Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1.Cl[C:13]1[N:18]=[CH:17][C:16]([B:19]([OH:21])[OH:20])=[CH:15][N:14]=1>>[S:8]([CH:5]1[CH2:6][CH2:7][N:2]([C:13]2[N:18]=[CH:17][C:16]([B:19]([OH:21])[OH:20])=[CH:15][N:14]=2)[CH2:3][CH2:4]1)(=[O:10])(=[O:9])[NH2:11]
Reactant: NS(=O)(=O)C1CCNCC1
Reactant: OB(O)c1cnc(Cl)nc1
Agent: Cl
Product: NS(=O)(=O)C1CCN(c2ncc(B(O)O)cn2)CC1

Procedure:
Prepared from piperidine-4-sulfonamide hydrochloride (1.27 g, 6.315 mmol) and (2-chloropyrimidin-5-yl)boronic acid (1 g, 6.32 mmol) in accordance with General Method C to give the title compound as an off-white semi-solid. HPLC-MS: m/z (M−H)+ 285.1, RT 0.14 minutes.
Reaction SMILES: O.[NH2:2][C:3]1[NH:7][N:6]=[N:5][N:4]=1.Cl.[O-:9][C:10]#[N:11].[K+]>O>[NH:4]1[C:3]([NH:2][C:10]([NH2:11])=[O:9])=[N:7][N:6]=[N:5]1
Reactant: N#C[O-]
Reactant: Nc1nnn[nH]1
Agent: Cl
Agent: [K+]
Solvent: O
Product: NC(=O)Nc1nnn[nH]1
Temperature: 10 °C
Reaction time: 2 h

Procedure:
5-Aminotetrazole hydrate (10.3 g, 0.1 mole) was slurried into 150 ml of water containing 10 ml of 37 percent HCl. A solution of potassium cyanate (10 g, 0.12 mole) was added at ambient temperature over the course of one hour. When a slight exotherm began, the solution was cooled to 10° C. The mixture was stirred two hours, filtered and recrystallized from ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]#[N:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:19]=[N+:20]=[N-:21].[Na+]>CC(O)C.O.C(OCC)(=O)C.[Br-].[Zn+2].[Br-]>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(C)O
Product: O=C(OCc1ccccc1)N1CCC(c2nnn[nH]2)CC1
Temperature: 120 °C
Reaction time: 72 h
Yield: 132.3 %

Procedure:
A mixture of 4-cyano-piperidine-1-carboxylic acid benzyl ester (0.73 g, 3.0 mmol), sodium azide (0.39 g, 6.0 mmol) and zinc bromide (0.33 g, 1.5 mmol) in 2-propanol (5 mL) and water (10 mL) was stirred at 120° C. for 3 days into a pressure tube. The reaction mixture was then partitioned between aqueous 3.0N HCl (1.5 mL) and ethyl acetate and then stirred vigorously until 2 clear phases were obtained. Aqueous layer was then extracted with ethyl acetate and combined ethyl acetate layers dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude residue. The residue was dissolved in ethyl acetate (10 mL) and washed with 0.25N aqueous sodium hydroxide. Aqueous layer was acidified to pH=1 with aqueous 3.0N HCl and extracted with ethyl acetate. Ethyl acetate layer was dried over Na2SO4, filtered, and the solvent evaporated in vacuo to yield a crude gum. The gum was purified via flash chromatography (4% methanol in dichloromethane) to yield 4-(1H-Tetrazol-5-yl)-piperidine-1-carboxylic acid benzyl ester as a gum (1.14 g, 66%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N+:14]([O-])=O.[H][H]>[Pd].CCO>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH2:14]
Reactant: [H][H]
Reactant: CC1CCCCN1c1ccncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CC1CCCCN1c1ccncc1N
Yield: 35.6 %

