Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C@@H:10]2[C@H:14]3[O:15][C:16]([CH3:19])([CH3:18])[O:17][C@H:13]3[C@H:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4Cl)[O:11]2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Ca+2].C(O)(=O)C.[Cl:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[C:42]([F:47])[CH:41]=1>C1(C)C=CC=CC=1>[C:1]([C:5]1[O:9][C:8]([C@@H:10]2[C@H:14]3[O:15][C:16]([CH3:18])([CH3:19])[O:17][C@H:13]3[CH:12]([N:20]3[CH:28]=[N:27][C:26]4[C:21]3=[N:22][CH:23]=[N:24][C:25]=4[NH:44][C:43]3[CH:45]=[CH:46][C:40]([Cl:39])=[CH:41][C:42]=3[F:47])[O:11]2)=[N:7][N:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Nc1ccc(Cl)cc1F
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](c1nnc(C(C)(C)C)o1)O[C@H]2n1cnc2c(Cl)ncnc21
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)O[C@@H]2[C@@H](c3nnc(C(C)(C)C)o3)OC(n3cnc4c(Nc5ccc(Cl)cc5F)ncnc43)[C@@H]2O1
Temperature: 76 °C

Procedure:
To a mixture of 40.0 g (95.1 mmol) of 9-[(3aR,4R,6S,6aS)-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-6-chloro-9H-purine and 9.52 g (95.1 mmol) of CaCO3 powder was successively added 200 mL of glacial acetic acid and 21.1 mL (190 mmol) of 4-chloro-2-fluoroaniline at ambient temperature under nitrogen. The light brown mixture was heated at 76° C. for 1.5 to 2.0 h. The mixture was cooled to below 30° C. and diluted with 200 mL of toluene. The mixture was concentrated to about 120 mL by distillation at 35-45° C. under vacuum below 50 torr. This azeotropic process was repeated with a second charge of 240 mL of toluene and distilled to about 200 mL. The above mixture was filtered by suction and the filtrate was concentrated to about 80 mL at 35-45° C. under vacuum to provide a toluene solution of crude product of N-{9-[(3aR,6S,6aS)-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-2,2-dimethyltetrahydrofuro [3,4-d][1,3]dioxol-4-yl]-9H-purin-6-yl}N-(4-chloro-2-fluorophenyl)amine.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.S(OC)(OC)(=O)=O.[CH2:13]([NH2:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][N:2]([CH3:5])[CH:3]=[N:21][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCN
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: CCCCCCCCN=CN(C)C
Temperature: 25 °C

Procedure:
Dimethylformamide (8.8 g, 0.12 mole), dimethyl sulfate (19.3 g, 0.15 mole) and toluene (20 ml) were placed in a 100 ml round bottom flask and heated at reflux for 30 minutes. During this time a light brown oil separated. The reaction was cooled to room temperature and the toluene was decanted. The dimethylformamide/dimethyl sulfate complex was washed with dry toluene (2×20 ml) and the toluene was decanted. n-Octylamine (15.5 g, 0.12 mole) in toluene (20 ml) was added rapidly with stirring. The reaction temperature rose briefly to 60° C. The reaction was stirred for 90 minutes, then extracted with a solution of sodium hydroxide (7.2 g, 0.18 mole) in water (40 ml). The organic phase was washed with brine (40 ml), dried over anhydrous Na2SO4, and filtered. GLC showed the product to be about 72% pure after concentration.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2N=CC=C[C:11]=2N=N1.[NH2:25][C:26]1[N:27]=[C:28]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:29]2[CH:34]=[C:33]([C:35]([OH:37])=O)[S:32][C:30]=2[N:31]=1.C(N(C(C)C)CC)(C)C.Cl.C(NCC)C>CN(C)C=O>[CH2:12]([NH:8][C:35]([C:33]1[S:32][C:30]2[N:31]=[C:26]([NH2:25])[N:27]=[C:28]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:29]=2[CH:34]=1)=[O:37])[CH3:11]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1nc(-c2ccccc2)c2cc(C(=O)O)sc2n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCNCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1cc2c(-c3ccccc3)nc(N)nc2s1
Temperature: 100 °C

