under reduced pressure to afford N-(3-methyl-5,7,8,9-tetrahydrospiro[benzo[7]annulene-6,2′-[1,3]dioxolan]-2-yl)acetamide (78) (900 g, 73% yield). 1H NMR (300 MHz, CDCl3): δ 7.45 (s, 1H), 7.03 (s, 1H), 6.92 (s, 1H), 3.96 (m, 4H), 3.02 (s, 2H), 2.76 (m, 2H), 2.20 (s, 3H), 2.18 (s, 3H), 1.98 (m, 2H), 1.74 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[N+:22]([O-])=O>CO.[Ni]>[NH2:22][C:4]1[CH:5]=[C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: COc1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1N
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of the product of Example 46A (260 mg, 0.77 mmol) and Raney-Ni (50 mg) in methanol (10 mL) was stirred under hydrogen at ambient temperature for 15 hours. The solution was filtered through diatomaceous earth and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (200-300 mesh) eluting with a gradient of 3/1 to 2/1 petroleum/ethyl acetate to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.O.O.O.O.O.O.O.O.O.[S-2].[Na+].[Na+].N>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(CCOc2ccc([N+](=O)[O-])cc2)cc1
Agent: N
Agent: [Na+]
Agent: [S-2]
Solvent: O
Solvent: CCO
Product: Cc1ccc(CCOc2ccc(N)cc2)cc1
Yield: 94.6 %

Procedure:
4-[2-(4-Methylphenyl)ethoxy]nitrobenzene (VI) (5.14 g, 0.02 mole) and sodium sulfide nonahydrate (9.6 g, 0.04 mole) were added to a mixture of 95% aqueous ethanol (50 ml) and 29% aqueous ammonia (50 ml), followed by heating under reflux for 20 hours. Sulfur deposited was filtered while hot, and the filtrate was cooled, extracted with ether and treated in the same manner as in Example 17 to obtain 4.3 g of 4-[2-(4-methylphenyl)ethoxy]aniline (V) (yield, 95%).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][CH2:5]N1C(=O)C2N(C)C=NC=2N(C)C1=O.[Mg].II.C(Br)C[C@H](CCC=C(C)C)C.C=[O:40].[Cl-].[NH4+]>O1CCCC1>[CH3:1][C@@H:2]([CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])[CH2:3][CH2:4][CH2:5][OH:40]
Reactant: C=O
Reactant: CC(C)=CCC[C@H](C)CCCn1c(=O)c2c(ncn2C)n(C)c1=O
Agent: CC(C)=CCC[C@H](C)CCBr
Agent: II
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC(C)=CCC[C@H](C)CCCO
Reaction time: 0.5 h
Yield: 84 %

Procedure:
This example illustrates the synthesis of 1-(4-(S)-Methyl-8-methylnon-7-enyl)-3,7-dimethylxanthine (CT2536S). To a suspension of magnesium (2.74 g, 140 mmol) and a crystal of iodine in tetrahydrofuran (15 ml) was added (S)-citronellyl bromide (5.0 g, 22.8 mmol) in tetrahydrofuran (10 ml) over 30 min and the reaction stirred for a further 30 min after the addition was complete. The solution was added via a canula over 5 min to a suspension of paraformaldehyde (1.80 g, 60.0 mmol) in tetrahydrofuran (15 ml) and stirred at 25° C. for 6 hr. Saturated ammonium chloride (40 ml) was added and extracted with diethyl ether (2×30 ml). The combined organic extracts were dried (magnesium sulfate) and evaporated to give 4-(S)-methyl-8-methylnon-7-enyl alcohol as a clear liquid (3.25 g, 84%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[C:24]([O:30][CH3:31])[CH:23]=3)[CH2:18][CH2:17]2)=[O:15])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[CH3:32][Mg+].[Br-]>O1CCCC1>[OH:3][C:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[C:24]([O:30][CH3:31])[CH:25]=[C:26]([O:28][CH3:29])[CH:27]=3)[CH2:18][CH2:17]2)=[O:15])[C:7]([O:11][CH3:12])=[N:8][C:9]=1[CH3:10])([CH3:32])[CH3:2]
Reactant: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)=O)c(C)nc3OC)CC2)c1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc(OC)cc(N2CCN(C(=O)Nc3cc(C(C)(C)O)c(C)nc3OC)CC2)c1
Yield: 84 %

