Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@H:5]2[C:14]3[C:19]([C:20](=[O:21])[C@@H:4]2[CH2:3]1)=[CH:18][CH:17]=[CH:16][CH:15]=3.[BH4-].[Na+].Cl>C(O)C.C1COCC1>[OH:21][C@@H:20]1[C@H:4]2[C@H:5]([N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:2](=[O:1])[CH2:3]2)[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: CC(C)(C)OC(=O)N1C(=O)C[C@H]2C(=O)c3ccccc3[C@H]21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1C(=O)C[C@@H]2[C@H]1c1ccccc1[C@@H]2O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (3aR,8bS)-2,4-dioxo-3a,8b-dihydro-3H-indeno[1,2-b]pyrrole-1-carboxylate F 26 (1.60 g, 5.56 mmol) in ethanol (20 mL) and THF (20 mL) was added at 0° C. NaBH4 (0.316 g, 8.15 mmol). The solution was stirred for 2 h at 0° C. 1M HCl was carefully added and the solution was concentrated in vacuo. The residue was partitioned between ethyl acetate and water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried and concentrated. The residue was purified by flash chromatography (2/1 cyclohexane/ethyl acetate) to give tert-butyl (3aR,4R,8bS)-4-hydroxy-2-oxo-3,3a,4,8b-tetrahydroindeno[1,2-b]pyrrole-1-carboxylate F27 (800 mg, 50%). LCMS (method E): 0.78 min; ES+: 601 (2M+Na+).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][C:7]=1[CH3:15].O.[C:17]1([O:23][CH3:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([C:20]2[CH:21]=[CH:22][C:17]([O:23][CH3:24])=[CH:18][CH:19]=2)=[O:11])=[CH:8][C:7]=1[CH3:15]
Reactant: COc1ccccc1
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: COc1ccc(C(=O)c2ccc(Br)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
AlCl3 (3.63 g, 27.2 mmol) was added portionwise to 4-bromo-3-methylbenzoyl chloride (5.30 g, 22.7 mmol) dissolved in anisole (7 mL) at 0° C. The reaction mixture was warmed to RT, stirred for 1 h, and then cooled to 0° C. Water (200 mL) was cautiously added dropwise, and the mixture was extracted with ether (3×100 mL). The combined ethereal extracts were washed with water (250 mL), brine (250 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 6.42 g (93%) of 65 as a white solid. 1H NMR (400 MHz, CDCl3): δ 2.45 (s, 3H), 3.88 (s, 3H), 6.96 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.1 Hz, 1H), 7.62 (m, 2H), 7.79 (d, J=8.8 Hz, 2H).
Reaction SMILES: C([Li])CCC.[Br-].COC(C)([O:11][CH2:12][CH2:13][CH2:14][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.[C:35]1([CH2:41][O:42][C:43]2[CH:50]=[CH:49][C:46]([CH:47]=O)=[CH:45][CH:44]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CCCCCC.C1COCC1>[C:35]1([CH2:41][O:42][C:43]2[CH:50]=[CH:49][C:46]([CH:47]=[CH:14][CH2:13][CH2:12][OH:11])=[CH:45][CH:44]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: COC(C)(C)OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCCC=Cc1ccc(OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
A solution of n-butyllithium in hexane (1.6 M, 20 ml) was added to a stirred suspension of finely powdered [3-(1-methoxy-1-methylethoxy)propyl] triphenylphosphonium bromide (14 g) in dry THF (100 ml) at 0°. The mixture was stirred at 0° for 30 min, treated with a solution of 4-(phenylmethoxy)benzaldehyde (5 g) in THF (25 ml), stirred at 0° for 2 h and filtered through silica. The filtercake was washed with ER, the combined filtrates evaporated in vacuo and the residual oil triturated with ER (50 ml) and filtered through silica. The filtrate was evaporated and the residue dissolved in THF-water-2 M hydrochloric acid (50:5:1, 56 ml) and kept at 23° for 20 min. The mixture was diluted with water (200 ml), extracted with ER (200 ml) and the extract was washed with water (100 ml), brine (50 ml) dried and evaporated to give a white solid which was stirred in hexane and filtered to give the title alcohol (5.2 g) m.p. 93°-95°.
Reaction SMILES: C(O)(C)C.[ClH:5].CNOC.Br[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25].C(=O)(O)[O-].[Na+]>C(N(CC)CC)C>[Cl:5][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25]
Reactant: Cl
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: CNOC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: O=C1c2ccccc2C(=O)N1CCCCCl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 42.7 %

