Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7](=[O:21])[N:6]3[N:22]=[CH:23][N:24]=[C:5]3[C:4]=2[CH:3]=1.[CH2:25]([O:32][C:33]([NH:35][CH2:36][CH2:37][B-](F)(F)F)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:9]3[N:10]=[CH:11][C:2]([CH2:37][CH2:36][NH:35][C:33](=[O:34])[O:32][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:3][C:4]=3[C:5]3=[N:24][CH:23]=[N:22][N:6]3[C:7]2=[O:21])=[CH:14][CH:15]=1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)cnc32)cc1
Reactant: O=C(NCC[B-](F)(F)F)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CCNC(=O)OCc4ccccc4)cnc32)cc1
Temperature: 80 °C
Yield: 0 %

Procedure:
9-Bromo-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (30 mg, 0.078 mol), potassium (2-(benzyloxycarbonylamino)ethyl)trifluoroborate (30 mg, 0.11 mol), cesium carbonate (122 mg, 0.38 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) DCM complex (5 mg, 0.01 mol), toluene (0.75 ml) and degassed water (0.25 ml) were added in order. The mixture was heated at 80° C. for 16 hours, concentrated under a stream of nitrogen, diluted with DMF (1.5 mL), filtered and purified by HPLC to afford 6 mg (12%) of 204 as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](=[O:7])[NH:3][CH:2]=1.CC(C)([O-])C.[K+].[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][C:23]([CH3:26])([CH3:25])[CH:22]3[O:27][CH:21]3[C:20]=2[CH:28]=1)#[N:15].O>CS(C)=O.C(OCC)(=O)C>[C:14]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][C:23]([CH3:26])([CH3:25])[C@@H:22]([OH:27])[C@H:21]([N:3]3[C:4](=[O:7])[CH:5]=[CH:6][N:1]=[CH:2]3)[C:20]=2[CH:28]=1)#[N:15]
Reactant: O=c1ccnc[nH]1
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](n2cnccc2=O)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
4(3H)-Pyrimidone (0.772 g, 8 mmol) was dissolved in dimethylsulphoxide (10 ml) and treated with potassium tert-butoxide (0.440 g, 4 mmol). The mixture was stirred for 30 minutes at ambient temperature and 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran (1.278 g, 6 mmol) added. The resulting mixture was heated at 90° C. for 30 minutes, cooled and poured into water. Extractive work up with ethyl acetate yielded a gum which was purified by chromatography on silica (ethyl acetate) to give trans-6-cyano-3,4-dihydro-2,2-dimethyl-4-(6(1H)-pyrimidinon-1-yl)-2H-1-benzopyran-3-ol 0.703 g, (38%), mpt 202°-3° (ethyl acetate/hexane).
Reaction SMILES: [CH:1]1([N:6]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[C:18]([NH2:24])[CH:17]=2)[S:7]([CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:25]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](=O)[C:35]([OH:37])=O)=[CH:29][CH:28]=1)#[N:26].[CH2:39](O)C>>[CH:1]1([N:6]([C:16]2[CH:17]=[C:18]3[C:19](=[CH:20][CH:21]=2)[N:22]([CH3:23])[C:35](=[O:37])[C:34]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:25]#[N:26])=[CH:32][CH:31]=2)=[N:24]3)[S:7]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:39])=[O:13])(=[O:9])=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CNc1ccc(N(C2CCCC2)S(=O)(=O)CCC(=O)OC)cc1N
Reactant: N#Cc1ccc(CC(=O)C(=O)O)cc1
Reactant: CCO
Product: CCOC(=O)CCS(=O)(=O)N(c1ccc2c(c1)nc(Cc1ccc(C#N)cc1)c(=O)n2C)C1CCCC1

