Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[N:6]=1)=[O:4].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O1CCCC1.CN(C)C=O.C(OCC)(=O)C>[Br:11][C:7]1[N:6]=[C:5]([C:3](=[O:4])[CH2:2][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:10]=[CH:9][CH:8]=1
Reactant: C1COCCN1
Reactant: O=C(CBr)c1cccc(Br)n1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(CN1CCOCC1)c1cccc(Br)n1
Reaction time: 0.75 h

Procedure:
To a solution of 2-bromo-1-(6-bromopyridin-2-yl)ethanone (250 mg, 0.90 mmol) in tetrahydrofuran (1 mL) and dimethylformamide (1 mL) was added morpholine (0.18 mL, 2.0 mmol). After 45 minutes, the reaction mixture was diluted with ethyl acetate (30 mL) and washed with saturated aqueous sodium bicarbonate (15 mL) and brine (15 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated to afford the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]2[C:15]([OH:18])=[N:16][O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.OCCC1CCN(C(OC(C)(C)C)=O)CC1>>[CH2:1]([O:8][C:9]1[C:14]2[C:15]([O:18][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:23][CH2:22]3)=[N:16][O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1noc2cccc(OCc3ccccc3)c12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(OCc4ccccc4)c23)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 8 using 4-(benzyloxy)-1,2-benzisoxazol-3-ol (EXAMPLE 7, Step 1) and tert-butyl 4-(hydroxymethyl)-piperidine-1-carboxylate instead of 4-(benzyloxy)-1,2-benzisoxazol-3-ol and tert-butyl 4-(2-hydroxyethyl)-piperidine-1-carboxylate.
Reaction SMILES: [C:1]1([CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.Cl.C1(C(C2C=CC=CC=2)=CC[N:41]2[CH2:46][CH2:45][CH:44]([N:47]3[CH2:55][C:54]4[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:48]3=[O:56])[CH2:43][CH2:42]2)C=CC=CC=1>CN(C=O)C.ClCCl>[O:11]=[C:9]([N:41]1[CH2:46][CH2:45][CH:44]([N:47]2[CH2:55][C:54]3[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:48]2=[O:56])[CH2:43][CH2:42]1)[CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1c2ccccc2CN1C1CCN(CC=C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CC(c1ccccc1)c1ccccc1)N1CCC(N2Cc3ccccc3C2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a solution of 3,3-diphenylpropionic acid (500 mg, 2.21 mmol) and DMF (1 drop) in dichloromethane (5 mL) at RT was added dropwise a solution of oxalyl chloride in dichloromethane (2.0M, 1.66 mL, 3.32 mmol). Bubbling of escaping gasses continued for 10 min after addition. The reaction was stirred at RT for 60 min, then concentrated in vacuo to give a crude oil. To a solution of crude acid chloride and triethylamine (1.4 mL, 10.0 mmol) in dichloromethane (10 mL) at 0° C. under argon was added dropwise a solution of Example 2 Part A compound (434 mg, 2.00 mmol) in dichloromethane (2 mL). The reaction was stirred at 0° C. for 10 min. Dichloromethane (100 mL) was added to dilute the reaction and the resulting solution was washed with H2O (40 mL), saturated sodium bicarbonate solution (40 mL), brine (40 mL) and dried over MgSO4. Evaporation gave a crude gum. Purification was performed by flash chromatography on silica gel (100 g), loaded and eluted with 2.5% methanol in dichloromethane. Pure fractions were combined and evaporated to give title compound (610 mg, 72%) as a off-white solid.
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][N:20]=3)=[O:18])[CH2:13][CH2:12]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[NH2:53][CH2:54][C:55]1[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=1>C(Cl)Cl.O1CCCC1>[CH:1]([NH:4][C:5]1[C:6]([N:11]2[CH2:12][CH2:13][N:14]([C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:53][CH2:54][C:55]4[CH:56]=[N:57][CH:58]=[CH:59][CH:60]=4)=[O:25])=[CH:21][N:20]=3)=[O:18])[CH2:15][CH2:16]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)O)cn2)CC1
Reactant: NCc1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCc3cccnc3)cn2)CC1
Reaction time: 2 h
Yield: 75 %

