Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:9]1[C:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[CH:21][CH:20]=2)=[C:11]([C:16](O)=[O:17])[S:12][C:13]=1[CH2:14][CH3:15])#[N:8].C[N:31](C=O)C.N>ClCCl.O1CCOCC1>[C:7]([C:9]1[C:10]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[S:26][CH:27]=[CH:28][N:29]=3)=[CH:21][CH:20]=2)=[C:11]([C:16]([NH2:31])=[O:17])[S:12][C:13]=1[CH2:14][CH3:15])#[N:8]
Reactant: CN(C)C=O
Reactant: CCc1sc(C(=O)O)c(-c2ccc(-c3nccs3)cc2)c1C#N
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1sc(C(N)=O)c(-c2ccc(-c3nccs3)cc2)c1C#N
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Add oxalyl chloride (0.050 mL, 0.57 mmol) to a suspension of 4-cyano-5-ethyl-3-(4-thiazol-2-yl-phenyl)-thiophene-2-carboxylic acid (0.15 g, 0.44 mmol) and DMF (0.1 mL) in dichloromethane at 0° C. Stir 1 h at 23° C. and add 1M solution of ammonia in dioxane (5 mL). Concentrate in vacuo, suspend the solid in ethyl acetate and filter to give 0.052 g of the title compound as a white solid. Mass spectrum ESI positive (m/z): 340 (M+1), 362 (M+23).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][CH2:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH2:16]=[C:17]([CH3:19])[CH3:18].[OH-].[Na+]>CCOCC.C(COC)OC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[NH:6][CH2:7][C:8]([O:10][C:17]([CH3:19])([CH3:18])[CH3:16])=[O:9]
Reactant: O=C(O)CNc1cccs1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CNc1cccs1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 12.6 g of 2-thienylaminoacetic acid, 300 ml of dimethoxyethane, 15 ml of sulphuric acid and 100 ml of isobutene is stirred at room temperature in an autoclave for 5 h and poured into a mixture composed of 800 ml of ether and 800 ml of 1N sodium hydroxide solution. The ethereal phase is separated off, and the aqueous phase is extracted twice more by shaking with 200 ml of ether each time. After drying of the ether phases over MgSO4 and evaporation of the solvent there remains a yellowish oily residue.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10]>CN(C=O)C>[N:1]([CH2:6]/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)/C=C/CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C/CN=[N+]=[N-]
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To the solution of NaN3 (2.80 g, 43.01 mmol) in 100 ml of DMF at −20° C. was added methyl 4-bromocrotonate (5.00 ml, 85%, 36.10 mmol). After stirred at −20° C. for 30 min, the mixture was stirred at 0° C. for 4 h, evaporated, suspended with EtAc/Hexane (1:1), filtered, evaporated and chromatographic purification on SiO2 column eluted with EtAc/Hexane (1:25 to 1:10) to afford HRMS for 4.08 g (80%) of the title product. 1H NMR (CDCl3) 6.88 (m, 1H), 6.06 (ddd, 1H, J=1.7, 3.4, 15.6 Hz), 3.97 (dd, 2H, J=1.2, 4.96 Hz), 3.73 (s, 3H); 13C NMR 166.23, 140.86, 123.49, 51.95, 51.36; ESI MS m/z+182.5 (M+Na+H2O); HRMS m/z+(C5H7N3O2+H2O+Na) calcd 182.0542. found 182.0548.
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O-:11])=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16].C1(N=C=NC2CCCCC2)CCCCC1>>[Cl:12][C:13]1[CH:14]=[C:15]([NH:16][C:9]([CH:3]([CH2:1][CH3:2])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:11])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)C(CC)C(=O)[O-]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CCOC(=O)C(CC)C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 10 %