Procedure:
2-Methyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,4′]bipyridinyl (650 mg, 2.94 mmol) and 10% palladium on carbon (156 mg, 0.15 mmol) in EtOH were stirred under 1 atmosphere of hydrogen gas for 16 hours. Filtration followed by removal of volatiles under reduced pressure gave the title compound (200 mg, 36%) which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:30])([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][C:15](Br)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:21])[C:10]=2[N:9]=[C:8]1[CH2:22][O:23][CH2:24][CH3:25].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]([CH3:30])([S:26]([NH2:29])(=[O:28])=[O:27])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][C:15]([C:33]4[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:21])[C:10]=2[N:9]=[C:8]1[CH2:22][O:23][CH2:24][CH3:25]
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCC(C)(C)S(N)(=O)=O
Reactant: OB(O)c1cccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CCOCc1nc2c(N)nc3cc(-c4cccnc4)ccc3c2n1CCCCC(C)(C)S(N)(=O)=O
Reaction time: 14 h
Yield: 34.2 %

Procedure:
Dimethyl 5-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)pentane-1-sulfonamide (0.26 g, 0.53 mmol) and pyridine-3-boronic acid (0.78 g, 0.63 mmol) were coupled according to the method described in Part J of Example 1. The reaction was heated at 100° C. for 31 hours, at which time additional palladium acetate (0.002 equivalent) was added. Heating was resumed for 14 hours, and then additional pyridine-3-boronic acid (0.3 equivalent) was added. The reaction was heated for another 22 hours. The work-up procedure used in Part F of Examples 125-135 was followed. The crude product was purified twice by HPFC (eluting with chloroform:CMA in a gradient from 100:0 to 80:20) and then triturated with ethyl acetate and isolated by filtration. The product was finally recrystallized from isopropanol, isolated by filtration, and dried for eight hours under high vacuum at 100° C. to provide 0.090 g of dimethyl 5-[4-amino-2-ethoxymethyl-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-yl]pentane-1-sulfonamide as a white powder, mp 159-160° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH:7]1[CH2:12][C@@H:11]2[CH2:13][C@H:8]1[CH2:9][C@:10]2([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:14]#[N:15])(C)(C)C.[CH2:24]([Mg]Br)[CH3:25].C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1.C1COCC1>[NH2:15][CH:14]([C@@:10]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:9][C@@H:8]2[CH2:13][C@H:11]1[CH2:12][CH:7]2[OH:6])[CH2:24][CH3:25]
Reactant: CC[Mg]Br
Reactant: CC(C)(C)[Si](C)(C)OC1C[C@@H]2C[C@H]1C[C@@]2(C#N)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(N)[C@@]1(c2ccccc2)C[C@@H]2C[C@H]1CC2O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
930 mg (2.8 mmol) of (1S,2S,4S)-5-(tert-Butyl-dimethyl-silanyloxy)-2-phenyl-bicyclo[2.2.1]heptane-2-carbonitrile (88) were dissolved in 10 mL of anhydrous toluene. Afterwards, 5.7 mL of a 1M solution of ethylmagnesium bromide in THF was added and the mixture was heated under reflux for 12 h. The mixture was then treated with 3 mL ethanol and evaporated. The residue was dissolved in 20 mL of ethanol and 215 mg (5.7 mmol) of NaBH4 was added. The mixture was stirred at ambient temperature for 3 h and then evaporated. The residue was dissolved using 100 mL of water, the pH adjusted to 3 using aqueous HCl-solution to remove excess NaBH4 and then adjusted to pH=12 using saturated aqueous Na2CO3-solution. The mixture was extracted three times using 30 mL of t-butylmethylether each. Afterwards, the organic layer was extracted twice using 20 mL of a 1N aqueous HCl-solution each, the aqueous layer was adjusted to pH>11 using saturated aqueous Na2CO3-solution and extracted three times using 30 mL t-butylmethylether each. The organic layer was dried using MgSO4 and evaporated yielding 200 mg of the desired product 89, used without further purification. Rt=0.58 min (Method 18).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]1[N:19]2[CH:20]=[CH:21][N:22]=[C:18]2[CH:17]=[CH:16][CH:15]=1)(=[O:5])=[O:4].[CH2:25]=O>C(O)(=O)C>[F:24][C:2]([F:1])([F:23])[S:3]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:13][C:14]2[N:19]3[C:20](=[CH:21][N:22]=[C:18]3[CH:17]=[CH:16][CH:15]=2)[CH2:25]1)(=[O:5])=[O:4]
Reactant: C=O
Reactant: O=S(=O)(NCCCCCNCc1cccc2nccn12)C(F)(F)F
Solvent: CC(=O)O
Product: O=S(=O)(NCCCCCN1Cc2cccc3ncc(n23)C1)C(F)(F)F
Temperature: 100 °C
Yield: 69 %

