Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH2:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[N:16]1[S:20][N:19]=[C:18]2[C:21]([S:25]([NH:28][C:29]3[CH:37]=[C:36]([Cl:38])[C:35]([Cl:39])=[CH:34][C:30]=3[C:31](O)=[O:32])(=[O:27])=[O:26])=[CH:22][CH:23]=[CH:24][C:17]=12>>[CH3:2][O:3][C:4](=[O:15])[C@@H:5]([NH:14][C:31](=[O:32])[C:30]1[CH:34]=[C:35]([Cl:39])[C:36]([Cl:38])=[CH:37][C:29]=1[NH:28][S:25]([C:21]1[C:18]2=[N:19][S:20][N:16]=[C:17]2[CH:24]=[CH:23][CH:22]=1)(=[O:27])=[O:26])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)cc1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Cl)cc1)NC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
(S)-2-(tert-Butoxycarbonylamino)-3-(4-chloro-phenyl)-propionic acid was treated as in EXAMPLE 2, Part A, to produce (S)-2-amino-3-(4-chloro-phenyl)-propionic acid methyl ester hydrochloride as a white solid. This ester was coupled to 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid as in EXAMPLE 1, Part C, to afford the title compound. HPLC: RT=11.61 min. MS (ESI−): mass calcd. for C23H17Cl3N4O5S2, 597.97; m/z found, 597/599 [M−H]−. 1H NMR (500 MHz, CDCl3): 11.20 (s, 1H), 8.36 (d, J=6.3, 1H), 8.23 (d, J=8.7, 1H), 7.87 (s, 1H), 7.74-7.71 (m, 1H), 7.27-7.25 (m, 3H), 6.98 (d, J=8.3, 2H), 6.38 (d, J=7.3, 1H), 4.96-4.92 (m, 1H), 3.82 (s, 3H), 3.23-3.14 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=2[N:6]=1.[Br:12]Br>C(Cl)(Cl)Cl>[Br:12][C:7]1[C:5]2[N:6]=[C:2]([CH3:1])[S:3][C:4]=2[CH:10]=[CH:9][C:8]=1[CH3:11]
Reactant: BrBr
Reactant: Cc1ccc2sc(C)nc2c1
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(Br)c(C)ccc2s1
Temperature: 25 °C

Procedure:
A mixture of 2,5-dimethyl-1,3-benzothiazole (10.00 g, 61.26 mmol, Aldrich) and bromine (6.94 mL, 134.8 mmol) in chloroform (200 mL) was heated at reflux overnight. After cooling to room temperature, the mixture was washed with 1 N NaOH, followed by saturated sodium thiosulfate and brine, then dried over sodium sulfate and evaporated to dryness. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexane. The first peak had a retention time of 2.51 minutes, LCMS calculated for C9H9BrNS(M+H)+: m/z=242.0; found: 241.9. 1H NMR shown to be the desired product B (980 mg, 6.61%). 1H NMR (CDCl3, 400 MHz) 7.63 (1H, d, J=8.4 Hz), 7.22 (1H, d, J=8.4 Hz), 2.87 (3H, s), 2.55 (3H, s) ppm. The second peak had a retention time of 2.758 minutes, LCMS (M+H)+m/z=241.9; found: 242. 1H NMR showed no coupling for the two phenyl hydrogens confirming the 6-bromo isomer.
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1([CH3:20])[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)(C)(C)C.[OH-].[Na+].[CH:24](O)=O>>[CH2:13]([N:10]1[CH2:11][CH2:12][C:8]([N:7]([CH3:6])[CH3:24])([CH3:20])[CH2:9]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=CO
Reactant: CC1(NC(=O)OC(C)(C)C)CCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Product: CN(C)C1(C)CCN(Cc2ccccc2)C1