Procedure:
Mono-ethyl ethylmalonate (5.0 grams, 0.03 mole), 3,5-dichloroaniline (5.06 grams, 0.03 mole) and 1,3-dicyclohexylcarbodiimide (6.44 grams, 0.03 mole) were reacted in a manner similar to that described in Example LVII to give 0.87 gram (0.003 mole) of ethyl 2-(3,5-dichlorophenylaminocarbonyl)butanoate having a melting point of 96.5° C.-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:16]=[CH:15][C:10]([C:11](OC)=[O:12])=[C:9]([CH2:17][CH2:18][CH3:19])[N:8]=2)=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[N:8]=[C:9]([CH2:17][CH2:18][CH3:19])[C:10]([CH2:11][OH:12])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CCCc1nc(Oc2ccc(Cl)cc2)ccc1C(=O)OC
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCc1nc(Oc2ccc(Cl)cc2)ccc1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the product from Step 3 (48 g, 157 mmol) in toluene (500 mL) cooled at −75° C. was added a solution of diisobutylaluminum hydride (1.0 M in toluene, 314 mL, 314 mmol) over a 45 min period. After additional 30 min at −75° C., the reaction mixture was poured into a ice-cold solution of 1 N hydrochloric acid (1.5 L) and the mixture was stirred at room temperature for 30 min. The product was extracted with ethyl acetate (2×500 mL) and organic extracts were washed with a saturated solution of sodium bicarbonate and brine. After removal of the solvent, the crude product was purified by chromatography on silica gel eluting with 7:1 hexane:ethyl acetate to give the title product as an oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1.[CH3:18]I.O>CN(C=O)C>[F:3][C:4]1[C:12]2[N:11]([CH3:18])[C:10]3[CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:9]=3[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=C1NCCc2[nH]c3c(F)cccc3c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2c(c3cccc(F)c31)C(=O)NCC2
Reaction time: 0.25 h

Procedure:
Sodium hydride (60% dispersion in oil; 196 mg) was added to a stirred suspension of 6-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one (500 mg) in dry DMF (10 ml) under nitrogen. After 30 min the solution was cooled (0°), and methyl iodide (0.153 ml) was added. After stirring for 15 min the suspension was poured into water 950 ml) and extracted with dichloromethane (3×25 ml). The combined, dried organic extracts were evaporated to give a solid (ca. 530 mg) which was purified by FCC eluting with System A (250:10:1) to give the title compound (130 mg), m.p. 242°.
Reaction SMILES: [N:1]1([C:7]2[CH:40]=[CH:39][C:10]([O:11][CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]4[NH:23][C:22]5[CH:24]=[C:25](B6OC(C)(C)C(C)(C)O6)[CH:26]=[CH:27][C:21]=5[C:20](=[O:37])[NH:19][C:18]=4[CH:38]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F-].[Cs+].CO[CH2:45][CH2:46]OC>CO.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>[N:1]1([C:7]2[CH:40]=[CH:39][C:10]([O:11][CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]4[NH:23][C:22]5[CH:24]=[C:25]([C:46]6[C:45]7[C:17](=[CH:18][N:19]=[CH:20][CH:21]=7)[NH:23][CH:22]=6)[CH:26]=[CH:27][C:21]=5[C:20](=[O:37])[NH:19][C:18]=4[CH:38]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: COCCOC
Reactant: CC1(C)OB(c2ccc3c(c2)Nc2ccc(CCOc4ccc(N5CCOCC5)cc4)cc2NC3=O)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: O=C1Nc2cc(CCOc3ccc(N4CCOCC4)cc3)ccc2Nc2cc(-c3c[nH]c4cnccc34)ccc21
Temperature: 25 °C

