Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:10]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 92.2 %

Procedure:
A mixture of 4-cyanophenol (5.0 g, 42 mmol), benzylbromide (8.6 g, 50 mmol), potassium carbonate (11.6 g, 84.0 mmol) in DMF (40 mL) was stirred at 100° C. for 3 h. The precipitate was filtered off and the filtrate was diluted with EtOAc and washed with water. The organic layer was dried (Na2SO4) and concentrated. The resulting crude product was purified by silica gel column chromatography (eluting with petroleum ether/EtOAc from 20/1 to 5/1) to give 4-(benzyloxy)benzonitrile as a white solid (8.1 g, 92%).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[N:24]([CH2:25][C:26]([NH2:28])=[O:27])[N:23]=[N:22][N:21]=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[N:24]([CH2:25][C:26](=[O:27])[NH2:28])[N:23]=[N:22][N:21]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: NC(=O)Cn1nnnc1S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: NC(=O)Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 1 h

Procedure:
7-Aminocephalosporanic acid (5.44 g., 20 mmole) and 5-Mercapto-1H-tetrazol-1-ylacetamide (3.50 g., 2.2 mmole) were suspended in 50% aqueous acetone (200 ml) and solid sodium bicarbonate added until a clear solution was obtained, ~pH 7.0. The solution was heated at 60° for 6 hours, uncovered for the final hour which allowed most of the acetone to evaporate, then acidified to pH 4.0 and stirred in an ice bath for one hour. The solid product was collected, washed with a little cold water and dried in vacuo, 3.22 g (43.4%), δ(CF3CO2H) 4.00 (2H,bs, C2 methylene), 4.69 (2H,bs, --CH2S--), 5.56 (4H,s, --CH2CO2NH2 and β-lactam protons), 7.4-7.8 (2H,m, --CONH2).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]([CH3:25])([CH3:24])[CH2:10]2)[N:5]=[C:4]([O:26][CH:27]2[CH2:32][C:31]([CH3:34])([CH3:33])[N:30]([O:35][CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]3)[C:29]([CH3:43])([CH3:42])[CH2:28]2)[N:3]=1.[CH2:44]([CH2:46][NH2:47])[OH:45]>>[OH:45][CH2:44][CH2:46][NH:47][C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:11]([CH3:25])([CH3:24])[CH2:10]2)[N:5]=[C:4]([O:26][CH:27]2[CH2:32][C:31]([CH3:33])([CH3:34])[N:30]([O:35][CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)[C:29]([CH3:43])([CH3:42])[CH2:28]2)[N:3]=1
Reactant: CC1(C)CC(Oc2nc(Cl)nc(OC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Reactant: NCCO
Product: CC1(C)CC(Oc2nc(NCCO)nc(OC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)oxy]-1,3,5-triazine with ethanolamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([C:10]2[CH:14]=[C:13]([N:15]=[C:16]([NH2:23])[N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[O:12][N:11]=2)[CH3:9])[CH:5]=[CH:4][C:3]=1[C:24]1[CH:29]=[CH:28][C:27]([O:30]C)=[CH:26][CH:25]=1.C(Cl)Cl.B(Br)(Br)Br.[OH-].[Na+]>O1CCCC1>[NH2:23][C:16]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)=[N:15][C:13]1[O:12][N:11]=[C:10]([CH:8]([C:6]2[CH:5]=[CH:4][C:3]([C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)=[C:2]([F:1])[CH:7]=2)[CH3:9])[CH:14]=1
Reactant: COc1ccc(-c2ccc(C(C)c3cc(N=C(N)N4CCOCC4)on3)cc2F)cc1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(c1ccc(-c2ccc(O)cc2)c(F)c1)c1cc(N=C(N)N2CCOCC2)on1
Reaction time: 1 h
Yield: 53.5 %

Procedure:
The compound (5.16 g) obtained in Example 63 was dissolved in tetrahydrofuran (100 ml) under a nitrogen atmosphere and then a methylene chloride solution (40 ml) of boron tribromide (1.6 ml) was added at -78° C., after which the temperature was elevated to room temperature over one hour and the stirring was further conducted at room temperature for 3 hours. The reaction mixture was neutralized with a 15% aqueous sodium hydroxide solution and then subjected to extraction with ethyl acetate and methanol. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (chloroform alone→chloroform/methanol=50/1→33/1) to obtain the desired compound (2.67 g).
Reaction SMILES: [CH:1]([C:3]1[C:11]([Cl:12])=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[Cl:13])=[O:2].S(Cl)([Cl:16])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH:1]([C:3]1[C:11]([Cl:12])=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][C:4]=1[Cl:13])=[O:2]
Reactant: O=Cc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: O=Cc1c(Cl)cc(C(=O)Cl)cc1Cl
Temperature: 70 °C
Reaction time: 2 h
Yield: 115.8 %

