Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]2[N:7]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:8][C@@H:9](OS(C3C=CC(C)=CC=3)(=O)=O)[C@H:5]2[O:4][CH2:3]1.[CH3:28][S-:29].[Na+].[Cl-].[NH4+]>CC(N(C)C)=O>[OH:1][C@@H:2]1[C@H:6]2[N:7]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:8][C@H:9]([S:29][CH3:28])[C@H:5]2[O:4][CH2:3]1
Reactant: C[S-]
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CN(C(=O)OC(C)(C)C)[C@H]3[C@@H]2OC[C@@H]3O)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CS[C@H]1CN(C(=O)OC(C)(C)C)[C@H]2[C@@H]1OC[C@@H]2O
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A stirred solution of tosylate (35b) (250 mg, 0.63 mmol) and sodium thiomethoxide [CAS 5188-07-8] (88 mg, 1.25 mmol) in 3 ml of DMA was heated under an atmosphere of argon in a sealed pressure vessel at 90° C. for 2 hours. The mixture was then allowed to cool to ambient temperature then an aqueous saturated solution of ammonium chloride (10 mL) was added. The aqueous phase was extracted with tert-butyl methyl ether (3×7 ml). The organic phase was dried (MgSO4), filtered and reduced in vacuo to leave an oil. Flash chromatography over silica, eluting with diethyl ether:pentane 2:1 gave thiomethylether (54) as colourless oil (0.152 g, 88%). TLC(Rf=0.29, Et2O:pentane 2:1), HPLC-MS 220.1 [M+2H−tBu]+, 573.2 [2M+H]+; δH (500 MHz, CDCl3) mixture of rotamers 1:1; 1.46 (4.5H, s, CCH3), 1.49 (4.5H, s, CCH3), 2.16 (3H, s, SCH3), 3.20 (1H, brs, BocNCH2), 3.47-4.05 (4H, m, OCH2CHOH, BocNCH2 and CHSCH3), 4.24-4.45 (2H, m, BocNCH and OCH2CHOH), 4.63 (1H, s, OCHCHSCH3).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]=[C:9]=[O:10])=O)=[CH:4][C:3]=1[C:13]([F:16])([F:15])[F:14].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[NH:32][NH:33]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:20][C:19]=1[N:32]1[C:9](=[O:10])[NH:8][C:6]([C:5]2[CH:11]=[CH:12][C:2]([Cl:1])=[C:3]([C:13]([F:16])([F:15])[F:14])[CH:4]=2)=[N:33]1
Reactant: O=C=NC(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(Cl)c(C(F)(F)F)c3)[nH]c2=O)c1
Yield: 65.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 4-chloro-3-(trifluoromethyl)benzoyl isocyanate (Intermediate-100, 2.0 g), tert-butyl 2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-94, 1.0 g), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.900 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.12 (s, 9H), 4.29 (d, J=5.1 Hz, 2H), 7.36 (d, J=9.3 Hz, 1H), 7.43 (s, 1H), 7.61 (d, J=8.4 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 8.10-8.18 (m, 2H), 8.27 (s, 1H), 12.82 (s, 1H); MS (m/z): 487.29 (M+H)+.
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].Cl[C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10](Cl)[N:9]=1.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)#[N:19]>CN(C=O)C>[C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:8]2[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[C:10]([O:4][C:1]3[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)[N:9]=2)=[CH:22][CH:21]=1)#[N:19]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: N#Cc1ccc(O)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc([N+](=O)[O-])c(Oc3ccc(C#N)cc3)n2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 71.1 %