Procedure:
6-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]nicotinic acid (2 g) was added to a co-solvent of tetrahydrofuran (30 ml) and methylene chloride (30 ml) and with the successive addition of 1,3-dicyclohexylcarbodimide (2.4 g) and 1-hydroxybenzotriazole (0.85 g) at 15° C.˜20° C., the mixture was reacted at the same temperature for 2 hours. With the addition of 3-(aminomethyl)pyridine (0.65 g) at 20° C., the reaction mixture was stirred at 20° C.˜25° C. for 2 hours. With the addition of methylene chloride (60 ml). The mixture was washed with water 3 times, dried over magnesium sulfate and concentrated under reduced pressure. The concentrated residue was chromatographed on column (hexane/chloroform/ethanol=5/2/1, v/v/v). The purified solution was concentrated under reduced pressure, and then, the residue was treated with ether for crystallization to give a desired compound of 1.87 g (yield: 75%).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15]([NH2:17])=O)=[CH:11]3)[CH2:3][CH2:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:35])=CC=1>O1CCCC1>[CH:1]1([CH2:4][N:5]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:14]=2[NH:13][C:12]([C:15](=[S:35])[NH2:17])=[CH:11]3)[CH2:3][CH2:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: NC(=O)c1cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c2[nH]1
Solvent: C1CCOC1
Product: NC(=S)c1cc2cccc(N(CC3CC3)S(=O)(=O)c3cccs3)c2[nH]1
Yield: 88.3 %

Procedure:
7-[(Cyclopropylmethyl)(2-thienylsulfonyl)amino]-1H-indole-2-carboxamide (264 mg), Lawesson's reagent (339 mg) and tetrahydrofuran (5 mL) were stirred at 60° C. for 2 hr. The reaction mixture was concentrated under reduced pressure, subjected to silica gel column chromatography, and eluted with an ethyl acetate-hexane (1:1) mixed solvent to give the title compound (243 mg, yield 88%) as an amorphous solid.
Reaction SMILES: C([Li])CCC.C(OP([CH2:14][C:15]([OH:17])=[O:16])(OCC)=O)C.[C:18]1([CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O1CCCC1.O>[C:18]1([CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=[CH:14][C:15]([OH:17])=[O:16])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=CC=CC=Cc1ccccc1
Reactant: CCOP(=O)(CC(=O)O)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C=CC=CC=Cc1ccccc1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 80.5 %

Procedure:
Butyllithium (12.8 mL of 2.5 N solution) was added to 65 mL of anhydrous tetrahydrofuran (THF) at −65° C. A solution of diethylphosphonoacetic acid (2.92 g) in 25 mL of anhydrous THF was added dropwise to the stirred solution at −65° C. The resulting solution was stirred at −65° C. for an additional 30 minutes and then a solution of 5-phenyl-2,4-pentadienal (2.4 g) in 15 mL of anhydrous THF was added to the reaction at −65° C. The reaction was stirred for one hour, allowed to warm to room temperature and then stirred overnight. To the reaction was added 30 mL of water, acidified with 5% hydrochloric acid (14 mL) to a pH of 4.7 and then added an additional 20 mL of water. The aqueous layer was extracted with 10 mL of ether twice and with 10 mL of ethyl acetate once. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The crude material was dissolved in 50 mL of hot methanol and then refrigerated overnight. The crystals formed were filtered and dried under vacuum to afford 2.4 g of the desired 7-phenyl-2,4,6-heptatrienoic acid. 1H NMR (DMSO-d6, 300 MHz), δ(ppm) 7.52 (m, 2H), 7.33 (m, 4H), 7.06 (m, 1H), 6.86 (m, 2H), 6.58 (m, 1H), 5.95 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19]>CN(C)C=O>[CH2:18]([N:20]([CH2:21][CH3:22])[C:2]1[C:3]2[N:4]([C:12]([CH:15]([CH3:17])[CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:19]
Reactant: CCNCC
Reactant: CC(C)c1nnc2c(Cl)nc3ccccc3n12
Solvent: CN(C)C=O
Product: CCN(CC)c1nc2ccccc2n2c(C(C)C)nnc12
Yield: 75 %

