Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31](O)=[CH:30][N:29]=1)=[O:27])[CH3:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:23]([O:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([O:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2/[CH:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:30][N:29]=1)=[O:27])[CH3:24]
Reactant: OCc1c(-c2ccc(F)cc2)noc1/C=C/c1ccccc1
Reactant: CCOC(=O)c1ccc(O)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2/C=C/c2ccccc2)cn1
Yield: 47.5 %

Procedure:
To a stirred solution of [3-(4-fluoro-phenyl)-5-((E)-styryl)-isoxazol-4-yl]-methanol (4.0 g, 13.5 mmol) and 5-hydroxy-pyridine-2-carboxylic acid ethyl ester (2.49 g, 14.9 mmol) in THF (130 mL) under argon was added triphenylphosphine (5.49 g, 20.31 mmol). Diethyl azodicarboxylate (9.3 mL, 20.31 mmol) was then added dropwise. After 3 h the reaction mixture was concentrated then purified by chromatography (silica, 10 to 40% ethyl actetate in heptane) afforded the title compound (2.85 g, 47%) as a white solid. MS: m/e=445.4 [M+H]+.
Reaction SMILES: [CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[N:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[C:11]([C:9]1[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([N:3]=[S@@:2]([CH3:1])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:17])#[CH:12]
Reactant: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Temperature: 0 °C

Procedure:
A solution of (S)—N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (806 mg, 2.3 mmol) in 70 mL THF/methanol (1:1 ratio) at room temperature was degassed with argon. The solution was cooled to 0° C. and K2CO3 (937 mg, 6.8 mmol) added. After 5 minutes the solution was decanted from the solids and partitioned between EtOAc and H2O. The EtOAc layer was washed with brine, dried with anhydrous Na2SO4 and concentrated. The brown oil was purified by chromatography (silica gel, CHCl3/EtOAc) to the title compound as a thick pale orange oil (630 mg, 98%).
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:45][O:46][CH2:47][CH2:48][CH2:49][NH2:50]>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([NH:50][CH2:49][CH2:48][CH2:47][O:46][CH3:45])[C:8]([C:12]([N:14]([CH2:32][CH:33]([CH3:35])[CH3:34])[C@@H:15]2[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18][C@H:17]([C:28]([O:30][CH3:31])=[O:29])[CH2:16]2)=[O:13])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@H](N(CC(C)C)C(=O)c2cnc(C(C)(C)C)nc2Cl)CN(C(=O)OC(C)(C)C)C1
Reactant: COCCCN
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)OC)CN(C(=O)OC(C)(C)C)C1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
1-tert-Butyl 3-methyl (3R*,5S*)-5-{[(2-tert-butyl-4-chloropyrimidin-5-yl)carbonyl](2-methylpropyl)amino}piperidine-1,3-dicarboxylate (2.46 g) and diisopropylethylamine (1.38 ml) were dissolved in N,N-dimethylformamide (50 ml), 3-methoxypropan-1-amine (990 μl) was added and the mixture was stirred at 80° C. for 30 min. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with hexane to ethyl acetate-hexane (35:65) was concentrated under reduced pressure to give the object compound (2.47 g).
Reaction SMILES: C1CO[C:8]23OCCO[C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([CH2:16][C@H:17]([CH:28]=[CH2:29])[CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.C([C@@H]1C2[C@](C)(CCC(=[O:50])C2)[C@@H]2[C@H]([C@H]3[C@@](CC2)(C)C(=O)CC3)C1)#N>>[CH:28]([C@@H:17]1[CH:18]2[C@:23]([CH3:24])([CH2:22][CH2:21][C:20](=[O:50])[CH2:19]2)[C@@H:25]2[C@H:15]([C@H:6]3[C@@:4]([CH2:27][CH2:26]2)([CH3:5])[C:3](=[O:2])[CH2:8][CH2:7]3)[CH2:16]1)=[CH2:29]
Reactant: C=C[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C=C[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 92 %