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.380 g, 1.0 mmol) was added to 2-amino-4-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (0.187 g, 0.69 mmol). This mixture was suspended in dimethylformamide (DMF) (5.0 ml) and diisopropylethylamine (0.696 ml; 4.0 mmol) added to afford a yellow solution. Diethylamine hydrochloride (0.122 g; 5.0 mmol) was added and the reaction mixture was heated for ten minutes at 100° C. in a sealed vial in a microwave synthesiser. DMF was removed in vacuo and the residue was partitioned between ethyl acetate (30 ml) and water (30 ml). The phases were separated and the organic phase was washed with saturated sodium chloride solution and dried over sodium sulphate. Mixture was filtered and the filtrate solvents were removed in vacuo to leave a yellow solid which was adsorbed onto silica gel and purified by flash chromatography on silica gel (20 g), eluting with a solvent gradient of 15 to 50% ethyl acetate in hexane. This affords 2-amino-4-phenyl-thieno[2,3-d]pyrimidine-6-carboxylic acid ethylamide as a pale yellow solid (0.051 g; 25%).
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[O:8]1[CH2:11][C:10](=O)[CH2:9]1>C1COCC1.CCOC(C)=O.[Cl-].[Na+].O>[CH3:1][C:2]([S@:5]([N:7]=[C:10]1[CH2:11][O:8][CH2:9]1)=[O:6])([CH3:4])[CH3:3]
Reactant: O=C1COC1
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[S@@](=O)N=C1COC1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 20.2 %

Procedure:
To a solution of Ti(OEt)4 (2.02 g, 7.53 mmol) in THF (20 mL) was added (R)-2-methylpropane-2-sulfinamide (0.854 g, 7.05 mmol) followed by oxetan-3-one (0.493 g, 6.84 mmol) in THF (5 mL) and the reaction mixture was heated to 50° C. over night. After cooling, the reaction mixture was diluted with EtOAc (50 mL) and a saturated solution of brine (20 mL) was slowly added under stirring. After 15 min, the mixture was filtered through a plug of Dicalite and washed with EtOAc. The organic phase was separated, dried over Na2SO4 and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 40% EtOAc-heptane gradient to give the title compound (0.242 g, 20%) as a light yellow oil. MS: 176.2 (M+H+).
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.C(=O)([O-])[O-].[K+].[K+].[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:22][SH:23]>CN(C=O)C>[NH2:7][C:6]1[C:5]2[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:4]=2[S:23][C:22]=1[C:21]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)CS
Reactant: N#Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc([N+](=O)[O-])ccc2c1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 32.4 %

Procedure:
2,4-Dinitrobenzonitrile (5.08 g, 26.3 mmol) was dissolved in DMF (55 ml). Potassium carbonate (4.36 g, 31.6 mmol) and ethyl thioglycolate (3.17 g, 26.3 mmol) were added, and the mixture was stirred at room temperature for three days. The reaction solution was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was recrystallized from ethyl acetate/hexane to obtain 2.27 g of the title compound as crystals (32%).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].Cl[CH2:13][CH:14]1[O:20][CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:15]1[CH2:16][CH2:17][CH2:18][CH2:19][O:20][CH:14]1[CH2:13][NH:5][C:4]1[C:6]([CH2:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:3]=1[CH2:1][CH3:2]
Reactant: ClCC1OCCCCO1
Reactant: CCc1cccc(CC)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1cccc(CC)c1NCC1OCCCCO1

Procedure:
2,6-Diethylaniline (75 grams), 2-chloromethyl-1,3-dioxepane (15 grams), potassium carbonate (34 grams) and dimethylformamide (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 18 hours. After this time the mixture is filtered and distilled to yield the desired product N-(1,3-dioxepan-2-ylmethyl)-2,6-diethylaniline.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.O.O.[Sn](Cl)Cl>C1COCC1.C(N(CC)CC)C>[C:11]1([S:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH2:8])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Sc1ccccc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccccc1Sc1ccccc1
Reaction time: 4 h