Procedure:
To a suspension of 50 ml of isopropanol containing N,O-dimethylhydroxylamine hydrochloride (3.97 g, 40.0 mmol) was added dropwise 5.56 ml of triethylamine. The resulting mixture became homogeneous after 5 minutes. There were added 2.00 g (7.09 mmol) of N-(4-bromobutyl)phthalimide and the mixture was refluxed for 58 hours. This was cooled to room temperature, then poured into 200 ml of saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was separated, was washed with water and dried over magnesium sulfate. Chloroform was distilled off and the residue was purified by column chromatography on silica gel. Development with 30% hexane-chloroform resulted in elution of 0.719 g of N-(4-chlorobutyl)-phthalimide and further development with chloroform resulted in 0.964 g (yield: 41%) of N-[4-(N-methoxy-N-methylamino)-butyl]phthalimide as an oil.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[H-].[Na+].[F:10][C:11]1[C:16]([CH:17]([S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26])[S:18]([C:21]([F:24])([F:23])[F:22])(=[O:20])=[O:19])=[C:15]([F:32])[C:14]([F:33])=[C:13](F)[C:12]=1[F:35].O.Cl>N1C=CC=CC=1>[CH2:1]([O:7][C:13]1[C:12]([F:35])=[C:11]([F:10])[C:16]([CH:17]([S:18]([C:21]([F:24])([F:22])[F:23])(=[O:19])=[O:20])[S:25]([C:28]([F:29])([F:30])[F:31])(=[O:26])=[O:27])=[C:15]([F:32])[C:14]=1[F:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCO
Reactant: O=S(=O)(C(c1c(F)c(F)c(F)c(F)c1F)S(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCOc1c(F)c(F)c(C(S(=O)(=O)C(F)(F)F)S(=O)(=O)C(F)(F)F)c(F)c1F
Temperature: -20 °C
Reaction time: 5 h
Yield: 99 %

Procedure:
Hexanol (1.5 mL, 12 mmol) was added to a pyridine (10 mL) solution dissolved with 60% sodium hydride containing mineral oil (0.56 g, 14 mmol) at 0° C., and the resultant solution was stirred for 1 hour at room temperature. After the solution was cooled to −20° C., pentafluorophenylbis(triflyl)methane (0.89 g, 2 mmol) was added. The reaction solution was stirred at −20° C. for 5 hours. After the reaction, the solution was acidified with 4 M hydrochloric acid water, and was extracted with diethylether. After drying with magnesium sulfate, the solution was filtrated, and the solvent was removed under reduced pressure. The crude product was purified by sublimation (0.2 to 0.3 torr, 65° C.), and 4-hexanoxy-2,3,5, 6-tetrafluorophenylbis(triflyl)methane was obtained at 99% yield (1.02 g, 1.98 mmol). 1H NMR (CDCl3, 300 MHz) δ 0.91 (t, J=7.1 Hz, 3H), 1.32 to 1.37 (m, 4H), 1.43 to 1.51 (m, 2H), 1.83 (quintet, J=6.8 Hz, 2H), 4.44 (t, J=6.8 Hz, 2H), 6.19 (s, 1H); 19F NMR (CDCl3, 282 MHz) δ−75.35 (s, 6F, 2CF3), −130.64 (dt, J=9.9, 21.2 Hz, 1F), −143.16 (br, 1F), −155.31 (d, J=21.2 Hz, 1F).
Reaction SMILES: [Na+].[F:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([NH:10][CH2:11][C:12]([O-])=[O:13])=[C:5]([N+:15]([O-])=O)[CH:4]=1.O.O.[Sn](Cl)Cl>C(O)C>[F:2][C:3]1[CH:4]=[C:5]2[C:6]([NH:10][CH2:11][C:12](=[O:13])[NH:15]2)=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1cc(NCC(=O)[O-])c([N+](=O)[O-])cc1F
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc2c(cc1F)NC(=O)CN2
Temperature: 25 °C
Yield: 32.4 %