Procedure:
4-Chloro-1-isopropyl-[1,2,4]-triazolo[4,3-a]quinoxaline (1.0 g., 0.004 mole), the product of Example 6, and 900 mg. (0.012 mole) of diethylamine in N,N-dimethylformamide (15 ml.) were stirred at room temperature for 4 hours. The reaction mixture was poured over ice and the precipitate was separated by means of filtration, washed with water and placed on a column of silica gel (175 ml.) and finally eluted with chloroform. The eluant was evaporated in vacuo to afford 850 mg. (75% yield) of pure 4-diethylamino-1-isopropyl-[1,2,4]triazolo[4,3-a]quinoxaline as a white solid (m.p. 93°-95° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:35][CH2:34][CH2:33][C@H:9]3[S:10](=[O:32])(=[O:31])[C:11]([CH3:30])([CH3:29])[C:12]([N:14](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C)=[N:13][C@:8]3([CH2:36][F:37])[C:6]=2[CH:7]=1.[Cl:38][C:39]1[CH:40]=[N:41][C:42]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[N:44][C:43]=2Cl.C(O)(C)C.OS(O)(=O)=O>[OH-].[Na+].C(Cl)Cl.CO>[NH2:14][C:12]1[C:11]([CH3:29])([CH3:30])[S:10](=[O:31])(=[O:32])[C@@H:9]2[CH2:33][CH2:34][O:35][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:43]4[N:44]=[CH:45][CH:46]=[C:47]5[C:42]=4[N:41]=[CH:40][C:39]([Cl:38])=[CH:48]5)=[CH:7][C:6]=3[C@@:8]2([CH2:36][F:37])[N:13]=1
Reactant: Clc1cnc2c(Cl)nccc2c1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(CF)c3cc(N)ccc3OCC[C@H]2S(=O)(=O)C1(C)C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: CC(C)O
Product: CC1(C)C(N)=N[C@]2(CF)c3cc(Nc4nccc5cc(Cl)cnc45)ccc3OCC[C@H]2S1(=O)=O
Temperature: 90 °C
Yield: 81.6 %

Procedure:
To a 15-mL reaction vial was added tert-butyl N-[(4aR,11bS)-10-amino-11b-(fluoromethyl)-3,3-dimethyl-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (103 mg, 0.190 mmol), 3,8-dichloro-1,7-naphthyridine (41.6 mg, 0.209 mmol), isopropanol (3 mL) and a couple of β-drops of H2SO4. The vial was closed and heated at 90° C. for 1 h. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with 1N NaOH (5 mL) and extracted with DCM (8 mL×3). The organic extracts were dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 0% to 2% 2M NH3.MeOH in DCM, to provide (4aR,11bS)-2-amino-10-((3-chloro-1,7-naphthyridin-8-yl)amino)-11b-(fluoromethyl)-3,3-dimethyl-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazine 4,4-dioxide (78 mg, 0.155 mmol, 81% yield) as yellow solid. MS m/z=503.9 (M+H).
Reaction SMILES: CN(C=O)C.I[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[C:9]([NH2:16])=[N:10][NH:11]2.[C:17]([C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22])#[CH:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu](I)I.C(N(CC)CC)C>[NH2:22][C:21]1[CH:20]=[C:19]([C:17]#[C:18][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[C:9]([NH2:16])=[N:10][NH:11]3)[CH:25]=[CH:24][CH:23]=1
Reactant: Nc1n[nH]c2cccc(I)c12
Reactant: C#Cc1cccc(N)c1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1cccc(C#Cc2cccc3[nH]nc(N)c23)c1
Temperature: 60 °C