Procedure:
To a solution of 2.52 g (6.91 mmol) of 5-[N-[5-(trifluoromethanesulfonamido)pentan-1-yl]aminomethyl]imidazo[1,2-a]pyridine in 8 ml of acetic acid was added 7.8 ml (103.7 mmol) of a 37% aqueous solution of formalin. The mixture was heated at 100° C. for 30 minutes. The solvent was then distilled off under reduced pressure. The residue was dissolved in 50 ml of a saturated aqueous solution of potassium carbonate. This solution was neutralized, under ice-cooling, with 1N HCl, which was extracted twice with 100 ml of chloroform. The organic layer was dried over magnesium sulfate, then the solvent was distilled off under reduced pressure. The residue was purified by silicagel column chromatography to give 1.79 g of the desired compound (69.0%, colorless liquid).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21](=[O:29])[NH:22][CH2:23][CH:24](OC)[O:25]C)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>CC(C)=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:13][C@H:12]1[C:21](=[O:29])[NH:22][CH2:23][CH:24]=[O:25])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(CNC(=O)[C@@H]1C[C@@H](OC(C)(C)C)CN1C(=O)OCc1ccccc1)OC
Agent: Cl
Solvent: CC(C)=O
Product: CC(C)(C)O[C@@H]1C[C@@H](C(=O)NCC=O)N(C(=O)OCc2ccccc2)C1
Reaction time: 8 h
Yield: 87.6 %

Procedure:
A mixture of (2S,4R)-4-tert-butoxy-2-(2,2-dimethoxy-ethylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (1.8 g, 4.41 mmol) and HCl (1M, 30 mL) in acetone (30 mL) was stirred at room temp. for 8 h. The reaction mixture was then extracted with ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give (2S,4R)-4-tert-butoxy-2-(2-oxo-ethylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester (1.4 g, crude) as a sticky liquid. The compound was used in the next step without further purification. MS calcd. for C19H27N2O5 [(M+H)+]363.0, obsd. 363.2.
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].O=[C:8]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.CCOCC>[CH:1](=[C:8]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: CC(C)(C)[O-]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Product: CC=C1CN(C(=O)OC(C)(C)C)C1
Reaction time: 4.5 h
Yield: 46 %

Procedure:
Potassium tert-butoxide (1.672 g, 14.9 mmol) and ethyltriphenylphosphonium bromide (5.538 g, 14.9 mmol) were stirred in ether (30 mL) at ambient for 1 h. 1,1-Dimethylethyl 3-oxoazetidine-1-carboxylate (954 mg, 6.0 mmol), prepared using procedures similar to those described in Example 3, was added and the mixture was 35° C. for 4.5 h. Mixture was filtered through celite and the solid was washed with ether. The filtrate was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 20% ether in hexanes) gave 1,1-dimethylethyl 3-ethylideneazetidine-1-carboxylate (506 mg, 2.76 mmol, 49% yield): 1H NMR (400 MHz, CDCl3): 5.37-5.28 (m, 1H), 4.47-4.39 (m, 4H), 1.56-1.51 (m, 3H), 1.45 (s, 9H).
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[ClH:13].[CH2:14]=O>CO>[ClH:13].[NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:14][Cl:13])[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: NC(C(=O)O)c1ccc(O)cc1
Reactant: C=O
Agent: Cl
Solvent: CO
Product: NC(C(=O)O)c1ccc(O)c(CCl)c1
Reaction time: 0.12 h

