Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]([O-:4])([O-])=[O:2].C.[Na+].[Na+].N1C=CC=C[CH:9]=1.Br[C:15]([CH3:22])([CH3:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17]>CN(C=O)C.C(OCC)(=O)C>[CH2:19]([O:18][C:16](=[O:17])[C:15]([S:1]([CH3:9])(=[O:4])=[O:2])([CH3:22])[CH3:21])[CH3:20]
Reactant: O=S([O-])[O-]
Reactant: c1ccncc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a suspension of 5 g (49 mmol) of sodium methane sulfite in DMF (50 mL) were added pyridine (6.3 mL) and ethyl α-bromoisobutyrate (2.9 mL). The reaction was stirred for 18 h at 50° C. under nitrogen. The reaction mixture was diluted with ethyl acetate (250 mL), washed with saturated aqueous NaHCO3 (2×100 mL), 2M aqueous HCl solution (50 mL), brine (1×50 mL) and dried over Na2SO4. Filtration, concentration under reduced pressure afforded 3.04 g of 2-methanesulfonyl-2-methyl-propionic acid ethyl ester.
Reaction SMILES: C(O[C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O)=[O:5])C.Cl.[C:13]([NH2:21])(=[NH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:13]2[N:21]=[C:4]([OH:5])[C:6]3[CH2:10][CH2:9][CH2:8][C:7]=3[N:20]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: N=C(N)c1ccccc1
Agent: Cl
Product: Oc1nc(-c2ccccc2)nc2c1CCC2

Procedure:
The title compound was prepared from 2-oxo-cyclopentanecarboxylic acid ethyl ester and benzamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 2.01 (tt, J=7.2, 7.2 Hz, 2H), 2.69 (t, J=7.2 Hz, 2H), 2.84 (t, J=7.2 Hz, 2H), 7.45-7.60 (m, 3H), 8.07 (d, J=7.1 Hz, 2H), 12.40 (br s, 1H); MS: m/z (ESI) 213 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[Cl:19][C:20]1[N:21]=[CH:22][C:23]([C:26](Cl)=[O:27])=[N:24][CH:25]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:26]([C:23]2[CH:22]=[N:21][C:20]([Cl:19])=[CH:25][N:24]=2)=[O:27])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(N)cc1OC
Reactant: O=C(Cl)c1cnc(Cl)cn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)c2cnc(Cl)cn2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
To a mixture of 3,4-dimethoxy phenylamine (0.306 g, 2 mmol) and triethylamine (0.557 ml, 4 mmol) in dichloromethane (20 ml) was added 5-chloro-pyrazine-2-carbonyl chloride (0.354 g, 2 mmol) at 0-5° C. The mixture was allowed to stir at room temperature for 3 hours. The mixture was diluted with methylene chloride (20 ml), washed with saturated NaHCO3 (20 ml), brine (20 ml), dried (anhyd. Na2SO4) and concentrated to get 0.42 g of crude 5-chloro-pyrazine-2 carboxylic acid (3,4-dimethoxy-phenyl)-amide, which was directly used in the next reaction.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19](=O)[CH2:20]Br>>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:17]=[C:18]([C:19]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=3)[C:7]([O:9][CH3:10])=[O:8])[S:3][CH:20]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: COC(=O)c1cccc(C(N)=S)c1
Product: COC(=O)c1cccc(-c2nc(-c3cccc(C(F)(F)F)c3)cs2)c1
Yield: 72 %

Procedure:
In the same manner as in Example 28, methyl 3-thiocarbamoylbenzoate was reacted with 3-trifluoromethylphenacyl bromide to obtain methyl 3-[4-(3-trifluoromethylphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 72%. Colorless prisms. Melting point: 105 to 106° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:23][O:24][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22].[CH3:25][S:26]([O-:28])=[O:27].[Na+].N1CCC[C@H]1C(O)=O>CS(C)=O.O.[Cu](I)I>[CH3:25][S:26]([C:2]1[CH:7]=[CH:6][C:5]2[C:8]3([CH2:23][O:24][C:4]=2[CH:3]=1)[C:16]1[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=1)[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]3=[O:22])(=[O:28])=[O:27]
Reactant: CCCCCN1C(=O)C2(COc3cc(Br)ccc32)c2ccccc21
Reactant: CS(=O)[O-]
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCN1C(=O)C2(COc3cc(S(C)(=O)=O)ccc32)c2ccccc21
Temperature: 100 °C
Yield: 5 %

