Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]([S:7]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:9])=[O:8])[C:5]([CH3:16])=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=1.[C:22]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:31]=1)([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([C:26]1[CH:27]=[C:28]([C:2]2[N:6]([S:7]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)(=[O:9])=[O:8])[C:5]([CH3:16])=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:3]=2)[CH:29]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:31]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)c1cc(Br)n(S(=O)(=O)N2CCCCC2)c1C
Reactant: CC(C)(C)c1cc(B(O)O)cc(C(C)(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2)n(S(=O)(=O)N2CCCCC2)c1C
Temperature: 100 °C
Yield: 61.4 %

Procedure:
A mixture of compound 4b (2.1 g, 5.0 mmol), (3,5-di-tert-butylphenyl)boronic acid (1.9 g, 8.1 mmol), Na2CO3 (1.9 g, 17.9 mmol) and Pd(PPh3)4 (100 mg) in dioxane (50 mL) and H2O (15 mL) was heated to 100° C. for 1 h, evaporated and dissolved in EA. The mixture was washed with water (4×80 mL) and brine, dried with Na2SO4, concentrated and purified by CC to afford compound 4c (1.5 g, 61%) as a right red oil.
Reaction SMILES: [C:1]1([C:11](=O)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[C:30]=1[OH:31])[CH:26]=O)[CH3:21].[NH2:35][C:36]([NH2:38])=[O:37].Cl>CCO>[CH2:20]([O:22][C:23]1[CH:24]=[C:25]([CH:26]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:11]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][CH:2]=3)[NH:38][C:36](=[O:37])[NH:35]2)[CH:28]=[C:29]([N+:32]([O-:34])=[O:33])[C:30]=1[OH:31])[CH3:21]
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1cccc2ccccc12
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3cccc4ccccc34)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Yield: 18.1 %

Procedure:
To a mixture of 1-(naphthalen-1-yl)-2-phenylethanone (Intermediate 41) (250 mg, 1.02 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (257.3 mg, 1.22 mmol), and urea (182.9 mg, 3.05 mmol) in anhydrous EtOH (5 mL) was added concentrated HCl solution (0.2 mL), and the reaction mixture was refluxed for 14 hours. The reaction mixture was concentrated under reduced pressure, and purified by column chromatography and preparative HPLC to afford Compound 81 as a yellow solid (89 mg, yield: 18.1%). 1H NMR (DMSO-d6 400 MHz): δ 10.30 (s, 1H), 8.84 (s, 1H), 6.49-7.89 (m, 8H), 6.87-7.23 (m, 7H), 5.26 (d, J=2.8 Hz, 1H), 4.02-4.11 (m, 2H), 1.32-1.36 (t, J=6.8 Hz, 3H); MS (ESI): m/z 482.1 [M+1]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.ClC(OC(Cl)C)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)[CH2:10][CH2:9]1
Reactant: FC(F)(F)c1csc(NC2CCN(Cc3ccccc3)CC2)n1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1csc(NC2CCNCC2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
To a stirred solution of (1-benzyl-piperidin-4-yl)-(4-trifluoromethyl-thiazol-2-yl)-amine (D8) (0.57 g, 1.68 mmol) and diisopropylethylamine (1.04 ml, 5.88 mmol) in dichloromethane (15 ml) at 0° C., was added 1-chloroethyl chloroformate (0.45 ml, 4.2 mmol). The reaction mixture was stirred at room temperature for 3 h. and after this period, diluted with dichloromethane and extracted with a saturated solution of sodium hydrogen carbonate (5 ml). The organic layer was separated, dried (Na2SO4) and the solvent evaporated in vacuo. The crude product was dissolved in methanol (5 ml) and the reaction mixture was stirred at reflux for 3 h. After evaporation of the solvent, the crude product was purified by column chromatography (silica gel; 5-8% ammonia in methanol (7M)/dichloromethane). The desired fractions were collected and evaporated in vacuo. The crude product was crystallized from acetonitrile to yield D9 (0.34 g, 81%) as a white solid. C9H12F3N3S requires 251. Found 252 (MH+).
Reaction SMILES: C(O[C:4](=[O:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])C.[Mg].[C:12]1([CH:18]([CH3:21])[CH2:19]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[NH4+]>C(OCC)C>[CH2:8]([O:7][C:5](=[O:6])[C:4](=[O:10])[CH2:19][CH:18]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH3:21])[CH3:9]
Reactant: CC(CCl)c1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)CC(C)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A Grignard solution, to which 15 ml of oxalic acid diethyl ester is added at −30° C. within 30 minutes, is prepared from 2.6 g of magnesium chips and 15 ml of 2-phenyl-1-chloropropane in diethyl ether. It is stirred for one hour at −20° C. and for 2 hours at 0° C., and then mixed with saturated ammonium chloride solution. The diethyl ether phase is separated, dried (Na2SO4) and concentrated by evaporation and distilled in a vacuum. 17.7 g of 2-oxo-4-phenylvaleric acid ethyl ester, boiling point 98-100° C./0.03 hpa, is obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][CH2:19][N:20]3[C:25](=[O:26])[CH:24]=[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:22]=[N:21]3)=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:28]([O:27][C:23]1[CH:22]=[N:21][N:20]([CH2:19][CH2:18][C:12]2[CH:11]=[C:10]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9]3)=[CH:14][CH:13]=2)[C:25](=[O:26])[CH:24]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(CCn3ncc(OCc4ccccc4)cc3=O)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1cc(OCc2ccccc2)cnn1CCc1ccc2c(c1)CNCC2