Procedure:
A room temperature solution of 2-fluoronitrobenzene (1.41 g, 10.0 mmol), thiophenol (1.21 g, 11.0 mmol), and triethylamine (2 mL) in THF (20 mL) was stirred for 16 hours, treated with 3M HCl (10 mL) and tin(II) chloride dihydrate (11.4 g, 50 mmol), stirred for 4 hour, and extracted with ethyl acetate (50 mL). The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 50% hexanes/dichloromethane to provide the desired product. MS (DCI) m/e 202 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]2)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]1[N:15]=[C:14]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][C:25]([O:27]C)=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=1.O[Li:47].O>C1COCC1.O.CO>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][CH:33]([C:5]2[CH:6]=[CH:7][C:8]([NH:9][C:10]3[N:15]=[C:14]([CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[CH2:24][C:25]([O-:27])=[O:26])[C:13]([C:29]([F:32])([F:31])[F:30])=[CH:12][N:11]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:44])[CH3:43].[Li+:47]
Reactant: [Li]O
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2OC)ncc1C(F)(F)F
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc(C(F)(F)F)c(CCc2ccccc2CC(=O)[O-])n1
Product: [Li+]

Procedure:
A solution of tert-butyl 4-(3-methoxy-4-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I21) (210 mg, 0.334 mmol) and LiOH.H2O (42 mg, 1.0 mmol) in THF (10 mL), water (2 mL) and MeOH (1 mL) was stirred at room temperature for 20 hours. The volatiles were evaporated under reduced pressure to give the title compound (I22) as a light yellow solid, 300 mg, excess mass due to inorganic salts present. LCMS Method C: rt 7.31 min; m/z 615.1 [M+1]+, 613.2 [M−1]−.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][N:35]1[C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCCC1CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 65.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), 2-(aminomethyl)-1N-Boc-pyrrolidine (20.9 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 25 mL/min, 220 nM, product retention=32.9 min) to provide (R/S)-tert-butyl 2-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)pyrrolidine-1-carboxylate (28 mg, 0.046 mmol, 65.6% yield): LCMS=614.3 [M+H]+. The (R/S)-tert-butyl 2-((2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)methyl)pyrrolidine-1-carboxylate (28 mg, 0.046 mmol) was added to TFA (1 mL, 12.98 mmol) and stirred for 30 min. The reaction mixture was concentrated to provide (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-(pyrrolidin-2-ylmethyl)acetamide, TFA (24 mg, 0.037 mmol, 80% yield): LCMS=514.3 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.18 (2 H, d, J=7.92 Hz), 7.54-7.79 (7 H, m), 5.21 (1 H, s), 3.66-3.81 (1 H, m), 3.48-3.62 (2 H, m), 3.16-3.30 (2 H, m), 1.91-2.18 (3 H, m), 1.70-1.82 (1 H, m); HPLC peak RT=8.3 min (Condition A).
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[OH-].[Na+].Cl[O:12]C(C)(C)C.[Br:17][C:18]1[CH:19]=[N:20][CH:21]=[C:22](/[CH:24]=[CH:25]/[C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[CH:23]=1>C(O)CC.CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C(OC)C=C4)N(CC2)C1>[C:4]([O:3][C:1](=[O:8])[NH:2][C@H:24]([C:22]1[CH:21]=[N:20][CH:19]=[C:18]([Br:17])[CH:23]=1)[C@@H:25]([C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])[OH:12])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(N)=O
Reactant: CC(C)(C)OCl
Reactant: Fc1ccc(F)c(/C=C/c2cncc(Br)c2)c1
Agent: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Product: CC(C)(C)OC(=O)N[C@H](c1cncc(Br)c1)[C@H](O)c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 134.2 %