Procedure:
A mixture of Example 695G (53 mg, 0.1 mmol), Example 695K (30 mg, 0.1 mmol), Pd(PPh3)4 (11 mg, 0.01 mmol), and CsF (46 mg, 0.3 mmol) in DME (4 mL) and MeOH (2 mL) was heated under reflux overnight. After the reaction mixture cooled to room temperature, it was partitioned between EtOAc and water. The organic layer was separated, and the aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified flash column chromatography on silica gel with 100:5:0.5 ethyl acetate/methanol/NH4OH. The desired fractions were collected and concentrated under vacuum, and the residue was further purified by preparative reverse phase HPLC to provide 8 mg of the title compound as a diTFA salt. MS (APCI) m/e 530 (M-H)+, 1H NMR (500 MHz, DMSO-d6): □ 13.30 (s, 1H), 9.78 (s, 1H), 9.26 (s, 1H), 8.71 (d, J=1.87 Hz, 1H), 8.38-8.45 (m, 2H), 7.96 (s, 1H), 7.80 (d, J=8.11 Hz, 1H), 7.47 (d, J=1.56 Hz, 1H), 7.30 (dd, J=8.11, 1.56 Hz, 1H), 6.82-6.96 (m, 7H), 4.05 (t, J=6.86 Hz, 2H), 3.71-3.73 (m, 4H), 2.97-2.99 (m, 4H), 2.87 (t, J=6.55 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[Cl:20])[CH:3]=1.C([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])(C)(C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:27]([CH3:29])([CH3:28])[C:26]([OH:31])=[O:25])=[C:4]([S:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][C:11]=2[Cl:20])[CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CS(=O)(=O)c1ccc(Sc2cc(Cl)ccc2O)c(Cl)c1
Product: CC(C)(Oc1ccc(Cl)cc1Sc1ccc(S(C)(=O)=O)cc1Cl)C(=O)O

Procedure:
The title compound was prepared by the method of example 1 step (iv) using the product from example 7 step (iii) and tert-butyl-2-bromoisobutyrate, yield 0.028 g.
Reaction SMILES: [N+:1]([CH2:4][C:5]([O:7]C)=[O:6])([O-:3])=[O:2].[CH3:9][N:10]1[CH2:14][CH2:13][N:12]=[C:11]1SC>C(O)(C)C>[CH3:9][N:10]1[CH2:14][CH2:13][NH:12][C:11]1=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)C[N+](=O)[O-]
Reactant: CSC1=NCCN1C
Solvent: CC(C)O
Product: CN1CCNC1=C(C(=O)O)[N+](=O)[O-]

Procedure:
35.7 g methyl nitroacetate was added slowly to a refluxing mixture of 39.0 g of 1A and 300 ml of isopropyl alcohol. The mixture then was refluxed for 1 hour with provision to remove the methyl mercaptan by-product. The mixture was cooled and filtered to give the methyl ester of (1-methyl-2-imidazolidinylidene)nitroacetic acid (1B) as a solid, m.p.: 214°-217° (with decomposition).
Reaction SMILES: [C:1]([S@@:5](/[N:7]=[CH:8]/[C:9]1[S:10][C:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][N:13]=1)=[O:6])([CH3:4])([CH3:3])[CH3:2].[CH3:21][Mg]Br>C(Cl)Cl>[CH3:2][C:1]([CH3:4])([S@@:5]([NH:7][C@@H:8]([C:9]1[S:10][C:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][N:13]=1)[CH3:21])=[O:6])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1cnc(/C=N/[S@@](=O)C(C)(C)C)s1
Reactant: C[Mg]Br
Solvent: ClCCl
Product: C[C@@H](N[S@@](=O)C(C)(C)C)c1ncc(C(=O)OC(C)(C)C)s1
Temperature: -70 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a solution of (S,E)-tert-butyl 2-((tert-butylsulfinylimino)methyl)thiazole-5-carboxylate (15 g, 47 mmol) in DCM (500 mL) at −70° C. was slowly added methylmagnesium bromide (63 mL, 3 M in ether). The mixture was stirred at −70° C. for 3 h then quenched with sat. NH4Cl solution. The solution was then warmed to rt. After separation, the aqueous phase was extracted with DCM (3×200 mL). Combined organic phases were dried (Na2SO4), and concentrated. Flash column chromatography (DCM: MeOH, 100:0 to 100:1) afforded tert-butyl 2-((R)-1-((S)-1,1-dimethylethylsulfinamido)ethyl)thiazole-5-carboxylate (10 g, 64%). 1H NMR (CDCl3, 400 MHz) δ 8.14 (s, 1H), 4.76 (m, 1H), 4.15 (m, 1H), 1.60 (d, J=6.8 Hz, 3H), 1.50 (s, 9H), 1.20 (s, 9H).
Reaction SMILES: [CH2:1]([O:19][C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[S:31][C:32]1[S:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1>>[CH2:1]([O:19][C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[S:33][C:32]2=[S:31])=[CH:24][CH:23]=1)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc(CBr)cc1
Reactant: CSc1nc2ccccc2s1
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc(Cn2c(=S)sc3ccccc32)cc1