Procedure:
To 30 mg (0.06 mmol) 7-[2-(4-benzyloxy-6-oxo-6H-pyridazin-1-yl)-ethyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example 25.1a) in 2.0 mL DCM is added 50 μL trifluoroacetic acid at RT. The solvent is evaporated and the residue is purified via reverse HPLC chromatography (Waters SunFire, C18; water (0.1% formic acid)/acetonitrile (0.1% formic acid) 95:5 to 10:90).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].C(#N)C.I[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>O>[CH2:21]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: C1CC2(CCN1)OCCO2
Reactant: CCCCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCCCCCCCN1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a mixture of 15 g (0.105 mol) of 1,4-dioxa-8-azaspiro[4.5]decane, 15.93 g (0.115 mol) of K2CO3, and 100 ml of acetonitrile is added dropwise 18.92 ml (0.105 mol) of iodooctane. The mixture is stirred overnight at room temperature and then at 65° C. for 2 hours. After cooling, the mixture was diluted with water and extracted with methylene chloride. The combined extracts are washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue is triturated with ether and filtered. The filtrate is concentrated in vacuo to yield 24.04 g (90%) of title compound as a clear oil: IR (neat) 2925 and 1094 cm-1 ; NMR (CDCl3) δ3.97 (s, 4H), 2.56 (br, 4H), 2.38 (m, 2H), 1.78 (m, 4H), 1.51 (br, 2H), 1.28 (s, 10H), 0.89 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[NH2:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[C:21]#[N:22]>C(O)C>[C:21]([C:20]1[CH:19]=[C:18]([NH:17][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Reactant: N#Cc1cccc(N)c1
Solvent: CCO
Product: N#Cc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Yield: 76 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-quinoline-3-carbonitrile, 200 ml ethanol, and 3.04 g (25.8 mmol) 3-aminobenzonitrile was heated to reflux. Removed heat at 3½ hours and made basic with saturated sodium bicarbonate. Stripped solvents and air dried. Slurried residue with hexane and collected solids. Washed with water and dried in vacuo. Boiled in large volume ethyl acetate, collected solids and dried in vacuo, giving 5.15 g of yellow-brown solid: mass spectrum (electrospray m/e): 316.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12]Br.C([O-])(O)=[O:15].[Na+]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[CH2:12][OH:15]
Reactant: O=C([O-])O
Reactant: FC(F)(F)c1cccc(Br)c1CBr
Agent: [Na+]
Product: OCc1c(Br)cccc1C(F)(F)F
Yield: 98 %

