Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.C[O:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:20][C:15]3[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:13]2=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: CC(N)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(c1ccc(Cl)cc1)N1Cc2ccccc2C1=O
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(4-chlorophenyl)-ethylamine (117 mg (0.75 mmol), 2-bromomethyl-benzoic acid methyl ester (172 mg, 0.75 mmol), and K2CO3 (207 mg, 1.5 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using a gradient of hexanes to ethyl acetate afforded 38 mg of 2-[1-(4-chlorophenyl)-ethyl]-2,3-dihydroisoindol-1-one, as the racemic mixture. Chromatography (HPLC) of this material through ChrialCel OD (250×20 mm i.d., 10 μm) using 5% isopropanol in hexanes afforded 11.6 mg of R-2-[1-(4-chlorophenyl)-ethyl]-2,3-dihydro-isoindol-1-one and 8.3 mg of S-2-[1-(4-chlorophenyl)-ethyl]-2,3-dihydro-isoindol-1-one. GC/MS for S-2-[1-(4-chlorophenyl)-ethyl]-2,3-dihydroisoindol-1-one gave: m/z (rel.int.) 274 (M+, 9), 272 (M+, 56), 258 (26), 256 (57), 160 (20), 138 (32), 119 (100), 103 (50), 91 (65), and 77 (61).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1.S(Cl)([Cl:12])=O>>[ClH:12].[Cl:12][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[N:4]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cccc(CO)n1
Product: Cc1cccc(CCl)n1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(Hydroxymethyl)-6-methylpyridine (3.7 g, 29.4 mmol) was added portion wise at 0° C. to thionylchloride (35 mL, 477 mmol). The reaction mixture was then stirred at room temperature for 18 h. Excess thionylchloride was removed under vacuum and the crude 2-chloromethyl-6-methyl-pyridine hydrochloride (5.1 g, light brown solid) was used without any further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH:8]([CH3:14])[C:9]([O:11]CC)=[O:10])=[CH:6][CH:5]=[C:4]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[N:3]=1.O[Li].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.C1COCC1.O>[CH3:1][C:2]1[C:7]([CH:8]([CH3:14])[C:9]([OH:11])=[O:10])=[CH:6][CH:5]=[C:4]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[N:3]=1
Reactant: CCOC(=O)C(C)c1ccc(-n2cnnn2)nc1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-n2cnnn2)ccc1C(C)C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of ethyl 2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]propanoate (300 mg, 1.1 mmol) in 8 mL of MeOH/THF/H2O (2:2:1) was added LiOH.H2O (75 mg, 1.8 mmol) and stirred for 30 min at room temperature. The reaction was acidified with citric acid until pH about 3˜4. Extracted with EtOAc, the combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated to give 2-[2-methyl-6-(1H-tetrazol-1-yl)pyridin-3-yl]propanoic acid. 1H-NMR (400 MHz, CDCl3) δ ppm 9.51 (s, 1H), 7.86-7.91 (m, 2H), 4.00-4.05 (m, 1H), 2.64 (s, 3H), 1.57 (d, J=7.8 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9](=[N:11]O)[CH3:10])[CH:6]=[CH:5][CH:4]=1>CO.[C].[Pd]>[NH2:11][CH:9]([C:7]1[N:8]=[C:3]([CH2:2][OH:1])[CH:4]=[CH:5][CH:6]=1)[CH3:10]
Reactant: CC(=NO)c1cccc(CO)n1
Agent: [Pd]
Solvent: CO
Product: CC(N)c1cccc(CO)n1
Reaction time: 7 h
Yield: 91 %

Procedure:
To a solution of 1.8 g of 1-[6-(hydroxymethyl)pyridin-2-yl]ethanone oxime in 36 ml of methanol was added 500 mg of 10% palladium-carbon (50% wet) under an argon atmosphere, followed by stifling for 7 hours under a hydrogen atmosphere. After filtration through Celite, the filtrate was evaporated under reduced pressure to obtain 1.5 g of [6-(1-aminoethyl)pyridin-2-yl]methanol.
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([CH3:8])=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[CH3:8][C:5]1[N:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][CH:10]([OH:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=1
Reactant: Cc1cnc(Br)cn1
Reactant: OC1CCNCC1
Product: Cc1cnc(N2CCC(O)CC2)cn1