Procedure:
A mixture of 6-bromo-1′-pentylspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one (0.60 g, 1.55 mmol), sodium methanesulfinate (0.19 g, 1.86 mmol), copper iodide (0.03 g, 0.16 mmol), and L-proline (0.04 g, 0.31 mmol) in dimethyl sulfoxide (3.00 mL) was heated at 100° C. for 2 days under N2. The reaction mixture was diluted with water (50.0 mL) and extracted with ethyl acetate (4×15.0 mL). The combined organics was dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 2/3) to give the title compound (0.03 g, 46%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.46-7.48 (m, 1H), 7.38 (dt, 1H), 7.34 (dt, 1H), 7.13-7.02 (m, 2H), 6.94 (d, 1H), 6.86 (d, 1H), 5.03 (d, 1H), 4.78 (d, 1H), 3.87-3.64 (m, 2H), 3.02 (s, 3H), 1.79-1.68 (m, 2H), 1.41-1.32 (m, 4H), 0.90 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.1, 161.2, 142.6, 142.1, 135.4, 131.5, 129.5, 124.3, 124.0, 123.5, 120.7, 109.5, 109.0, 80.5, 57.7, 44.5, 40.6, 29.0, 27.1, 22.3, 14.0; MS (ES+) m/z 386.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=C)[C:4]=1[C:5]([O:7][CH3:8])=[O:6].[O:15]=[O+][O-]>C(Cl)Cl>[CH:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]([O:7][CH3:8])=[O:6])=[O:15]
Reactant: O=[O+][O-]
Reactant: C=Cc1cccc(OC)c1C(=O)OC
Solvent: ClCCl
Product: COC(=O)c1c(C=O)cccc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.6 %

Procedure:
Into a solution of methyl 2-methoxy-6-vinylbenzoate (22 g, 0.11 mol) in anhydrous DCM (400 mL) was bubbled O3 at −78° C. over a 30 minute period. Next, nitrogen gas was bubbled into the solution until it turned colorless. Dimethylsulfane (20 mL) was added dropwise and the resulting mixture was warmed to RT and stirred for 2 hours. The mixture was washed with water (30 mL) and the aqueous layer was extracted with DCM (3×100 mL). The organic layers were combined, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography eluting with a gradient of EtOAc (0-90%) and PE to give the title compound (11.8 g, 53.6%). 1H NMR (400 MHz, CDCl3) δ ppm 9.97 (s, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 3.98 (s, 3H), 3.90 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:22][C:23](=[O:32])[C:24]4[C:29]([CH:30]=3)=[C:28](Br)[CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Al](CC)(CC)[CH2:34][CH3:35]>C1COCC1.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[NH:22][C:23](=[O:32])[C:24]4[C:29]([CH:30]=3)=[C:28]([CH2:34][CH3:35])[CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[Al](CC)CC
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cc4c(Br)cccc4c(=O)[nH]3)cc2)CC1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Solvent: C1CCOC1
Product: CCc1cccc2c(=O)[nH]c(-c3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
To a stirred solution of 4-[4-(5-Bromo-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.4 mmol) in anhydrous THF (4 mL) under N2 was added dichlorobis(tri-o-tolylphosphine)palladium(II) (14 mg, 0.02 mmol), CeCl3 (99 mg, 0.4 mmol) and AlEt3 (1M in hexanes, 1.5 mL, 1.2 mmol) and the reaction stirred at RT for 4 h. The reaction was quenched with ice, diluted with 0.5M aqueous Rochelle's salts (30 mL) and extracted with EtOAc (3×40 mL). The combined organics were washed with Rochelle's salts (2×50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo and the crude residue purified by reverse phase preparative HPLC-MS to afford 4-[4-(5-ethyl-1-oxo-1,2-dihydro-isoquinolin-3-yl)-benzyl]-piperazine-1-carboxylic acid tert-butyl ester as an orange solid (83 mg, 61%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:17]#[CH:18])=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:20])([CH3:19])[CH2:8][CH:7]=1)=[O:5])[CH3:2].[CH3:21][O:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][C:26]=1[F:32].C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[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>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:17]#[C:18][C:28]3[CH:29]=[CH:30][C:25]([CH2:24][C:23]([O:22][CH3:21])=[O:33])=[C:26]([F:32])[CH:27]=3)=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:19])([CH3:20])[CH2:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: C#Cc1cc2c(cc1C)C(C(=O)OCC)=CCC2(C)C
Reactant: COC(=O)Cc1ccc(I)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=CCC(C)(C)c2cc(C#Cc3ccc(CC(=O)OC)c(F)c3)c(C)cc21