Procedure:
To 1-bromo-2-(bromomethyl)-3-(trifluoromethyl)benzene (CXXVIII) (7.51 g, 23.62 mmol) was added an aqueous saturated solution of NaHCO3 (400 mL). The reaction mixture was vigorously stirred and refluxed overnight. The reaction mixture consisted of an upper aqueous layer and a bottom oily layer, which solidified in an ice bath. The water layer was decanted and the solid was dissolved in EtOAc, dried over anhydrous MgSO4, filtrated and evaporated to dryness to give (2-bromo-6-(trifluoromethyl)phenyl)methanol (CXXIX) as an orange oil (5.49 g, 23.16 mmol, 98%). 1H NMR (DMSO-d6) δ ppm 4.67 (d, J=4 Hz, 2H), 5.23 (t, J=5 Hz, 1H), 7.43 (dd, J=8 Hz, J=8 Hz, 1H), 7.75 (d, J=8 Hz, 1H), 7.96 (d, J=8 Hz, 1H); 19F NMR (DMSO-d6) δ ppm −56.33 (s, 3F); ESIMS found for C8H6BrF3O m/z 237.3 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(=O)O[CH2:13][CH2:12][O:11]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.ClCCl>[N:1]1([CH2:13][CH2:12][OH:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: OCCn1ccc2ccccc21

Procedure:
A mixture of indole (5.71 g, 48.7 mmol), ethylene carbonate (4.72 g, 53.6 mmol) and K2CO3 (6.73 g, 48.7 mmol) in DMF (20 mL) was heated under reflux for 2 h. The reaction mixture was diluted with dichloromethane, filtered, and concentrated in vacuo. The light brown oily residue was purified by chromatography on silica gel (13×6 cm) using n-hexane/ethyl acetate (1:1) as eluent. This gave 1.78 g (23%) of the title compound as a beige oil. HRMS m/z calcd for C10H11NO (M)+ 161.0841, found 161.0849. Anal. (C10H11NO.0.1H2O) C, H, N.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:26]2[N:27]=[C:28]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[S:29][CH:30]=2)\[C:23](O)=[O:24])[CH2:19][CH2:18]1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:72][C@H:73]1[C@@H:76]([CH2:77][N:78]2[N:82]=[C:81]([CH2:83][OH:84])[CH:80]=[N:79]2)[NH:75][C:74]1=[O:85]>C(Cl)Cl.CN(C=O)C>[C:35]([O:34][C:32]([NH:31][C:28]1[S:29][CH:30]=[C:26](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([O:14][CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[O:16])[CH2:18][CH2:19]2)/[C:23]([NH:72][C@@H:73]2[C:74](=[O:85])[NH:75][C@@H:76]2[CH2:77][N:78]2[N:82]=[C:81]([CH2:83][OH:84])[CH:80]=[N:79]2)=[O:24])[N:27]=1)=[O:33])([CH3:37])([CH3:36])[CH3:38]
Reactant: N[C@@H]1C(=O)N[C@@H]1Cn1ncc(CO)n1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2ncc(CO)n2)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of (Z)-2-((1-((benzhydryloxy)carbonyl)cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetic acid (218 mg, 0.39 mmol) in DCM (5 mL) and DMF (1 ml) at 0° C. was added DIPEA (0.11 mL, 0.61 mmol), HATU (170 mg, 0.446 mmol), and (3S,4R)-3-amino-4-((4-(hydroxymethyl)-2H-1,2,3-triazol-2-yl)methyl)azetidin-2-one (80 mg, 0.41 mmol). After stirring at 0° C. for 1 h, the reaction mixture was diluted with DCM, washed with water, brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-5%), affording the title compound (250 mg, 86%). LCMS: Rt=0.98 min, m/z=717.3 (M+1). Method 2m_acidic.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15][OH:16])[C:12]([OH:17])=[C:11]([CH3:18])[C:10]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]1(C)[C:21](S(O)(=O)=O)=CC=C[CH:25]=1>COC(OC)(C)C>[CH2:1]([O:8][C:9]1[C:10]([CH3:19])=[C:11]([CH3:18])[C:12]2[O:17][C:20]([CH3:21])([CH3:25])[O:16][CH2:15][C:13]=2[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: Cc1c(OCc2ccccc2)cc(CO)c(O)c1C
Solvent: COC(C)(C)OC
Product: Cc1c(OCc2ccccc2)cc2c(c1C)OC(C)(C)OC2
Yield: 709 %