Procedure:
The title compound is prepared from 2-bromo-5-methyl-pyrazine and 4-hydroxy-piperidine following a procedure analogous to that described in Intermediate 47. LC (method 8): tR=0.94 min; Mass spectrum (ESI+): m/z=194 [M+H]+.
Reaction SMILES: [N:1]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[N:4]([C:10]1[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=1)[CH2:3][CH2:2]2.[C:17]1([CH2:23][C:24]([Cl:26])=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OCC)C.Cl>C(O)C.C(N(CC)CC)C>[ClH:26].[N:1]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[N:4]([C:10]1[N:15]=[CH:14][C:13]([NH:16][C:24](=[O:25])[CH2:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][N:11]=1)[CH2:3][CH2:2]2
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Nc1cnc(N2CCN3CCC2CC3)nc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCO
Product: O=C(Cc1ccccc1)Nc1cnc(N2CCN3CCC2CC3)nc1
Reaction time: 15 h

Procedure:
2-(1,4-Diaza-bicyclo[3.2.2]non-4-yl)-pyrimidin-5-ylamine (0.877 g, 4.00 mmol) and ethanol (50 ml) was mixed with phenylacetyl chloride (0.742 g, 4.8 mmol) and was stirred for 15 hours at room-temperature, followed by addition of phenylacetyl chloride (74 mg, 0.48 mmol) and stirring for 15 hours. Diethylether (30 ml) was added. The mixture was made alkaline by adding triethylamine (20 ml). The crude mixture was purified by silica gel chromatography, using a 10:1+1% dichloromethane:methanol+aqueous ammonia mixture as eluent. The corresponding hydrochloride was prepared by solving the free base in ethanol (10 ml, 99%) followed by addition of HCl in ethanol (2 ml, 3 M). Yield 710 mg (47%). LC-ESI−HRMS of [M+H]+ shows 338.1976 Da. Calc. 338.198085 Da, dev. −1.4 ppm.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([N:16]([CH3:18])[CH3:17])[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.[C@@H]12N(C3C=NC4C(=CC=CC=4)N=3)C[C@@H]1CCNC2.[N:37]1[N:38]([C:42]2[CH:50]=[CH:49][CH:48]=[CH:47][C:43]=2[C:44](O)=[O:45])[N:39]=[CH:40][CH:41]=1.S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:18][N:16]([CH3:17])[C:11]1[N:10]=[C:9]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][N:3]([C:44]([C:43]4[CH:47]=[CH:48][CH:49]=[CH:50][C:42]=4[N:38]4[N:39]=[CH:40][CH:41]=[N:37]4)=[O:45])[CH2:2]3)[CH2:7]2)[CH:14]=[C:13]([CH3:15])[N:12]=1
Reactant: Cc1cc(N2C[C@@H]3CCNC[C@@H]32)nc(N(C)C)n1
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: O=C(O)c1ccccc1-c1cccs1
Agent: c1ccc2nc(N3C[C@@H]4CCNC[C@@H]43)cnc2c1
Product: Cc1cc(N2C[C@@H]3CCN(C(=O)c4ccccc4-n4nccn4)C[C@@H]32)nc(N(C)C)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[4-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-6-methyl-pyrimidin-2-yl]-dimethyl-amine (Intermediate L) for (1R,6S)-2-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-quinoxaline and 2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 14) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C22H26N8O, 418.501; m/z found 419.1 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.13-7.73 (m, 2H), 7.65-7.28 (m, 2H), 7.24-6.88 (m, 1H), 5.51-5.10 (m, 1H), 4.66-2.65 (m, 14H), 2.32-1.85 (m, 5H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10].[F-].[K+].O>C1(C)C=CC=CC=1>[C:9]([C:13]1[CH:18]=[CH:17][C:16]([C:2]2[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: Oc1ccc(Cl)nc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(-c2ccc(O)cn2)cc1
Temperature: 25 °C
Yield: 37.9 %