Procedure:
The title compound II-ak was prepared in 92% yield from 3,3:17,17-bis(ethylendioxy)-6α-vinylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 5.51 (m, 1H), 4.97 (m, 2H), 2.53-0.82 (m, 21H), 1.14 (s, 3H), 0.98 (s, 3H),
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])/[C:5](/[N+:10]#[C-:11])=[CH:6]/[N:7]([CH3:9])C)[CH3:2].[CH:13]1(N)C[CH2:14]1>>[CH2:1]([O:3][C:4]([C:5]1[N:10]=[CH:11][N:7]([CH:9]2[CH2:14][CH2:13]2)[CH:6]=1)=[O:12])[CH3:2]
Reactant: NC1CC1
Reactant: [C-]#[N+]/C(=C\N(C)C)C(=O)OCC
Product: CCOC(=O)c1cn(C2CC2)cn1
Temperature: 75 °C

Procedure:
The stirred mixture of (Z)-3-dimethylamino-2-isocyano-acrylic acid ethyl ester (17.0 g, 100 mmol) and cyclopropylamine (17.21 g, 300 mmol) was heated for 5 h at 75° C. The reaction mixture was cooled to rt and concentrated. Purification of the residue by flash chromatography (EtOAc/hexane, 5:1) gave the title compound as an orange oil. tR: 0.61 min (LC-MS 2); ESI-MS: 181.2 [M+H]+ (LC-MS 2); 1H-NMR (DMSO-d6, 400 MHz) δ ppm 7.85 (s, 1H), 7.79 (s, 1H), 4.18 (q, 2H), 3.55 (m, 1H), 1.23 (t, 3H), 0.91-1.02 (m, 4H).
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:16])[CH3:3].[CH:17](=[O:19])[CH3:18].B(F)(F)F.CCOCC>ClCCCl>[CH3:3][C:2]1=[CH:4][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5](=[O:16])[O:19][CH:17]([CH3:18])[CH2:1]1
Reactant: CC=O
Reactant: C=C(C)C1CCCCCCCCCCC1=O
Agent: C/C1=C\CCCCCCCCCCC(=O)OC(C)C1
Agent: FB(F)F
Solvent: ClCCCl
Solvent: CCOCC
Product: CC1=CCCCCCCCCCCC(=O)OC(C)C1

Procedure:
Following the general procedure as described in Example 1, 2-(prop-1-en-2-yl)cyclododecanone (2.22 g, 10 mmol), acetaldehyde (0.53 g, 12 mmol) and boron trifluoride etherate (0.14 g, 1.0 mmol) in 1,2-dichloroethane (10 mL) were reacted to give the title product as a colorless liquid (2.34 g, 88% yield. Mixture of E/Z isomers in a ratio of 8:1.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[C:6]([O:12][CH:13]=[CH2:14])(=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8].O>CO.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[C:6]([O:12][CH:13]=[CH:14][CH2:4][CH:3]([CH3:5])[CH:2]=[CH2:1])(=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: C=CC(=C)C
Reactant: C=COC(=O)C(C)(C)C
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O
Solvent: CO
Product: C=CC(C)CC=COC(=O)C(C)(C)C
Temperature: 100 °C