Procedure:
1-{(5-Acetyl-2-methoxy-6-methylpyridin-3-yl)aminocarbonyl]-4-(3,5-dimethoxyphenyl)piperazine(214 mg, 0.50 mmol) was dissolved in tetrahydrofuran(10 ml) and CH3MgBr(0.50 ml, 1.50 mmol) was added slowly. The mixture solution was refluxed for 15 hrs and concentrated under the reduced pressure to remove the solvent and extracted with ethylacetate, dried and filtered. The resultant was purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:2]12.[Cl-].[Li+]>>[C:2]1(=[O:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1CCCCCC2OC2CCCC1
Agent: [Cl-]
Agent: [Li+]
Product: O=C1CCCCCCCCCCC1
Temperature: 200 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
25 g of epoxy-cyclododecane and 1 g of lithium chloride were dissolved in 20 g of N,N'-dimethyl ethylene urea and the solvent was stirred at 200° C. for 6 hours. The reaction mixture was analyzed to have a 94% yield of cyclododecanone.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH-].[Na+]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)[CH:12]=[O:13]
Reactant: OCc1cc(I)cc(C(F)(F)F)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=Cc1cc(I)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
A solution of [3-iodo-5-(trifluoromethyl)phenyl]methanol (287 mg, 0.95 mmol) in CH2Cl2 (10 mL) was cooled to 0° C. and then Dess-Martin periodinane (604 mg, 1.42 mmol) was added. The reaction was slowly warmed to room temperature. After stirring at room temperature for twenty minutes, the reaction was poured into 1N NaOH (25 mL). The mixture was extracted with EtOAc (50 mL) and the organic extracts were washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 0% to 10% EtOAc/hexanes afforded 3-iodo-5-(trifluoromethypbenzaldehyde. Rf=0.54 (15% EtOAc/hexanes). 1H NMR (CDCl3, 600 MHz) δ 9.98 (s, 1H), 8.39 (s, 1H), 8.19 (s, 1H), 8.09 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1.[OH-].[Na+]>C(O)CO>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Product: Brc1cn2cncc2s1
Temperature: 25 °C
Yield: 49.2 %

Procedure:
A solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (28 mg, 0.11 mmol) in ethylene glycol (1 ml) was stirred at 180° C. for 2.5 hr. The reaction solution was allowed to cool to room temperature, a 2.7 M aqueous solution (5 ml) of sodium hydroxide was added to the cooled solution, and the mixture was extracted with ethyl acetate (5 ml×3). The organic layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure to give 2-bromoimidazo[5,1-b]thiazole (11 mg, 48%) as a crude product.
Reaction SMILES: [OH:1][C@H:2]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:33])[C:16]2[CH:21]=[CH:20][C:19]([O:22]CC3C=CC=CC=3)=[C:18]([NH:30][CH:31]=[O:32])[CH:17]=2)=[CH:7][CH:6]=1.C>C(O)C>[OH:1][C@H:2]([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:33])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([NH:30][CH:31]=[O:32])[CH:17]=2)=[CH:7][CH:6]=1
Reactant: O=CNc1cc([C@@H](O)CNCCc2ccc(NC[C@H](O)c3ccccc3)cc2)ccc1OCc1ccccc1
Solvent: CCO
Product: O=CNc1cc([C@@H](O)CNCCc2ccc(NC[C@H](O)c3ccccc3)cc2)ccc1O
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 89.6 %

Procedure:
Intermediate 6 (2.5 g, 4.8 mmol) was dissolved in 8.0 mL of ethanol and treated with activated charcoal, Darco G-60 (1.25 g). The suspension was stirred at 50° C. for 20 min and then filtered to remove the Darco. To the filtrate was added 10% palladium on activated carbon (250 mg) and the suspension placed on a Parr shaker. The reaction was shaken for 10 h under 30 psi hydrogen gas. The reaction was filtered through celite and concentrated under vacuum to afford compound 1 as a brown gelatinous solid (1.9 g, 4.3 mmol, 91%). 1H NMR (300 MHz, DMSO-d6) δ 2.40-2.68 (m, 6H), 2.92-3.18 (m, 2H), 4.35-4.45 (m, 1H), 4.60-4.69 (m, 1H), 5.22-5.30 (m, 1H), 6.82 (s, 1H), 6.85 (s, 1H), 6.68-6.86 (m, 4H), 7.12-7.36 (m, 5H), 7.95 (d, 1H, J=1.4 Hz), 8.19 (s, 1H), 9.49 (br s, 1H). m/z: [M+H+] calcd for C25H29N3O4 436.2; found 436.4.
Reaction SMILES: C(OC([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([C:33]([O:35][C:36]2[CH:44]=[CH:43][C:39]([C:40]([OH:42])=[O:41])=[CH:38][CH:37]=2)=[O:34])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:45].O1CCOCC1>>[ClH:45].[C:11]1([C@H:9]([NH:8][CH2:21][C@@H:22]2[C@@H:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:25][N:24]([C:33]([O:35][C:36]3[CH:37]=[CH:38][C:39]([C:40]([OH:42])=[O:41])=[CH:43][CH:44]=3)=[O:34])[CH2:23]2)[CH3:10])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)Oc2ccc(C(=O)O)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NC[C@H]1CN(C(=O)Oc2ccc(C(=O)O)cc2)C[C@@H]1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C