Procedure:
A mixture of N-(4-fluoro-5-methyl-2-nitrophenyl)glycine sodium salt (0.125 g, 0.548 mmol) and tin (II) chloride dihydrate (0.370 g, 1.64 mmol, Aldrich, used as received) in ethanol (3.0 mL) was refluxed for 30 min. It was then cooled to room temperature and the solvent was removed under vacuum. The residue was diluted with water (4.0 mL) and basified with saturated NaHCO3 to pH ~8. The resulting suspension was extracted with ethyl acetate (30 mL). The extract was dried over Na2SO4 and evaporated to yield 0.032 g of the title compound as a yellow powder, which was used for the next reaction; 1H NMR (DMSO-d6): 2.024 (s, 3H), 3.607 (s, 2H), 5.751 (s, 1H), 6.453 (d, 1H, J=9.9 Hz), 6.456 (d, 1H, J=8.1 Hz), 10.162 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[O:11][C:12](=[O:14])[CH3:13].[I:15]I>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[C:12]([O:11][C:4]1[C:3]([O:2][CH3:1])=[C:8]([I:15])[CH:7]=[CH:6][C:5]=1[O:9][CH3:10])(=[O:14])[CH3:13]
Reactant: COc1cccc(OC)c1OC(C)=O
Reactant: II
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: COc1ccc(I)c(OC)c1OC(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To an ice-cooled suspension of acetic acid 2,6-dimethoxy-phenyl ester (1.0 g, 5.1 mmol) and silver trifluoroacetate (5.1 mmol) in CHCl3 (16 ml) was added iodine (1.3 g, 5.1 mmol) and the reaction stirred for 1 hour. The crude mixture was filtered through celite to remove the precipitated silver iodide and the filtrate was washed with 10% Na2S2O3 (aq). An emulsion was formed and the mixture was again passed through celite and the filtrate washed with brine, dried over MgSO4 and concentrated under reduced pressure to give the product as a tan solid (1.57 g, 96%). 1H-NMR (300 MHz, CDCl3) δ 7.55 (d, J=8.9 Hz, 1H), 6.54 (d, J=8.9 Hz, 1H), 3.80 (s, 6H), 2.33 (s, 3H).
Reaction SMILES: C1(NC(OCC)=O)C=CC=CC=1.O[C:14]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:15]=1[CH:16]([CH3:20])[C:17]([OH:19])=[O:18].[H][H]>C(O)(=O)C.[Pd]>[CH3:25][C:23]1[CH:22]=[CH:21][C:15]([CH:16]([CH3:20])[C:17]([OH:19])=[O:18])=[CH:14][CH:24]=1
Reactant: Cc1ccc(C(C)C(=O)O)c(O)c1
Reactant: [H][H]
Agent: [Pd]
Agent: CCOC(=O)Nc1ccccc1
Solvent: CC(=O)O
Product: Cc1ccc(C(C)C(=O)O)cc1
Yield: 67 %

Procedure:
3 g. of 2-hydroxy-4-methyl-hydratropic acid phenylurethane are dissolved in acetic acid. To the solution 0.4 g. of a 5% palladium-on-charcoal catalyst are added, and the mixture is hydrogenated at 25° C. until the calculated amount of hydrogen is used up. The catalyst is filtered off and the filtrate is evaporated. The residue is admixed with a 10% aqueous hydrochloric acid solution and the separated oil is extracted with chloroform. The chloroform solution is dried over sodium sulphate and evaporated. 1.1 g. (67%) of 4-methyl-hydratropic acid are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12](/[CH:13]=[N:14]\[OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18]N1C(=O)CCC1=O>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12](/[C:13](/[Cl:18])=[N:14]\[OH:15])=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O/N=C\c1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Cl
Product: O/N=C(/Cl)c1ccc(OCc2ccccc2)cc1
Reaction time: 3 h