Procedure:
(Benzene)ruthenium dichloride dimer (14 mg, 0.056 mmol Ru), silver triflate (20 mg, 0.078 mmol) and 2,2-methylenebis(4-phenyl-2-oxazoline) (17.8 mg, 0.058 mmol) were dissolved in 2 ml of methanol. To the mixed solution were added isoprene (2 ml) and vinyl pivalate (1 ml) and the mixture was stirred under heat at 100° C. for 10 hours. The resulting product was poured into water and the separated organic layer was subjected to a GLC analysis. As a result, it was confirmed that a co-dimer was produced with the conversion rate being 72% and the ratio of an isomer being 4:1.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[Na+].C(O[C@@H:10]1[NH:13][C:12](=[O:14])[C@H:11]1[O:15][CH3:16])(=O)C.O1CCOCC1>P([O-])([O-])([O-])=O>[C:1]([S:3][C@H:10]1[NH:13][C:12](=[O:14])[C@@H:11]1[O:15][CH3:16])(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: CO[C@@H]1C(=O)N[C@H]1OC(C)=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CO[C@H]1C(=O)N[C@@H]1SC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.5 equivalents of an aqueous sodium thioacetate solution are added to a solution of 40 mg of (3S,4S)-4-acetoxy-3-methoxy-2-oxoazetidine (for manufacture see below) in 1.5 ml of phosphate buffer of a pH of 7 and 0.1 ml of dioxan, and the mixture is stirred for 30 minutes at room temperature. The reaction mixture is extracted with methylene chloride and the separated organic solution is then dried over sodium sulphate. The solvent is evaporated off in vacuo and the residue is purified by chromatography over silica gel with toluene/ethyl acetate (3:1). The IR spectrum of the resulting title compound (in methylene chloride) is identical to that of the product obtained according to a).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:18])[CH2:16][CH3:17])=[CH:10][CH:9]=1)[CH2:5][OH:6].Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH3:3][CH:4]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH:15]([CH3:18])[CH2:16][CH3:17])=[CH:12][CH:13]=1)[CH2:5][O:6][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1
Reactant: CCC(C)Oc1ccc(OC(C)CO)cc1
Reactant: Clc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(C)Oc1ccc(OC(C)COc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of sodium hydride (0.08 g) in 5 ml of tetrahydrofuran (THF) and 2 ml of hexamethylphosphoramide (HMPA), cooled in an ice bath, is added, dropwise, 2-methyl-2-[4-(1-methylpropoxy)phenoxy]ethanol (0.63 g). The mixture is stirred at RT for 2 hours, after which a solution of 2-chloropyridine (0.38 g) in 5 ml of THF is added and the mixture is stirred at 60° for 3 hours. The THF is then removed by rotoevaporation and the residue is purified by column chromatography on silica gel to give the product, 2-{2-methyl-2-[4-(1-methylpropoxy)phenoxy]ethoxy}pyridine, MS m/e 302 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][S:28]2(=[O:33])=[O:32])[CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([C:20]2[CH:21]=[N:22][CH:23]=[C:24]([CH2:26][N:27]3[CH2:31][CH2:30][CH2:29][S:28]3(=[O:32])=[O:33])[CH:25]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=S1(=O)CCCN1Cc1cncc(Br)c1
Reactant: CC1(C)OB(c2ccc(C#N)c(Cl)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2cncc(CN3CCCS3(=O)=O)c2)cc1Cl
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To 2-chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (217 mg, 0.824 mmol) in DMF (4 mL) were added 3-bromo-5-(1,1-dioxo-isothiazolidin-2-ylmethyl)-pyridine (200 mg, 0.687 mmol) and 2M aqueous sodium carbonate (0.687 mL, 1.374 mmol). The reaction mixture was flushed and evacuated with N2 thrice followed by the addition of PdCl2(dppf).CH2Cl2 adduct (28.0 mg, 0.034 mmol). The reaction mixture was stirred at 100° C. for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate and washed with water thrice. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The crude was dissolved in DMF (5 mL) and purified using Xbridge C18 eluting with a 10 to 100% ACN-water to afford 2-chloro-4-[5-(1,1-dioxo-isothiazolidin-2-ylmethyl)-pyridin-3-yl]-benzonitrile as a white solid. HRMS: (ESI) m/z 348.0575 [(M+H)+ Calcd for C16H14ClN3O2S 348.0573]. 1H NMR (400 MHz, MeOD) δ ppm 2.33-2.47 (m, 2H), 3.24-3.33 (m, 4H), 4.37 (s, 2H), 7.87 (dd, J=8.2, 1.6 Hz, 1H), 7.97 (d, J=8.1 Hz, 1H), 8.06 (d, J=1.5 Hz, 1H), 8.22 (t, J=2.1 Hz, 1H), 8.68 (d, J=2.0 Hz, 1H), 8.87 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH:3](OC)[C:4]1[C:12]2[S:11][C:10]([NH:13][C:14](=[O:18])[NH:15][CH2:16][CH3:17])=[N:9][C:8]=2[CH:7]=[C:6]([C:19]2[CH:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][C:28]([CH2:36][CH3:37])([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]3)=[N:23][CH:24]=2)[CH:5]=1.[SiH](CC)(CC)CC.B(F)(F)F.O(CC)CC>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:36]([C:28]1([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:29][CH2:30][N:25]([C:22]2[N:23]=[CH:24][C:19]([C:6]3[CH:5]=[C:4]([CH2:3][O:2][CH3:1])[C:12]4[S:11][C:10]([NH:13][C:14](=[O:18])[NH:15][CH2:16][CH3:17])=[N:9][C:8]=4[CH:7]=3)=[CH:20][N:21]=2)[CH2:26][CH2:27]1)[CH3:37]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(C(OC)OC)c2s1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: ClCCl
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(CC)(C(=O)OCC)CC4)nc3)cc(COC)c2s1
Temperature: 0 °C
Yield: 67.2 %

