Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:2]1=2.[N+:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[C-:14].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C>CN(C)C=O>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([C:10]3[O:12][CH:14]=[N:13][C:15]=3[C:16]([O:18][CH3:19])=[O:17])[CH:8]=[CH:9][C:2]1=2
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C(O)c1ccc2occc2c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1ncoc1-c1ccc2occc2c1
Reaction time: 8 h
Yield: 58.5 %

Procedure:
To a solution of benzo[b]furan-5-carboxylic acid (1.30 g) and of methyl isocyanoacetate (834 mg) in N,N-dimethylformamide (10 ml) were added diethyl cyanophosphate (1.33 ml) and triethylamine (3.6 ml) at room temperature, and the mixture was stirred overnight. After removing the solvent under reduced pressure, an aqueous citric acid solution and ethyl acetate were added to the residue, the organic layer was collected, washed successively with an aqueous citric acid solution, water, a saturated aqueous sodium hydrogen carbonate solution and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (solvent: n-hexane:ethyl acetate=1:1) to obtain a crude product of methyl 5-(5-benzo[b]furyl)oxazol-4-carboxylate (1.14 g).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:6]=1[C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)=[O:8].[OH-].[Na+]>C(O)(=O)C.O>[CH3:1][C:2]1[NH:3][CH:4]=[N:5][C:6]=1[C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)=[O:8]
Reactant: Cc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C(=O)c1ccc2cccnc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1[nH]cnc1C(=O)c1ccc2cccnc2c1
Temperature: 25 °C

Procedure:
A solution of (8) in acetic acid/water (12 mL/8 mL) was heated at 110° C. for 1.5 h. The reaction was cooled to room temperature. Crushed ice was added, and basification of reaction with NaOH (s) to pH˜6 was followed. The aqueous layer was extracted with chloroform/isopropanol (3:1, 200 mL). The pooled organic layers were dried over magnesium sulfate. The mixture was filtered, and the solvents were removed under vacuum. The residue was purified by chromatography on silica gel with 3% saturated ammonia methanol in dichloromethane to give (5-methyl-1H-imidazol-4-yl)(quinolin-7-yl)methanone (9) as a white solid (0.53 g, 2.24 mmol, 35% over 3 steps).
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[CH:14][S:13][C:12]=2[CH:16]=1.[CH2:17]1[O:19][CH2:18]1.Cl>O1CCCC1>[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[CH:15]=[C:14]([CH2:17][CH2:18][OH:19])[S:13][C:12]=2[CH:16]=1
Reactant: COc1ccc2ccsc2c1
Reactant: C1CO1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2cc(CCO)sc2c1
Temperature: -30 °C
Reaction time: 0.17 h

Procedure:
Butyl lithium (0.27 mol of a 2.5 M solution) was added dropwise to 6-methoxybenzo[b]thiophene [prepared analogous to the procedure described in J. Med. Chem. 1989, 32(12), 2548-2554] (0.25 mol) in tetrahydrofuran (1000 ml), stirred at −30° C. The mixture was stirred for 10 minutes at −30° C. Ethylene oxide (0.38 mol in 100 ml tetrahydrofuran) was added dropwise at −30° C. The mixture was allowed to warm to room temperature and stirred for 3 hours. The mixture was acidified with dilute HCl solution. The solvent was evaporated. The residue was diluted with water and this mixture was extracted with CH2Cl2. The separated organic layer was dried, filtered and the solvent evaporated. The residue was stirred in hexane, filtered off and dried, yielding 41.3 g of 6-methoxybenzo[b]thiophene-2-ethanol (interm. 2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][S:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=[O:11].[CH3:20]I>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][S:7][C:8]1[N:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([O:12][CH3:20])=[O:11]
Reactant: CI
Reactant: COc1cccc(CSc2ncccc2C(=O)O)c1
Solvent: CC#N
Product: COC(=O)c1cccnc1SCc1cccc(OC)c1
Yield: 91.7 %