Procedure:
Potassium carbonate (2.09 g, 15.1 mmol) was added to a stirred solution of 2,6-Dichloro-3-nitro pyridine (1.0 g, 5.3 mmol), dissolved in 10 ml of DMF, at a temperature of 5° C. The flask was stirred for 10 min at the same temperature. 4-Cyano phenol (1.26 g, 10.6 mmol), dissolved in 5 ml of DMF was added dropwise to the reaction mixture over a period of 10 min and the flask was heated to 80° C. for 10-12 h. The reaction mixture was poured into ice-cold water and the product was extracted with 250 ml of ethyl acetate. Ethyl acetate layer was washed with water and brine solution. The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford 1.35 g of the required 2,6-Bis-(4-cyano phenoxy)-3-nitro pyridine which was used in the next step without further purification. 1H NMR (DMSO-d6): δ 7.06 (1H, d), 7.32 (4H, dd), 7.82 (411, t), 8.74 (1H, d).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[NH:8][C:7]=1[Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[Cl:15][C:12]1[CH:13]=[C:14]2[C:6]([CH2:5][CH2:4][NH2:1])=[C:7]([Si:16]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:21][CH3:22])[NH:8][C:9]2=[N:10][CH:11]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CC[Si](CC)(CC)c1[nH]c2ncc(Cl)cc2c1CCN
Yield: 62 %

Procedure:
A mixture of 3-(2-azidoethyl)-5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridine (0.900 g; 2.68 mmol) and triphenylphosphine 1.05 g; 4.02 mmol) in methanol (25 ml) was stirred at 80° C. for 1 hour and was concentrated under reduced pressure. The residue was dissolved in toluene (15 mL). Hydrochloric acid (2 mL) and water 15 mL were added. After separation of the two layers, the aqueous solution was extracted with toluene (3×15 mL) and was made alkaline by addition of an aqueous solution of sodium hydroxide 2N. The formed precipitate was filtered off. The filtrate was extracted with dichloromethane (5×15 mL). Combined dichloromethane extracts were dried over magnesium sulfate and was concentrated in vacuo to give 0.515 g (62%) of 2-(5-chloro-2-(triethylsilyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanamine as an oily residue.
Reaction SMILES: S(=O)(=O)(O)O.[CH:6]([OH:9])([CH3:8])[CH3:7].CC1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18]O)[C:13](C)([CH3:20])[CH:12]=1.C1CCCCC=1>O>[CH3:7][C:6]12[CH2:18][CH2:17][CH:14]([C:13]([CH3:20])([CH3:12])[CH2:8]1)[CH:15]([CH3:16])[O:9]2
Reactant: CC(C)O
Reactant: CC1=CC(C)(C)C(CCO)CC1
Agent: O=S(=O)(O)O
Solvent: C1=CCCCC1
Solvent: O
Product: CC1OC2(C)CCC1C(C)(C)C2
Temperature: 25 °C

Procedure:
Into a 500 ml reaction flask equipped with reflux head, thermometer and stirrer is added 50 g of 40% sulfuric acid and 50 g of anhydrous isopropyl alcohol. The resulting mixture is heated to reflux and 1,3,3-trimethyl-1-cyclohexene-4-ethanol, prepared according to Example II (50 g) (fraction 2 according to Example II) is added slowly to the reaction mass while maintaining the temperature thereof at 86°-88° C. The addition takes place over a period of one hour. At the end of the addition of the cyclohexene derivative, the reaction mass is cooled to room temperature and water is added. The reaction mass now exists in two phases. The phases are separated and the organic phase is washed with aqueous sodium carbonate and saturated sodium chloride. The organic phase is then distilled using a microdistillation set-up (micro Vigreux column) yielding the following fractions:
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][CH2:11][CH2:12][N:13]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:16](=[O:26])[C:15]([C:27]([OH:29])=O)=[CH:14]1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[NH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[C:65]([NH2:71])=[N:66][CH:67]=[C:68]([Br:70])[CH:69]=2)=[CH:60][CH:59]=1>CN(C=O)C.O>[NH2:71][C:65]1[C:64]([C:61]2[CH:60]=[CH:59][C:58]([NH:57][C:27]([C:15]3[C:16](=[O:26])[C:17]([C:19]4[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=4)=[CH:18][N:13]([CH2:12][CH2:11][F:10])[CH:14]=3)=[O:29])=[CH:63][CH:62]=2)=[CH:69][C:68]([Br:70])=[CH:67][N:66]=1
Reactant: O=C(O)c1cn(CCF)cc(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(-c2cc(Br)cnc2N)cc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Nc1ncc(Br)cc1-c1ccc(NC(=O)c2cn(CCF)cc(-c3ccc(F)cc3)c2=O)cc1
Reaction time: 0.33 h
Yield: 81.2 %