Procedure:
A solution of (1-benzyl-3-methyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (682 mg) in aqueous formic acid/aqueous formaldehyde 1:2 (7 mL) was stirred at 90° C. for 4 h. The mixture was neutralized with sodium hydroxide solution, extracted with dichloromethane, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. In this way the product was obtained with molecular weight 218.34 (C14H22N2); MS (ESI): 219 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[ClH:11]>O>[Cl:11][C:7]1[C:2]([OH:1])=[N:3][CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(O)nc1
Reactant: Cl
Solvent: O
Product: O=[N+]([O-])c1cnc(O)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a warm (50° C.) solution of 2-hydroxy-5-nitro-pyridine (17 g, 121 mmol) in concentrated HCl (80 mL) was added dropwise NaClO3 (4.5 g, 42.5 mmol) in water (70 mL), keeping the internal temperature below 60° C. The reaction mixture was stirred for 15 min and then cooled to 0° C. The resulting precipitate was collected by vacuum filtration and dried to provide 19.7 g of the title compound. tR: 5.45 min (HPLC 3); ESI-MS: 173 [M−H]− (LC-MS 2); Rf=0.55 (hexane/EtOAc, 1:1).
Reaction SMILES: C[Si](C)(C)[N:3]=[CH:4][C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8].[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[Li]>>[NH2:3][CH:4]([C:5]#[C:6][Si:7]([CH3:10])([CH3:9])[CH3:8])[CH2:14][C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)C#CC=N[Si](C)(C)C
Agent: [Li]
Product: CC(C)(C)OC(=O)CC(N)C#C[Si](C)(C)C

Procedure:
The present invention relates to a novel process for the preparation of ethyl 3S-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate and pharmaceutically acceptable acid addition salt thereof which comprises treating (trimethylsilyl)acetylene sequentially with n-butyllithium and 4-formylmorpholine followed by acid hydrolysis to give 3-(trimethylsilyl)-2-propynal; treating 3-(trimethylsilyl)-2-propynal with lithium bis(trimethylsilyl)amide to give in situ N,3-bis(trimethylsilyl)-2-propyn-1-imine; condensation of N,3-bis(trimethylsilyl)-2-propyn-1-imine with lithium t-butyl acetate to give (±)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate; treating (±)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate- with p-toluenesulfonic acid to give (±)1,1-dimethylethyl 3-amino-5-(trimethylsilyl)-4-pentynoate, mono p-toluenesulfonic acid salt, treatment of resulting salt with ethanol in the presence of p-toluenesulfonic acid to give (±)ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate; desilylation of (±)ethyl 3-amino-5-(trimethylsilyl)-4-pentynoate to give in situ (±)ethyl 3-amino-4-pentynoate; resolution of (±)ethyl 3-amino-4-pentynoate using (R)-(-)-mandelic acid and treatment of the resolved product with gaseous hydrochloric acid to give ethyl 3S-amino-4-pentynoate, monohydrochloride; coupling the ethyl 3S-amino-4-pentynoate, monohydrochloride to 4-[[4-(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid, monohydrochloride in the presence of isobutyl chloroformate and N-methylmorpholine to give ethyl 3S-[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]amino]-4-pentynoate, monohydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([F:11])[CH:5]=1.[H-].[Na+].Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>C(COC)OC>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:6]([F:11])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(F)c1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(OCC(=O)OC(C)(C)C)c(F)c1
Temperature: 70 °C
Yield: 84.5 %

Procedure:
A mixture of 3-fluoro-4-hydroxy-benzoic acid methyl ester (2.5 g, 14.7 mmol), NaH suspension in oil (55%) (641 mg, 14.7 mmol), KI (244 mg, 14.7 mmol, 0.1 eq.) and tert.butyl bromoacetate (3.44 g, 17.6 mmol 1.2 eq.) in dimethoxyethane (20 ml) was heated to 70° C. for 16 hrs. After evaporation of the solvent the residue was chromatographed over 120 g SiO2 (Merck 230-400 mesh) with EtOAc/nHexane 7:93, affording the title compound (3.53 g, 85% yield) as a colorless liquid. MS: m/e=284 (M+).
Reaction SMILES: O[C:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:4]([CH3:13])[C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl.[NH2:20][OH:21]>N1C=CC=CC=1>[OH:21][N:20]=[C:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH:4]([CH3:13])[CH:3]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCCCCN1C(=O)C(O)=C(C(=O)OCC)C1C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCN1C(=O)C(=NO)C(C(=O)OCC)C1C
Reaction time: 120 h
Yield: 59.5 %

