Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:17][CH2:16][C:15]4[N:18]=[C:19]([C:21]5[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=5)[S:20][C:14]=4[C:13]3=[O:28])=[CH:8][C:7]=2[O:29][CH3:30])[CH2:2]1.[C:31](O)(=O)C.C=O.C([BH3-])#N.[Na+]>O.CO>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[S:20][C:14]3[C:13](=[O:28])[N:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH:3]5[CH2:4][N:1]([CH3:31])[CH2:2]5)=[C:7]([O:29][CH3:30])[CH:8]=4)[CH2:17][CH2:16][C:15]=3[N:18]=2)=[CH:26][CH:25]=1
Reactant: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CNC1
Reactant: CC(=O)O
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(N2CCc3nc(-c4ccc(Cl)cc4)sc3C2=O)ccc1OC1CN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
Mix 5-[4-(azetidin-3-yloxy)-3-methoxy-phenyl]-2-(4-chloro-phenyl)-6,7-dihydro-5H-thiazolo[5,4-c]pyridin-4-one (3.1 g, 7.01 mmol) with anhydrous MeOH (100 mL) and treat with acetic acid (4.0 mL, 69.8 mmol) and formaldehyde (1.6 mL, 21.30 mmol, as a solution in water). Stir the mixture at room temperature for 30 min and then treat with sodium cyanoborohydride (1.3 g, 19.6 mmol). Stir the mixture at room temperature overnight and concentrate in vacuo. Partition the resulting residue between CH2Cl2 (100 mL) and saturated NaHCO3 (100 mL). Remove the organic solution and extract the aqueous phase with additional CH2Cl2 (2×100 mL). Combine the organic solutions and wash with water (50 mL), then dry, filter, and concentrate in vacuo. Purify the crude material by flash chromatography, using 8% MeOH (2M NH3)/CH2Cl2 as eluent, to give 1.6 g (50%) of the title compound as a yellow solid. ES/MS m/z (35Cl) 456 [M+1]+.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH2:16][C:17]([OH:19])=O)=[C:10]3[N:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20](N1C=CN=C1)([N:22]1C=CN=C1)=O.C(N)C.O>O1CCCC1>[CH3:20][NH:22][C:17](=[O:19])[CH2:16][C:15]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]2[CH:14]=[CH:13][CH:12]=[N:11][C:10]=12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1c(-c2ccccc2)nn2cccnc12
Agent: CCN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)Cc1c(-c2ccccc2)nn2cccnc12
Reaction time: 3 h
Yield: 85.5 %

Procedure:
A mixture of 3.5 g (0.013 mole) of 2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid and 2.24 g (0.013 mole) of 1,1'-carbonyldiimidazole in 150 ml of anhydrous tetrahydrofuran was stirred for 3 hours under a nitrogen atmosphere. A solution of monoethylamine in tetrahydrofuran (16 ml; 0.041 mole; 2.59M) was added, and the mixture was stirred at room temperature for one hour. Water (50 ml) was added to dissolve a precipitate that had formed. The solvents were evaporated under reduced pressure, and the residue was triturated in isopropanol to give 2.96 g of solid, mp 211°-213° C. Recrystallization from a mixture of isopropanol and water provided 2.58 g (70%) of product, mp 212°-214° C.
Reaction SMILES: [H-].[Li+].[CH2:3]([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[C:4]([CH3:6])=[O:5].[Cl:15][C:16]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22]I>>[C:4]([CH:3]([P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])[CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:17]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:16]=1[Cl:15])(=[O:5])[CH3:6]
Reactant: CCOP(=O)(CC(C)=O)OCC
Reactant: COc1ccc(OCCCCI)c(Cl)c1
Agent: [H-]
Agent: [Li+]
Product: CCOP(=O)(OCC)C(CCCCOc1ccc(OC)cc1Cl)C(C)=O
Yield: 15.9 %