Procedure:
To 8 ml of DMF was added 4-iodo-1H-indazol-3-amine (690 mg, 2.65 mmol) and 3-ethynylaniline (480 mg, 1.5 eq., 4.1 mmol). Following that, Bis(triphenylphosphine) palladium(II) dichloride (180 mg, 0.25 mmol, 10 mol %), Copper Iodide (100 mg, 0.52 mmol, 20 mol %), Triphenylphosphine (18 mg, 0.07 mmol, 3 mol %) and 8 ml of triethylamine was added. Nitrogen was bubbled through the reaction mixture for 15 minutes. The reaction was then set with a reflux condenser, set under nitrogen atmosphere, and heated at 60° C. for 2 hours. After that, the reaction was cooled to room temperature and 40 ml of ethyl acetate was added. The organic layer was extracted with aqueous sodium bicarbonate (3×40 ml), brine (3×40 ml), dried using anhydrous sodium sulfate, loaded onto silica and columned to give 4-((3-aminophenyl)ethynyl)-1H-indazol-3-amine.
Reaction SMILES: C[O:2][C:3](=[O:35])[C:4]([CH3:34])([CH3:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH:15]2[CH2:19][N:18]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[C:17](=[O:31])[N:16]2[CH3:32])=[CH:8][CH:7]=1.[OH-].[Na+].Cl>CO>[CH3:33][C:4]([CH3:34])([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][CH2:14][CH:15]2[CH2:19][N:18]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=3)[C:17](=[O:31])[N:16]2[CH3:32])=[CH:10][CH:11]=1)[C:3]([OH:35])=[O:2]
Reactant: COC(=O)C(C)(C)Cc1ccc(OCCC2CN(Cc3ccc(C(F)(F)F)cc3)C(=O)N2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN1C(=O)N(Cc2ccc(C(F)(F)F)cc2)CC1CCOc1ccc(CC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of the ester obtained from Step A (61 mg, 0.12 mmol) in methanol (1.5 ml) is added 5N NaOH (0.3 ml, 1.5 mmol), and the mixture stirred for 20 hours at ambient temperature. The mixture is poured into 1N HCl (20 ml), then extracted with ethyl acetate (2×15 ml). The combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), and concentrated to a foam (56 mg, 97%.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9]O>>[C:6]1([CH3:9])[C:1]([OH:7])=[CH:2][CH:3]=[CH:4][CH:5]=1.[CH3:9][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[O:7][CH3:8]
Reactant: CO
Reactant: COc1ccccc1
Product: COc1ccccc1C
Product: Cc1ccccc1O
Reaction time: 2 h

Procedure:
A sample of HZSM-5, having a silica to alumina mole ratio of 130, was steamed for 2 hours at 800° C. When a mixture of anisole and methanol (mole ratio=2:1) was subsequently passed over the catalyst at 350° C. and a feed WHSV of 1.8 hr-1, an ortho-rich cresol fraction (66% ortho) and a para-rich methylanisole fraction (65% para) were produced. The results are summarized in TABLE II.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][N:10]=1)#N.[OH-:20].[K+].Cl.[CH2:23]([OH:29])COCCO>>[CH2:15]([C:12]1[CH:13]=[CH:14][C:9]([C:4]2[CH:3]=[CH:8][C:7]([C:23]([OH:29])=[O:20])=[CH:6][CH:5]=2)=[N:10][CH:11]=1)[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCc1ccc(-c2ccccc2C#N)nc1
Reactant: OCCOCCO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: CCCCCc1ccc(-c2ccc(C(=O)O)cc2)nc1
Temperature: 175 °C

Procedure:
A mixture of 3.026 g of 2-(cyanophenyl)-5-pentylpyridine, 125 ml of diethylene glycol and 13.8 g of potassium hydroxide was heated to 175° C. for 1.5 hours while stirring and gassing with nitrogen. The reaction mixture was then left to cool, adjusted to pH 8 with semi-concentrated hydrochloric acid and extracted with methylene chloride. The organic phase was washed with water, dried over sodium sulphate, filtered and concentrated. The crude p-(5-pentyl-2-pyridyl)benzoic acid obtained was recrystallized from acetone/hexane.
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:4]=[C:5]3[C:17]4[C:8](=[CH:9][CH:10]=[CH:11][C:12]=4[C:13]=2[CH2:14][CH2:15][CH:16]=1)[CH2:7][CH2:6]3>O1CCOCC1.C(OCC)(=O)C.O>[CH3:1][C:2]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:3]=1[CH:4]=[C:5]1[C:17]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]2=3)[CH:7]=[CH:6]1
Reactant: CC1=CCCc2c1cc1c3c(cccc23)CC1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc2c1cc1c3c(cccc32)C=C1
Yield: 54.9 %