Procedure:
A suspension of 7.15 g (0.026 mole) of 2-(3-methoxybenzylthio)nicotinic acid in 75 ml of dry acetonitrile was treated with 3.95 g (0.026 mole) of 1,8-diazabicyclo[5,4,0]-under-7-ene (DBU). A solution formed and 4.26 g (0.030 mole) of methyl iodide was added over one minute. After keeping the reaction mixture at room temperature for 24 hours, the solution was evaporated in vacuo. The residue was partitioned between 100 ml of ether and 50 ml of water. The ether layer was washed with 50 ml of H2O, dried, and evaporated to a small volume. The addition of hexane with cooling yielded 6.9 g (92% of theory) of methyl 2-(3-methoxybenzylthio)nicotinate; m.p. 69°-70° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6](O)[C:7]2[CH:12]=[CH:11][C:10]([CH2:13][S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O.C1(C)C=CC=CC=1>CN(C)C=O>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH:6]([Cl:24])[C:7]2[CH:12]=[CH:11][C:10]([CH2:13][S:14]([CH2:17][CH3:18])(=[O:16])=[O:15])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCS(=O)(=O)Cc1ccc(C(O)c2ccc(Cl)cc2)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCS(=O)(=O)Cc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Yield: 75 %

Procedure:
4-chloro-4'-ethane sulfonylmethylbenzhydrol (6.0 g), thionyl chloride (5.4 g), toluene (200 ml) and a catalytic amount of N,N-dimethylformamide were mixed and gradually heated with stirring to a refluxing temperature. The mixture was stirred for 4 hours under reflux and then left to cool. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the desired product as a slight yellow viscous substance (4.6 g, nD20 : 1.6044, yield: 75%).
Reaction SMILES: [OH-].[K+].CS(C)=O.[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([NH2:17])[C:13]=1[C:14]([OH:16])=[O:15].I[CH3:19]>CCOCC>[CH3:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([NH2:17])[C:13]=1[C:14]([O:16][CH3:19])=[O:15]
Reactant: Cc1cccc(N)c1C(=O)O
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOCC
Product: COC(=O)c1c(C)cccc1N
Reaction time: 0.08 h
Yield: 38.8 %

Procedure:
Powdered potassium hydroxide (7.4 g, 0.132 mol) was admixed with dimethyl sulfoxide (DMSO) (100 ml), and the mixture was stirred for 5 minutes. 6-Methylanthranilic acid (10.0 g, 0.066 mol) was then added to the mixture and iodomethane (4.52 ml, 0.073 mol) added dropwise. The reaction mixture was stirred for 30 minutes at room temperature, then diluted with 250 ml of ether, washed with water (3×100 ml), dried over magnesium sulfate and concentrated. The crude product was filtered through a pad of flash grade (32-63) silica gel and eluted with 1:9 ether:hexane to afford 4.23 g (39%) of methyl 6-methylanthranilate as an oil.
Reaction SMILES: CCN(CC)CC.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[O:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH:21]([C:30]2[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=2)[C:22](=[O:29])[NH:23][C:24]2[S:25][CH:26]=[CH:27][N:28]=2)[CH2:16][CH2:15]1>CN(C=O)C>[N:8]1([S:36]([C:33]2[CH:34]=[CH:35][C:30]([CH:21]([CH2:20][CH:17]3[CH2:18][CH2:19][O:14][CH2:15][CH2:16]3)[C:22]([NH:23][C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[O:29])=[CH:31][CH:32]=2)(=[O:38])=[O:37])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1nccs1)C(CC1CCOCC1)c1ccc(S(=O)(=O)N2CCOCC2)cc1
Reaction time: 0.17 h

Procedure:
NEt3 (120 μL, 868 μmol) and morpholine (76 μL, 868 μmol) were added to a stirred solution of 4-[2-(tetrahydropyran-4-yl)-1-(thiazol-2-ylcarbamoyl)ethyl]benzenesulfonyl chloride (Preparation 59, 300 mg, 723 μmol) in anhydrous DMF (4 mL). After 10 min, the solvents were removed in vacuo, then the residue was taken up in CH2Cl2 (50 mL). The CH2Cl2 solution was washed with H2O (20 mL), 1M HCl (20 mL), H2O (20 mL), saturated aqueous Na2CO3 (20 mL), and brine 20 mL), before being dried (MgSO4). Filtration, solvent evaporation, and recrystallisation (CH2Cl2-IH) gave the title compound: RTA=3.15 min; m/z (ES+)=466.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][C:11]=1[Cl:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]2[NH:42][CH2:41][C:40]3[CH:39]=[N:38][N:37]([CH3:43])[C:36]=3[NH:35][C:34]=2[CH:44]=1>ClCCl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:42]2[CH2:41][C:40]3[CH:39]=[N:38][N:37]([CH3:43])[C:36]=3[NH:35][C:34]3[CH:44]=[C:30]([Cl:29])[CH:31]=[CH:32][C:33]2=3)=[O:16])=[CH:12][C:11]=1[Cl:19])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1Cl
Reactant: Cn1ncc2c1Nc1cc(Cl)ccc1NC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2c1Nc1cc(Cl)ccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)c(Cl)c1)C2
Reaction time: 3 h
Yield: 63 %