Procedure:
[II; Ar is 2-Cl-4-CH3OC6H3, Y is O(CH2)4, R is C2H5, R' is CH3CO] was prepared from 0.79 g of lithium hydride, 19.4 g of diethyl acetonylphosphonate and 34.0 g of 4-(2-chloro-4-methoxyphenoxy)butyl iodide according to the procedure of Example 12(b). The product was chromatographed on Florisil to give 6.45 g of diethyl [1-acetyl-5-(2-chloro-4-methoxyphenoxy)pentyl]phosphonate as a yellow oil; MIC vs. herpes simplex type 2=12 mcg/ml. The NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:19]([OH:21])=O)=[N:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[CH:44]([O:46][CH2:47][CH2:48][O:49][NH2:50])=[CH2:45]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:19]([NH:50][O:49][CH2:48][CH2:47][O:46][CH:44]=[CH2:45])=[O:21])=[N:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)nn(C)c1=O
Reactant: C=COCCON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=COCCONC(=O)c1nn(C)c(=O)c(C)c1Nc1ccc(I)cc1F
Reaction time: 1.5 h

Procedure:
To a suspension of 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (41 mg, 0.10 mmol) and HOBt (28 mg, 0.21 mmol) in DMF (1.5 mL) was added EDCl (40 mg, 0.21 mmol) al room temperature. The resulting mixture was stirred for 1.5 hours. O-(2-Vinyloxy-ethyl)-hydroxylamine (21 mg, 0.20 mmol) and TEA (0.030 mL, 0.22 mmol) was added to the activated ester at room temperature. After stirring for 1.5 hours, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3 (2×), and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to give 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide that was used directly without further purification. The title compound was prepared by the procedure previously described in Example 1 (step J) using the crude 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide (40% yield over two steps). MS APCI (−) m/z 461 (M−1) detected; 1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (d, 1H), 6.63 (t, 1H), 3.98 (t, 2H), 3.80 (s, 3H), 3.74 (t, 2H), 1.78 (s, 3H).
Reaction SMILES: [C:1]1(=[C:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:14](Cl)[CH:15]=[CH2:16].O>C1COCC1>[C:1]1([C:6]2([CH2:16][CH:15]=[CH2:14])[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[CH2:2][CH2:3][CH2:4][CH:5]=1
Reactant: C=CCCl
Reactant: O=C1CCCC1=C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCC1(C2=CCCC2)CCCC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
To a stirring solution of 2-cyclopentylidenecyclopentan-1-one (62.5 g, 0.417 moles) in dry THF (450 mL) at room temperature under nitrogen, was added NaH (60% oil dispersion, 20.0 g, 0.5 moles) in one portion. The mixture was stirred at room temperature for 30 min and then a solution of allyl chloride (38.3 g, 0.5 moles) in THF (100 mL) was added dropwise over 30 min. When the addition was complete, the reaction was warmed gently to approximately 40° C. It was determined by TLC and GC that the reaction was complete after 18 hours. Water was added to the reaction mixture and the layers were separated, with the organic layer being washed successively with 10% HCl (aqueous), saturated NaHCO3 (aqueous), and brine. The resulting organic layer was dried with MgSO4, filtered, and concentrated. The brown oil was distilled under vacuum to give 2-cyclopent-1-enyl-2-prop-2-enylcyclopentan-1-one (54.5 g, 69.0% yield).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[F:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:13](=[O:15])[CH3:14])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(F)cc1C(F)(F)F
Product: CC(=O)Nc1ccc(F)cc1C(F)(F)F