Procedure:
A solution of 7-methyl-9,10-dihydroacephenanthrene (0.13 g, 0.59 mmol) and dichlorodicyanoquinone (0.27 g, 1.18 mmol) in dioxane (10 ml) was heated at reflux for 0.5 h. The reaction mixture was allowed to cool and was diluted with ethyl acetate (50 mL) and water (20 mL). The organic layer was separated, washed with water (3×20 mL) and brine solution (3×20 mL), dried (MgSO4), and concentrated under reduced pressure. The resulting solid was purified by flash chromatography to give 0.07 g (57%) of the product: 1H NMR (CDCl3, 300 MHz) δ 8.54 (d, 1H, J=8.0 Hz), 8.40 (dd, 1H, J=7.3, 6.9 Hz), 8.24 (s, 1H), 7.66 (m, 2H), 7.58 (dd, 1H, J=8.4, 7.3 Hz), 7.46 (d, 1H, J=7.3 Hz), 7.20 (d, 1H, J= 5.1 Hz), 7.16 (d, 1H, J=5.4 Hz), 2.82 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]2=[O:24])[CH:5]=[CH:6][C:7]=1[NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1.Cl[C:26]1[N:35]=[C:34]2[C:29]([C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[CH:32][N:33]2[CH:36]2[CH2:38][CH2:37]2)=[CH:28][C:27]=1[F:43].C(N(CC)CC)C.C[Si](C)(C)Cl>CS(C)=O>[C:21]([NH:20][CH2:19][C@@H:17]1[O:16][C:15](=[O:24])[N:14]([C:4]2[CH:5]=[CH:6][C:7]([NH:8][C@@H:9]3[CH2:13][CH2:12][N:11]([C:26]4[N:35]=[C:34]5[C:29]([C:30](=[O:42])[C:31]([C:39]([OH:41])=[O:40])=[CH:32][N:33]5[CH:36]5[CH2:38][CH2:37]5)=[CH:28][C:27]=4[F:43])[CH2:10]3)=[C:2]([F:1])[CH:3]=2)[CH2:18]1)(=[O:23])[CH3:22]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(NC3CCNC3)c(F)c2)C(=O)O1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N[C@@H]3CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)C3)c(F)c2)C(=O)O1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
A suspension of 119 mg N-{(5S)-3-[3-fluoro-4-(pyrrolidin-3-ylamino)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (0.35 mmol), 100 mg 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 148 μl triethylamine (1.05 mmol) and 89 μl trimethylchlorosilane (0.70 mmol) in 2 ml DMSO was stirred in a microwave oven at 150° C. for 10 min. The DMSO was evaporated, the residue digested in water and the solid filtrated. The solid was purified by chromatography using a 95/5 dichloromethane/methanol mixture.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[N:12]([CH3:13])[C:11]([CH:14]=O)=[N:10][CH:9]=1.Cl.[NH2:17][OH:18]>CCO>[Br:7][C:8]1[N:12]([CH3:13])[C:11](/[CH:14]=[N:17]/[OH:18])=[N:10][CH:9]=1
Reactant: NO
Reactant: Cn1c(Br)cnc1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cn1c(Br)cnc1/C=N/O
Temperature: 120 °C
Reaction time: 1 h
Yield: 94.1 %