Procedure:
To the title compound of Example J (21.6 g, 0.085 mol) in pyridine (150 ml) was added hydroxylamine hydrochloride (10.6 g, 0.17 mol) and the solution was stirred for 5 days. The solvent was removed in vacuo to give an orange oil which was chromatographed on silica gel eluting with 2% EtOH/CH2Cl2 to give the title compound (13.67 g, 59%) as an oil. Calculated C13H22N2O4 1/2H2O: C, 55.90; H, 8.30; N, 10.02. Found: C, 55.99; M, 8.38; N, 10.00. MS calcd for C13H22N2O4 270, found 270.
Reaction SMILES: [CH3:1][C:2]([O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])([CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:3][C:4]#[CH:5].[CH2:15]([SnH:19]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18].N(C(C)(C)C#N)=NC(C)(C)C#N>>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])/[CH:5]=[CH:4]/[CH2:3][C:2]([CH3:1])([O:10][Si:11]([CH3:13])([CH3:14])[CH3:12])[CH2:6][CH2:7][CH:8]=[CH2:9])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCC(C)(CCC=C)O[Si](C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Product: C=CCCC(C)(C/C=C/[Sn](CCCC)(CCCC)CCCC)O[Si](C)(C)C
Temperature: 140 °C
Reaction time: 1.5 h

Procedure:
A mixture of 30 g. of 4-methyl-4-trimethylsilyloxy-oct-1-yn-7-ene, 58.66 g. of tri-n-butylstannane and 200 mg. of azobisisobutyronitrile is placed in a bath at 95° C. and stirred under argon. The mixture is heated at 140° C. for one hour and then at 140° C. under vacuum for 1.5 hours. The mixture is distilled via a Kugelrohr at 140° C., 0.06 mm. to give the product as a colorless liquid.
Reaction SMILES: Cl.[CH:2]12[NH:11][CH:6]([CH2:7][C:8](=[O:10])[CH2:9]1)[CH2:5][O:4][CH2:3]2.[C:12](Cl)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>ClCCl>[O:10]=[C:8]1[CH2:9][CH:2]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH:6]([CH2:5][O:4][CH2:3]2)[CH2:7]1
Reactant: O=C1CC2COCC(C1)N2
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: O=C1CC2COCC(C1)N2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
3-oxa-9-azabicyclo[3.3.1]nonan-7-one hydrochloride (CAS 1126795-00-3) (10 g) was dissolved in 200 ml of dichloromethane which was cooled to 0° C. Then, CbzCl (14.3 g, 84.7 mmol) was added to the mixture followed by the dropwise addition of a solution of TEA (14.6 ml, 112.8 mmol) in 20 ml of dichloromethane. The mixture was allowed to warm up to room temperature. After stirring 2 h, it was quenched with 20 ml of a saturated aqueous solution of NaHCO3. The two layers were separated and the aqueous layer was extracted with dichloromethane (3×150 ml). The combined organic layers were washed with water, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by chromatography on silica gel, yielding 10.1 g of benzyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 100b (64%).
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[O:69]=[C:70]([N:83]1[C@H:88]([C:89]2[NH:90][C:91]([C:94]3[CH:103]=[CH:102][C:101]4[C:96](=[CH:97][CH:98]=[C:99]([C:104]5[CH:105]=[C:106]6[C:119](=[CH:120][CH:121]=5)[C:110]5[NH:111][C:112]([C@@H:114]7[CH2:118][CH2:117][CH2:116][NH:115]7)=[N:113][C:109]=5[CH:108]=[CH:107]6)[CH:100]=4)[CH:95]=3)=[CH:92][N:93]=2)[C@@H:87]2[CH2:122][C@H:84]1[CH2:85][CH2:86]2)[C@@H:71]([NH:78][C:79](=[O:82])[O:80][CH3:81])[CH:72]1[CH2:77][CH2:76][O:75][CH2:74][CH2:73]1>>[CH3:60][O:59][C:57](=[O:58])[NH:56][C@H:49]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:48]([N:115]1[CH2:116][CH2:117][CH2:118][C@H:114]1[C:112]1[NH:111][C:110]2[C:119]3[C:106]([CH:107]=[CH:108][C:109]=2[N:113]=1)=[CH:105][C:104]([C:99]1[CH:98]=[CH:97][C:96]2[C:101](=[CH:102][CH:103]=[C:94]([C:91]4[NH:90][C:89]([C@@H:88]5[C@@H:87]6[CH2:122][C@@H:84]([CH2:85][CH2:86]6)[N:83]5[C:70](=[O:69])[C@@H:71]([NH:78][C:79]([O:80][CH3:81])=[O:82])[CH:72]5[CH2:73][CH2:74][O:75][CH2:76][CH2:77]5)=[N:93][CH:92]=4)[CH:95]=2)[CH:100]=1)=[CH:121][CH:120]=3)=[O:61]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7CCCN7)[nH]c65)c4)ccc3c2)[nH]1)C1CCOCC1
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1ncc(-c2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)c4)ccc3c2)[nH]1)C1CCOCC1