Procedure:
A solution of 4-(tert-butoxycarbonylamino-methyl)-3-chloro-benzoic acid from Example E2b (568 mg, 2.0 mmol) in dichloromethane (25 ml) at room temperature was treated with DMAP (244 mg, 2.0 mmol), DIEA (11.0 ml, 6.0 mmol) then WSCD (500 mg, 2.6 mmol). The mixture was stirred for 3 h then 6-chloro-3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E1 (430 mg, 1.8 mmol) was added. The mixture was stirred for 4 days then washed with saturated NaHCO3, brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (570 mg, 63%).
Reaction SMILES: Cl.[CH3:2][CH:3]1[C:8](=O)[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2.Cl.[NH2:13][OH:14].O.O.O.C([O-])(=O)C.[Na+]>CCO>[CH3:2][CH:3]1[C:8](=[N:13][OH:14])[CH:7]2[CH2:10][CH2:11][N:4]1[CH2:5][CH2:6]2
Reactant: NO
Reactant: CC1C(=O)C2CCN1CC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1C(=NO)C2CCN1CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
2-Methylquinuclidin-3-one hydrochloride from Step L (5.3 g, 30.2 mmol, 1 eq), hydroxylamine hydrochloride (2.5 g, 36.4 mmol, 1.2 eq) and sodium acetate trihydrate (12.4 g, 90.9 mmol, 3 eq) are suspended in 70 mL EtOH and stirred at room temperature. After 24 h, the mixture is concentrated in vacuo. The residue is suspended in CHCl3 and the solids are filtered. The solids are rinsed with excess CH3CN. The combined organic washes are concentrated in vacuo to give 4.65 g (100%) of 2-methyl-1-azabicyclo[2.2.2]octan-3-one oxime. MS (ESI) for C8H14N2O m/z 155.2 (M+H)30 .
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH:37]([NH2:47])CC2C=CC=CC=2OC)[CH:6]=1.NCC[CH2:51][O:52][C:53]1[CH:81]=[C:80](OC)[CH:79]=[CH:78][C:54]=1[C:55](NC1C=C([N+]([O-])=O)C=CC=1C(NC1C=CC(OC)=CC=1)=O)=O.COC1C=CC=CC=1C=O>>[CH3:3][O:4][C:5]1[CH:33]=[CH:32][C:8]([C:9]([NH:11][C:12]2[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=[CH:25][C:13]=2[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:15])=[O:10])=[C:7]([O:34][CH2:35][CH2:36][CH2:37][NH:47][CH2:55][C:54]2[CH:78]=[CH:79][CH:80]=[CH:81][C:53]=2[O:52][CH3:51])[CH:6]=1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCCN)cc1
Reactant: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCC(N)Cc2ccccc2OC)cc1
Agent: COc1ccccc1C=O
Agent: [BH4-]
Agent: [Na+]
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2NC(=O)c2ccc(OC)cc2OCCCNCc2ccccc2OC)cc1

Procedure:
Using methods substantially equivalent to those described in Example 94-E except that sodium borohydride was the reducing agent, 2-[4-methoxy-2-[3-(2-methoxybenzyl)-aminopropoxy]benzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide (52 mg, 0.085 mmol, 56%) was prepared from 2-[2-(3-aminopropoxy)-4-methoxybenzoylamino]-N-(4-methoxyphenyl)-4-nitrobenzamide and 2-methoxybenzaldehyde.
Reaction SMILES: [Cl:1][CH2:2]C(CCl)=O.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:26]([OH:28])=O)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Na]>CO.O1CCCC1>[CH2:7]([O:14][C:15]([NH:17][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:26]([OH:28])[CH2:2][Cl:1])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=C(CCl)CCl
Agent: [Na]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 60 °C
Yield: 42.8 %