Procedure:
A mixture of K2CO3 (360 mg, 2.61 mmol), 5-bromo-1-methyl-1H-imidazole-2-carbaldehyde (98.5 mg, 0.521 mmol) and hydroxylamine hydrochloride (109 mg, 1.563 mmol) in EtOH (4 mL) was stirred at 120° C. under microwave irradiation for 60 minutes. The resulting suspension was filtered, washing through with EtOAc and MeOH. The filtrate was concentrated in vacuo to afford the title compound as a white solid (100 mg, 94%).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH:27]1([C:30]2[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=2)[CH2:29][CH2:28]1.O>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:34]([C:33]1[CH:36]=[CH:37][C:30]([CH:27]2[CH2:28][CH2:29]2)=[CH:31][CH:32]=1)[OH:35])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: OC(c1ccc(C2CC2)cc1)c1ccccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (2.6 M, 3.5 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (2.2 g, 8.3 mmol) in THF (83 mL) at −78° C. and the mixture was stirred at the same temperature for 30 minutes. To this solution, a solution of 4-cyclopropylbenzaldehyde (1.1 g, 6.9 mmol) in THF (280 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for one hour. Water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (1.7 g, 75%).
Reaction SMILES: C1([C@@H]2COC=N2)C=CC=CC=1.[C:12]([O:20][C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][CH2:27]2)=[CH:23][CH:22]=1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N+](=[CH:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[N-]>ClCCl>[C:12]([O:20][C:21]1[CH:22]=[CH:23][C:24]2[C@@H:25]3[C@@H:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[C@@H:26]3[CH2:27][C:28]=2[CH:29]=1)(=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: O=C(Oc1ccc2c(c1)CC=C2)c1ccccc1
Agent: C1=N[C@H](c2ccccc2)CO1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1[C@@H]2Cc3cc(OC(=O)c4ccccc4)ccc3[C@@H]21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(+)-2,2′-Isopropylidenebis[(4R)-4-phenyl-2-oxazoline (849 mg, 2.542 mmol) was added to a stirring solution of 1H-inden-6-yl benzoate from Step D (30 g, 127.119 mmol) and Cu(I) triflate (657 mg, 1.271 mmol) in dichloromethane (300 mL) at rt under nitrogen. The solution was stirred at rt for 4 h. A solution of ethyl diazoacetate (29 g, 254.237 mmol) in dichloromethane (100 mL) was added at it through a syringe pump over a period of 72 h. Solvent was removed under reduce pressure, and the residue was purified by column chromatography on silica gel (PE) to give the title compound (about 50% enantiomeric excess). 1H-NMR (400 MHz, CDCl3): δ 8.18 (d, J=7.1 Hz, 2H), 7.63 (t, J=7.6 Hz, 1H), 7.51 (t, J=7.1 Hz, 2H), 7.37 (d, J=8.1 Hz, 1H), 6.96-7.02 (m, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.29-3.35 (m, 1H), 2.95-3.10 (m, 2H), 2.46-2.50 (m, 1H), 1.26-1.33 (m, 4H) ppm. MS: m/z 323.2 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.F[C:13]1[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=1[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28]COC)=[C:23]([O:32][CH3:33])[CH:22]=1>CS(C)=O>[Cl:1][C:2]1[C:7]([NH:8][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:32][CH3:33])[CH:22]=2)=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12
Reactant: COCCOc1ccc(-c2cncc(C#N)c2F)cc1OC
Reactant: Nc1cnc2[nH]ccc2c1Cl
Solvent: CS(C)=O
Product: COc1ccc(-c2cncc(C#N)c2Nc2cnc3[nH]ccc3c2Cl)cc1OC
Temperature: 100 °C
Yield: 24.6 %

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridin-5-amine (see e.g., Tetrahedron Lett., 45(11), 2317-2319 (2004)) (0.30 mmol, 51 mg) and 4-fluoro-5-[3-methoxy-4-(2-methoxyethoxy)phenyl]nicotinonitrile (0.23 mmol, 60 mg) in 2 mL DMSO was heated to 100° C. overnight. The product was purified by a preparative HPLC followed by silica gel chromatography (CH2Cl2/MeOH) to give 4-[(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)amino]-5-(3,4-dimethoxyphenyl)nicotinonitrile (23 mg). HPLC retention time: 7.9 min.(g) and MS: 406.2 (M+H) and HRMS: 406.10747.