Procedure:
To a solution of tert-butyl carbamate (83 g, 709 mmol) in 1-propanol (780 mL) was added 0.5 M of aqueous sodium hydroxide (1418 mL, 709 mmol), followed by tert-butyl hypochlorite (77 g, 709 mmol) (internal temperature 28.2° C.). The reaction mixture was stirred at ambient temperature for 10 min. To this reaction mixture was added (DHQD)2PHAL (5.52 g, 7.09 mmol) and 1-propanol (780 mL), followed by (E)-3-bromo-5-(2,5-difluorostyryl)pyridine (70.0 g, 236 mmol) and 1-propanol (780 mL). This white mixture was cooled to 0° C. with a methanol/ice bath. Then potassium osmate dihydrate (2.61 g, 7.09 mmol) was added to this mixture. After 30 min of stirring, the ice bath was removed. The reaction was stirred at room temperature overnight. After 16 h, the reaction mixture was partitioned with water (1 L) and EtOAc (2.4 L). The organic layer was washed with 5% sodium sulfite three times (Note: Each wash was mechanically stirred for 10 min to ensure reduction of osmium. The first two washes were dark; the third wash was clear. The organic layer was washed with brine (3×500 mL), dried (sodium sulfate), filtered, and concentrated to give 136 g of crude tert-butyl((1R,2R)-1-(5-bromopyridin-3-yl)-2-(2,5-difluorophenyl)-2-hydroxyethyl)carbamate and tert-butyl((1R,2R)-2-(5-bromopyridin-3-yl)-1-(2,5-difluorophenyl)-2-hydroxyethyl)carbamate (ca. 6:1 ratio). LC/MS (ES+) 430.9 (M+H, 100).
Reaction SMILES: C1(C)C(C)=CC=CC=1.[CH2:9]([C@H:12]1[CH2:17][CH2:16][C@H:15]([C@H:18]2[CH2:23][CH2:22][C@H:21]([CH2:24][CH2:25][CH2:26]O)[CH2:20][CH2:19]2)[CH2:14][CH2:13]1)[CH2:10][CH3:11].[BrH:28]>O>[Br:28][CH2:26][CH2:25][CH2:24][C@H:21]1[CH2:20][CH2:19][C@H:18]([C@H:15]2[CH2:14][CH2:13][C@H:12]([CH2:9][CH2:10][CH3:11])[CH2:17][CH2:16]2)[CH2:23][CH2:22]1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCO)CC2)CC1
Reactant: Br
Solvent: Cc1ccccc1C
Solvent: O
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCBr)CC2)CC1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
To 350 ml of xylene were added 341 g (1280 mmol) of the crude 3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propanol obtained by the procedures described above and 881 g (5120 mmol) of 47% hydrobromic acid, water was removed by azeotropic distillation, and then the mixture was stirred at 150° C. for 2 hours. To the reaction mixture was added 1.0 l of toluene, and it was washed with 300 ml of saturated aqueous sodium carbonate solution twice and with 400 ml of water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: heptane) to obtain 156 g of a crude 1-bromo-3-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)propane.
Reaction SMILES: [OH:1][CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].N1C=CN=C1>CN(C=O)C>[Si:10]([O:1][CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: C=C(CO)C(=O)OCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C=C(CO[Si](C)(C)C(C)(C)C)C(=O)OCC
Reaction time: 2 h
Yield: 72.5 %

Procedure:
10.8 g of ethyl 2-(hydroxymethyl)acrylate (Organic Synthesis, Coll, Vol 8, 265, 1993) was diluted with 80 ml of N,N′-dimethylformamide, and 18.8 g of tert-butyldimethylsilyl chloride and 11.3 g of imidazole were added thereto. The resulting mixture was incubated at room temperature for two hours. After the reaction terminated, water was added, and the resulting solution was extracted with ethyl acetate. The organic layer was washed five times with water and saturated chloride water, dried over anhydrous sodium sulfate, filtered and distilled under a reduced pressure. The resulting residue was purified by column chromatography (ethyl acetate:n-hexane=1:30) to obtain the title compound (14.7 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:15])/[CH:12]=[CH:13]/[CH3:14])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C1CCN2C(=NCCC2)CC1.[N+:27]([CH3:30])([O-:29])=[O:28]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11](=[O:15])[CH2:12][CH:13]([CH3:14])[CH2:30][N+:27]([O-:29])=[O:28])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C/C=C/C(=O)Nc1ccc(C#N)c(Cl)c1
Reactant: C[N+](=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CC(CC(=O)Nc1ccc(C#N)c(Cl)c1)C[N+](=O)[O-]
Yield: 76.3 %