Procedure:
Ethyl 1-[5-[7-(dimethoxymethyl)-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-ethyl-piperidine-4-carboxylate (35 mg, 0.063 mmol) was dissolved in DCM (2 mL), cooled to 0° C. and treated sequentially with Et3SiH (50 μL, 0.313 mmol) and BF3:OEt2 (15 μL, 0.119 mmol) and the mixture stirred for 10 mins then allowed to warm to rt. After 40 mins additional Et3SiH (50 μL, 0.313 mmol) was added at rt followed by BF3:OEt2 (15 μL, 0.119 mmol) and the mixture stirred for 2.5 h after which time the reaction was diluted with sat. NaHCO3 (aq), extracted with DCM (3×), dried and the solvent evaporated to yield the crude product (31.7 mg). The crude product was purified on 12 g SiO2 using EtOAc/Cyclohexane gradient 0-0% 3CV, 0-100% 30CV, 100-100% 5CV to yield the desired compound (22.3 mg, 73%). 1H NMR (CDCl3) δ 8.59 (s, 2H), 7.79 (d, J=1.2 Hz, 1H), 7.25 (d, J=0.9 Hz, 1H), 4.66 (s, 2H), 4.53 (dt, J=13.7, 3.5 Hz, 2H), 4.22 (q, J=7.1 Hz, 2H), 3.51-3.40 (m, 2H), 3.38 (s, 3H), 3.22-3.07 (m, 2H), 2.23 (d, J=13.4 Hz, 2H), 1.59 (q, J=7.5 Hz, 2H), 1.48-1.43 (m, 2H), 1.29 (dd, J=10.0, 4.1 Hz, 6H), 0.85 (t, J=7.5 Hz, 3H). MS: 527.15 [M+H]+
Reaction SMILES: [Br:1][CH2:2][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][C:17](Cl)=[O:18].[CH-:20]1[CH:24]=[CH:23][CH:22]=[CH:21]1.[CH-:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1.[Fe+2:30]>>[C-:20]1([C:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[O:18])[CH:24]=[CH:23][CH:22]=[CH:21]1.[CH-:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1.[Fe+2:30]
Reactant: O=C(Cl)CCCCCCCCCCCCCCCBr
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Product: O=C(CCCCCCCCCCCCCCCBr)[c-]1cccc1
Yield: 87.1 %