Procedure:
A solution of 4-fluoro-2-(trifluoromethyl)aniline (5.0 g, 27.91 mmol) in acetic anhydride (25 mL) was stirred at ambient temperature for 3 hours to produce a white needle precipitate. The reaction mixture was poured onto ice water, filtered then dried to give 6.0 g of N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide as an off-white solid which was used without further purification. The N-[4-fluoro-2-(trifluoromethyl)phenyl]acetamide (2.0 g, 9.04 mmol) was dissolved in concentrated H2SO4 (15 mL) and cooled to 0 degrees Centigrade using an ice bath. 70% HNO3 (1.5 mL) was added drop wise and the reaction stirred at 0 degrees Centigrade for 30 min and then at ambient temperature for 3 hours. The reaction mixture was poured onto ice-water, filtered then dried to give 2.4 g of the desired N-[4-fluoro-2-nitro-6-(trifluoromethyl)phenyl]acetamide.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:5]([NH2:11])=[N:6][C:7]([CH3:10])=[N:8][CH:9]=1.[CH2:12]([C:20]1[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=1)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>CN(C)C=O>[CH3:10][C:7]1[N:6]=[C:5]([NH2:11])[C:4]([CH2:3][N:23]2[CH2:22][CH:21]=[C:20]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:25][CH2:24]2)=[CH:9][N:8]=1
Reactant: Cc1ncc(CCl)c(N)n1
Reactant: C1=C(CCc2ccccc2)CCNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ncc(CN2CC=C(CCc3ccccc3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.8 %

Procedure:
A warm solution of 0.5 g (0.0026 mol) of 5-chloromethyl-2-methyl-pyrimidin-4-ylamine hydrochloride in 40 ml of dimethylformamide was treated with 0.4 g (0.0021 mol) of 4-phenethyl-1,2,3,6-tetrahydro-pyridine and 0.9 ml (0.0064 mol) of triethylamine and the mixture was stirred at room temperature for 24 hours. The mixture was completely freed from the solvents. The residue was partitioned between dichloromethane and water, extracted, chromatographed over silica gel with acetonitrile/ethanol 8:1 as the eluent and digested in diethyl ether. 0.18 g (22%) of 2-methyl-5-(4-phenethyl-3,6-dihydro-2H-pyridin-1-ylmethyl)-pyrimidin-4-ylamine was obtained as white crystals; m.p. 152°-154°. A further 0.03 g of yellowish crystals was recovered from the mother liquor.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].I[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1.CN(C)C=O>[CH:13]1([S:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1ccccc1S
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1SC1CCCC1
Yield: 96.6 %

Procedure:
(Step 1) A solution of methyl 2-sulfanylbenzoate (7.0 g), iodocyclopentane (10.6 g) and potassium carbonate (7.48 g) in tetrahydrofuran-N,N-dimethylformamide (100 ml+10 ml) was stirred at 70° C. for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The reaction mixture was washed successively with 1N hydrochloric acid and saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel chromatography (ethyl acetate:hexane=1:4) to give methyl 2-(cyclopentylsulfanyl)benzoate (9.5 g) as an oil. The obtained methyl 2-(cyclopentylsulfanyl)benzoate (5.0 g) was dissolved in ethyl acetate (150 ml), and m-chloroperbenzoic acid (11.5 g, containing water: Wako Pure Chemical Industries, Ltd.) was added at 0° C. The mixture was stirred at room temperature for 0.5 hr, and quenched with aqueous sodium thiosulfate solution. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and filtered. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=1:4) to give methyl 2-(cyclopentylsulfonyl)benzoate (4.11 g).
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].Br[CH2:22][CH:23]=[CH2:24].C(#N)C>ClCCl.C(=O)([O-])[O-].[K+].[K+]>[CH3:3][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:18]([NH:19][CH2:24][CH:23]=[CH2:22])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: C=CCNc1cccnc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]-piperazine (International Publication 88/08424, 2.78 g), 3-bromopropene (1.87 g), anhydrous potassium carbonate (3.3 g) and acetonitrile (100 ml) is refluxed for 36 hr. The mixture is cooled and then diluted with dichloromethane and aqueous potassium carbonate solution. The phases are separated and the organic phase is washed with saline and than concentrated in vacuo. Purification by flash column chromatography (2% methanol/chloroform) provided of the title compound. Capillary GC analysis (HP1 column, initial temperature at 100° for 1 min, then programmed to rise 20° per minute to 250°) gave a peak at 6.06 (96%) minutes.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([O:12]C)=[O:11])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([CH:20]3[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[C:3]=1[F:23].O.O.[OH-].[Li+]>C1COCC1.CO>[NH2:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([C:10]([OH:12])=[O:11])[N:5]=[C:4]([C:14]2[CH:15]=[N:16][C:17]([CH:20]3[CH2:21][CH2:22]3)=[CH:18][CH:19]=2)[C:3]=1[F:23]
Reactant: COC(=O)c1nc(-c2ccc(C3CC3)nc2)c(F)c(N)c1OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1c(C(=O)O)nc(-c2ccc(C3CC3)nc2)c(F)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 52.4 %