Procedure:
To a solution of 6-Chloro-pyridin-3-ol (3.10 g, 23.9 mmol) in toluene (30 ml) is added 4-tert-butyl-phenylboronic acid (5.46 g, 30.6 mmol), potassium fluoride (2.82 g, 47.9 mmol), and palladium tetrakis triphenylphosphine (1.20 g, 1.20 mmol). Water (15 mL) is added and the reaction mixture is heated to reflux overnight. After cooling to rt, the reaction mixture is partitioned between ethyl acetate and water. The aqueous layer is back-extracted with ethyl acetate, the combined organic layers are dried and concentrated. The resulting residue is applied to silica gel and eluted using hexanes with an ethyl acetate gradient to give the title compound (2.06 g).
Reaction SMILES: NC(N)=O.S(=NC(N)=O)(=O)=O.[NH2:12][C:13]1[N:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]3[CH:26]=[C:27]([F:32])[C:28]([NH:30][CH3:31])=[CH:29][C:22]=3[O:21][CH2:20]2)=[CH:15][CH:14]=1.C([O:35][C:36](=O)[NH:37][S:38]([C:41]1[S:42][C:43]([Cl:46])=[CH:44][CH:45]=1)(=[O:40])=[O:39])C>>[Cl:46][C:43]1[S:42][C:41]([S:38]([NH:37][C:36]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([N:19]3[C:24](=[O:25])[C:23]4[CH:26]=[C:27]([F:32])[C:28]([NH:30][CH3:31])=[CH:29][C:22]=4[O:21][CH2:20]3)=[CH:17][N:18]=2)=[O:35])(=[O:40])=[O:39])=[CH:45][CH:44]=1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(Cl)s1
Reactant: CNc1cc2c(cc1F)C(=O)N(c1ccc(N)nc1)CO2
Agent: NC(=O)N=S(=O)=O
Agent: NC(N)=O
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(NC(=O)NS(=O)(=O)c3ccc(Cl)s3)nc1)CO2
Yield: 23.6 %

Procedure:
Analogous to the sulfonylurea urea formation described in Ex 5, 3-(6-aminopyridin-3-yl)-6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.017 g, 0.058 mmol) and (5-Chloro-thiophene-2-sulfonyl)-carbamic acid ethyl ester (0.026 g, 0.096 mmol) were coupled to give 1-(5-chlorothiophen-2-ylsulfonyl)-3-(5-(6-fluoro-7-(methylamino)-4-oxo-2H-benzo[e][1,3]oxazin-3(4H)-yl)pyridin-2-yl)urea (0.007 g, 24%). RP-HPLC: 2.7 min; ES-MS (M+H)+=512.0; 1H-NMR (MeOH-d4) δ (ppm): 2.82 (s, 3), 5.4 (s, 2), 6.2 (d, 1), 6.9 (d, 1), 7.3 (d, 1), 7.6 (dd, 1), 8.0 (d, 1), 8.1 (d, 1).
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1I)\[CH3:5].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([S:30]([O-:32])=[O:31])[CH:24]=[CH:23]3)=[CH:16][CH:15]=1.[Na+]>>[CH3:1][O:2]/[N:3]=[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:30]([C:25]1[CH:24]=[CH:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=3)[CH:21]=2)[CH:26]=1)(=[O:31])=[O:32])\[CH3:5]
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: CO/N=C(\C)c1ccccc1I
Agent: [Na+]
Product: CO/N=C(\C)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1