Procedure:
16-Bromohexadecanoic acid (4.5 g, 14 mmol) in SOCl2 (50 mL) was heated at 50° C. under argon for 1 h. The excess SOCl2 was removed by water pump distillation with benzene (3×50 mL). 4.3 g (95%) of 16-bomohexadecanoyl chloride was obtained as a colorless oil and used in the subsequent reaction without further purification. 16-Bromohexadecanoyl chloride (4.5 g, 13 mmol) was treated with ferrocene (2.5 g, 14 mmol) following the same procedure as described for 22 to form a brown oil (5.7 g, 85%): 1H NMR δ 1.25 (s, 22H), 1.68 (m, 2H), 1.84 (m, 2H), 2.68 (m, 2H), 3.39 (m, 2H), 4.18 (s, 5H), 4.47 (A2B2, J=1.5 Hz, 2H), 4.76 (A2B2, J=1.5 Hz, 2H); 13C NMR δ 25.3, 28.8, 29.4, 30.1, 30.2, 30.3, 34.8, 40.4, 70.0, 70.4, 72.7, 89.1, 205.4; FAB-MS obsd 502.1533, calcd exact mass 502.1535 (C26H39BrFeO).
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[Li]CCCC.CCCCCC.[Al](Cl)(CC)CC.[N:26]1[C:35]2[C:30](=[CH:31][C:32]([C:36](Cl)=[O:37])=[CH:33][CH:34]=2)[N:29]=[CH:28][CH:27]=1>C1COCC1>[CH3:7][C:6]1[N:1]=[C:2]([CH2:8][C:36]([C:32]2[CH:31]=[C:30]3[C:35](=[CH:34][CH:33]=2)[N:26]=[CH:27][CH:28]=[N:29]3)=[O:37])[CH:3]=[CH:4][CH:5]=1
Reactant: O=C(Cl)c1ccc2nccnc2c1
Reactant: Cc1cccc(C)n1
Agent: CC[Al](Cl)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cccc(CC(=O)c2ccc3nccnc3c2)n1
Temperature: 20 °C
Reaction time: 0.33 h
Yield: 60.8 %

Procedure:
A stirred solution of 2,6-lutidine (1.4 g, 13 mmole) in dry THF (100 ml) at −60° C. under Ar was treated dropwise with a solution of BuLi in hexane (2.5 M, 5.2 ml, 13 mmole). After 30 mins a solution of Et2AlCl in hexane (14 ml, 14 mmole) was added dropwise and the solution warmed to 20° C. After a further 30 mins the solution was cooled to −50° C. and transferred via canula to a stirred solution of quinoxaline-6-carbonyl chloride (2.0 g, 10.3 mmole) in THF (100 ml) at −60° C. Stirring was continued for 20 min and the solution quenched with sat. aq. NH4Cl solution and warmed to 20° C. The mixture was filtered through Kieselguhr and the filtrate worked up as normal (EtOAc, water, Na2SO4). Filtration through silica eluting with EtOAc gave the product as a yellow solid (1.65 g, 51%). m/z [ESMS]: 264 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH:9]=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:11][C:12]([S:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[C:12]([S:15]([N:17]=[CH:9][CH2:8][CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:16])([CH3:14])([CH3:13])[CH3:11]
Reactant: CCOC(=O)C(C)CC=O
Reactant: CC(C)(C)S(N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CCOC(=O)C(C)CC=NS(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A yellow solution of ethyl 2-methyl-4-oxobutanoate (35.16 mmol) in DCM (72 ml) was treated with 2-methylpropane-2-sulfinamide (4.261 g; 35.16 mmol) and with anh. CuSO4 (11.223 g; 70.32 mmol). The resulting beige heterogeneous mixture was further stirred at rt, under nitrogen, for 24 h. The resulting heterogeneous mixture was then filtered over a short pad of celite, and the separated solids were further washed with DCM. The obtained yellow filtrate was concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=25/1) afforded ethyl 4-((tert-butylsulfinyl)imino)-2-methylbutanoate as a yellow oil. LC-MS (conditions B): tR=0.78 min.; [M+H]+: 248.38 g/mol.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CCN(C(C)C)C(C)C.O>C(#N)C>[F:12][C:9]([F:10])([F:11])[C:7]1[CH:6]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([N:21]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH3:22])[C@@H:17]2[C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH3:14])[CH:4]=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:8]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CN[C@@H]1CC[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O[C@H]1CC[C@@H](N(C)CC(=O)OC(C)(C)C)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 50 °C

Procedure:
To a solution of 250 mg of non-racemic 1-(S)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-(methylamino)cyclopentane from Example 39 in 6 mL of acetonitrile was added 0.108 mL of t-butyl bromoacetate and 0.36 mL of DIPEA. The reaction was heated at 50° C. for 5 h and then poured into water and extract twice with ethyl acetate. The organic layers were washed with a portion of brine, combined, dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with 0 to 2.5% methanol in methylene chloride to give 294 mg of title compound as an oil. Mass spec (NH3 /CI): 564 (M+1).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH2:4].[C:5]1(=[O:10])[O:9][CH:7]([CH3:8])[CH2:6]1>O>[OH:9][CH:7]([CH3:8])[CH2:6][C:5]([NH:1][CH2:2][CH2:3][NH2:4])=[O:10]
Reactant: NCCN
Reactant: CC1CC(=O)O1
Solvent: O
Product: CC(O)CC(=O)NCCN
Reaction time: 96 h