Procedure:
To a solution of methyl 4-amino-6′-cyclopropyl-3-fluoro-5-methoxy-[2,3′-bipyridine]-6-carboxylate (100 mg, 0.315 mmol) in THF (1.00 mL), MeOH (1.000 mL), and Water (0.500 mL), lithium hydroxide hydrate (65 mg, 1.549 mmol) was added as a solid. The reaction was allowed to stir at room temperature for 18 hrs. The reaction solution was then concentrated under vacuum to dryness. The resulting solid was suspended in H2O and the pH was adjusted to 4.0, forming a ppt. The suspension was extracted with EtOAc (3×25 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under vacuum to yield 4-amino-6′-cyclopropyl-3-fluoro-5-methoxy-[2,3′-bipyridine]-6-carboxylic acid (50.0 mg, 0.165 mmol, 52.3% yield). ESIMS for m/z 304 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ 0.92-1.06 (m, 4H), 2.17 (tt, J=7.8, 5.1 Hz, 1H), 3.78 (s, 3H), 6.49 (s, 2H), 7.42 (dd, J=8.3, 0.9 Hz, 1H), 8.05 (ddd, J=8.2, 2.2, 1.1 Hz, 1H), 8.81 (t, J=2.0 Hz, 1H), 13.03 (s, 1H). 19F NMR (376 MHz, DMSO-d6) δ −141.73.
Reaction SMILES: [CH2:1](Cl)Cl.Br[C:5]1[CH:6]=[C:7]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[N:9][CH:10]=1.C(N([CH2:25][CH3:26])CC)C>C(O)(C)C.O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]=[C:25]([C:5]1[CH:6]=[C:7]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[N:9][CH:10]=1)[CH3:26]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCc1cncc(Br)c1
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CC(C)O
Solvent: O
Product: C=C(C)c1cncc(CNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of potassium isopropenyl trifluoroborate (464 mg, 3.13 mmol), PdCl2(dppf).CH2Cl2 (153 mg, 0.06 mmol), tert-butyl (5-bromopyridin-3-yl)methylcarbamate (900 mg, 3.13 mmol) and triethylamine (475 mg, 4.69 mmol) in i-PrOH—H2O (2:1, 30 mL) was heated under reflux in a nitrogen atmosphere. The reaction mixture was heated at reflux for 4 h, then cooled to rt and diluted with water (40 mL) followed by extraction with diethylether. The organic layers were combined and washed with brine, dried over sodium sulfate and then filtered. The solvent was removed under vacuum, and the crude product was purified by silica gel chromatography (eluting with 45% EtOAc/hexanes) to afford tert-butyl (5-(prop-1-en-2-yl)pyridin-3-yl)methylcarbamate as a white solid in 85% yield. (5-(prop-1-en-2-yl)pyridin-3-yl)methanamine was then generated by removal of the Boc protecting group by treatment with HCl (in methanol or dioxane) or trifluoroacetic acid in dichloromethane.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][Cl:15])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[Si:1]([O:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][Cl:15])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)[Si](C)(C)OCCC#CCCCl
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCC/C=C\CCCl