Procedure:
Prepared according to the method of Example 6, Step 4 using (1E)-1-(2-iodophenyl)ethanone O-methyloxime and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate. 1H NMR (400 MHz, d6-DMSO): δ 8.56 (1H, s), 8.35 (1H, s), 8.29-8.27 (2H, m), 8.17 (1H, d, J=8.8 Hz), 8.02 (1H, dd, J=1.7, 8.6 Hz), 7.91 (2H, dd, J=5.5, 8.8 Hz), 7.83-7.71 (3H, m), 7.44 (1H, dd, J=1.7, 7.4 Hz), 7.37 (2H, t, J=8.8 Hz), 3.56 (3H, s), 2.14 (3H, s); m/z (ES+) 434 [MH+].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH:7]1([Mg]Cl)[CH:11]=[CH:10][CH:9]=[CH:8]1>>[CH2:2]([C:11]1[CH2:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCBr
Reactant: Cl[Mg]C1C=CC=C1
Product: CCCCCC1=CC=CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 1-bromopentane (109.8 g, 0.727 mol) was added cyclopentadienyl magnesium chloride (800 mL of 1 M solution in THF, 0.8 mol) at 0° C. in 15 minutes. After stirring for an additional 2 hours at 0° C., the mixture was warmed to room temperature. After stirring overnight, the reaction was quenched with a mixture of ice and water. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at room temperature gave a brown liquid (101.4 g, crude pentylcyclopentadiene). To the crude pentylcyclopentadiene (50 g) dissolved in THF (200 mL) was added n-BuLi (35 mL of 10 M in hexanes, 0.35 mol) at 0° C. The mixture was warmed up to room temperature and stirred overnight. The anion solution was added to benzophenone (60.7 g, 0.334 mol) dissolved in THF (280 mL) at 0° C. in 25 minutes. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at 50° C. gave a dark red viscous oil. The oil was dissolved in heptane and filtered through silica gel. The product was collected by washing the silica gel with 5-10% CH2Cl2 in heptane. Removal of the solvent gave the desired product (74.3 g) as a dark red viscous oil.
Reaction SMILES: [S:1]1(=[O:9])(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=O)[CH2:2]1.[N+:10]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O)([O-:12])=[O:11].[NH2:21]/[C:22](/[CH3:28])=[CH:23]\[C:24]([O:26][CH3:27])=[O:25]>CO>[CH3:28][C:22]1[NH:21][C:3]2[CH2:4][CH2:5][CH2:6][S:1](=[O:9])(=[O:8])[C:2]=2[CH:16]([C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=2)[C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=C1CCCS(=O)(=O)C1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CO
Product: COC(=O)C1=C(C)NC2=C(C1c1cccc([N+](=O)[O-])c1)S(=O)(=O)CCC2
Yield: 29.3 %