Procedure:
Following General Procedure B and using 6-ethynyl-4,4,7-trimethyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 185, 0.2 g, 0.75 mmol), 2-fluoro-4-iodo phenyl acetic acid methyl ester (0.22 g, 0.75 mmol), triethyl amine (2 mL), copper(I)iodide (0.03 g, 0.16 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.1 g, 0.14 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10-12% ethyl acetate in hexane as the eluent, the title compound was obtained as a viscous oil (0.23 g, 73%).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3=[CH:8][CH:9]=[C:10]([OH:22])[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=43)[CH2:4][CH2:3]1)=[O:15].C([O-])([O-])=O.[K+].[K+].Cl[C:30]1[N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:33]=[N:32][N:31]=1>CN(C=O)C>[O:12]1[CH:13]2[C@@:5]34[CH2:4][CH2:3][N:2]([CH3:1])[C@@H:19]([C@:18]3([OH:21])[CH2:17][CH2:16][C:14]2=[O:15])[CH2:20][C:7]2=[C:6]4[C:11]1=[C:10]([O:22][C:30]1[N:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:33]=[N:32][N:31]=1)[CH:9]=[CH:8]2
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Reactant: Clc1nnnn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1CC[C@]23c4c5ccc(Oc6nnnn6-c6ccccc6)c4OC2C(=O)CC[C@@]3(O)[C@H]1C5
Temperature: 25 °C
Reaction time: 20 h
Yield: 134 %

Procedure:
A mixture of 2.4 g (79.6 mmol) oxymorphone, 24 g (173.6 mmol) anhydrous K2CO3 and 14.55 g (80.1 mmol) 5-chloro-1-phenyl-1H-tetrazole in 300 ml dry DMF was stirred at room temperature under argon for 20 hours. Then the reaction mixture was filtered, washed with CHCl3 and the filtrate was evaporated in vacuo. The oily residue was dissolved in 200 ml CHCl3, extracted with 1 N NaOH, water and brine. The organic layer was dried and evaporated to give 47.5 g of an oil, which was converted to the oxalate salt to yield 41.5 g (91%) of 4,5-epoxy-14-hydroxy-N-methyl (-3-(1-phenyl-1H-5-tetrazolyloxy) morphinan-6-one.(CO2H)2.2H2O, m.p. 143°-148°. The base was crystallized with ethyl acetate, m.p. 99°-102°, [α]D --179.0° (C 0.83, CHCl3).
Reaction SMILES: [Br:1][C:2]1[O:3][C:4]([C:11](Cl)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:23][CH2:22]2)=[N:19][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[O:3][C:4]([C:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:22][CH2:23][CH:24]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)=[N:19][CH:20]=2)=[O:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1
Reactant: Nc1ccc(N2CCC(c3ccccc3)CC2)nc1
Reactant: O=C(Cl)c1oc(Br)nc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccc(N2CCC(c3ccccc3)CC2)nc1)c1oc(Br)nc1C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 38.4 %

Procedure:
A solution of 2-bromo-4-trifluoromethyloxazole-5-carbonyl chloride (A-39) (0.34 g, 1.2 mmol) and 1-(5-aminopyridin-2-yl)-4-phenylpiperidine (B-6) (0.25 g, 1.0 mmol) in CH2Cl2 (10 mL) was cooled to −78° C. then triethyl amine (0.16 mL, 1.2 mmol) was added. The reaction mixture was stirred for 2 h while the temperature was warmed slowly up to 0° C. The solvent was concentrated, and the residue was purified by chromatography on a silica-gel column (eluant: 0-50% EtOAc/hexane gradient) to yield 1-(5-(2-bromo-4-(trifluoromethyl)oxazole-5-carboxamido)pyridin-2-yl)-4-phenylpiperidine (A-40) (0.19 g, 35% yield) as a yellow solid. Note: the product A-40 contains compound with the bromine atom exchanged for a chlorine atom. 1H NMR (500 MHz, CDCl3) δ 9.58 (br s, 1H), 8.59 (br s, 1H), 8.34 (dd, 1H, J=9.5, 1.8 Hz), 7.35 (m, 2H), 7.30-7.22 (m, 3H), 6.89 (d, 1H, J=9.4 Hz), 4.42 (d, 2H, J=13.3 Hz), 3.17 (t, 2H, J=12.7 Hz), 2.85 (m, 1H), 2.05 (m, 2H), 1.84 (m, 2H); LCMS (ESI) calcd for [M+1]+ for chloride 451.1. found 451.4.
Reaction SMILES: [Li]CCCC.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[C:21](Cl)(=[O:23])[CH3:22]>CCCCCC.C1COCC1.CCOCC.[Cl-].[Zn+2].[Cl-]>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([F:19])([F:20])[C:15]([F:16])([F:17])[F:18])=[CH:12][C:13]=1[C:21](=[O:23])[CH3:22]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(F)(F)C(F)(F)F)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(F)(F)C(F)(F)F)cc1C(C)=O
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
7.4 ml of BuLi at 2.5M in hexane are added, at −70° C., to a solution of 3.5 g of 1-methoxy-4-pentafluoroethylbenzene in 50 ml of anhydrous THF. The medium is stirred for 30 minutes at −70° C. and then for 45 minutes at 0° C. 15.5 ml of a 1M solution of zinc chloride in ether are then added. After stirring for 10 minutes at 0° C., 1.33 ml of acetyl chloride are added. The medium is then deoxygenated with nitrogen and 332 mg of benzyl(chloro)bis(triphenylphosphine)palladium in 5 ml of anhydrous THF are introduced. The medium is stirred for 2 hours 30 minutes at 0° C. and then for 72 hours at RT. The medium is poured onto 2.5M HCl solution and then extracted with ether. The organic phase is washed with 5% NaHCO3 in water, with water and then with saturated NaCl solution. After drying over MgSO4 and evaporation, the crude product is purifed by flash chromatography on silica to give 2.25 g of a white solid. m.p.=47° C.
Reaction SMILES: [CH:1](OCC)(OCC)OCC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[NH2:28][C:29]1[CH:30]=[N:31][C:32]2[C:37]([C:38]=1[NH:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:36][CH:35]=[CH:34][CH:33]=2>C1(C)C=CC=CC=1>[N:39]1([CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])[C:38]2[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:31]=[CH:30][C:29]=2[N:28]=[CH:1]1
Reactant: CCOC(OCC)OCC
Reactant: CCOC(=O)CCCCCNc1c(N)cnc2ccccc12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCn1cnc2cnc3ccccc3c21
Temperature: 25 °C