Procedure:
A mixture of 4-formyl-3,5-dichlorobenzoic acid (15.0 g, 0.06 moles), thionyl chloride (12.1 g, 0.107 moles), and dimethylformamide (5 ml) in toluene (100 ml) was slowly warmed to 70° C. and stirred at that temperature for 2 hours. The toluene was eliminated in the rotavap to yield 16.5 g of 4-formyl-3,5-dichlorobenzoyl chloride used in the next step as such.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[C:15]1([CH2:21][CH2:22][CH2:23][NH2:24])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:24][CH2:23][CH2:22][CH2:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)#[N:2]
Reactant: NCCCc1ccccc1
Reactant: CC(C)OC(=NC#N)c1cccnc1
Solvent: CO
Product: N#CNC(=NCCCc1ccccc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 78.1 %

Procedure:
Isopropyl N cyano-3-pyridinecarboximidate (0.60 g, 3.2 mmol) was dissolved in methanol (10 ml), and 3-phenylpropylamine (0.47 g, 3.5 mmol) was added. The mixture was stirred at room temperature for 50 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure. The residual concentrate thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C 200, 30 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.67 g, 2.5 mmol, yield: 80%) as colorless needles.
Reaction SMILES: [CH2:1]1COCC1.C[O:7][C:8]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)[CH:11]=[CH:10][N:9]=1.C(=O)([O-])[O-].[K+].[K+].CI>C(Cl)Cl>[CH3:1][N:9]1[CH:10]=[CH:11][C:12]([C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:18][CH:19]=2)=[CH:13][C:8]1=[O:7]
Reactant: COc1cc(-c2ccc(N3C[C@H](CNC(C)=O)OC3=O)cc2)ccn1
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Product: CC(=O)NC[C@H]1CN(c2ccc(-c3ccn(C)c(=O)c3)cc2)C(=O)O1
Temperature: 85 °C
Yield: 69 %

Procedure:
To a stirred anhydrous THF (10 mL) mixture of N-({(5S)-3-[4-(2-methoxypyridin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (0.667 g, 1.95 mmol) in a sealed tube, is added potassium carbonate (0.807 g, 6.0 mmol) and methyl iodide (1 mL, 17 mmol). The mixture is heated to 85° C. for 16 hours. The reaction is cooled to RT and diluted to 300 mL with CH2Cl2. The K2CO3 is filtered. The solution is concentrated to dryness, dissolved in MeOH (20 mL) and treated with saturated Na2S2O3. The solution is concentrated to dryness on silica. The residue is loaded onto a SIM and purified on a Biotage 12M column with 2–4% MeOH in CH2Cl2 to yield the desired compound (0.460 g, 69%). 1H-NMR (DMSO) δ: 8.26, 7.77, 7.64, 6.68, 6.60, 4.74, 4.17, 3.78, 3.43, 1.83
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC#Cc1ccc2c(ccn2-c2ccc(Br)cc2)c1
Product: CS(=O)(=O)OCCCC#Cc1ccc2c(ccn2-c2ccc(Br)cc2)c1