Procedure:
To a solution of 75.0 g (0.226 mol) of N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of 807 mL of methanol and 807 mL of tetrahydrofuran at -2° C., was added 13.17 g (0.348 mol, 1.54 equiv.) of solid sodium borehydride over one hundred minutes. The solvents were removed under reduced pressure at 40° C. and the residue dissolved in ethyl acetate (approx. 1L). The solution was washed sequentially with 1M potassium hydrogen sulfate, saturated sodium bicarbonate and then saturated sodium chloride solutions. After drying over anhydrous magnesium sulfate and filtering, the solution was removed under reduced pressure. To the resulting oil was added hexane (approx. 1L) and the mixture warmed to 60° C. with swirling. After cooling to room temperature, the solids were collected and washed with 2L of hexane. The resulting solid was recrystallized from hot ethyl acetate and hexane to afford 32.3 g (43% yield) of N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp 150°-151° C. and M+Li+ =340.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH2:23]>CO.C(Cl)Cl>[CH3:19][O:20][C:21](=[O:24])[CH2:22][NH:23][C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)CN
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CNC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and glycine methyl ester hydrochloride (Bachem), the title compound was prepared as a solid (mp=158-160° C.). The reaction was monitored by tlc (Rf=0.61 in 10%MeOH/DCM) and the product was purified by silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[N+:20]([C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1)([O-:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:32]1[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([N+:20]([O-:22])=[O:21])=[CH:28][CH:27]=3)[CH2:30][CH2:31]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 96 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(4-nitrophenyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 96%). 1H NMR (300 MHz, DMSO-d6): δ 3.57-3.65 (m, 8H), 4.17 (s, 3H), 7.05 (d, J=9.5 Hz, 2H), 7.55 (dd, J=8.9 and 2.2 Hz, 1H), 7.74-7.79 (m, 2H), 8.08 (d, J=9.4 Hz, 2H), 9.40 (s, 1H).
Reaction SMILES: C1N=CN([C:6](N2C=NC=C2)=[O:7])C=1.[I:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([NH:19][NH2:20])=[O:18].C(N(CC)CC)C>C1COCC1>[I:13][C:14]1[CH:15]=[C:16]([C:17]2[O:18][C:6](=[O:7])[NH:20][N:19]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: NNC(=O)c1cccc(I)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2cccc(I)c2)o1
Temperature: 25 °C

Procedure:
A solution of N,N-carbonyldiimidazole (800 mg, 5.0 mmol) in 5 mL of dry THF was added dropwise to an ice-cold solution of the product from Step A (1.048 g, 4.0 mmol) and triethylamine (0.60 mL, 4.0 mmol) in 12 mL of dry THF. The resultant mixture was allowed to warm to room temperature overnight, and was then concentrated under reduced pressure. The residue was partitioned between diethyl ether and water, and the ether layer was washed sequentially with 5% aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous brine, dried (magnesium sulfate), and concentrated under reduced pressure to afford a white powder. Recrystallization from ethyl acetate-hexanes afforded the title compound as a fluffy white solid. LC/MS 289.2 (M+1).
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[C:9]1([C:15]#[CH:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1.[Cu]I>[C:9]1([C:15]#[C:16][C:2]2[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Br)o1
Reactant: C#Cc1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: O=Cc1ccc(C#Cc2ccccc2)o1
Reaction time: 48 h
Yield: 68.3 %