Procedure:
Triethyl orthoformate (12.74 mL, 76.64 mmol) and pyridinium p-toluenesulfonate (0.200 g) were sequentially added to a solution of ethyl 6-[(3-aminoquinolin-4-yl)amino]hexanoate (16.5 g, 54.7 mmol, prepared as described in Part A of Example 8) in toluene (200 mL), and the reaction was heated at reflux under a Dean-Stark trap for four hours, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in dichloromethane, and the resulting solution was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 16.4 g of ethyl 6-(1H-imidazo[4,5-c]quinolin-1-yl)hexanoate.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([N:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH3:15][CH2:16]OCC.S(OCC)(OCC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[CH2:15]([N:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[NH:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2)[CH3:16]
Reactant: c1ccc2nc3ccccc3nc2c1
Reactant: CCOCC
Agent: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCN1c2ccccc2Nc2ccccc21

Procedure:
Scheme 6 illustrates the synthesis of N-ethyl phenazine 1-hydroxybutyl methyl ether. The phenazine ether (21) is prepared by the alkylation of the 1-hydroxyphenazine (1) with 4-methoxybutylbromide (Aldrich Chemical Company, USA) to give phenazine derivative (21). N-ethyl phenazine (22) is prepared by reaction of compound (21) with diethyl sulfate in the presence of potassium carbonate.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:7]=[CH:8][C:9]=1[OH:10])[CH:2]=[CH2:3].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl.N1CCCCC1.[OH-].[Na+]>ClCCl>[CH2:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:18][CH:20]1[O:22][CH2:21]1)[CH:2]=[CH2:3]
Reactant: ClCC1CO1
Reactant: C=CCc1cc(C2=NNC(=O)CC2)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCNCC1
Product: C=CCc1cc(C2=NNC(=O)CC2)ccc1OCC1CO1
Yield: 47.6 %