Procedure:
To a solution of (-)-α-amino-4-hydroxybenzeneacetic acid (100 g, 0.6 mole) in a minimum amount of concentrated hydrochloric acid at 35°-40° C. is added 50 ml of aqueous formaldehyde (35-37%) (0.6 mole). The addition of hydrogen chloride gas is begun. After 5-10 minutes, a solid begins to precipitate. Stirring is continued for 30 minutes, and the solid is then collected. The crude product is washed with ether and with acetone. A second crop is obtained from the filtrate after standing at room temperature overnight. Total yield is 102 g (67%) m.p. >300° C., [α]D18 =-134° (c 4.75, CH3OH) NMR (DMSO--D6) ppm (δ) 4.68 (s,2), 4.9 (broad s,1), 6.9-7.6 (superimposed q and s,3).
Reaction SMILES: C(C1C=C[C:10]2[C:9](=[O:13])[CH2:8][CH2:7][CH2:6][C:5]=2N=1)=C.C[N+:15]1([O-])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C1C[O:25][CH2:24]C1>C(OCC)(=O)C.[Os](=O)(=O)(=O)=O>[OH:18][CH:19]([C:20]1[CH:6]=[CH:7][C:8]2[C:9](=[O:13])[CH2:10][CH2:5][CH2:17][C:16]=2[N:15]=1)[CH2:24][OH:25]
Reactant: C=Cc1ccc2c(n1)CCCC2=O
Reactant: C1CCOC1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Product: O=C1CCCc2nc(C(O)CO)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 47 %

Procedure:
To a mixture of 2-vinyl-7,8-dihydroquinolin-5(6H)-one (Preparation 54C, 0.400 g, 2.31 mmol) and N-methylmorpholine-N-oxide (50% in water, 0.479 mL, 2.31 mmol) in THF (11 mL) at room temperature was added osmium tetroxide (4% in water, 0.725 mL, 0.092 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (50 mL). The organic layer was washed with brine (50 mL), the combined aqueous layers were extracted with ethyl acetate (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford 2-(1,2-dihydroxyethyl)-7,8-dihydroquinolin-5(6H)-one (0.226 g, 1.09 mmol, 47% yield) as a yellow oil. The compound had an HPLC ret. time=0.330 min. (condition A); LC/MS M+1=207.9.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[NH:11][C:10]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:25]I>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=3)[N:11]([CH3:25])[C:10]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:6][CH:7]=1
Reactant: COC(=O)c1[nH]c2ccc(C)cc2c1Sc1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(Sc2ccc(Cl)cc2)c2cc(C)ccc2n1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Compound 7 (200 mg, 0.6 mmol) was added in portions to a mixture of sodium hydride (60 mg, 1.2 mmol) in DMF (5 mL) at 0° C. After 15 min, methyl iodide (50 μL, 0.9 mmol) was added and the mixture was stirred for 1 h. The reaction was allowed to warm to rt and stirred overnight under N2. The reaction mixture was then quenched with ice water and extracted with EtOAc. The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with a linear gradient ranging from 0 to 50% EtOAc-hexanes to provide 166 mg (63%) of product 4 as an off white solid, mp 110-111° C. 1H NMR (300 MHz, DMSO-d6) δ 2.35 (s, 3H), 3.83 (s, 3H), 4.00 (s, 3H), 7.06 (d, J=9 Hz, 2H), 7.23-7.29 (m, 4H), 7.63 (d, J=9 Hz, 1H). LC-MS (CI): m/z 346.1 [(M+H)+ C18H16ClNO2S requires 345.06]. Purity (100%). Calcd for C18H16ClNO2S: C, 62.51; H, 4.66; N, 4.05; S, 9.27; Cl, 10.25. Found: C, 62.79; H, 4.64; N, 3.98; S, 9.05; Cl, 10.03.
Reaction SMILES: [CH3:1][N:2]([C:8](=[O:31])[CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[NH:26][N:25]=[C:24]([C:27]([F:30])([F:29])[F:28])[CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)[CH2:3][C:4]([O:6]C)=[O:5].O1CCCC1.[OH-].[Li+].Cl>O>[CH3:1][N:2]([C:8](=[O:31])[CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[NH:25][N:26]=3)=[CH:20][CH:21]=2)[CH2:14][CH2:15]1)[CH2:3][C:4]([OH:6])=[O:5]
Reactant: COC(=O)CN(C)C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(CC(=O)O)C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Reaction time: 6 h