Procedure:
In analogy to example 5.4, 5-[1-(4-Bromo-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol and methanesulfonyl chloride were converted to yield Methanesulfonic acid 5-[1-(4-bromo-phenyl)-1H-indol-5-yl]-pent-4-ynyl ester as light yellow viscous oil, MS: 431 (M, 1Br).
Reaction SMILES: [I-].[I-].[I-].[In+3:4].[CH2:5]([Mg]Cl)[C:6]([CH3:9])([CH3:8])[CH3:7]>C(OCC)C>[CH2:5]([In:4]([CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: [In+3]
Reactant: CC(C)(C)C[Mg]Cl
Agent: [I-]
Solvent: CCOCC
Product: CC(C)(C)C[In](CC(C)(C)C)CC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A flask, charged with 29.13 g (58.3 mmol) of indium triiodide dissolved in 100 ml. of dry diethyl ether (from sodium/benzophenone), was fitted with a condenser, magnetic stir bar and a pressure equalizing addition funnel. Under a cover of argon, 100 ml., 2.32 M neopentyl magnesium chloride in diethyl ether solutin (previously prepared from purified neopentyl chloride and magnesium turnings) was transferred to the addition funnel. The Grignard reagent was then added to the indium triiodide solution over a period of 20 minutes. After the addition was complete, the reaction mixture was stirred at room temperature for 18 hours. The condenser and addition funnel were then replaced by a stopper and a Teflon valve adapter and the diethyl ether was removed by vacuum distillation at room temperature. The crude product, a trisneopentyl indium etherate mixture, was isolated by vacuum distillation at 110° C. into a side-arm flask (cooled to -196° C.) attached to the reaction flask by means of an 85° elbow. The distillation must be continued for approximately 8 hours. The diethyl ether was then removed from the crude trisneopentyl indium by simple vacuum distillation at room temperature for 12 hours. The product, a crystalline solid, is finally purified by vacuum sublimation at 30° C. with the receiving flask at -10° C. The yield of purified trisneopentyl indium was 17.7 g (53.9 mmol, 92.4% based on indium triiodide).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=1[Cl:29])[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:31]1CCCC1.C(O)(C)(C)C.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:30])[C@H:15]([CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([O:27][CH3:28])=[CH:22][C:21]=1[Cl:29])[CH2:16][CH:17]=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: C=CC[C@@H](Cc1c(Cl)cc(OC)cc1Cl)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1cc(Cl)c(C[C@H](CC=O)C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c(Cl)c1
Yield: 49 %

Procedure:
Treat a mixture of (R)-4-benzyl-3-[(S)-2-(4-methoxy-2,6-dichloro-benzyl)-pent-4-enoyl]-oxazolidin-2-one (6.65 g, 14.87 mmol), tetrahydrofuran (140 mL) and water (45 mL) with 2.5% osmium tetroxide in t-butanol (378 mL, 1.487 mmol). Add sodium periodate (9.55 g, 44.63 mmol) and stir the reaction 4 hr at room temperature. Quench the reaction with water and extract with ethyl acetate. Wash the organic phase with aqueous 1N sodium thiosulfate then brine. Dry the organic layer over magnesium sulfate, filter, and concentrate under vacuum. Purify the crude material by silica gel chromatography using hexanes:ethyl acetate to elute the pure product. Concentrate the fractions containing product under vacuum to afford 3.35 g (49%) of desired product. MS (m/z): 451 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([OH:37])[C@H:12]([OH:36])[C@@H:13]([CH2:15][O:16][C:17]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[O:14][C@H:8]3[N:7]([CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])[C:6]=2[CH:45]=1>CC(C)=O.Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C@H:9]3[C@@H:11]([OH:37])[C@H:12]([OH:36])[C@H:13]([CH2:15][O:16][C:17]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[O:14][C@H:8]3[N:7]([CH2:38][CH2:39][N:40]([CH2:43][CH3:44])[CH2:41][CH3:42])[C:6]=2[CH:45]=1
Reactant: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](O)[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H]21
Agent: Cl
Solvent: CC(C)=O
Product: CCN(CC)CCN1c2cc(Cl)ccc2S[C@H]2[C@@H](O)[C@H](O)[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H]21
Reaction time: 0.17 h
Yield: 166.6 %

Procedure:
To the solution of 500 mg of the compound (34) obtained in Example 33 in 3 ml of acetone, 1.5 ml of hydrochloric acid-saturated diethyl ether was added at 0° C., and the mixture was stirred for 10 minutes. The precipitate was filtered to obtain 440 mg (yield 82.2%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[CH3:25][C:26]1([CH3:42])[O:31][CH:30]([C:32]([NH:34][CH2:35][CH2:36][C:37](O)=[O:38])=[O:33])[C:29]([CH3:41])([CH3:40])[CH2:28][O:27]1>>[CH3:25][C:26]1([CH3:42])[O:31][CH:30]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:38])=[O:33])[C:29]([CH3:41])([CH3:40])[CH2:28][O:27]1
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(=O)NCCCO
Product: CCCCC/C=C\C/C=C\CCCCCCCC(=O)NCCCOC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 67 %