Procedure:
Prepared analogously to Example 7f from methyl 3-[cyclopentyl-(3-amino-4-methylamino-phenyl)-sulphamoyl]-propionate and 3-(4-cyano-phenyl)-2-oxo-propionic acid in ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[C:10]#[N:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[SH2:14].C(N(CC)CC)C>C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:13])([CH3:12])[C:10](=[S:14])[NH2:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C#N)NC(=O)OC(C)(C)C
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)NC(C)(C)C(N)=S
Reaction time: 19 h

Procedure:
2-tert-Butyloxycarbonylamino-2-methylpropiononitrile (80.00 g) in Benzene (700 ml) was stirred at 0° C., and saturated with hydrogen sulfide. To the reaction mixture was dropped triethyl amine (1000 ml) and bubbled hydrogen sulfide at ambient temperature for 9 hours, and left at the same temperature for 19 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogencarbonate, water and brine, and dried over magnesium sulfate. After filtration, the filtrate was evaporated in vacuo. The residue was washed with n-hexane, to give 2-tert-butyloxycarbonylamino-2-methylpropanethioamide (80.14 g).
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:18](Br)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCO>[CH2:18]([N:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:10])=[CH:3][CH:4]=1)[NH2:9])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1ccc(N(N)CCc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 26 %

Procedure:
p-Tolylhydrazine hydrochloride (10.0 g, 63 mmol) was suspended in EtOH (45 mL). To this suspension was added triethylamine (9.0 mL, 63 mmol) drop-wise over a period of 5-10 minutes. The reaction mixture was stirred for additional 10 minutes. Phenethyl bromide (9 mL, 63 mmol) was added drop-wise at 25° C. over a period of 10 to 15 minutes. The reaction mixture was heated at 80° C. for 2 h at which point the reaction was found complete by TLC and LC-MS. The reaction mixture was concentrated under reduced pressure, the residue was suspended in saturated aqueous NaHCO3 (pH 9) and extracted with ethyl acetate (100 mL×2). The organic layer was separated, dried (Na2SO4) and concentrated to obtain crude product as a dark brown oil (14 g). Purification of crude product by flash column chromatography (silica gel, 230-400 mesh, eluent: 8-10% ethyl acetate-hexanes) furnished 3.7 g of pure product as yellow oil. Yield: 26% (unoptimized).
Reaction SMILES: [OH-].[K+].C(O)(C)(C)C.[CH2:8]1[O:16][C:15]2[CH:14]=[CH:13][C:12]([OH:17])=[CH:11][C:10]=2[O:9]1.[Br:18][CH2:19][CH2:20][CH2:21]Br>O>[Br:18][CH2:19][CH2:20][CH2:21][O:17][C:12]1[CH:13]=[CH:14][C:15]2[O:16][CH2:8][O:9][C:10]=2[CH:11]=1
Reactant: BrCCCBr
Reactant: Oc1ccc2c(c1)OCO2
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: BrCCCOc1ccc2c(c1)OCO2
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a solution prepared by dissolving 7.3 g of potassium hydroxide in 7 ml of water and then adding 120 ml of t-butanol are added 15 g of 3,4-methylenedioxyphenol and 88 g of 1,3-dibromopropane and the mixture is stirred for 3 hours under heating at reflux. After completion of the reaction, the solvent is distilled off and benzene is added and washed with water. The benzene layer is dried over anhydrous sodium sulfate and the solvent is distilled off. The residue is subjected to vacuum distillation to give 23 g of 5-(3-bromopropoxy)-1,3-benzodioxole boiling at 120° C./1 mmHg.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[S:23]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[O:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)(Cl)[Cl:49].CO>>[ClH:49].[S:23]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[N:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:4][CH2:3]3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24]1
Reactant: NC1CCN(C[C@H]2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Reactant: ClC(Cl)Cl
Reactant: O=Cc1cc2c(cn1)OCS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=c1ccc2ncc(=O)n3c2n1C[C@@H]3CN1CCC(NCc2cc3c(cn2)OCS3)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
(2S)-2-[(4-Amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (for a preparation see Example 16A(j) (100 mg, 0.332 mmol) was stirred with [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144 Example 61) (45 mg, 0.811 eq.) in chloroform:methanol (9:1, v:v, 5 ml) at room temperature for 2 hours; the mixture was then treated with sodium triacetoxyborohydride (211 mg, 3.0 eq.) with vigorous stirring at room temperature for 30 mins. The mixture was quenched by addition of saturated aqueous sodium hydrogen carbonate (1 ml). DCM (10 ml) was added and vigorous stirring was continued for 10 mins, followed by separation of the phases (hydrophobic frit). The organic phase was evaporated under reduced pressure and the crude product was purified by column chromatography on silica (2M NH3 in MeOH) in DCM. Appropriate fractions were combined and evaporated under reduced pressure and dried on the vacuum line over the weekend to give the free base of the title compound as a pale yellow foam (91 mg, 61%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=[N:28][O:29][CH2:30][CH2:31][OH:32])[CH3:27])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:8][S:9]([O:32][CH2:31][CH2:30][O:29][N:28]=[C:26]([C:23]1[CH:24]=[CH:25][C:20]([C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:19][CH:18]=2)=[CH:21][CH:22]=1)[CH3:27])(=[O:11])=[O:10]
Reactant: CC(=NOCCO)c1ccc(-c2ccc(F)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=NOCCOS(C)(=O)=O)c1ccc(-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triethylamine (2.83 ml) was added dropwise at 0° C. to a solution of methanesulfonyl chloride (1.15 ml) and 2-[[1-(4′-fluoro-4-biphenylyl)ethylidene]aminoxy]ethanol (3.70 g) obtained from Reference example 26(a) in dichloromethane (40 ml), and the reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained crystals were filtered off and washed with hexane and isopropyl ether to afford the target compound (4.70 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][CH2:16][C:17]([OH:19])=[O:18].C(=O)([O-])[O-].[K+].[K+]>O.CS(C)=O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[NH:15][CH2:16][C:17]([OH:19])=[O:18])([O-:14])=[O:13]
Reactant: NCC(=O)O
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 6 h