Procedure:
A solution of 4-benzyloxy-6-hydroxymethyl-2,3-dimethyl-phenol (86 mg, 0.33 mmol) in dimethoxypropane (10 mL) in the presence of toluene sulfonic acid (7 mg) was stirred at RT for 15 h. It was added 30 mg of anion-exchange resin and stirring was continued for 20 more min. The resin was then filtered off and the solution was concentrated. The crude product was purified on silicagel column chromatography to afford 6-benzyloxy-2,2,7,8-tetramethyl-4H-benzo[1,3]dioxine as a white sticky solid (86 mg). 1H-NMR (CDCl3, 300 MHz) δ (ppm): 7.51-7.35 (m, 5H), 6.45 (s, 1H), 5.02 (s, 2H), 4.85 (s, 2H), 2.26 (s, 3H), 2.19 (s, 3H), 1.59 (s, 6H); 13C-NMR δ (ppm): 150.6, 143.3, 137.8, 128.5, 127.8, 126.3, 125.8, 115.9, 105.4, 99.1, 70.9, 61.1, 24.9, 12.2, 11.5.
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=[O:4].O[C:7]([CH3:16])([CH3:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]>O1CCCC1>[Br:1][CH2:2][C:3]([O:5][C:7]([CH3:16])([CH3:15])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:4]
Reactant: O=C(O)CBr
Reactant: CC(C)(C)OC(=O)C(C)(C)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)OC(=O)CBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
Bromoacetic acid (16.01 grams, 0.1 mole) is dissolved in tetra-hydrofuran (200 ml.) and 1,1-carbonyldiimidazole (16.22 grams, 0.1 mole) is added and the mixture stirred for an hour at 25° C. tert.-Butyl 2-hydroxy-2-methylpropanoate (10.41 grams, 0.1 mole) is added and the mixture stirred for 18 hours at 25° C. The solvent is removed by evaporation in vacuo to give tert. butyl 2-(2-bromoacetoxy)-2-methylpropanoate acid (0.1 mole). This compound is dissolved in ether, dried over anhydrous magnesium sulfate, filtered and the solvent removed by evaporation in vacuo. The product is dissolved in 1-propanol (100 ml.) and bis-(2-hydroxyethyl)amine (10.51 grams, 0.1 mole) and triethylamine (11.1 grams, 0.1 mole) are added and the mixture is stirred and heated at reflux for 3 hours. The volatile material is evaporated in vacuo, the residue dissolved in ether (250 ml.), washed with water and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation in vacuo and dissolved in toluene (300 ml.). Methanesulfonic acid (2 grams) is added and the mixture refluxed for 2 hours. The mixture is cooled, extracted with water and the organic layer dried over anhydrous magnesium sulfate. The solvent is removed by evaporation in vacuo. The yield of 2-[N,N-bis-(2-hydroxyethyl)aminoacetoxy]-2-methylpropanoic acid is 17.45 g. (70%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[CH:9][C:4]=2[CH:3]=[CH:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)CCOCCc1ccc2sccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(O)CCOCCc1ccc2sccc2c1
Yield: 85.4 %