Procedure:
4-Octadecyloxycarbonylbenzyl bromide (4.7 g, Step 2) and 2-methylmercaptobenzothiazole (2.5 g) were heated together for 35 minutes/190°-195° C. The mixture was cooled and triturated with ligroin to produce a solid which was recrystallized from pyridine/methanol to form the product; yield 4.5 g (81%), m.p. 105°-107° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(=O)[C:12](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[C:8]([C:6]1[N:7]=[C:2]([CH3:1])[CH:3]=[CH:4][CH:5]=1)(=[O:10])[C:12]1[CH:11]=[CH:4][CH:3]=[CH:2][CH:1]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cccc(C(=O)O)n1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cc1cccc(C(=O)c2ccccc2)n1
Reaction time: 1 h

Procedure:
To 15 g of 6 -methyl-2-pyridylcarboxylic acid (122 mmol) in 200 ml benzene is added dropwise 19.1 g (150 mmol) oxalyl chloride (dissolved in 30 ml benzene) with ice bath cooling. After 1 hr, solvent and excess chloride are removed. Concentrate is taken up in 100 ml benzene, cooled to ~10° & 175 mmol AlCl3 added. The solution is heated to 25° for 1 hour, then heated to reflux for 2 hours, and finally cooled and stirred overnight. The mixture is poured onto ice/conc. HCl, then washed with ether. Fifty Percent (50%) sodium hydroxide is added until the precipitate is dissolved. The solution is extracted with CHCl3, washed with water, dried and stripped, leaving 6-benzoyl-2-methylpyridine.
Reaction SMILES: [C:1]([C:3]1C=CC(C(C2C(=O)CCCC=2OCC)NC(NC2C=CC=C(C(F)(F)F)C=2)=O)=C(F)C=1)#N.[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:57]2[C:62](=[O:63])[CH2:61][CH2:60][CH2:59][C:58]=2[OH:64])[NH:43][C:44]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:56])([F:55])[F:54])[CH:48]=2)=[O:45])=[C:38]([O:65][CH3:66])[CH:37]=1>>[Br:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:57]2[C:58](=[O:64])[CH2:59][CH2:60][CH2:61][C:62]=2[O:63][CH2:1][CH3:3])[NH:43][C:44]([NH:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([C:53]([F:55])([F:54])[F:56])[CH:48]=2)=[O:45])=[C:38]([O:65][CH3:66])[CH:37]=1
Reactant: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(C#N)cc2F)C(=O)CCC1
Reactant: COc1cc(Br)ccc1C(NC(=O)Nc1cccc(C(F)(F)F)c1)C1=C(O)CCCC1=O
Product: CCOC1=C(C(NC(=O)Nc2cccc(C(F)(F)F)c2)c2ccc(Br)cc2OC)C(=O)CCC1