Procedure:
N-(3-Hydroxypropyl)linoleamide (3.38 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain of the title compound (yield: 67%)
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:8][C@@H:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH2:6][CH2:5][CH2:4]1.[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26].O>N1C=CC=CC=1>[S:25]([O:1][CH2:2][C@@H:3]1[O:8][C@@H:7]([O:9][CH:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[CH2:6][CH2:5][CH2:4]1)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]
Reactant: OC[C@H]1CCC[C@H](OC(Cn2ccnc2)c2ccc(Cl)cc2Cl)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCC[C@H](OC(Cn3ccnc3)c3ccc(Cl)cc3Cl)O2)cc1
Yield: 94.2 %

Procedure:
A solution of 5.10 g of 1-[trans-β-(6-hydroxymethyltetrahydropyran-2-yloxy)-2,4-dichlorophenethyl]imidazole in 40 ml of dry pyridine was stirred overnight at room temperature with 2.88 g of tosyl chloride. The reaction mixture was poured into water and extracted with diethyl ether. The ethereal extract was washed with aqueous sodium chloride and dried over anhydrous sodium sulphate, and the solvent was removed by evaporation under reduced pressure. The residue was purified by column chromatography through silica gel eluted with a 20:20:1 by volume mixture of benzene, ethyl acetate and ethanol, to give 6.8 g of the title compound, as a colourless liquid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].I[CH2:27]C>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH2:23][CH3:27])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCn1c(=O)n(-c2cn(C)nc2C)c2c3cc(Br)ccc3ncc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Stage A.1, 0.698 mmol) in DMF (5 ml) cooled with an ice-bath was added 55% NaH in oil (1.398 mmol). The RM was stirred for 30 min at rt then was added iodoethane (0.085 ml) and the RM was stirred for 30 min at rt. The RM was diluted with EtOAc and washed with saturated aqueous NaHCO3, with brine (2×), dried over Na2SO4, filtered and evaporated. The residue was absorbed on silica gel and purified by flash chromatography (CH2Cl2/MeOH 0% to 3.5%). The fractions containing product were evaporated together to give the title compound as a brown solid. (HPLC: tR 2.41 min (Method A); M+H=386, 388 MS-ES)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][C@H:18]3[CH3:30])=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.Cl.O1CCOCC1>CO>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]3[CH3:30])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H]1CNCCN1c1ccc(Nc2cc(Br)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
To a mixture of 115c (600 mg, 1.26 mmol) in methanol (20 mL) was added HCl/dioxane (4M, 4 mL). The reaction mixture was stirred at room temperature for 4 h. It was then concentrated under reduced pressure. The residue was basified with aqueous 1M NaOH and extracted with dichloromethane (3×30 mL). The combined organic layer was washed with brine and concentrated under reduced pressure to afford 115d (450 mg, 95%) as a yellow solid. MS-ESI: [M+H]+ 378.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][N:10](CC3C=CC(OC)=CC=3)[C:6]=2[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][N:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)(C(F)(F)F)=O.C1(OC)C=CC=CC=1.S(=O)(=O)(O)O>[Cl:1][C:2]1[C:7]2[CH:8]=[CH:9][NH:10][C:6]=2[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:4][N:3]=1
Reactant: CCOC(=O)c1cnc(Cl)c2ccn(Cc3ccc(OC)cc3)c12
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOC(=O)c1cnc(Cl)c2cc[nH]c12
Reaction time: 2 h
Yield: 76.7 %