Procedure:
In 22.8 mL of toluene was dissolved 7.60 g of tert-butyl 3-[2-(1-benzothiophen-5-yl) ethoxy]propionate, and 94 mg of p-toluenesulfonic acid monohydrate was added thereto, after which the resulting mixture was refluxed for 6 hours. After the reaction mixture was cooled, water and ethyl acetate were added thereto and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was crystallized from a toluene-cyclohexane mixture (1:4, 23 mL) to obtain 5.30 g of 3-[2-(1-benzothiophen-5-yl)ethoxy]propionic acid as light-red crystals.
Reaction SMILES: CC1N=C(SC[C:9]2[CH2:16][S:15][CH:14]3[N:11]([C:12](=[O:18])[CH:13]3N)[C:10]=2[C:19]([O:21]C(C2C=CC=CC=2)C2C=CC=CC=2)=[O:20])SN=1.C(N(CC)CC)C.S=C(SCC(O)=O)C>C(Cl)Cl>[O:18]=[C:12]1[N:11]2[CH:14]([S:15][CH2:16][CH:9]=[C:10]2[C:19]([OH:21])=[O:20])[CH2:13]1
Reactant: Cc1nsc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3SC2)n1
Agent: CC(=S)SCC(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)C1=CCSC2CC(=O)N12
Reaction time: 3 h

Procedure:
0.01 mol. of 7-[D-2-amino-2-(2-thienyl)acetamido]-3-[[(3-methyl-1,2,4-thiadiazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trifluoroacetate salt (prepared by the procedure of Example 7, but substituting 3-[[(3-methyl-1,2,4-thiadiazol-5-yl)thio]methyl]-7-amino- 8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester in part b) is brought into solution with triethylamine in methylene chloride and 0.015 mol. of [(1-thioxoethyl)thio]acetic acid (prepared as described in U.S. Pat. No. 3,341,518) is added. The reaction mixture is permitted to stand for three hours and worked up according to the procedure of Example 7 to obtain 7-[D-2-[(2-thienyl)-2-[(1-thioxoethyl)amino]acetyl]amino]-3-[[3-methyl-1,2,4-thiadiazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]-oct-2-ene-2-carboxylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)(=O)C.[O-:17][C:18]#[N:19].[K+].[OH-].[Na+]>O>[CH3:12][O:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:18](=[O:17])[NH:19][C:4]2=[O:6]
Reactant: N#C[O-]
Reactant: COc1ccc(N)c(C(=O)O)c1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2[nH]c(=O)[nH]c(=O)c2c1
Reaction time: 4 h
Yield: 64.4 %

Procedure:
2-Amino-5-methoxybenzoic acid (13.0 g, 77.8 mmol, 1.0 eq.) was suspended in water (200 mL) and glacial acetic acid (5.2 mL) at 35° C. A freshly prepared solution of potassium cyanate (8.21 g, 101.4 mmol, 1.3 eq.) in water (86 mL) was added dropwise to the stirred mixture. After 4 h, NaOH (104.0 g, 2600 mL, 33.4 eq.) was added in portions, keeping the reaction temperature below 40° C. A clear solution was obtained momentarily before a precipitate formed. After cooling, the precipitate was filtered off and dissolved in hot water which was acidified to pH 5. The precipitate was collected and washed with water, dried by lyophilization to afford 9.63 g of 6-methoxyquinazoline-2,4(1H, 3H)-dione as a white solid (65%). LCMS m/z=193.1 (M+1) (Method B) (retention time=1.22 min). 1H NMR (400 MHz, DMSO-d6): δ 11.26 (s, 1H), 11.01 (s, 1H), 7.31-7.25 (m, 2H), 7.10 (d, 1H, J=8.8 Hz), 3.77 (s, 3H).
Reaction SMILES: [CH2:1]1[CH:8]2[N:4]([C:5](=[O:9])[CH2:6][CH2:7]2)[C:3](=[O:10])[CH2:2]1.[O:11]([C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[O:9]=[C:5]([CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:19]=1)[CH2:6][CH2:7][CH:8]1[NH:4][C:3](=[O:10])[CH2:2][CH2:1]1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Reactant: O=C1CCC2CCC(=O)N12
Product: O=C(CCC1CCC(=O)N1)Cc1cccc(Oc2ccccc2)c1
Yield: 61.1 %