Procedure:
The title compound is prepared in analogy to 1-((4-cyano-2-fluorophenyl)(2-ethoxy-6-oxocyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 41) using ici 1-((4-bromo-2-methoxyphenyl)(2-hydroxy-6-oxocyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 48, 900 mg, 1.75 mmol) as starting material. Yield: 910 mg; ESI mass spectrum [(79Br)-M+H]+=541, [(81Br)-M+H]+=543; Retention time HPLC: 0.92 min (Z011_S03).
Reaction SMILES: I[C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>CCOC(C)=O>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[S:6][C:2]=2[C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[CH:13][CH:14]=1
Reactant: COc1ccc(Oc2c(I)sc3ccccc23)cc1
Reactant: COc1ccc(B(O)O)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(-c3ccc(OC)cc3)sc3ccccc23)cc1
Yield: 70 %

Procedure:
By essentially following the procedure detailed in Example 1, Part B, the title compound was prepared from 2-iodo-3-(4-methoxyphenoxy)benzo[b]thiophene (Part B) and (4-methoxyphenyl)boronic acid (Part C) in 70% yield following chromatography (SiO2; 5% EtOAc in hexanes).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:15]3[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[C:12](=[O:29])[N:11]([CH2:30][CH2:31][CH3:32])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:40][C:41]#[C:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([F:53])([F:52])[F:51])=[CH:45][CH:44]=1>CC(C)=O>[CH2:26]([N:13]1[C:14](=[O:25])[C:15]2[N:16]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([O:1][CH2:40][C:41]#[C:42][C:43]4[CH:44]=[CH:45][C:46]([O:49][C:50]([F:51])([F:52])[F:53])=[CH:47][CH:48]=4)=[CH:7][CH:6]=3)=[N:9][C:10]=2[N:11]([CH2:30][CH2:31][CH3:32])[C:12]1=[O:29])[CH2:27][CH3:28]
Reactant: FC(F)(F)Oc1ccc(C#CCBr)cc1
Reactant: CCCn1c(=O)c2c(nc(-c3ccc(O)cc3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCn1c(=O)c2c(nc(-c3ccc(OCC#Cc4ccc(OC(F)(F)F)cc4)cc3)n2COCC[Si](C)(C)C)n(CCC)c1=O
Temperature: 80 °C
Yield: 36.7 %

Procedure:
A mixture of 8-(4-hydroxy-phenyl)-1,3-dipropyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione (0.100 g, 0.22 mmol) and potassium carbonate (0.076 g, 0.53 mmol), 1-(3-bromo-prop-1-ynyl)-4-trifluoromethoxy-benzene (prepared as given in example E1) (0.073 g, 0.26 mmol) in acetone (10 ml) was heated at 80° C. for 2 hours. The mixture was cooled to room temperature, filtered and washed with acetone. Solvent was evaporated to obtain a residue which was purified by preparative TLC to obtain 1,3-dipropyl-8-{4-[3-(4-trifluoromethoxy-phenyl)-prop-2-ynyloxy]-phenyl}-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione as a pale yellow solid (0.053 g, 37%).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11](O)[N:12]1[CH:15]([CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:14][C:13]1=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:32])=O>C1COCC1>[CH2:1]([O:8][C:9]([CH:11]([Cl:32])[N:12]1[CH:15]([CH2:16][CH2:17][O:18][C:19](=[O:21])[CH3:20])[CH2:14][C:13]1=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OCCC1CC(=O)N1C(O)C(=O)OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OCCC1CC(=O)N1C(Cl)C(=O)OCc1ccccc1
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
1-(Benzyloxycarbonyl hydroxymethyl)-4-(2-acetoxyethyl)-2-azetidinone (1.8 g) is dissolved in 30 ml THF under N2 and cooled to -20° C. Pyridine 0.45 ml is added and then thionylchloride (0.390 ml in 4 ml THF) is added dropwise over 2 minutes. The reaction mixture is stirred at -20° C., for 5 minutes. The cooling bath is removed and the reaction mixture is stirred for another 25 minutes. The reaction mixture is diluted with 30 ml benzene and filtered. The filtrate is evaporated under reduced pressure at 5° C. The residue is 1-(benzyloxycarbonylchloromethyl)-4-(2-acetoxyethyl)-2-azetidinone which is used directly in the next reaction.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CO.CN(C=O)C>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2ccccc2)ccn1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1cc(-c2ccccc2)ccn1)NO
Reaction time: 24 h
Yield: 23 %