Procedure:
4-Chloro-3-nitrobenzotrifluoride (10 grams), glycine (7 grams), and potassium carbonate (10 grams) were mixed in a mixture of 40 ml. each of water and dimethyl sulfoxide. The mixture was heated to 80°-100°C. and held for 6 hours, then poured into 600 ml. of water, acidified, and chilled to 5°C. The mixture was filtered, yielding N-(2-nitro-4-trifluoromethylphenyl)-glycine. The product was dissolved in 5 percent sodium bicarbonate and reprecipitated by acidification. It was separated and recrystallized from a mixture of ethanol and water, m.p., 167°-170°C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](F)[C:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1.[CH3:16][C:17](C)([O-:19])C.[K+].C([O-])(O)=O.[Na+]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([O:19][CH2:17][CH3:16])[C:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)nc1F
Reactant: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(N)ccc1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 76.3 %

Procedure:
tert-Butyl 6-amino-2-fluoropyridine-3-carboxylate (0.7 g, 0.0033 mol) in EtOH (25 ml) was treated with potassium tert-butoxide (0.39 g, 0.0035mol) and the mixture was heated under reflux overnight. After cooling to room temperature, saturated NaHCO3 solution was added and the precipitated solid was collected by filtration and dried/n vacuo to give tert-butyl 6-amino-2-ethoxypyridine-3-carboxylate(0.6 g).
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C:24](=[CH2:25])[C@@H:23]([F:26])[CH2:22]/[C:21](=[CH:27]/[C:28](OC)=[O:29])/[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[Si:1]([O:18][C@H:19]1[C:24](=[CH2:25])[C@@H:23]([F:26])[CH2:22]/[C:21](=[CH:27]/[CH2:28][OH:29])/[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C1[C@@H](F)C/C(=C/C(=O)OC)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C=C1[C@@H](F)C/C(=C/CO)C[C@H]1O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 90.1 %