Procedure:
A mixture of tetrahydrothiopyran-3-one-1,1-dioxide (0.830 g, 0.0056 moles), 3-nitrobenzaldehyde (0.846 g, 0.0056 moles) and methyl 3-aminocrotonate (0.644 g, 0.0056 moles) in methanol (20 mL) was refluxed for 16 hours. After cooling, the resulting solid was isolated by filtration and washed with diethyl ether. This solid was dried at 40° C. for 4 hours under vacuum to give 0.620 g product; mp 236°-238° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.C([Li])CCC.Cl>C1(C)C=CC=CC=1.O1CCCC1>[C:4]([C:3]1[CH:6]=[C:7]([F:10])[CH:8]=[CH:9][C:2]=1[B:11]([OH:16])[OH:12])#[N:5]
Reactant: N#Cc1cc(F)ccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: N#Cc1cc(F)ccc1B(O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-Bromo-5-fluorobenzonitrile (6.00 g, 30.0 mmol) and triisopropyl borate (8.28 mL, 36.0 mmol) were dissolved in a mixture of toluene (48 mL) and tetrahydrofuran (12 mL), and the solution was cooled in a dry ice/acetone bath. A solution of n-butyllithium in hexanes (2.5M, 14.4 mL, 36.0 mmol) was added drop-wise over 1 hour, and the reaction was then allowed to warm to room temperature with stirring over 18 hours. The mixture was cooled in an ice bath and treated with a 2N aqueous hydrochloric acid solution until the pH reached 1, then allowed to warm to room temperature, at which time the layers were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed twice with water, once with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate-heptane to provide (2-cyano-4-fluorophenyl)boronic acid as a white solid. Yield: 2.20 g, 13.3 mmol, 44%. 1H NMR (400 MHz, CD3OD) δ 7.43 (ddd, J=8.6, 8.6, 2.5 Hz, 1H), 7.55 (dd, J=8.8, 2.5 Hz, 1H), 7.69 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-].[K+].[Br:10][CH2:11][CH3:12].[K+].[Br-].Br[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=1>C(#N)C>[Br-:10].[CH2:11]([C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH3:16])[C:26]=1[N+:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[NH:5][CH:4]=1)[CH3:12]
Reactant: Clc1nc[nH]c1Cl
Reactant: CCBr
Reactant: BrCc1ccc2ccccc2c1
Agent: [Br-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCc1c(-[n+]2c[nH]c(Cl)c2Cl)c(C)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
4,5-Dichloroimidazole (1.23 g, 9 mmol) was dissolved into 27 mL of acetonitrile. Potassium hydroxide (0.61 g, 9.9 mmol) was added and the mixture was allowed to stir for 0.5 h. Bromoethane (0.66 mL, 9 mmol) was added and the solution was allowed to reflux overnight. The solution was filtered hot to remove a white precipitate (presumed to be KBr) and 2-bromomethylnaphthalene (1.98 g, 9 mmol) was added and the mixture was returned to reflux overnight. The mixture was then allowed to cool to room temperature, resulting in a white precipitate (0.3538, 10% yield). 1H NMR (500 MHz, DMSO-d6) 9.62 (1H, s, NCHN), 7.61 (4H, m, Ar), 7.58 (3H, m, Ar),), 5.66 (2H, s, NCH2), 4.27 (2H, q, NCH2), 1.47 (3H, t, CH3). MS: m/z=304.8 (theor for C16H15Cl2N2Br1=386.12).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O.Cl[CH2:17][C:18](=[O:26])[C:19]([CH2:24][CH3:25])([CH3:23])[CH2:20][CH2:21][Cl:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:17][C:18](=[O:26])[C:19]([CH2:24][CH3:25])([CH3:23])[CH2:20][CH2:21][Cl:22])=[CH:4][CH:3]=1
Reactant: CCC(C)(CCCl)C(=O)CCl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(C)(CCCl)C(=O)COc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 71.8 %

Procedure:
79.7 g (0.62 mole) of 4-chlorophenol and 85.6 g (0.62 mole) of potassium carbonate in 600 ml of toluene are heated under reflux for 2 hours, using a water separator. 104 g (0.53 mole) of 1,5-dichloro-3-ethyl-3-methyl-2-pentanone in 100 ml of toluene are then added at 70° C. The reaction mixture is stirred at 100° C. for 5 hours and is then allowed to cool and is stirred with 500 ml of water. The organic phase is separated off, washed with dilute sodium hydroxide solution and with water, dried over sodium sulphate and concentrated. 110 g (71.8% of theory) of 1-(4-chlorophenoxy)-5-chloro-3-ethyl-3-methyl-2-pentanone of refractive index nD20 1.5092 are obtained. ##STR101##
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.C[Si]([N:21]=[C:22]=[S:23])(C)C.FC(F)(F)C([O-])=O.FC(F)(F)C([O-])=O.C1([I+2])C=CC=CC=1>FC(F)(F)C(O)C(F)(F)F>[CH3:1][O:2][C:3](=[O:16])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([S:23][C:22]#[N:21])=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2
Reactant: COC(=O)COc1cccc2c1CCCO2
Reactant: C[Si](C)(C)N=C=S
Agent: O=C([O-])C(F)(F)F
Agent: [I+2]c1ccccc1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: COC(=O)COc1ccc(SC#N)c2c1CCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.5 %