Procedure:
DIPEA (114 μl) was added to a solution of the compound obtained in Step 2 of Example 8 (91 mg) and COMU (181 mg) in DMF (2.0 ml) at room temperature, and the mixture was stirred for 20 minutes. The compound obtained in Step 1 of Example 1 (95 mg) was added at room temperature. The mixture was stirred for six hours, followed by the addition of water. After extraction with ethyl acetate, the organic layer was washed with brine and then dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [chloroform:methanol=300:1->30:1 (v/v)] to give 139 mg of the title compound as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:7][CH2:8][C:9]([C:11]1[CH:24]=[CH:23][C:22]2[O:21][C:20]3[C:15](=[CH:16][C:17]([C:25](=[O:28])[CH2:26]Cl)=[CH:18][CH:19]=3)[CH2:14][C:13]=2[CH:12]=1)=[O:10].[I-].[K+]>O1CCCC1>[ClH:7].[ClH:7].[N:1]1([CH2:8][C:9]([C:11]2[CH:24]=[CH:23][C:22]3[O:21][C:20]4[C:15](=[CH:16][C:17]([C:25](=[O:28])[CH2:26][N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)=[CH:18][CH:19]=4)[CH2:14][C:13]=3[CH:12]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(CCl)c1ccc2c(c1)Cc1cc(C(=O)CCl)ccc1O2
Reactant: C1CCNCC1
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cl
Product: O=C(CN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CN3CCCCC3)ccc1O2
Reaction time: 168 h

Procedure:
To a solution of 200 ml of piperidine in 500 ml of tetrahydrofuran are added 33.5 g (0.1 mole) of 2,7-bis(2-chloroacetyl)xanthene and 2g of potassium iodide with warming. The reaction mixture is allowed to stand for 7 days, filtered and the filtrate evaporated to dryness, leaving a residue which is treated with dilute acid and filtered. The filtrate is made alkaline, and the resulting oily product is extracted with methylene chloride. The methylene chloride solution is acidified with ethereal HCl which gives an oily product that is recrystallized from methanol-diethyl ether then vacuum dried to give 2,7-bis(piperidinoacetyl)xanthene dihydrochloride, M.P. 260°-262°C.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1F)[C:11]#[N:12].[CH2:17]([OH:20])[CH2:18][OH:19]>>[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:19][CH2:18][CH2:17][OH:20])[C:11]#[N:12]
Reactant: OCCO
Reactant: N#Cc1ccc(F)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: N#Cc1ccc(OCCO)c(F)c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To potassium tert-butoxide (19.35 g) was added ethylene glycol (160 mL). The mixture was then heated to 50° C. At 50° C., 3,4-difluorobenzonitrile (20 g) was added and this was washed in with ethylene glycol (40 mL). The combined solution was heated to 80° C., and held at this temperature for two hours, before being cooled to 20° C. over one hour. The reaction mixture was filtered and washed with ethylene glycol (40 mL). To the filtrate was added water (200 mL) and dichloromethane (200 mL). The layers were separated and the organic layer was concentrated in vacuo, to give the sub-title compound as a waxy white solid (26.1 g, 100% yield).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1I)[CH3:2].[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[CH:25])=[CH:20][CH:19]=1.CN(C=O)C.CCN(CC)CC>O.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[C:5]([C:14]#[N:15])=[C:4]1[C:25]#[C:24][C:21]1[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=1)[CH3:2]
Reactant: C#Cc1ccc(F)cc1
Reactant: CCn1c(I)c(C#N)c2ccc(OC)cc21
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCn1c(C#Cc2ccc(F)cc2)c(C#N)c2ccc(OC)cc21
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A mixture of 1-ethyl-2-iodo-6-methoxy-1H-indole-3-carbonitrile (150 mg, 0.46 mmol), prepared as described in example 1Ga, step A, 4-fluorophenylacetylene (80 mg, 0.0.69 mmol), bis(triphenylphosphine) palladium (II) dichloride (6 mg, 0.009 mmol) and CuI (4 mg, 0.018 mmol) was added to a sealable tube and alternatively evacuated and flushed with N2. To the tube was then added DMF (4 mL) and Et3N (0.25 mL, 1.84 mmol) and the reaction was heated at 80° C. for 20 h and then cooled to room temperature. The reaction mixture was diluted with H2O and extracted with EtOAc (2×). The combined organic phases were washed with H2O (3×) and saturated NaCl and then dried over MgSO4 and concentrated. The crude reaction mix was absorbed on silica gel (0.6 g) and chromatographed over silica gel using EtOAc/hexanes (10-20%) as eluent to afford 120 mg (82%) of 1-ethyl-2-(4-fluorophenylethynyl)-6-methoxy-1H-indole-3-carbonitrile as a yellow solid.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CN(C)C(=O)[C@H:12]([CH:25]([CH3:27])[CH3:26])[CH2:13]/[CH:14]=[CH:15]/[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)(=O)C.[C:34](=[O:37])(O)[O-:35].[Na+].S([O-])([O-])=O.[Na+].[Na+]>O.O1CCCC1>[CH2:18]([O:17][CH2:16][C@H:15]([C@H:14]1[O:35][C:34](=[O:37])[C@H:12]([CH:25]([CH3:27])[CH3:26])[CH2:13]1)[Br:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C([O-])O
Reactant: CC(C)[C@H](C/C=C/COCc1ccccc1)C(=O)N(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)[C@@H]1C[C@@H]([C@H](Br)COCc2ccccc2)OC1=O
Reaction time: 3 h
Yield: 50 %