Procedure:
A mixture of finely ground 6-(3-allyl-4-hydroxyphenyl)-4,5-dihydro-3(2H)-pyridazinone (50 g, 0.22 mole), epichlorohydrin (200 g, 2.2 mole) and piperidine (2 g) was heated on a steam bath for 90 minutes. Evaporation under reduced pressure gave a viscous oil which was dissolved in dichloromethane and stirred for 10 minutes with dilute sodium hydroxide (500 ml). The organic phase was washed with water, dried and evaporated to an oil which slowly solidified. Addition of ethanolether gave 6-[3-allyl-4-(2,3-epoxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone (30 g, 47%, m.p. 92.5°-95°C) which was recrystallised from aqueous ethanol to give the pure pyridazinone (m.p. 93.5°-95°C).
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[NH:4][N:3]=1.[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C.O>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH3:12])[N:3]=1
Reactant: Clc1ccc2[nH]nc(Br)c2c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(Br)c2cc(Cl)ccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-bromo-5-chloro-1H-indazole (7.5 g, 32.4 mmol) was dissolved in anhydrous DMF (60 mL) then cooled to 0° C. With vigorous stirring, cesium carbonate (13.36 g, 41 mmol) was added in one portion followed by dropwise addition of iodomethane (2.55 mL, 41 mmol). The reaction was then stirred at 0° C. for 1 hour. The reaction was diluted with distilled water (80 mL), and extracted with EtOAc (3×60 mL). The organic extracts were washed with brine (2×), dried over Na2SO4, and purified by column chromatography (gradient 0 to 15% EtOAc/hexanes) to afford the product. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J=1.8 Hz, 1H), 7.38 (dd, J=8.9, 1.9 Hz, 1H), 7.30 (d, J=8.9 Hz, 1H), 4.04 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:40]1[CH2:45][CH2:44][C:43]2([O:50][C:49]3[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=3[N:47]3[CH:55]=[CH:56][CH:57]=[C:46]23)[CH2:42][CH2:41]1.CCN(CC)CC>CN(C=O)C>[N:40]1([C:9]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=2)=[O:11])[CH2:41][CH2:42][C:43]2([O:50][C:49]3[CH:51]=[CH:52][CH:53]=[CH:54][C:48]=3[N:47]3[CH:55]=[CH:56][CH:57]=[C:46]23)[CH2:44][CH2:45]1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cc1
Reactant: c1ccc2c(c1)OC1(CCNCC1)c1cccn1-2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCC(F)(F)F)cc1)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
4-(2,2,2-Trifluoroethoxy)benzoic acid (22 mg, 0.10 mmol), HATU (42 mg, 0.11 mmol), and DMF (0.8 mL) were combined and allowed to sit at room temperature for 10 minutes. The activated acid was then added to spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine] (28 mg, 0.10 mmol) followed by the addition of Et3N (84 μL, 0.60 mmol). The reaction mixture was stirred at room temperature for 17 h before it was filtered and purified by prep-HPLC (5 mM HCl/H2O and MeOH) to provide spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl(4-(2,2,2-trifluoroethoxy)phenyl)methanone. ESI-MS m/z calc. 442.2. found 443.4 (M+1)+. Retention time: 2.05 minutes (4 min run).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24]O.[Br:30]C(Cl)(Cl)C(Cl)(Cl)Br>C(OCC)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[CH2:24][Br:30]
Reactant: OCc1cc(Cl)cc(Cl)c1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Clc1cc(Cl)cc(CBr)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of triphenylphosphine (8.1 g) in diethyl ether (100 cm3) was added to a stirred solution of 3,5-dichlorobenzyl alcohol (5 g) and 1,2-dibromotetrachloroethane (9.9 g) in diethyl ether whilst maintaining the reaction temperature below 5° C. When the addition was complete the reaction mixture was allowed to warm to the ambient temperature (ca. 25° C.), and the mixture stirred for a further 2 hours. The precipitated solid was removed by filtration, and the filtrate concentrated by evaporation of the solvent to give 3,5-dichlorobenzyl bromide (6.8 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](O)([CH3:23])([CH3:22])[CH3:21].O.NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][CH2:13][CH:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:15][CH2:16]1
Reactant: CC(C)(C)O
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: CN(C)c1ccncc1
Agent: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a 5 L flange flask was charged 1-benzyloxycarbonylpiperidine-4-carboxylic acid 20 (200 g, 759.6 mmol) in DCM (500.0 mL) followed by additional DCM (2.000 L), t-butanol (140.8 g, 181.7 mL, 1.899 mol) and DMAP (46.40 g, 379.8 mmol). The mixture was cooled on ice/salt/water bath (internal −3.4° C.). 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine (Hydrochloric Acid (1)) (145.6 g, 759.6 mmol) was added portionwise over 15 mins, with addition funnel rinsed with DCM (500.0 mL). Mixture was stirred on ice bath for approx. 2 h. Ice bath was then removed (internal 3° C.) and allowed to warm to room temperature overnight. Mixture was washed with 5% citric acid (2×500 mL), then saturated NaHCO3 (500 mL), water (500 mL), and organics dried over MgSO4, which was then filtered and concentrated in vacuo to leave product 21 as a viscous light yellow oil which turned to a white solid on standing. (246.1 g, 101%). 1H NMR (500 MHz, DMSO-d6) δ 7.40-7.31 (m, 5H), 5.08 (s, 2H), 3.90 (dt, 2H), 2.93 (br s, 2H), 2.43 (tt, 1H), 1.80-1.76 (m, 2H) and 1.45-1.37 (m, 11H).