Procedure:
A 20 mL scintillation vial was charged with the product from Example 26D (12 mg, 0.027 mmol), 80% tetrahydrofuran in water, and lithium hydroxide (2.00 mg, 0.048 mmol) and shaken for 6 hours. After this time the reaction mixture was acidified with 1N HCl, filtered, and evaporated to dryness to afford the title product. The NMR spectrum includes a mixture of rotamers, with the major rotamer being reported. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.02-1.20 (m, 2 H), 1.41-1.55 (m, 2 H), 1.74-1.91 (m, 5 H), 2.22-2.31 (m, 2 H), 2.78-2.80 (m, 1 H), 2.96-3.10 (m, 3 H), 3.98 (s, 2 H), 7.05-7.19 (m, 1 H), 7.27-7.45 (m, 2 H), 7.60-7.85 (m, 2 H), 13.98 (s, 1H): MS (ESI) m/z 424 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7](/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[OH:27])[CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)#[N:2].[C:28]([C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:28]([C:32]1[CH:33]=[CH:34][C:35]([CH2:36][O:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2/[CH:20]=[CH:19]/[CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[CH:38][CH:39]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2O)CCCCC#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCCCC#N)cc1
Yield: 92.2 %

Procedure:
A solution of 2.976 g (8.19 mmol) of methyl E-4-{6-cyano-2-[2-(2-hydroxyphenyl)vinyl]hexyl}-benzoate from Example 119A in 100 ml of dry acetonitrile is mixed with 2.789 g (12.28 mmol) of 4-(tert-butyl)benzyl bromide and 1.697 g (12.28 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then filtered and the filtrate is concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 8:1→4:1). 3.85 g (92% yield) of a solid are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][CH:3]=1.[CH2:17]([N:20]=[C:21]=[O:22])[CH2:18][CH3:19].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:17]([NH:20][C:21]([O:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[CH2:11][N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:4][CH:3]=1)=[O:22])[CH2:18][CH3:19]
Reactant: CCCN=C=O
Reactant: CCN(CC)CC1CCc2ccc(O)cc21
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCNC(=O)Oc1ccc2c(c1)C(CN(CC)CC)CC2
Yield: 39.6 %

Procedure:
2 g of 6-hydroxy-N,N-diethyl-1-indan-methylamine and 1.5 g of propylisocyanate were refluxed in 25 ml of dry toluene for 16 hours. The reaction mixture was poured into 100 ml of 0.1M acetic acid, and the organic phase was separated. The water phase was made alkaline with dil. NH4OH and extracted with 2×50 ml diethyl ether. The combined organic phases were dried (MgSO4) and the solvent evaporated. The residue was purified by column chromatography yielding 1.1 g of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Br:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([O:23][CH3:24])[C:20]=1[O:21][CH3:22])[CH:16]=O.[C:25](#[N:29])[CH2:26][C:27]#[N:28].C1N2CCN(CC2)C1>C(O)C.O>[NH2:29][C:25]1[O:1][C:2]2[C:11]([CH:16]([C:15]3[CH:18]=[C:19]([O:23][CH3:24])[C:20]([O:21][CH3:22])=[C:13]([Br:12])[CH:14]=3)[C:26]=1[C:27]#[N:28])=[CH:10][CH:9]=[C:8]1[C:3]=2[CH:4]=[CH:5][CH:6]=[N:7]1
Reactant: N#CCC#N
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: Oc1cccc2ncccc12
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CCO
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2ncccc32)cc(Br)c1OC
Temperature: 80 °C
Reaction time: 21 h
Yield: 36 %