Procedure:
A solution of ethyl 4-chloro-1-{[4-(methyloxy)phenyl]methyl}-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (1.00 g) in TFA (5 ml) and anisole (0.92 ml) was stirred at room temperature for 2.5 h. Sulphuric acid (5 drops) was added to the reaction mixture and stirring continued for 2 h then sulphuric acid (2 ml) was added and the reaction mixture stirred for 24 h at room temperature. The solution was added to saturated sodium bicarbonate at 0° C. and extracted with ethyl acetate. The aqueous layer was separated and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a brown solid (0.50 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[Li]CCCC.[NH2:14][C:15]1[C:26]([O:27][CH:28]2[CH2:30][CH2:29]2)=[CH:25][CH:24]=[CH:23][C:16]=1[C:17](N(OC)C)=[O:18].Cl>O1CCCC1>[NH2:14][C:15]1[C:26]([O:27][CH:28]2[CH2:29][CH2:30]2)=[CH:25][CH:24]=[CH:23][C:16]=1[C:17]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:18]
Reactant: CON(C)C(=O)c1cccc(OC2CC2)c1N
Reactant: Fc1cccc(I)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Nc1c(OC2CC2)cccc1C(=O)c1cccc(F)c1
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A solution of 1-fluoro-3-iodobenzene (1.009 mL, 8.59 mmol) in tetrahydrofuran (100 mL) was cooled to −78° C. in a dry ice/acetone bath under nitrogen. Then a solution of n-BuLi (1.8 M in hexanes, 5.37 mL, 8.59 mmol) was added via syringe over 15 minutes and stirred for 60 minutes to give gave a dark-yellow suspension. Then a solution of 2-amino-3-cyclopropoxy-N-methoxy-N-methylbenzamide (0.58 g, 2.455 mmol) in 10 mL of THF was added via syringe and the reaction mixture was stirred for 40 minutes at −78° C. After 40 minutes the mixture was poured into a mixture of ice and 1N HCl and extracted into ethyl acetate to give a light-yellow solution. The organic layer was washed with water and brine and concentrated to give a dark-yellow oil residue. The crude product mixture was purified via ISCO (0%-100% of EtOAC/heptane in 15 minutes, 40 g column) to give (2-amino-3-cyclopropoxyphenyl)(3-fluorophenyl)methanone (0.46 g, 1.696 mmol, 69.1% yield). HPLC: RT=3.481 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=272.16 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ 7.48-7.40 (m, 2H), 7.36 (ddd, J=9.3, 1.9, 1.1 Hz, 1H), 7.27-7.18 (m, 2H), 7.08 (dd, J=8.3, 1.2 Hz, 1H), 6.58 (t, J=8.0 Hz, 1H), 6.39 (br. s., 2H), 3.83 (t, J=4.5 Hz, 1H), 0.86 (d, J=4.4 Hz, 4H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:19])=[C:7]([O:9][C:10]2[CH:11]=[C:12]([CH:15]=[C:16]([Cl:18])[CH:17]=2)[C:13]#[N:14])[CH:8]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2.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>[Cl:19][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([O:21][CH3:20])=[CH:30][CH:29]=3)=[O:32])=[CH:8][C:7]=1[O:9][C:10]1[CH:11]=[C:12]([C:13]#[N:14])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: N#Cc1cc(Cl)cc(Oc2cc(CN)ccc2Cl)c1
Reactant: COc1ccc2[nH]c(C(=O)O)cc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3)cc2c1
Yield: 37.8 %

Procedure:
N-({4-Chloro-3-[(3-chloro-5-cyanophenyl)oxy]phenyl}methyl)-5-(methyloxy)-1H-indole-2-carboxamide was prepared in a similar manner as described herein from 3-{[5-(aminomethyl)-2-chlorophenyl]oxy}-5-chlorobenzonitrile (0.025 g, 0.085 mmol), 5-(methyloxy)-1H-indole-2-carboxylic acid, (0.025 g, 0.13 mmol), HATU (0.05 g, 0.13 mmol), DIPEA (0.025 mL, 0.13 mmol) and DMF (1 mL). The crude material was purified by Reverse-Phase HPLC (water/acetonitrile with 0.1% TFA). The desired fractions were neutralized and extracted with EtOAc. The organic extracts were combined, dried over Na2SO4, filtered and evaporated to afford the title compound (0.015 g, 36%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.42 (d, 1H), 8.98 (t, 1H), 7.76 (d, 1H), 7.59 (d, 1H), 7.43 (dd, 1H), 7.35 (d, 1H), 7.25-7.28 (m, 2H), 7.23 (d, 1H), 7.03 (dd, 2H), 6.80 (dd, 1H), 4.48 (d, 2H), 3.72 (s, 3H). MS: m/z 466.1 (M+1).
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]2[O:15][N:14]=[C:13]([CH2:16]O)[CH:12]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C1(C)C=CC=CC=1>[Cl:3][CH2:16][C:13]1[CH:12]=[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[O:15][N:14]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(-c2ccccc2)on1
Solvent: O
Solvent: Cc1ccccc1
Product: ClCc1cc(-c2ccccc2)on1
Temperature: 80 °C
Reaction time: 3 h
Yield: 88 %

Procedure:
Thionyl chloride (7.55 ml) was added to a solution of (5-phenyl-3-isoxazolyl)methanol (12.1 g) in toluene (50 ml) and stirred at 80° C. for 3 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The remaining crystals were recrystallized from ethyl acetate-hexane to obtain 3-(chloromethyl)-5-phenylisoxazole (11.8 g, yield 88%) as pale-yellow crystals. m.p. 46-47° C.