Procedure:
192 ml. 1,2-diaminoethane are mixed with 60 ml. water and, with stirring and gentle cooling at 20°-30° C., 74 ml. β-butyrolactone are added dropwise thereto. After 4 days, the reaction mixture is distilled off in a vacuum and the crystal slurry obtained is dried over sulphuric acid in a desiccator. There are obtained 122.4 g. (93% of theory) of the desired base; m.p. 71°-73° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19]C)=[O:17])[CH:9]=[CH:8][C:7]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27]C1CCCCO1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:9]=[CH:8][C:7]=1[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]
Reactant: CCOC(=O)CCCOc1ccc(CCCCCCOC2CCCCO2)c(CCC(=O)OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(=O)CCCOc1ccc(CCCCCCO)c(CCC(=O)OC)c1
Yield: 59 %

Procedure:
A solution of 4.26 g (8.91 mmol) of rac-2-[6-[(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy]hexyl]-5-(4-ethoxy-4-oxobutoxy)benzenepropanoic acid methyl ester, 0.16 g of p-toluenesulfonic acid monohydrate, and 75 mL of methanol was stirred and refluxed for 24 hr. The solvent was removed in vacuo and the residue was dissolved in ether. The ether solution was washed with saturated sodium bicarbonate solution and processed in the usual manner giving an oil. This material was flash-chromatographed on silica gel, eluting with 1:1 hexane-ethyl acetate. There was obtained 2.0 g (59%) of 2-(6-hydroxyhexyl)-5-(4-methoxy-4-oxobutoxy)benzenepropanoic acid methyl ester as a colorless oil.
Reaction SMILES: [BH4-].[Li+].[C:3]([O:7][C:8]([N:10]([CH3:18])[C:11]1([C:14](OC)=[O:15])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O1CCCC1.CCOCC>[OH:15][CH2:14][C:11]1([N:10]([CH3:18])[C:8](=[O:9])[O:7][C:3]([CH3:4])([CH3:5])[CH3:6])[CH2:12][CH2:13]1
Reactant: COC(=O)C1(N(C)C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C(=O)OC(C)(C)C)C1(CO)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
100 ml of a 2M solution of lithium borohydride in tetrahydrofuran is added to a solution of 23 g of the compound obtained in Step 2 in 100 ml of tetrahydrofuran. After stirring for 20 hours at ambient temperature and then refluxing for 8 hours, the reaction mixture is cooled to 0° C., hydrolysed, diluted with ether, separated, dried and concentrated. Chromatography of the residue over silica gel (dichloromethane/tetrahydrofuran: 95/5) allows the expected product to be isolated.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]([NH2:16])[C:8]([NH:17][CH2:18][CH3:19])=[N:7][C:6]=1[CH3:20])[CH3:2].[N:22]([O-])=O.[Na+]>>[CH2:1]([O:3][C:4]([C:5]1[C:10]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])=[C:9]2[N:16]=[N:22][N:17]([CH2:18][CH3:19])[C:8]2=[N:7][C:6]=1[CH3:20])=[O:21])[CH3:2]
Reactant: CCCCNc1c(N)c(NCC)nc(C)c1C(=O)OCC
Reactant: O=N[O-]
Agent: [Na+]
Product: CCCCNc1c(C(=O)OCC)c(C)nc2c1nnn2CC
Yield: 73 %

Procedure:
5-Amino-4-butylamino-6-ethylamino-2-methylnicotinic acid ethyl ester is treated with sodium nitrite following the procedure of Example 3c. 7-Butylamino-3-ethyl-5-methyl-3H-[1,2,3]-triazolo[4,5-b]pyridine-6-carboxylic acid ethyl ester is obtained, yield 73%, m.p. 42°-43°. Treatment with 2N hydrochloric acid in ethanol yields the hydrochloride salt.