Procedure:
A stirred solution of (chroman-5-yloxy)-acetic acid methyl ester (2.1 g, 9.4 mmol) and trimethylsilyl isothiocyanate (2 mL, 14.1 mmol) in 30 mL 1,1,1,3,3,3-hexafluoro-propan-2-ol under a N2 atmosphere was treated with phenyliodine(III) bis(trifluoroacetate). The reaction mixture stirred at room temperature for 1 h and concentrated in vacuo. Purification by flash column chromatography (gradient elution: 10% EtOAc/hexanes to 40% EtOAc/hexanes) gave the title compound (1.3 g, 50%) as a pale yellow solid. 400 MHz 1H NMR (DMSO-d6) δ 7.31 (d, 1H, J=8.8 Hz), 6.54 (d, 1H, J=8.8 Hz), 4.83 (s, 2H), 4.21 (t, 2H, J=4.9 Hz), 3.64 (s, 3H), 2.60 (t, 2H, J=6.4 Hz), 1.89 (m, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([C:24](=[O:25])[NH:34][CH2:33][C:32]2[CH:35]=[CH:36][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[CH:12][N:11]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COc1cc2c(C(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNC(=O)c2cnc(CNC(=O)OC(C)(C)C)c3cc(OC)c(OC)cc23)cc1
Yield: 79 %

Procedure:
As described in example 1E, 80 mgs of 1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinoline-4-carboxylic acid was coupled with 4-methoxybenzylamine to give 84 mgs (79%) of [6,7-Dimethoxy-4-(4-methoxy-benzylcarbamoyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester: 1H NMR (CDCl3) δ 1.50 (s, 9H), 2.78 (s, 2H), 3.18 (s, 1H), 3.77 (s, 2H), 4.02 (d, 4H, J=7.17 Hz), 4.15-4.33 (m, 1H), 4.42 (s, 1H), 4.87-4.90 (m, 1H), 6.10-6.22 (m, 1H), 6.93 (s, 0.6H), 7.06-7.12 (m, 1H), 7.16 (s, 0.4H), 7.27-7.42 (m, 4H), 7.50 (d, 1H, J=7.60 Hz), 8.32 (d, 1H, J=7.19 Hz); MS: APCI (M+H) calc'd for C26H31N3O6 482.2; found 482.0.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](Cl)=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[NH3:12].C(OCC)(=O)C>O1CCOCC1.[Cl-].[Na+].O>[Br:1][C:2]1[C:6]2[C:7]([NH2:12])=[N:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: N
Reactant: Clc1nccc2occ(Br)c12
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Nc1nccc2occ(Br)c12
Temperature: 150 °C
Reaction time: 120 h

Procedure:
To the solution of 3-bromo-4-chloro-furo[3,2-c]pyridine (3.0 g) in 40 ml of dioxane was added 28% ammonia solution (15 ml) in an autoclave and put into the oil bath. The reaction mixture was allowed to heat up to 150° C. and stir for 5 days at 150° C. The resultant mixture was poured into ethyl acetate and brine. The organic phases was separated, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on a silica gel column to afford 3-bromo-furo[3,2-c]pyridin-4-ylamine (1.3 g). 1H NMR (400 MHz, CDCl3) ppm 7.93 (d, J=6.1 Hz, 1H), 7.52 (s, 1H), 6.87 (d, J=5.8 Hz, 1H). MS: m/z 213, 215 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:8]=[C:7]([O:12][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:6]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Yield: 197.8 %

Procedure:
(3,5-dihydroxy-phenyl)-acetic acid methyl ester (5 g, 27.4 mmol) in anhydrous DMF (20 mL) was treated with K2CO3 (11.4 g, 82.5 mmol) and benzyl bromide (6.5 mL, 55 mmol). The resultant mixture was stirred overnight at room temperature. Water was added to the reaction mixture and the aqueous layer extracted with EtOAc (3×50 mL). The organic layers were combined, washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a brown solid (9.82 g, 99%).