Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[I-].[Na+].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.[OH-].[Na+]>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=C(O)c1ccccc1Cl
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccccc1Oc1ccc(Cl)cc1

Procedure:
To a well stirred mixture of 15.7 g. (0.1 mole) of 2-chlorobenzoic acid and 15.0 g. (0.1 mole) of sodium iodide in 250 ml. of 4-chlorophenol was rapidly added a solution of 16 g. (0.4 mole) of sodium hydroxide dissolved in 16 ml. of water. The reaction mixture was heated and concentrated under reduced pressure to an internal temperature of about 145° C. to remove the water and excess 4-chlorophenol. The residue was then stirred at 170° C. for about 7 hours, cooled and diluted with 250 ml. of water. The aqueous solution was extracted with ethyl acetate after acidifying with dilute hydrochloric acid. The ethyl acetate extractions were washed with water, dried and concentrated under reduced pressure. The residue was recrystallized from a benzene-hexane mixture to give pure 2-(4'-chlorophenoxy)benzoic acid, m.p. 114°-115° C.
Reaction SMILES: [H-].[Na+].[N:3]([C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:7]1)=[N+:4]=[N-:5].[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.O>C1COCC1.C(OCC)(=O)C>[N:3]([C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C@H:8]([C:15]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]([S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])[CH:16]=2)[CH2:7]1)=[N+:4]=[N-:5]
Reactant: COc1ccc2c([C@@H]3C[C@@H](N=[N+]=[N-])c4ccccc43)c[nH]c2c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c([C@@H]3C[C@@H](N=[N+]=[N-])c4ccccc43)cn(S(=O)(=O)c3ccc(C)cc3)c2c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
1 g Sodium hydride (60% in mineral oil) was added to 2 g 3-((1R,3R)-3-azido-indan-1-yl)-6-methoxy-1H-indole in 50 mL dry THF at 5° C. and the reaction mixture was stirred 1 hour at 5° C. 2 g p-toluene sulfonic acid chloride was added in portions at 5° C. and stirring was continued for another 4 hours. Ice was added and after 1 hour water and ethyl acetate was added. The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in vacuo. After flash chromatography (heptane/ethyl acetate, silica gel), 2.5 g 3-((1R,3R)-3-azido-indan-1-yl)-6-methoxy-1-(toluene-4-sulfonyl)-1H-indole was isolated.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:8])([F:7])[CH2:5][OH:6].[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])[C:11]=1F.Cl>C1COCC1>[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])[C:11]=1[O:6][CH2:5][C:4]([F:8])([F:7])[F:3]
Reactant: CS(=O)(=O)c1c(C(=O)O)ccc(Cl)c1F
Reactant: OCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1c(C(=O)O)ccc(Cl)c1OCC(F)(F)F
Yield: 99.9 %

Procedure:
Sodium hydride (1.05 g of 80% powder) was suspended in THF and to this was added a solution of 2,2,2-trifluoroethanol (1.9 g) in THF, followed by a solution of 4-chloro-3-fluoro-2-methylsulphonylbenzoic acid (4 g) in THF. The resultant mixture was stirred for 2 hours and then acidified with 2 M HCl. The mixture was extracted with ether, washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness yielding 4-chloro-2-methylsulphonyl-3-(2,2,2-trifluoroethoxy)benzoic acid (5.26 g) as a whim solid, NMR (DMSO d6) 2.5(s,3H), 4.8(q,2H), 7.5(d,1H), 8.0(d,1H).
Reaction SMILES: [OH:1][C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[N:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].[CH3:23][O:24][CH2:25]Cl>O1CCCC1>[CH3:23][O:24][CH2:25][O:1][C:2]1[C:3]2[CH:16]=[CH:15][CH:14]=[N:13][C:4]=2[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Oc1c(-c2ccccc2)sc2ncccc12
Reactant: COCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCOc1c(-c2ccccc2)sc2ncccc12