Procedure:
Analogous to the procedure described for Example 1B, Step A, tetrahydro-pyrrolizine-3,5-dione (650 mg, 4.68 mmol) and 3-phenoxybenzyl chloride (1.20 g, 5.49 mmol) were reacted over 3.5 h to provide 5-[3-oxo-4-(3-phenoxy-phenyl)-butyl]-pyrrolidin-2-one (924 mg). 1H NMR (CDCl3) δ7.30 ( m, 3H), 7.10 (m, 1H), 6.99 (m, 2H), 6.92-6.84 (m, 3H), 3.66 (s, 2H), 3.57 (m, 1H), 2.52 (t, 2H), 2.27 (m, 2H), 2.17 (m, 1H), 1.80-1.58 (m, 3H),
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:5]=[CH:4][CH:3]=1.CO.[H][H]>[C].[Pd].C(OCC)(=O)C>[CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: Cc1cccc(CCOc2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cccc(CCOc2ccc(N)cc2)n1
Yield: 90.5 %

Procedure:
To a solution of 2.8 g of 4-[2-(6-methyl-2-pyridyl)ethoxy]nitrobenzene in the mixture consisting of 30 ml of methanol and 20 ml of ethyl acetate is added 0.5 g of 10% palladium carbon, and then the mixture is shaken in a stream of hydrogen. After absorption of hydrogen ceased, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and washed with water, dried over anhydrous magnesium sulfate and then concentrated to give 2.24 g of 4-[2-(6-methyl-2-pyridyl)ethoxy]aniline as yellowish brown powder.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C@H:23]2[CH2:28][CH2:27][C@H:26]([OH:29])[CH2:25][CH2:24]2)[C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[CH:6]=1.F[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.[H-].[Na+].C(OCC)(=O)C>CN(C=O)C>[CH3:31][C:2]([CH3:30])([CH3:1])[C:3]#[C:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[C:7]([N:13]([C:14]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)=[O:15])[C@H:23]2[CH2:28][CH2:27][C@H:26]([O:29][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=3)[CH2:25][CH2:24]2)[CH:6]=1
Reactant: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](O)CC2)c(C(=O)O)s1
Reactant: Fc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)C#Cc1cc(N(C(=O)[C@H]2CC[C@H](C)CC2)[C@H]2CC[C@H](Oc3ccccn3)CC2)c(C(=O)O)s1
Reaction time: 0.5 h

Procedure:
A mixture of 5-(3,3-Dimethyl-but-1-ynyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (78 mg, 0.175 mmol) and 2-fluoro-pyridine (145 μL, 1.68 mmol) in DMF (0.6 mL) was treated with sodium hydride (67 mg, 1.68 mmol, 60% oil dispersion) in two or three portions. The mixture was stirred until the bubbling slowed, and was sealed and heated by microwave at 100 deg C. for 30 min. After cooling, ethyl acetate (2-3 mL) was added and the mixture was carefully quenched with citric acid (10% aqueous solution, 2-3 mL). Water was added and the mixture was extracted with ethyl acetate (2×30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by HPLC (Gemini column, 35% acetonitrile:water, 2 min, 35-50% acetonitrile:water, 2 min, 50-95% acetonitrile:water 13 min, both solvents containing 0.1% trifluoroacetic acid). This resulted in 65 mg (58% yield) of the title compound as a white powder (TFA salt): MS (m/z): 520.9 [M−H]−; HPLC retention time: 4.61 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).