Procedure:
5.7 of 6-chlorohex-3-yn-1-ol t-butyldimethylsilyl ether in 50 ml of ethanol was hydrogenated under 1 atmosphere of hydrogen in the presence of 0.3 g of Lindlar catalyst until 370 ml of hydrogen had been absorbed. The catalyst was removed by filtration through celite and the ethanol evaporated in vacuo. The crude product was chromatographed on 200 g of silica gel, eluting with 1-4% ether/hexane. Distillation of the appropriate fractions gave 3.7 g of 6-chlorohex-3Z-en-1-ol t-butyldimethylsilyl ether, bp 80° C./0.5 mm.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:18]3)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])[CH2:3]1.C(N(CC)CC)C.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>CN(C)C1C=CN=CC=1.ClCCl>[C:26]1([C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([S:14]([C:11]3[CH:10]=[CH:9][C:8]([C:6]([N:4]4[CH2:5][CH:2]([O:1][C:41](=[O:42])[N:40]([CH3:44])[CH3:39])[CH2:3]4)=[O:7])=[CH:13][CH:12]=3)(=[O:16])=[O:15])[CH:18]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CN(C)C(=O)Cl
Reactant: O=C(c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3ccccc32)cc1)N1CC(O)C1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)OC1CN(C(=O)c2ccc(S(=O)(=O)n3cc(-c4ccccc4)c4ccccc43)cc2)C1
Reaction time: 15 h
Yield: 74 %

Procedure:
Combine (3-Hydroxy-azetidin-1-yl)-[4-(3-phenyl-indole-1-sulfonyl)-phenyl]-methanone (95 mg, 0.219 mmol), triethylamine (0.200 mL, 1.43 mmol, excess) and 4-dimethylaminopyridine (5 mg, 0.04 mmol) in dichloromethane (1.0 mL) and treat with N,N-dimethylcarbamoyl chloride (0.050 mL) at room temperature. Stir for 15 h, load directly onto pre-packed silica gel column and purify by flash column chromatography (EtOAc/Hexanes) to yield 82 mg of Dimethyl-carbamic acid 1-[4-(3-phenyl-indole-1-sulfonyl)-benzoyl]-azetidin-3-yl ester as a white foam (74%). LRMS: MH+ 503.97.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[O:12]=[C:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[N:23][C:18]=2[CH2:17][CH2:16][CH2:15][N:14]1[CH:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[CH2:26][CH2:25]1.S(OS([O-])=O)([O-])=O.[Na+].[Na+]>ClCCl>[O-:9][N+:23]1[C:18]2[CH2:17][CH2:16][CH2:15][N:14]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]([O:32][CH2:33][C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)=[O:31])[CH2:28][CH2:29]3)[C:13](=[O:12])[C:19]=2[CH:20]=[CH:21][CH:22]=1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CCCc3ncccc3C2=O)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])OS(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(N2CCCc3c(ccc[n+]3[O-])C2=O)CC1
Reaction time: 0.33 h
Yield: 53.3 %

Procedure:
m-Chloroperbenzoic acid (2.45 g) was added to a mixture of benzyl 4-(5-oxo-5,7,8,9-tetrahydro-6H-pyrido[3,2-c]azepin-6-yl)piperidine-1-carboxylate (1.8 g) and dichloromethane (50 mL), and the resultant mixture was stirred at room temperature for 3 hours. A 10% aqueous sodium disulfite solution was added to the reaction mixture, and the mixture was stirred for 20 minutes, followed by extraction with dichloromethane. The organic layer was washed with water and saturated saline and dried over sodium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (1.0 g).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([I:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].[CH2:15]([O:17][P:18]([C:23]([C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)([O:26][CH2:27][CH3:28])[PH2:24]=[O:25])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16].CCN(C(C)C)C(C)C>CCO>[CH2:15]([O:17][P:18]([C:23]([O:26][CH2:27][CH3:28])([C:29]1[CH:30]=[CH:31][C:32]([NH:35][C:2]2[N:10]=[C:9]([I:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]([CH3:14])[CH3:13])=[CH:33][CH:34]=1)[PH2:24]=[O:25])(=[O:22])[O:19][CH2:20][CH3:21])[CH3:16]
Reactant: CCOC([PH2]=O)(c1ccc(N)cc1)P(=O)(OCC)OCC
Reactant: CC(C)n1cnc2c(Cl)nc(I)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC([PH2]=O)(c1ccc(Nc2nc(I)nc3c2ncn3C(C)C)cc1)P(=O)(OCC)OCC
Temperature: 105 °C