Procedure:
A suspension of 4.54 g (20 mmol) of 3-hydroxy-2-phenyl-7-azabenzo[b]thiophene and 2.75 g (22 mmol) of potassium t-butoxide in 50 mL of tetrahydrofuran was stirred until the solid dissolved. Then 2.0 g (25 mmol) of chloromethyl methyl ether was added and the solution was stirred at room temperature for 2 hours. The solution was partitioned between ether and water and the aqueous layer was washed with two portions of ether. The ether extracts were washed with brine, dried over MgSO4, and concentrated to 4.33 g (80%) of an oil that crystallized upon standing, m.p. 54° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](CO)=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH2:10][CH2:11]O)[CH3:9].S(Cl)([Cl:17])=O.Cl[CH2:20][Cl:21]>>[ClH:1].[Cl:1][C:2]1[C:3]([CH2:20][Cl:21])=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH2:10][CH2:11][Cl:17])[CH3:9]
Reactant: ClCCl
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)c1ccnc(CO)c1Cl
Product: CN(CCCl)c1ccnc(CCl)c1Cl
Product: Cl
Reaction time: 0.5 h

Procedure:
A solution of 3-chloro-4-[N-(2-hydroxyethyl)-N-methylamino]-2-hydroxymethylpyridine (2.3 g) in dichloromethane (30 ml) is treated dropwise at 0° C. with a solution of thionyl chloride (4 ml) in dichloromethane (20 ml). The temperature is then allowed to climb to 20° C. (20 min) and the temperature is then kept at 400° C. for 30 min. After stripping off the solvent in vacuo, the residue which remains is chromatographed on silica gel (petroleum ether/ethyl acetate 7/3 mixture which contains 1 ml of conc. NH3 ×aq/L). Yield: 2.6 g.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([OH:11])[C:5]2[N:6]([N:8]=[CH:9][CH:10]=2)[CH:7]=1.Br.Br[CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.[H-].[Na+]>CN(C=O)C>[CH3:7][N:6]1[CH:5]=[C:10]([C:2]2[CH:3]=[C:4]([O:11][CH2:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[C:5]3[N:6]([N:8]=[CH:9][CH:10]=3)[CH:7]=2)[CH:9]=[N:8]1
Reactant: BrCc1cccnc1
Reactant: Oc1cc(Br)cn2nccc12
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(OCc3cccnc3)c3ccnn3c2)cn1
Reaction time: 1 h

Procedure:
6-bromopyrazolo[1,5-a]pyridin-4-ol (10.0 mg, 0.047 mmol), 3-(bromomethyl)pyridine hydrobromide (14.2 mg, 0.056 mmol), and NaH (6.7 mg, 0.168 mmol, 60 wt %) were suspended in DMF (1 ml) and stirred for 1 h. The reaction mixture was quenched by the addition of saturated aqueous ammonium chloride. The reaction mixture was diluted in ethyl acetate, then washed with water (5 mL) and brine (5 mL). The combined aqueous layers were extracted with ethyl acetate (2×10 mL), and the combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/ethyl acetate gradient) to afford 6-(1-methyl-1H-pyrazol-4-yl)-4-(pyridin-3-ylmethoxy)pyrazolo[1,5-a]pyridine.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=2[CH:5]=[CH:4]1.C(#N)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>O.CO>[CH3:19][S:20]([N:3]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH3:15])=[O:13])[C:6]=2[CH:5]=[CH:4]1)(=[O:22])=[O:21]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1cccc2c1ccn2S(C)(=O)=O
Temperature: 25 °C
Yield: 118.1 %