Procedure:
The compound of Example 18B (130 mg, 0.3 mmol) was dissolved in 1 mL of 1:1 dichloromethane/toluene and cooled to −78° C. Diisobutylaluminum hydride (1 M in hexanes, 0.7 mL, 2.5 equivalents) was added, and the mixture was stirred for 30 minutes. Reaction was quenched by the addition of methanol, followed by saturated aqueous NH4Cl; the mixture was warmed to ambient temperature and extracted with ethyl acetate. The organics were washed with brine and dried over Na2SO4. The solvents were removed in vacuo; the residue was purified by chromatography on an Analogix Intelliflash 280™, eluting with 15% ethyl acetate in hexanes, to give the titled compound (111 mg, 95%).
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([C:25]#[N:26])[CH2:24][CH2:23]4)=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][C:29]1[CH:30]=[N:31][C:32]2[N:33]([N:35]=[C:36]([CH:38]=O)[N:37]=2)[CH:34]=1>CO>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4([C:25]#[N:26])[CH2:23][CH2:24]4)=[C:18]([F:27])[CH:17]=3)[CH2:11][C:10](=[O:12])[CH:9]([CH2:38][C:36]3[N:37]=[C:32]4[N:31]=[CH:30][C:29]([CH3:28])=[CH:34][N:33]4[N:35]=3)[C:8](=[O:13])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc2nc(C=O)nn2c1
Reactant: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CC1
Solvent: CO
Product: Cc1cnc2nc(CC3C(=O)CC(CCc4ccc(C5(C#N)CC5)c(F)c4)(C4CCCC4)OC3=O)nn2c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 1-{4-[2-(2-cyclopentyl-4,6-dioxo-tetrahydro-pyran-2-yl)-ethyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile (568 mg, 1.54 mmol) in anhydrous MeOH (6.0 mL) was treated with 6-methyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde (324 mg, 2.0 mmol), followed by borane-dimethylamine complex (118 mg, 2.0 mmol) at room temperature. The reaction was stirred for 1 hour before it was cooled to −10° C. for 2 hours. The precipitate was removed by filtration, and the filtrate was concentrated to an oil. The oil was purified by flash chromatography (50 g SiO2, 1:3->1:0 (93.5% ethyl acetate, 6% methanol, 0.5% acetic acid):(81.5% hexanes, 12% ethyl acetate, 6% methanol, 0.5% acetic acid)) to give the desired product as an oil. It was further purified by crystallization from ethyl acetate/hexanes to give a white powder (146 mg, 18%). 1H NMR (400 MHz, CDCl3) δ: 1.41-1.64 (m, 8H), 1.84-1.88 (m, 2H), 2.22-2.28 (m, 2H), 2.42 (s, 3H), 2.49-2.59 (m, 4H), 2.65-2.74 (m, 3H), 3.97-4.05 (m, 2H), 6.72-6.82 (m, 2H), 7.05-7.10 (m, 1H), 8.55 (s, 1H), 8.67 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])[NH2:5].[ClH:13].[Cl:14]Cl>O>[Cl:13][C:3]1[C:2]([Cl:1])=[C:8]([C:9]([F:10])([F:11])[F:12])[CH:7]=[C:6]([Cl:14])[C:4]=1[NH2:5]
Reactant: Cl
Reactant: Nc1ccc(C(F)(F)F)c(Cl)c1
Reactant: ClCl
Solvent: O
Product: Nc1c(Cl)cc(C(F)(F)F)c(Cl)c1Cl
Reaction time: 0.25 h