Procedure:
The compound obtained in Step 1 (21.69 g, 98.31 mmol), DBU (16.30 mL, 108.14 mmol) and nitromethane (6.00 g, 98.31 mmol) were stirred at room temperature for 14 hr. To the reaction solution was added brine at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 5 to 30% ethyl acetate/hexane) to give N-(3-chloro-4-cyanophenyl)-3-methyl-4-nitrobutanamide (21.20 g, 75 mmol, 77%) as a pale-orange powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][NH:12][CH3:13])[C:4]=2[S:5][CH:6]=1.[Cl:14][CH:15]=[CH:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][N:12]([CH2:17]/[CH:16]=[CH:15]/[Cl:14])[CH3:13])[C:4]=2[S:5][CH:6]=1
Reactant: ClC=CCCl
Reactant: CNCc1cccc2c(Cl)csc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C/C=C/Cl)Cc1cccc2c(Cl)csc12
Temperature: 50 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
To a solution of 0.22 g (1.0 mmol) of 3-chloro-N-methylbenzo[b]thiophene-7-methanamine in 3 ml of dimethyl sulfoxide were added 0.12 ml (1.2 mmol) of 1,3-dichloropropene (E/Z=9/1) and 0.21 g (1.5 mmol) of ground potassium carbonate. The mixture was stirred for 17 hours at 50° C., and poured into 50 ml of ethyl acetate. The organic layer was washed with 25 ml ×2 of water and 10 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-heptane→n-heptane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 0.21 g (yield: 73%) of the above identified compound as an oil.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[S:19][C:20]([NH2:23])=[N:21][N:22]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[Li+].[OH-].Cl>C1COCC1.CO.O>[NH2:23][C:20]1[S:19][C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:24])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)=[N:22][N:21]=1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1cc(Oc2nnc(N)s2)cc2c1C(CC(=O)O)OB2O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 74.6 %

Procedure:
To a solution [6-(5-amino-[1,3,4]thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl]-acetic acid ethyl ester (0.6 g, 1.72 mmol) in THF (15 mL) and methanol (2 mL) was added a solution of LiOH (0.165 g, 6.87 mmol) in water (15 mL) at 0° C. The resulting mixture was stirred at room temperature for 1.5 hours then acidified to pH=2 with dilute hydrochloric acid at 0° C. After removal of the volatile organics, the residue was neutralized to pH 7 using saturated sodium bicarbonate. The precipitated solid was filtered and stirred with ethyl acetate (20 mL) for 1 hour. The solid was filtered, washed with cold ethyl acetate and water then dried to give the product (0.412 g, 75%). 1HNMR (400 MHz, DMSO-d6) δ9.26 (br. s., 1H), 7.32 (d, J=2.05 Hz, 1H), 7.16 (d, J=1.76 Hz, 1H), 7.05 (s, 2H), 5.48 (dd, J=9.37, 2.05 Hz, 1H), 3.04 (dd, J=15.37, 2.49 Hz, 1H), 2.29 (s, 3H), 2.12 (dd, 1H). MS (ESI) m/z=322 [M+H]+.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])(=[O:3])[CH3:2].C(N(CC)CC)C>C(O)C>[C:1]([O:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:3])[CH3:2].[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])(=[O:3])[CH3:2]
Reactant: C=CCCCC=CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCC=CCOC(C)=O
Product: CCCCCCCCOC(C)=O
Reaction time: 3 h
Yield: 23.6 %
Yield: 63.7 %

Procedure:
A mixture of 33.6 grams of 1-acetoxyocta-2,7-diene (I), 0.30 g RuCl2 (PPh3)3, 1.5 ml triethylamine and 120 ml ethanol was heated in a 300 ml stainless steel autoclave under a hydrogen pressure of 450 psi at 30° C. After three hours the rate of hydrogenation was greatly decreased and the pressure drop corresponded to approximately the theoretical amount (0.2 moles). The reaction was stopped, the catalyst filtered off and the crude product analyzed by GC to give 12.5% I, 63.7% 1-acetoxyoct-2-ene (II), and 23.6% 1-acetoxyoctane (III). This corresponds to a selectivity of 72.8% for the formation of II at a 87.5% conversion of I.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].N1C=CN=C1.[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].O>CN(C)C=O>[C:15]([Si:19]([CH3:21])([CH3:20])[O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1cccc(O)c1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
A mixture of 3-hydroxy-benzonitrile (5.0 g, 42.0 mmol) and imidazole (7.15 g, 105 mmol) in N,N-dimethylformamide (100 mL) was treated with tert-butyl-chloro-dimethyl-silane (7.6 g, 50.4 mmol) in N,N-dimethylformamide (50 mL) over 10 min. The reaction was stirred at rt overnight. The reaction mixture was poured into water, and extracted with ethyl acetate (2×). The solvent was removed, and the resulting residue was chromatographed using hexane/ethyl acetate (10:1) to give the title compound (9.27 g, 95%). MS (DCI/NH3) m/z 234 (M+1)+. 1HNMR (500 MHz, DMSO-d6) δ ppm 0.26 (s, 6H) 1.00 (s, 9H) 7.26 (dq, J=7.93, 1.22 Hz, 1H) 7.35 (t, J=2.44 Hz, 1H) 7.50 (m, 2H).