Procedure:
Sodium hydride (1.1 g of a 80% dispersion in mineral oil), methyl 1H-indole 4-carboxylate (5.46 g) and anhydrous acetonitrile were mixed under an inert atmosphere at 0° C. and stirred at room temperature for an hour. Methanesulphonyl chloride (1.8 g) was added at 0° C. and the mixture stirred at room temperature for 18 hours. Methanol and then water were then added and the mixture extracted with dichloromethane. The organic phase was washed with 2N hydrochloric acid, water, 1M sodium carbonate and water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by column chromatography eluting with ethyl acetate/hexane obtaining methyl 1-(methylsulphonyl)indole-4-carboxylate (4.7 g) as a white solid, m.p. 102°-104° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:11][CH2:10]2)=[CH:5][C:4]=1C)#[CH:2].[CH3:19][O:20][C:21](=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][C:26](I)=[CH:25][CH:24]=1.[CH2:31](N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:17][C:14]([CH3:15])([CH3:16])[CH2:13][O:12][C:9]1([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:26]3[CH:27]=[CH:28][C:23]([CH2:22][C:21]([O:20][CH3:19])=[O:30])=[CH:24][CH:25]=3)=[CH:8][C:7]=2[CH3:31])[CH2:10][CH2:11]1
Reactant: COC(=O)Cc1ccc(I)cc1
Reactant: CCN(CC)CC
Reactant: C#Cc1ccc(C2(OCC(C)(C)C)CC2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCC(C)(C)C)CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
Using General Procedure F; 4-ethynyl-1-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-benzene (Intermediate 85, 75.0 mg, 0.31 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 86.0 mg, 0.31 mmol) in triethylamine (6 mL) was treated with copper(I)iodide (21.0 mg, 0.11 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (78 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 100.0 mg (83%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[CH:15][C:14]3[C:9](=[C:10]([C:17]([OH:19])=O)[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1.[S:20]1[CH:24]=[CH:23][N:22]=[C:21]1[NH2:25].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[CH:15][C:14]3[C:9](=[C:10]([C:17]([NH:25][C:21]4[S:20][CH:24]=[CH:23][N:22]=4)=[O:19])[CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:2]=1
Reactant: Nc1nccs1
Reactant: O=C(O)c1cccc2cnc(-c3cccnc3)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)c1cccc2cnc(-c3cccnc3)nc12
Temperature: 50 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
A mixture of 2-(pyridin-3-yl)quinazoline-8-carboxylic acid (250 g, 1.0 mmol), thiazole-2-amine (94 mg, 1.0 mmol), HATU (760 mg, 2.0 mmol) and DIPEA (260 mg, 2.0 mmol) in DMF (15 mL) was stirred at 50° C. for 12 hours. Water (20 mL) was added and the precipitate was collected by filtration, washed with water (3×10 mL) and methanol (3×5 mL) to obtain 2-(pyridin-3-yl)-N-(thiazol-2-yl)quinazoline-8-carboxamide (150 mg, 46% yield). MS (ESI) calcd for C17H11N5OS (m/z): 333.07. found: 334 [M+1].
Reaction SMILES: [H-].[Na+].[C:3](=[N:16][OH:17])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:19][CH2:20][C:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:24]=2[O:23][C:22]=1[CH3:36].C(O)(=O)C>CN(C=O)C.O>[C:4]1([C:3](=[N:16][O:17][CH2:19][CH2:20][C:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[C:29]([O:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:24]=3[O:23][C:22]=2[CH3:36])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)COc1cccc2c(CCBr)c(C)oc12
Reactant: ON=C(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)COc1cccc2c(CCON=C(c3ccccc3)c3ccccc3)c(C)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Sodium hydride (60%, 30 mg) was suspended in DMF (1 ml) and a solution of benzophenoneoxime (157 mg) in DMF (2 ml) was added dropwise thereto, followed by stirring the resulting mixture at room temperature for 1 hour. To this solution, a solution of methyl (3-(2-bromoethyl)-2-methylbenzofuran-7-yloxy)acetate (201 mg) in DMF (3 ml) was added dropwise and the solution was stirred at room temperature for 30 minutes. Acetic acid was added to this reaction solution and the resulting solution was added to water layer (50 ml) followed by extraction of the resultant twice with ethyl acetate (20 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1) using silica gel to obtain the desired compound (177 mg, yield: 65%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[N:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([O:41][CH3:42])[CH:35]=2)[CH2:30][CH2:29]1)=[O:27].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([N:31]2[CH2:32][CH2:33][N:28]([C:26](=[O:27])[CH2:25][N:5]3[C:6]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=4)=[C:2]([Cl:1])[C:3]([C:14]([F:15])([F:17])[F:16])=[N:4]3)[CH2:29][CH2:30]2)=[CH:35][C:36]=1[O:41][CH3:42]
Reactant: Fc1cccc(-c2[nH]nc(C(F)(F)F)c2Cl)c1
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3-c3cccc(F)c3)CC2)ccc1Cl