Procedure:
25.81 g of N-bromosuccinimide (145 mmol) was added to a solution of 21.20 g of (2S,4E)-6-(benzyloxy)-2-isopropylhex-4-enoic acid dimethylamide obtained in Example (1c) (72.5 mmol) and 8.3 ml of acetic acid (145 mmol) in a mixed solvent of tetrahydrofuran (290 ml) and water (145 ml) under ice-cooling, and the mixture was stirred at the same temperature for three hours. 100 ml of a saturated sodium bicarbonate aqueous solution and 100 ml of a 1.5 M sodium sulfite aqueous solution were added to the reaction mixture, and the mixture was further stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to about ⅔ of the volume, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:n-hexane/ethyl acetate=6/1-5/1) to obtain 22.73 g of the title compound (total yield over three steps: 50%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]2)=[CH:8][CH:7]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26].C(=O)([O-])O.[Na+].[ClH:40]>CS(C)=O.C(O)C.N1C=CC=CC=1>[ClH:1].[ClH:40].[CH3:28][O:27][C:23]1[CH:22]=[C:21]([N:29]2[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][O:5][C:6]3[CH:15]=[C:14]4[C:9]([CH2:10][CH2:11][C:12](=[O:16])[NH:13]4)=[CH:8][CH:7]=3)[CH2:31][CH2:30]2)[CH:20]=[C:19]([O:18][CH3:17])[C:24]=1[O:25][CH3:26]
Reactant: COc1cc(N2CCNCC2)cc(OC)c1OC
Reactant: O=C1CCc2ccc(OCCCCl)cc2N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: COc1cc(N2CCN(CCCOc3ccc4c(c3)NC(=O)CC4)CC2)cc(OC)c1OC
Reaction time: 5 h
Yield: 61 %

Procedure:
12.4 Grams of 7-(3-chloropropoxy)-3,4-dihydrocarbostyril, 1 g of pyridine and 2.6 g of 4-(3,4,5-trimethoxyphenyl)piperazine are mixed in 20 ml of dimethylsulfoxide, then stirred at 80°-90° C. for 5 hours. The reaction mixture is poured into 80 ml of 2% aqueous solution of sodium hydrogencarbonate and the organic layer is extracted with chloroform. The chloroform layer is washed with water, dried and chloroform is removed by distillation. The residue thus obtained is dissolved in 30 ml of ethanol and dried hydrogen chloride gas is blown into the ethanol solution. The crystals thus precipitated are collected by filtration and recrystallized from methanol-ethanol to obtain 3.2 g (yield: 61%) of 7-{3-[4-(3,4,5-trimethoxyphenyl)piperazinyl]propoxy}-3,4-dihydrocarbostyril dihydrochloride in the form of colorless needle-like crystals with a melting point of 225°-227° C.
Reaction SMILES: [OH-].[NH4+:2].S(F)([O:6][C:7](F)(F)[C:8]([F:14])([I:13])[C:9]([F:12])([F:11])[F:10])(=O)=O>C(Cl)Cl>[I:13][C:8]([F:14])([C:9]([F:12])([F:11])[F:10])[C:7]([NH2:2])=[O:6]
Reactant: O=S(=O)(F)OC(F)(F)C(F)(I)C(F)(F)F
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC(=O)C(F)(I)C(F)(F)F
Temperature: 12.5 °C
Yield: 68.3 %