Procedure:
A mixture of 3-chloro-4-trifluoromethylaniline [20 g; described in British Patent Specification No. 459890] and hydrochloric acid (d: 1.18; 12 ml) was suspended in water (600 ml). Chlorine gas (from 13 ml of liquid chlorine) was then passed into the stirred suspension with heating at reflux. On completion of the addition of chlorine gas, stirring was continued for a further 15 minutes. After cooling, the solution thus obtained was extracted with dichloromethane (3×250 ml). The combined organic extracts were washed with water, saturated aqueous solid bicarbonate solution and water, dried over anhydrous sodium sulphate and evaporated. The red oil thus obtained was distilled (bp 143°-147° C./20 mmHg) to give an orange oil which crystallized on standing to give 2,3,6-trichloro-4-trifluoromethylaniline (12.26 g), m.p. 37°-39° C., in the form of an orange solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:13]3[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=3[S:15][CH:16]=2)=[CH:8][CH:7]=1.[F:21][C:22]1C=[C:28]([F:30])[CH:27]=[CH:26][C:23]=1CN.C(=O)([O-])[O-].[K+].[K+].[C:37](#[N:39])[CH3:38]>>[S:15]1[CH:16]=[C:12]([C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:39][CH2:37][C:38]3[C:22]([F:21])=[CH:23][CH:26]=[CH:27][C:28]=3[F:30])=[CH:7][CH:8]=2)[C:13]2[CH:20]=[CH:19][CH:18]=[CH:17][C:14]1=2
Reactant: BrCCCOc1ccc(-c2csc3ccccc23)cc1
Reactant: CC#N
Reactant: NCc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cccc(F)c1CNCCCOc1ccc(-c2csc3ccccc23)cc1

Procedure:
The title compound is prepared from 3-[4-(3-bromo-propoxy)-phenyl]-benzo[b]thiophene, 2,4-difluorobenzylamine, potassium carbonate and acetonitrile essentially as described above in Example 118. Purity by LC/MS=98%, [M+H]+=410.
Reaction SMILES: [N+:1]([C:4]1[N:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[N+:1]([C:4]1[N:8]=[CH:7][N:6]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:10]([F:21])([F:20])[F:9])[CH:16]=2)[N:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1nc[nH]n1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ncn(-c2cccc(C(F)(F)F)c2)n1
Temperature: 30 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
Into a 250-mL round bottom flask, was placed a solution of 3-nitro-1H-1,2,4-triazole (2 g, 17.54 mmol, 1.00 equiv) in dichloromethane (100 mL), 3-(trifluoromethyl)phenylboronic acid (6.66 g, 35.05 mmol, 2.00 equiv), Cu(OAc)2 (4.79 g, 26.32 mmol, 1.50 equiv), pyridine (2.77 g, 35.06 mmol, 2.00 equiv), and molecular sieves (5.2 g). The resulting solution was stirred overnight at 30° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20-1:10) to give 2.2 g (49%) of product as a white solid.
Reaction SMILES: [OH2:1].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].Cl.[NH2:11]O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[NH2:3][C:2](=[N:11][OH:1])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC#N
Reactant: NO
Reactant: O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(N)=NO
Temperature: 25 °C
Yield: 66 %

Procedure:
Water (500 ml) is added dropwise over a period of 2 hours to a vigorously stirred, room temperature mixture of ethyl cyanoacetate (100 g, 0.884 mol), hydroxylamine hydrochloride (3 g, 1.328 mol) and sodium carbonate (70 g, 0.66 mol ) in ethanol (1 L.) After stirring for an additional 12 hours at room temperature, the reaction mixture is heated to 50° C. for 1 hour. The resulting light red colored solution is allowed to cool to room temperature and then stirred for an additional 2 hours. The solids formed are removed via filtration and the filtrate is concentrated in vacuo. The resulting residue is extracted with methylene chloride (3×200 ml). The combined organic extracts are washed with brine (300 ml), dried (Na2SO4), filtered and concentrated to afford 85.2 g (66%) of compound 2b as a slightly colored solid. Compound 2b can be further purified by crystallization from chloroform and hexanes. 1H NMR (CDCl3): δ8.45 (br s, 1H), 5.25 (br s, 2H) 4.25(q, 2H), 3.15 (s, 2H), 1.35 (t, J=7 Hz, 3H).
Reaction SMILES: CC([CH2:4][C:5]([OH:7])=[O:6])=O.[C:8]1([CH:15]=[CH:14][C:12]([OH:13])=[CH:11][CH:10]=1)[OH:9].C(OC(=O)C)(=O)C.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:5]([OH:7])(=[O:6])[CH3:4].[C:8]1([CH:15]=[CH:14][C:12]([OH:13])=[CH:11][CH:10]=1)[OH:9]
Reactant: CC(=O)CC(=O)O
Agent: CN(C)c1ccncc1
Agent: Oc1ccc(O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)O