Procedure:
Protocol T was followed using 4-Chloro-5-[3-Fluorophenyl]-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3, Rf=0.59) afforded the title compound as a white solid. 1H NMR (400 MHz, CDCl3): 7.64–7.68 (d, 1H), 7.56–7.62 (d, 1H), 7.36–7.42 (m, 1H), 7.22–7.24 (m, 2H), 7.08–7.12 (m, 1H), 6.42–6.52 (m, 2H), 5.2 (s, 2H), 3.9 (s, 3H), 3.62–3.82 (m, 4H), 3.12–3.22 (m, 4H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:7]1[CH2:12][CH2:11][CH:10]([S:13][C:14]2[C:15]([F:37])=[CH:16][C:17]3[O:26][CH2:25][CH2:24][N:23]4[C:19](=[N:20][C:21]([C:27]5[N:28]([CH:33]([CH3:35])[CH3:34])[N:29]=[C:30]([CH3:32])[N:31]=5)=[CH:22]4)[C:18]=3[CH:36]=2)[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O>C1COCC1>[F:37][C:15]1[C:14]([S:13][CH:10]2[CH2:11][CH2:12][N:7]([C:4]([CH3:6])([CH3:5])[CH2:3][OH:2])[CH2:8][CH2:9]2)=[CH:36][C:18]2[C:19]3[N:23]([CH2:24][CH2:25][O:26][C:17]=2[CH:16]=1)[CH:22]=[C:21]([C:27]1[N:28]([CH:33]([CH3:35])[CH3:34])[N:29]=[C:30]([CH3:32])[N:31]=1)[N:20]=3
Reactant: COC(=O)C(C)(C)N1CCC(Sc2cc3c(cc2F)OCCn2cc(-c4nc(C)nn4C(C)C)nc2-3)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2cn3c(n2)-c2cc(SC4CCN(C(C)(C)CO)CC4)c(F)cc2OCC3)n(C(C)C)n1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
To an ice-cooled solution of 2-{4-[8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropionic acid methyl ester (0.394 mmol) in THF (20 mL) was added LiAlH4 (1.0M in THF, 0.79 mL) and the mixture was stirred at 0° C. for 5 min. To the reaction mixture was added EtOAc (1 mL) and stirring was continued for 10 min. Volatiles were removed under reduced pressure and the resulting residue was partitioned between DCM (40 mL) and 10% aq. solution of Rochelle's salt (50 mL). The suspension was then filtered through a pad of Celite®. The filtrate was extracted with additional DCM and the combined organic layers were washed with water, then brine, dried and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-10% 2M NH3/MeOH in DCM) affording 2-{4-[8-Fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}-2-methylpropan-1-ol (148 mg, 73% over two steps). LCMS: RT 2.17 min [M+H]+ 515.0
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([CH:8]=O)=[CH:5][CH:4]=1)#[CH:2].[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[C:1]([C:3]1[S:7][C:6]([CH2:8][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1)#[CH:2]
Reactant: C1COCCN1
Reactant: C#Cc1ccc(C=O)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: C#Cc1ccc(CN2CCOCC2)s1
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
To a solution of 5-ethynylthiophene-2-carbaldehyde (88 mg, 0.646 mmol), morpholine (56 uL, 0.646 mmol) in 1,2-dichloroethane (3.0 mL) was added a drop of AcOH. The mixture was stirred for 15 min and then NaBH(OAc)3 (205 mg, 0.969 mmol) was added and stirred at room temperature for 18 h. The reaction was diluted with CH2Cl2 (30 mL) and washed with saturated NaHCO3 (2×5 mL), brine (5 mL), and the organic layer dried over MgSO4. The solvent was removed and the residue purified by column chromatography (silica gel, hexanes/EtOAc, 3:1) to give the title product (80 mg, 60%); MS ESI [M+H]+ 208.08, calcd for [C11H13NOS+H]+ 207.8.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[C@H:7]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:26])[CH2:18][CH2:19][S:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].CN([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43]N=1)C.O>C(Cl)(Cl)Cl.C(N(CC)CC)C.C(Cl)CCCCCCCCCCCCCCCCC>[C:1]([O:5][C:6](=[O:37])[C@H:7]([CH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:8][C:9](=[O:27])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:26])[CH2:18][CH2:19][S:20][CH2:21][CH:22]([O:25][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:6][CH2:7][CH3:28])[CH2:23][O:24][CH2:41][CH2:46][CH2:45][CH2:44][CH2:43][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH2:2][CH2:1][CH3:3])=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)c1ccccn1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(NC(=O)CCSCC(O)CO)cc1)C(=O)OC(C)(C)C
Agent: CCCCCCCCCCCCCCCCCCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCCCCCCCCCCCCCOCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1)OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 76 %