Procedure:
A 1.05 g portion of 4-({[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}oxy)benzoic acid was dissolved in 10 ml of 4 M hydrogen chloride/1,4-dioxane solution and stirred at room temperature for 1Hour, and then the reaction solution was concentrated under a reduced pressure. In order to remove excess hydrogen chloride, the residue was dissolved in chloroform and again concentrated under a reduced pressure. By suspending the thus obtained residue in THF-toluene, 784 mg of 4-({[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}oxy)benzoic acid hydrochloride was obtained as a crude product. A 235 mg portion of the thus obtained crude product was suspended in THF-toluene and heated under reflux for 50 minutes, and then the resulting precipitate was collected by filtration to obtain 217 mg of 4-({[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]carbonyl}oxy)benzoic acid hydrochloride as a white solid.
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:20][C:21]1[CH:22]=[C:23]([NH:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH:29]2[C:33]([OH:35])=O)[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:26]=[CH:25][C:24]2[C:33](=[O:35])[C@H:29]3[CH2:30][CH2:31][CH2:32][C@H:28]3[NH:27][C:23]=2[CH:22]=1
Reactant: O=C(O)C1CCCC1Nc1cccc(F)c1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=C1c2ccc(F)cc2N[C@@H]2CCC[C@H]12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Eaton's reagent (100 mL, 630 mmol, 6.6 equiv.) was added to 2-[(3-fluorophenyl)amino]cyclopentanecarboxylic acid 6A (21.3 g, 95 mmol, 1 equiv). The mixture was heated to 70° C. and stirred for one hour. The reaction mixture was then cooled to 23° C. and quenched with the addition of wet ice. The mixture was then neutralized to pH=10 with the portionwise addition of solid sodium hydroxide pellets. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The filtrate was purified by flash-column chromatography (hexanes, grading to 50% ethyl acetate-hexanes) to afford 6B. [M+H]+: 206.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[N:8]=[CH:9][CH:10]=[N:11][C:12]=2[C:13]([C:16]2[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=2[Cl:27])=[CH:14][CH:15]=1)=O)C.[CH2:28]([N:30]1[CH2:35][CH2:34][N:33]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)[CH2:32][CH2:31]1)[CH3:29].C[Al](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CO.C(Cl)Cl>[CH2:28]([N:30]1[CH2:31][CH2:32][N:33]([CH2:36][C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:4]([C:6]3[C:7]4[N:8]=[CH:9][CH:10]=[N:11][C:12]=4[C:13]([C:16]4[C:21]([F:22])=[C:20]([O:23][CH3:24])[CH:19]=[C:18]([O:25][CH3:26])[C:17]=4[Cl:27])=[CH:14][CH:15]=3)=[O:3])=[N:41][CH:42]=2)[CH2:34][CH2:35]1)[CH3:29]
Reactant: CCN1CCN(Cc2ccc(N)nc2)CC1
Reactant: CCOC(=O)c1ccc(-c2c(F)c(OC)cc(OC)c2Cl)c2nccnc12
Agent: C[Al](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCN1CCN(Cc2ccc(NC(=O)c3ccc(-c4c(F)c(OC)cc(OC)c4Cl)c4nccnc34)nc2)CC1
Temperature: 80 °C
Reaction time: 7 h

Procedure:
The title compound was prepared in analogy to the procedure described in Example 115 but using 8-(2-chloro-6-fluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid ethyl ester (Step 144.1), 5-(4-ethyl-piperazin-1-ylmethyl)-pyridin-2-ylamine (Example 26.1; purified by silica gel column chromatography), 2 equiv of trimethyl aluminum, stirring the reaction mixture for 7 h at 80° C., pouring it onto a saturated aqueous solution of NaHCO3 and DCM. Title compound: ESI-MS: 564.8 [M+H]+; tR=3.57 min (System 1); TLC: Rf=0.25 (DCM/MeOH/NH3aq, 94:5:1).