Procedure:
5-Hydroxyquinoline (174 mg, 1.2 mmol), 3-bromo-4,5-dimethoxy-benzaldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) were taken in 25 ml ethanol at room temperature, charged with DABCO (11 μl, 0.1 mmol) and then stirred at 80° C. under LC-MS control for 21 h. The reaction mixture was cooled down to the room temperature, diluted with water to about 100 ml and stirred for over night. The solids were collected by filtration, washed with well 1:1 mixture of ethanol/water and dried under high vacuum yielding 134 mg (0.36 mmol, 36%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1CCCCC1>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccncc1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a solution of 4-nitrobenzenesulfonyl chloride 40 g 0.181 mole in dichloromethane 400 ml was added over 30 mins a solution of pyridine 15 g 15.3 ml and piperidine 16.15 g 18.8 ml in dichloromethane 100 ml. The mixture was stirred at room temperature for 2 h and then washed with water, 2M hydrochloric acid and brine, dried MgSO4 and evaporated in vacuo to give 1-(4-nitro-benzenesulfonyl)-piperidine 44.5 g. 1HNMR CDCl3 7.76 (2H, d), 7.40 (2H, d), 3.21 (6H, q), 1.07 (6H, t).
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][N:6]=[N:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].N1C(C)=CC=CC=1C.O([Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[CH:29]([CH3:31])[CH3:30])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH:29]([Si:28]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[O:1][CH2:2][C:3]1[S:7][N:6]=[N:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9])([CH3:31])[CH3:30]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: COC(=O)c1nnsc1CO
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1nnsc1CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
To a solution of methyl 5-(hydroxymethyl)-1,2,3-thiadiazole-4-carboxylate (1.22 g, 0.007 mol) in DCM (20 mL) at 0° C. was added 2,6-lutidine (2.0 mL, 0.018 mol) followed by triisopropylsilyl triflate (2.4 mL, 0.0091 mol). The solution was stirred at 0° C. for 5 minutes. The reaction was then concentrated and purified by flash chromatography to give the desired product (2.0 g, 87%). 1H NMR (400 MHz, CDCl3): δ□; MF=C14H26N2O3SSi; LCMS calculated for C14H27N2O3SSi (M+H)+: m/z 331.1.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].C[O-].[Na+].[NH2:9][C:10]1[C:11]([C:22]([O:24]C)=[O:23])=[N:12][C:13]([S:17][C:18]([F:21])([F:20])[F:19])=[C:14]([NH2:16])[N:15]=1.O>CO>[OH2:23].[C:3]([NH:5][C:22]([C:11]1[C:10]([NH2:9])=[N:15][C:14]([NH2:16])=[C:13]([S:17][C:18]([F:19])([F:20])[F:21])[N:12]=1)=[O:24])(=[NH:2])[NH2:4]
Reactant: COC(=O)c1nc(SC(F)(F)F)c(N)nc1N
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N=C(N)NC(=O)c1nc(SC(F)(F)F)c(N)nc1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Guanidine hydrochloride (3.34 g., 0.035 mole) is added to a solution of sodium methoxide (1.67 g., 0.032 mole) in methanol (20 ml.) with stirring at 25° C. After 15 minutes, methyl 3,5-diamino-6-trifluoromethylthio-2-pyrazinoate (1.85 g., 0.007 mole) is added, and the mixture is heated on a steam bath for 15 min. Crushed ice--H2O (20 ml.) is added to the reaction mixture to precipitate 390 mg. of N-amidino-3,5-diamino-6-trifluoromethylthio-2-pyrazinecarboxamide, m.p. 195° C.