Procedure:
6-Chloro-2-iodo-9-isopropyl-9H-purine (1.7 g, 5.2 mmol), [(4-amino-phenyl)-ethoxy-phosphinoylmethyl]-phosphonic acid diethyl ester (2.6 g, 7.7 mmol), and DIPEA (2.7 mL, 15.5 mmol) were dissolved in EtOH (27 mL) and heated in a sealed tube at 105° C. for 48 h. After cooling, the EtOH was evaporated. The residue was poured into water and extracted with EtOAc. The combined extracts, were washed with water, sat'd NaCl, then dried over MgSO4 and filtered. Concentration yielded an oil which was purified by silica gel chromatography (11% MeOH/EtOAc) to a glassy solid (1.8 g, 53%): MS [M+H]+ 621.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[F:34][C:35]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:36]=1[S:42](Cl)(=[O:44])=[O:43].O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:42]([C:36]4[CH:37]=[CH:38][C:39]([F:41])=[CH:40][C:35]=4[F:34])(=[O:44])=[O:43])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C#N)c1ccc(-n2c(=O)n(S(=O)(=O)c3ccc(F)cc3F)c3cnc4ccc(Br)cc4c32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (49.75 mg, 0.49 mmol) in dichloromethane (6 ml) was added 2,4-difluorobenzene-1-sulfonyl chloride (52 mg, 0.25 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 30 mg (42%); 1H NMR (DMSO-d6, 300 MHz): δ9.31(s, 1H), 8.21-8.24(m, 1H), 7.968-7.998 (d, 1H, J=9.0 Hz.), 7.63-7.81 (m, 6H), 7.374-7.440 (m, 1H), 6.741-6.748 (d, 1H, J=2.1 Hz), 1.77(s, 6H); Mass m/z: 583 (M+).
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:8][CH:9]=[CH:10][C:11]([CH3:14])([OH:13])[CH3:12])[CH2:3][CH2:4][CH2:5][CH2:6]O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:17].[NH+]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[NH+]1C=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[OH:17][C@@H:26]1[CH2:32]/[C:33](=[CH:34]/[CH:35]=[CH:6]/[CH2:5][CH2:4][CH2:3][C:2]([CH3:15])([CH3:1])[CH2:8][C:9]#[C:10][C:11]([CH3:14])([OH:13])[CH3:12])/[C:29](=[CH2:30])[CH2:28][CH2:27]1
Reactant: CC(C)(O)C=CCC(C)(C)CCCCO
Reactant: c1cc[nH+]cc1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: ClCCl
Product: C=C1CC[C@H](O)C/C1=C/C=C/CCCC(C)(C)CC#CC(C)(C)O
Yield: 38.4 %

Procedure:
410 mg of 5,5,9-Trimethyl-dec-7-ene-1,9-diol (1.93 mmol) ) was oxidized by reaction with 2.76 g of pyridinium-dichromate (3.8 eq.) in 61 ml of CH2Cl2 at room temperature over night. Filtration over a pad of Celite, removal of the solvent and flash chromatography (SiO2, hexane/ethylacetate=8/2) furnished 245 mg of the title compound as colourless oil.