Procedure:
To a solution of 5-bromofuraldehyde (1.0 g, 5.71 mmol, 1 eq), copper (I) iodide (0.163 g, 0.857 mmol, 0.15 eq), trans-dichlorobis(triphenylphosphine) palladium(II) (0.20 g, 0.287 mmol, 0.05 eq), and TEA (3.98 mL, 28.6 mmol, 5 eq) in THF (45 mL) is added dropwise phenyl acetylene (1.25 mL, 11.4 mmol, 2 eq). After 48 hr, the reaction appears complete. The reaction is filtered over a pad of celite, and the solvent is removed under reduced pressure. The reaction is purified by silica gel chromatography using a Biotage Flash 40M column (10% EtOAc/heptane) to give 5-phenylethynyl-furan-2-aldehyde as a yellow orange crystalline solid (0.765 g, 68.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=S)[CH:18]=2)=[CH:15][CH:14]=[C:13]([O:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:12]=3)=[CH:5][CH:4]=1.Cl.[NH2:31][OH:32]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[N:31][OH:32])[CH:18]=2)=[CH:15][CH:14]=[C:13]([O:20][CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:12]=3)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(-c2cc(=S)c3ccc(OCCCN4CCOCC4)cc3o2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2cc(=NO)c3ccc(OCCCN4CCOCC4)cc3o2)cc1
Temperature: 110 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
To a solution of 2-(4-methoxy-phenyl)-7-(3-morpholin-4-yl-propoxy)-chromene-4-thione (222.0 mg, 0.38 mmol) in 4.0 mL of pyridine was added 80.0 mg (1.15 mmol) of hydroxylamine hydrochloride. The solution was stirred at 110° C. for 2 h. The solvent was removed under vacuum and the residue was treated with ice. The resulting slurry was filtered. The filter cake was washed with H2O purified by prep HPLC to afford 71.4 mg (35.5% yield) of desired product, I-26, as a yellow syrup (TFA salt). 1H NMR (500 MHz, DMSO-d6) δ 10.71 (s br, 1H), 9.99 (s, 1H), 7.88 (d, 2H), 7.79 (d, 1H), 7.08 (d, 2H), 7.02 (d, 1H), 6.99 (s, 1H), 6.88(dd, 1H), 4.16(t, 2H), 4.02(d, 2H), 3.84 (s, 3H), 3.67(t, 2H), 3.52(d, 2H), 3.31(t, 2H), 3.12(m, 2H), 2.17 (m, 2H) ppm. LC/MS: 411.2 (M+H), HPLC/Method A (Rt 4.03 min, 98.0% purity).
Reaction SMILES: Br[C:2]1[C:7]([Br:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18].BrCl>>[Br:8][C:7]1[C:2]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[N:3][CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH:6]=1
Reactant: Clc1ccc(-c2cnc(Br)c(Br)c2)cc1
Reactant: C#C[Si](C)(C)C
Agent: ClBr
Product: C[Si](C)(C)C#Cc1ncc(-c2ccc(Cl)cc2)cc1Br

Procedure:
The product was prepared analogously to Example 7.1b starting from 2,3-dibromo-5-(4-chlorophenyl)pyridine and trimethylsilylacetylene. Yield: 1.00 g (95% of theoretical); C16H15BrClNSi (M=364.739); calc.: molpeak (M+H)+: 364/366/368 (BrCl); found: molpeak (M+H)+: 364/366/368 (BrCl).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=O)[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[N:17][OH:18])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)C(C)(C)C(=NO)CC2
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 7-methoxy-1,1-dimethyl-3,4-dihydro-1H-napthalen-2-one (25.4 g, 98 mmol) in methanol (175 mL) was added a solution of hydroxylamine hydrochloride (20.5 g, 295 mmol) and sodium acetate (24.2 g, 295 mmol) in water (175 mL) and the reaction mixture was heated at 70° C. for 3 h, and cooled in ice over 30 min. The solid was collected on a Buchner funnel, stirred with methanol (125 mL) at 50° C. for 30 min, and then stirred at RT overnight. The reaction mixture was cooled to 0° C.; solid was collected on a Buchner funnel, rinsed with cold methanol (20 mL) and dried under vacuum to give the title compound (14.7 g).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][NH2:15].Cl>>[CH3:14][NH:15][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CN
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Product: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 55 °C
Reaction time: 0.21 h

Procedure:
500 g of 4-chloro-3-nitrobenzoic acid and 2 L of mono methyl amine were added stirred for 10-15 minutes at 25° C. to 35° C. The reaction mixture was heated to 55° C. and maintained for 12 hours. The reaction mixture was dumped in ice-water and stirred for 15 minutes and pH was adjusted to 2 by conc. HCl. The reaction mixture was stirred for 15 minutes and filtered. The wet-cake was washed with water and dried to obtain 4-(methylamino)-3-nitrobenzoic acid of Formula (A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([NH:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH:3]=1)[O:28][C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][NH:19][C:17](=[O:18])[O:16][C:12]([CH3:14])([CH3:13])[CH3:15])[CH:27]=[CH:26][CH:25]=1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)NCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCc1cccc(Oc2cc(Cl)ccc2[N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (7.0 g, 40 mmols), N-tert-butoxycarbonyl-3-hydroxyphenethylamine (9.5 g, 40 mmols), potassium carbonate (5.5 g, 40 mmols) and N,N-dimethylformamide (100 ml) was stirred at 100° C. for 12 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give an oil of tert-butyl 2-[3-(5-chloro-2-nitrophenoxy)phenyl]ethylcarbamate (15.2 g, 96.6%).