Procedure:
To a solution of (4-(6,7-dihydroxy-4-thiaheptanoylamino)benzoyl)glutamic acid di-t-butyl ester as obtained in Reference Example 6 (50 mg) in chloroform (1 ml), triethylamine (0.258 ml), stearyl chloride (0.25 ml) and dimethylaminopyridine (1 mg) were added, followed by stirring at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to yield the title compound (75 mg, yield 76%) as a wax-like substance.
Reaction SMILES: [N:1]([CH2:4][CH2:5][OH:6])=[N+:2]=[N-:3].CN(C)C=O.CC([N:16]([C@H:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]#[CH:31])[CH:28]=2)[N:23]([C:32](=[O:34])[CH3:33])[C@@H:22]([CH3:35])[CH2:21]1)[C:17](=[O:19])[O-:18])(C)C>[Cu]I.CO>[C:32]([N:23]1[C:24]2[C:29](=[CH:28][C:27]([C:30]3[N:3]=[N:2][N:1]([CH2:4][CH2:5][OH:6])[CH:31]=3)=[CH:26][CH:25]=2)[C@H:20]([NH:16][C:17](=[O:19])[O:18][C:27]([CH3:30])([CH3:28])[CH3:26])[CH2:21][C@@H:22]1[CH3:35])(=[O:34])[CH3:33]
Reactant: [N-]=[N+]=NCCO
Reactant: C#Cc1ccc2c(c1)[C@H](N(C(=O)[O-])C(C)(C)C)C[C@H](C)N2C(C)=O
Agent: [Cu]I
Solvent: CO
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(-c3cn(CCO)nn3)cc2[C@H](NC(=O)OC(C)(C)C)C[C@@H]1C
Temperature: 25 °C
Yield: 83 %

Procedure:
A flask was charged with 2-azidoethanol (318 mg, 3.65 mmol) and copper(I) iodide (17.40 mg, 0.091 mmol) then filled with N,N-dimethylformamide (DMF) (13 mL) and methanol (1.5 mL). This mixture was treated with 1,1-dimethylethyl[(2S,4R)-1-acetyl-6-ethynyl-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 113) (600 mg, 1.827 mmol) and the resulting mixture was at 100° C. for 2 h under microwave irradiation then cooled to room temperature and partitioned between EtOAc and water. The layers were separated and the aqueous phase was extracted three times with EtOAc. The combined organic layers were washed twice with brine, and then dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 0 to 5% MeOH in DCM) gave 1,1-dimethylethyl {(2S,4R)-1-acetyl-6-[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (659 mg, 1.523 mmol, 83% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](Cl)=[O:10])[CH:5]=[N:6][C:7]=1[Cl:8].O[NH:13][C:14](=[NH:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[C:15]([C:14]1[N:19]=[C:9]([C:4]2[CH:5]=[N:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:10][N:13]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: O=C(Cl)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)(C)C(=N)NO
Solvent: Cc1ccccc1
Product: CC(C)(C)c1noc(-c2cnc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
A mixture of 5,6-dichloro-pyridine-3-carbonyl chloride (1.8 g, 8.6 mmol) and N-hydroxy-2,2-dimethylpropanimidamide (1.0 g, 8.6 mmol) in toluene (40 mL) was stirred at room temperature for two hours and then heated under reflux for four hours. The mixture was cooled to room temperature and filtered through celite, the solids being washed with toluene (20 mL). Evaporation of the combined filtrates under reduced pressure gave the desired product (1.3 g, 56%) as a clear oil which crystallised on standing to a white solid, MP 98-101° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C@H:10]([OH:13])[CH2:11]Cl)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O-:24])(=[O:23])[CH3:22].[K+].C(C1C=CC=CC=1)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[C:21]([O:24][CH2:11][C@@H:10]([OH:13])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CCc1ccccc1
Solvent: CC#N
Product: CC(=O)OC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Yield: 44.7 %

Procedure:
A mixture composed of 2.0 mmol (0.599 g) of (2S, 3S)-3-(t-butoxycarbonylamino)-1-chloro-2-hydroxy-4-phenylbutane, 0.1 mmol (0.032g) of tetrabutylammoniumbromide, 5.0mmol (0.49 g) of potassium acetate and 10 ml of acetonitrile was stirred under reflux for 50 hours. Thereafter, the solvent was distilled off under reduced pressure, 20 ml of water and 20 ml of ethyl acetate were added, and the organic layer was separated, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a crude product. Quantitative analysis was curried out by high performance liquid chromatography using ethylbenzene as an internal standard. Thus was obtained 0.289 g (45%) of the title compound.