Procedure:
Into a glass flask was placed a mixture of aqueous ammonium hydroxide (28 wt. %, 40.5 mL, 0.6 mol) and methylene chloride (80 mL) which was cooled to 10-15° C. 2-Iodohexafluoropropyl fluorosulfate from Experiment 5 (37.6 g, 0.1 mol) was added slowly with vigorous stirring while the reaction temperature was kept at <15° C. After addition, the mixture was warmed to ambient temperature, the bottom organic layer was separated, washed with aqueous sodium bisulfite solution, dried over MgSO4. The solvent was removed in vacuo to give the title product as a white solid (18.5 g, 68.3 % yield), mp. 75-77° C., 1H NMR (300 MHz, CDCl3): δ6.98, 6.53 (2 broad singlets); 19F NMR (188.24 MHz, CDCl3): -76.3 (2 singlets, 3F), -138.5 (m, 1F); IR: 1690 cm-1 (C=O); Anal. Calcd. for C3H2F4INO: C: 13.30, H: 0.74, F: 28.05, N: 5.17. Found: C: 13.68, H: 0.83, F: 28.43, N: 5.21. Mass. Calcd. for [M+ ]: 270.9117; Found: 270.9093.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[CH:10]([C:13]1[S:17][CH:16]=[C:15]([C:18]([N:20]2[CH2:25][C:24]3([CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[O:23][CH2:22][CH2:21]2)=[O:19])[CH:14]=1)([CH3:12])[CH3:11].C(N(CC)CC)C>C(#N)C>[OH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:28]1[CH2:29][CH2:30][C:24]2([O:23][CH2:22][CH2:21][N:20]([C:18]([C:15]3[CH:14]=[C:13]([CH:10]([CH3:11])[CH3:12])[S:17][CH:16]=3)=[O:19])[CH2:25]2)[CH2:26][CH2:27]1
Reactant: CC(C)c1cc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: OCCCCCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C(=O)N2CCOC3(CCN(CCCCCCCO)CC3)C2)cs1
Temperature: 60 °C
Reaction time: 16 h

Procedure:
A solution of 7-bromo-1-heptanol (380 mg) in acetonitrile (3.9 mL) was added to a solution of (5-isopropylthiophen-3-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (Example 275, step i) (400 mg) and triethylamine (0.361 mL) in acetonitrile (8.6 mL). The resulting mixture was stirred at 60° C. for 16 hours. The solvent was removed under vacuum and the residue taken up in DCM (25 mL) and washed with brine (25 mL) and water (20 mL), then dried over sodium sulphate, filtered and evaporated. Purification was by silica gel chromatography eluting with 0 to 10% methanol in DCM to afford the subtitled compound as a pale brown solid. Yield 0.305 g.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31]I)[O:11][C@@H:10]1[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:42]([O:49]CC)([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45]>>[CH2:24]([O:23][C@H:13]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:10]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:11][C@@H:12]1[CH2:31][P:42](=[O:49])([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: IC[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1)OCC
Yield: 70 %