Procedure:
HONH2 (50% aqueous, 4 mL) was added to II (120 mg, 0.3 mmol) in MeOH (4 mL) and DMF (2 mL) at rt. The reaction mixture was stirred for 24 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (3×5 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:2 to 100:8) to furnish III as a yellow oil (28 mg, 23%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]3[CH:23]=[C:22]([Sn](CCCC)(CCCC)CCCC)[N:21]=[CH:20]3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:37][C:38]([NH:41][S:42]([C:45]1[S:49][C:48](Br)=[CH:47][CH:46]=1)(=[O:44])=[O:43])([CH3:40])[CH3:39].CCCCCC>C1(C)C=CC=CC=1>[C:38]([NH:41][S:42]([C:45]1[S:49][C:48]([C:22]2[N:21]=[CH:20][N:19]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=4)[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=3)[CH:23]=2)=[CH:47][CH:46]=1)(=[O:43])=[O:44])([CH3:40])([CH3:37])[CH3:39]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Br)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(F)c(F)c3)cc(C(F)(F)F)n2)cn1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4ccc(F)c(F)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 129.9 %

Procedure:
A stirred mixture of 4-(3,4-difluoro-phenyl)-2-(4-tributylstannanyl-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example G.13) (0.21 g, 0.34 mmol), commercially available 5-bromothiophene-2-N-tert-butylsulfonamide (0.11 g, 0.37 mmol), tetrakis(triphenyl-phosphine)palladium (0.024 g, 0.02 mmol) in toluene (3 ml) was heated under reflux conditions for 15 h, hexane (10 ml) was added and the mixture was stirred at RT for 1 h. The precipitate was collected by filtration and further purified by flash chromatography on silica gel (ethyl acetate/heptane) to yield 5-{1-[4-(3,4-difluoro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.24 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH3:8])[CH:3]=1.[Br:9]N1C(=O)CCC1=O>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][CH3:8])[C:3]=1[Br:9]
Reactant: CCc1cc(N)on1
Reactant: O=C1CCC(=O)N1Br
Product: CCc1noc(N)c1Br

Procedure:
5-Amino-4-bromo-3-ethylisoxazole was prepared from 5-amino-3-ethylisoxazole and N-bromosuccinimide as described in Example 25a.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:7][CH2:6][CH:5]([OH:8])[CH2:4][O:3]1.O[N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][C:2]1([CH3:9])[O:7][CH2:6][CH:5]([O:8][N:11]2[C:15](=[O:16])[C:14]3[C:13](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:12]2=[O:21])[CH2:4][O:3]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC1(C)OCC(O)CO1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC1(C)OCC(ON2C(=O)c3ccccc3C2=O)CO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of 2,2-dimethyl-[1,3]dioxan-5-ol (1.50 g, 11.35 mmol), N-hydroxyphthalimide (1.85 g, 11.35 mmol) and triphenylphosphine (2.98 g, 11.35 mmol) in anhydrous tetrahydrofuran (30 mL) at 0° C. was added diethyl azodicarboxylate (2.3 mL, 14.75 mmol). The resultant solution was allowed to warm to room temperature. After stirring for 3 hours, the mixture was concentrated in vacuo and charged with chloroform affording white solids. The solids were filtered off and filtrate was collected and concentrated. The residue was purified via silica column chromatography (4:1 hexanes/ethyl acetate) affording 2-(2,2-dimethyl-[1,3]dioxan-5-yloxy)-isoindole-1,3-dione as clear crystals (1.74 g, 55% over 2 steps): 1H NMR (400 MHz; DMSO-d6) δ 7.83 (s, 4H), 4.11-4.12 (m, 1H), 4.04-4.09 (m, 2H), 3.92-3.96 (m, 2H), 1.32 (s, 3H), 1.25 (s, 3H); MS (APCI+)=278.0.