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-oxo-2-((1R,3S,4S)-3-(5-(6-(2-((S)-pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 915.83 [M+H]+. (59 mg, 88%).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10](O)=[O:11])#[N:6]>CN(C)C=O.ClCCl>[C:5]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([Cl:3])=[O:11])#[N:6]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)Cl)c1

Procedure:
Thionyl chloride (10 ml) and dimethylformamide (1 drop) were added to a solution of 3-cyanobenzoic acid (10 g) in dichloromethane (100 ml), and the mixture was refluxed far 3 hours. After the reaction, the solvent was evaporated under reduced pressure to give 3-cyanobenzoyl chloride. Then, the oil was dissolved in dichloromethane (25 ml), and the solution was dropwise added to a solution of 4-aminopyridine (5 g) and diisopropylethylamine (8.9 g) in dichloromethane (50 ml), which was followed by stirring at room temperature for 1 hour. The precipitated crystals were collected by filtration, and recrystallized from chloroform-methanol-ether to give 5.3 g of N-(4-pyridyl)-3-cyanobenzamide.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([OH:19])(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:9]=1)(=[O:18])[CH3:17]
Reactant: BrCc1cccc(Oc2ccccc2)c1
Reactant: CC(=O)O
Product: CC(=O)OCc1cccc(Oc2ccccc2)c1

Procedure:
The resulting m-phenoxybenzyl bromide can be easily esterified in a solvent such as acetic acid to produce m-phenoxybenzyl acetate. The product can be easily converted into m-phenoxybenzyl alcohol by a hydrolysis with a base in a solvent such as methanol. In accordance with the aforementioned treatment, m-phenoxybenzylidene dibromide is converted into m-phenoxybenzaldehyde. Thus, m-phenoxybenzyl acetate and m-phenoxybenzaldehyde are produced by the treatment of the mixture of m-phenoxybenzyl bromide and m-phenoxybenzylidene dibromide, m-phenoxybenzyl acetate and m-phenoxybenzaldehyde can be separated from the mixture by a distillation under a reduced pressure.
Reaction SMILES: [CH3:1][C:2]1[O:3][N:4]=[C:5]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=12.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[Cl:15][CH2:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][C:5]2=[N:4][O:3][C:2]([CH3:1])=[C:6]2[CH2:7]1
Reactant: ClCCCBr
Reactant: Cc1onc2c1CNCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: Cc1onc2c1CN(CCCCl)CC2
Temperature: 25 °C
Yield: 39 %

Procedure:
A mixture of 3-methyl-4,5,6,7-tetrahydroisoxazolo[4,3-c]pyridine (1.60 g), 1-bromo-3-chloropropane (3.50 mL) and cesium carbonate in acetone was heated to reflux for 24 h. The reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as yellow oil (0.97 g, 39.00%), HPLC: 85.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 215.2 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)([CH2:5][CH3:6])[CH2:3][CH3:4].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].O.S(=O)(=O)(O)O>C1C=CC=CC=1>[CH3:1][C:2]([CH:7]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]1)([CH2:5][CH3:6])[CH2:3][CH3:4]
Reactant: CCC(C)(CC)C1CCC(O)CC1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCC(C)(CC)C1CCC(=O)CC1
Temperature: 50 °C

Procedure:
The 4-(3-methylpent-3-yl)cyclohexanol (350 g, 1.9 mol) prepared above was added slowly over a 3 hour period to a stirring solution of sodium dichromate (614 g, 2.06 mol), water (3.0 liters) and 98% sulfuric acid (526 g) while maintaining the batch temperature at 50°-55° C. Upon completion of the addition, the mixture was stirred an additional hour at 50° C. The reaction mixture was cooled and three liters of benzene was added. The layers were separated and the organic layer washed with one liter portions of water until a neutral pH was indicated. The solvent was removed on a rotary evaporator. Distillation of the residual oil under vacuum gave the desired 4-(3-methylpent-3-yl)cyclohexanone: 274 g, 79% theory; bp 105° C. (0.5 mm); mol wt 182 (ms); nmr, 0.75 (3H, s, methyl, 0.8 (6H, t, J=7, methyls), 1.15-2.0 (9H, m, CH, CH2), 2.15-2.5 (4H, m, Hα to carbonyl); ir, 2980, 2890, 1720, 1465, 1390, 1170 cm-1.
Reaction SMILES: [F:1][C:2]1[C:3]([F:24])=[CH:4][C:5]2[CH:6]=[C:7]3[C:22](=[O:23])[NH:21][CH2:20][CH2:19][N:8]3[C:9]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[CH3:25]OC1C=CC(B(O)O)=CC=1>>[F:1][C:2]1[C:3]([F:24])=[CH:4][C:5]2[CH:6]=[C:7]3[C:22](=[O:23])[NH:21][CH2:20][CH2:19][CH2:25][N:8]3[C:9]=2[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1
Reactant: COc1ccc(-c2c(F)c(F)cc3cc4n(c23)CCNC4=O)cc1
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2c(F)c(F)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, light yellow solid (46 mg, 54%), MS (ISP) m/z=343.2 [(M+H)+], mp 182.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-8,9-difluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 7) (78.8 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[CH3:30][C:21]1[CH:26]=[CH:25][C:24]([C:27]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)NCCCSc2ccncc2)cc1
Yield: 76.6 %