Procedure:
The preparation of monoacetates of hydroquinone and catechol has been investigated, according to early publications, with varying results. Oltcott (J. Am. Chem. Soc. 59, 1937, 392-393) has found, that the monacetylation of these two dihydroxybenzenes can be performed by careful reaction with an acetylating agent, e.g. acetic anhydride, in aqueous alkaline solution. The desired mono-acetate was obtained in a yield of only 20-30%, whereas the major product obtained was the diacetate. Johnston (Chem. Ind. 1982, 1000) has succeeded in improving the formation of the mono-acetate of hydroquinone from hydroquinone and acetic anhydride by using triethyl amine as a base and 4-dimethylaminopyridine (DMAP) as a catalyst, in a polar organic solvent, viz. in ethyl acetate solution. Under such reaction conditions, Johnston has succeeded in obtaining hydroquinone mono-acetate in yields of 58-65%.
Reaction SMILES: [CH2:1]([O:8][NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].C(ON(CCCCC#N)C(=O)CCCCCl)C1C=CC=CC=1.CCCCCC.CCOC(C)=O>C(Cl)Cl.[OH-].[Na+]>[Br:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24](=[O:25])[N:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]#[N:15]
Reactant: N#CCCCCNOCc1ccccc1
Reactant: O=C(Cl)CCCCCCCBr
Agent: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#CCCCCN(OCc1ccccc1)C(=O)CCCCCCCBr

Procedure:
Compound 2 (n=4) (3.2 g, 15.7 mmol) was treated with 8-bromooctanoyl chloride (4.55 g, 18.8 mmol) in CH2Cl2 and 1N NaOH following the procedure used for (3). Silica gel column chromatography with 2:1 hexane/EtOAc afforded 3.8 g (59%) of [I] as an oil: NMR δ 1.17-2.00 (m, 14 H), 2.23-2.50 (m, 4 H), 3.37 (t, 2 H, J=6), 3.63 (t, 2 H, J=6), 4.77 (s, 2 H), 7.33 (s, 5 H). Anal. (C20H29BrN2O2) C, H, N.
Reaction SMILES: ClC1C=CC=CC=1.[C:8]([N:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2)#[N:9].[OH2:25]>>[C:8]([N:10]1[C:11]2[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=2[CH:13]([OH:25])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2)#[N:9]
Reactant: O
Reactant: N#CN1c2ccccc2CCc2ccccc21
Solvent: Clc1ccccc1
Product: N#CN1c2ccccc2CC(O)c2ccccc21
Temperature: 87.5 °C

Procedure:
190 ml of chlorobenzene, 25 g of (I) and 17 g of N,N-dibromohydantoin are loaded into a 500 ml pyrex round-bottom flask, under nitrogen, and irradiated from the outside with a 300 watt halogen lamp, keeping temperature between 70 and 75° C. for 3 hours. 150 ml of water and 5 g of PEG 6000 are added, heating to 85-90° C for 2 hours. After decanting at 60° C., water is removed and the organic phase is washed with further water (2×100 ml). Chlorobenzene is evaporated off under vacuum at 5 mm/Hg and the residue is taken up with 50 ml of ethyl acetate. The mixture is cooled to 0° C., filtered and dried at 60° C. for 4 hours, to obtain 16 g of (VI), m.p. 110-111° C., with good purity.