Procedure:
A solution of (2R,3R,4S,5S,6S)-3,4,5-tris(benzyloxy)-2-((benzyloxy)methyl)-6-(iodomethyl)tetrahydro-2H-pyran (0.7 g, 0.75 mmol, 1.0 equiv) in anhydrous triethyl phosphite (9.0 mL) was heated to 160° C. in a 50 mL sealed tube for 16 hours. The solvent was removed using a Kugelrohr distillation setup, and the material thus obtained was purified by silica gel chromatography, eluting with 50% EtOAc in petroleum ether, to give diethyl (((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phosphonate as a pale yellow oil (0.5 g, 70%). 1H NMR (300 MHz, CDCl3) δ 7.52-6.98 (m, 20H), 4.77-4.66 (m, 1H), 4.63 (d, J=6.2 Hz, 2H), 4.60-4.42 (m, 6H), 4.16-3.99 (m, 4H), 3.91 (dq, J=8.1, 5.1, 3.9 Hz, 1H), 3.88-3.82 (m, 1H), 3.78 (q, J=4.0 Hz, 4H), 2.25-1.95 (m, 2H), 1.33-1.22 (m, 6H). ESI (M+1) 675.2; calc for C39H47O8P 674.3.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:14]=[CH:13][C:7]2[S:8][C:9]([CH3:12])([CH3:11])[S:10][C:6]=2[CH:5]=1)=[O:3].[BH4-].[Na+]>C(O)C>[CH3:1][CH:2]([C:4]1[CH:14]=[CH:13][C:7]2[S:8][C:9]([CH3:11])([CH3:12])[S:10][C:6]=2[CH:5]=1)[OH:3]
Reactant: CC(=O)c1ccc2c(c1)SC(C)(C)S2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc2c(c1)SC(C)(C)S2
Temperature: 0 °C
Reaction time: 3 h
Yield: 101 %

Procedure:
28.9 g of aluminum chloride were added portionwise at 0° C. to 16.8 ml of acetyl chloride in 360 ml of methylene chloride. After an additional 30 minutes at 0° C., a solution of 35.9 g of 2,2-dimethyl-1,3-benzodithiol in 180 ml of methylene chloride was slowly added dropwise and the mixture was stirred at 0° C. for an additional 12 hours and thereafter at 20° C. for 5 hours. Thereafter, the mixture was poured on to ice, extracted with methylene chloride and the extracts were washed neutral with dilute sodium hydroxide solution and water, dried over sodium sulfate and evaporated. After recrystallization from methanol/water, there were obtained 41.8 g or 2,2-dimethyl-1,3-benzodithiol-5-yl methyl ketone, melting point 75°-76° C. Then, 41.8 g of this ketone were dissolved in 1 l of ethanol, cooled to 0° C. and 7 g of sodium borohydride were added portionwise. Thereafter, the mixture was stirred at 20° C. for 3 hours, evaporated in a vacuum to a large extent, 200 ml of water were added, the mixture was adjusted slowly to pH 4 with 1N sulfuric acid while cooling and extracted three times with ether. The extracts were washed with water, dried and evaporated, and 42.6 g of α,2,2-trimethyl-1,3-benzodithiol-5-methanol were obtained. Thereafter, 39.5 g of this alcohol were reacted with 65.9 g of triphenylphosphine hydrobromide in 500 ml of acetonitrile and worked-up as described in Example 8 and 96.3 g of [1-(2,2-dimethyl-1,3-benzodithiol-5-yl) ethyl]triphenylphosphonium bromide were obtained. Then, 17.0 g of this phosphonium salt were reacted with methyl 4-formyl-benzoate in analogy to Example 8. After working up and recrystallization from ethyl acetate/hexane, there were obtained 4.9 g of methyl p-[(E)-2-(2,2-dimethyl-1,3-benzo-dithiol-5-yl)propenyl]benzoate in the form of colorless crystals, melting point 86°-87° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:15][OH:16])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.[Br:17]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:17][C:6]1[C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:10][C:9]([O:11][CH2:12][O:13][CH3:14])=[CH:8][C:7]=1[CH2:15][OH:16]
Reactant: COCOc1cc(CO)cc(OCOC)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1cc(CO)c(Br)c(OCOC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
The above-obtained 3,5-bis(methoxymethoxy)phenylmethanol (5.3 g, 23 mmol) was dissolved in N,N-dimethylformamide (20 mL) and obtained solution was added with N-bromosuccinimide (4.3 g, 24 mmol) followed by stirring at a room temperature for 5 hours. The reaction mixture was added with water and extracted with chloroform 3 times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 5/1 to 2/1) to obtain [2-bromo-3,5-bis(methoxymethoxy)phenyl]methanol (4.9 g, 69%).