Procedure:
To a solution of 1.00 g (4.15 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 2.77 ml (19.8 mmol) of triethylamine in 40 ml of methylene chloride was added 0.65 ml (4.96 mmol) of 4-toluoyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain the powder which was washed with ether and dried to obtain 910 mg of the desired compound (76.6%, colorless powder), mp: 110.0°-111.0° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][Si](C)(C)C)[CH:5]=[CH:4][N:3]=1.I[C:15]1[NH:19][C:18]([CH:20]([CH3:22])[CH3:21])=[N:17][CH:16]=1>>[CH:20]([C:18]1[NH:17][CH:16]=[C:15]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:19]=1)([CH3:22])[CH3:21]
Reactant: Cc1cc(C#C[Si](C)(C)C)ccn1
Reactant: CC(C)c1ncc(I)[nH]1
Product: Cc1cc(C#Cc2c[nH]c(C(C)C)n2)ccn1

Procedure:
4-(2-Isopropyl-1H-imidazol-4-ylethynyl)-2-methyl-pyridine (II-2) [MS: m/e=226.4 (M+H+)] was prepared in analogy to the method as described in example II-1, method A2, step 3 from 2-methyl-4-trimethylsilanylethynyl-pyridine and 5-iodo-2-isopropyl-1H-imidazole.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10]Br.[C-:12]#[N:13].[Na+]>CO.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[CH2:10][C:12]#[N:13]
Reactant: Clc1cc(Cl)c(Cl)c(CBr)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CCc1cc(Cl)cc(Cl)c1Cl
Temperature: 35 °C
Reaction time: 4.5 h
Yield: 70 %

Procedure:
A solution of 19.2 grams (0.070 mole) of 2,3,5-trichlorophenylmethyl bromide in 50 mL of methanol was stirred, and a solution of 4.1 grams (0.084 mole) of sodium cyanide in 10 mL of water was added dropwise during a 10 minute period. The addition caused an exothermic reaction which raised the reaction mixture temperature to about 35° C. Upon completion of addition, the reaction mixture was warmed to reflux, where it was stirred for 4.5 hours. The reaction mixture was allowed to cool to ambient temperature, where it was stirred for about 60 hours. After this time the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with two portions of water, two 25 mL portions of aqueous 10% hydrochloric acid, and then with three portions of water. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 10.8 grams of 2,3,5-trichlorophenylacetonitrile. The infrared spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:21])([CH3:20])[N:4]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].C(=O)=O.CC(C)=O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([C@H:7]2[O:6][C:5]([CH3:21])([CH3:20])[N:4]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:3]2[CH2:2][F:1])=[CH:13][CH:12]=1)#[CH:15]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(C#C[Si](C)(C)C)cc2)OC1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C=O
Agent: [F-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C#Cc1ccc([C@H]2OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]2CF)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a THF (20 ml) solution of (4S,5R)-tert-butyl 4-(fluoromethyl)-2,2-dimethyl-5-(4-((trimethylsilyl)ethynyl)phenyl)oxazolidine-3-carboxylate (1.65 g, 4.1 mmol) that had been cooled to −78° C. (dry ice/acetone) is added tetra-n-butyl-ammonium fluoride (5 ml of 1M solution in tetrahydrofuran, 5 mmol). The reaction is stirred at −78° C. for 1 hour. The reaction mixture is quenched (while at −78° C.) by the addition of of saturated aqueous ammonium chloride solution (2 ml). The reaction mixture is warmed to room temperature and diluted with ethyl acetate (50 ml). The organic phase is washed with water (3×25 ml), dried over sodium sulfate and the volatiles removed by evaporation to give the title product (1.35 g).