Procedure:
To (Z)-4-(benzyloxy)benzaldehyde oxime (11.3 g) in N,N′-Dimethyl formamide (57 ml), N-Chlorosuccinimide (7.98 g) was added and the reaction mixture was stirred for 3 hours and then solvent was evaporated to dark brown residue. To this residue water was added and extracted with Ethyl acetate. Organic layer was collected and dried over Na2SO4 and concentrated to obtain pale brown solid, which was crystallized from DCM-Petroleum ether to obtain the title compound as white solid. Yield: 7.9 g (60%); 1HNMR (DMSO-d6; 300 MHz): δ 12.17 (s, 1H), 7.73 (d, 2H), 7.33-7.47 (m, 5H), 7.11 (d, 2H) 5.16 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:17]=[C:16]([OH:18])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]=2[N:3]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:1][C:2]1[N:17]=[C:16]([O:18][S:25]([C:22]2[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=2)(=[O:27])=[O:26])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:4]=2[N:3]=1
Reactant: Nc1nc(O)c2c(n1)-c1ccccc1CCCC2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCCc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 20B (950 mg, 2.4 mmol) in CH2Cl2 (30 mL) was added para-toluenesulfonyl chloride (1.09 g, 5.7 mmol), 4-dimethylaminopyridine (50 mg, 0.41 mmol) and triethylamine (1.1 mL. 7.9 mmol) and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with CH2Cl2 (100 mL), washed with H2O, dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified on silica gel eluting with EtOAc:hexanes (25:75) to provide the title compound.
Reaction SMILES: [O:1]([Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])S(C(F)(F)F)(=O)=O.[Br:16][C:17]1[CH:21]=[CH:20][O:19][C:18]=1[CH2:22]O.N1C=CC=CC=1>C(Cl)Cl>[Br:16][C:17]1[CH:21]=[CH:20][O:19][C:18]=1[CH2:22][O:1][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: OCc1occc1Br
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCc1occc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 102.9 %

Procedure:
tert-Butyldimethylsilanyl triflate (17.13 g) was added slowly to a stirred, cooled solution of 3-bromo-2-hydroxymethylfuran (Intermediate 39, 10.1 g) in DCM (160 mL) and pyridine (9.57 g) while maintaining the temperature at 0° C. The mixture was allowed to warm to room temperature and stirred for 1 hour. The mixture was washed with aqueous citric acid solution, brine, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness to give 3-bromo-2-(tert-butyldimethylsilanyloxymethyl)furan (17.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=[O:15])[CH2:8]2.Br[CH2:17][C:18]([O:20]CC)=[O:19]>C1(C)C=CC=CC=1.C1C=CC=CC=1.[Zn]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7]([OH:15])([CH2:17][C:18]([OH:20])=[O:19])[CH2:8]2
Reactant: CCOC(=O)CBr
Reactant: COc1ccc(OC)c2c1CCC(=O)C2
Agent: [Zn]
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(OC)c2c1CCC(O)(CC(=O)O)C2

Procedure:
A fifth of a solution of 20.6 g of 3,4-dihydro-5,8-dimethoxy-2(1H)-naphthalenone and 18.4 g of ethyl bromoacetate in 100 ml of toluene/benzene (1:1) was added to 7.4 g of activated zinc dust. An exothermic reaction set in after heating to reflux for a few minutes. The remainder of the solution was then added dropwise within 10 minutes. The reaction mixture was then heated to reflux for 11/2 hours, cooled and partitioned between 300 ml of benzene and 300 ml of 3N aqueous sulfuric acid. The organic phase was washed with water and saturated aqueous sodium bicarbonate solution and evaporated. The residue was dissolved in 200 ml of methanol, treated with a solution of 10 g of sodium hydroxide in 100 ml of water and the mixture was heated to reflux for 3 hours. The solution was concentrated to half of the volume, treated with 500 ml of water and the neutral constituents were extracted with 500 ml of chloroform. The aqueous phase was made acid with sulfuric acid and the product was extracted in 900 ml of ether. The extract was dried over magnesium sulfate and evaporated. Recrystallization of the residue yielded 5,8-dimethoxy-1,2,3,4-tetrahydro-2-hydroxy-2-naphthaleneacetic acid, m.p. 112°-114°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CCN(CC)CC.[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[O:20][C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[CH2:23][N:24]([C:25](Cl)=[O:26])[C:18]=2[CH:17]=1>C(Cl)Cl>[Cl:15][C:16]1[CH:33]=[CH:32][C:19]2[O:20][C:21]3[CH:31]=[CH:30][CH:29]=[CH:28][C:22]=3[CH2:23][N:24]([C:25]([NH:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=3)=[O:26])[C:18]=2[CH:17]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: Nc1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1ccncc1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 89.3 %

Procedure:
By the method described in Example 18, 4-aminopyridine (1.3 g, 14.0 mmol) in 40 mL of CH2Cl2 with molecular sieves #5A (5 g) and Et3N (1.4 g, 15.0 mmol) was reacted with the title compound of Example 2 (4.1 g, 14.0 mmol) to produce 4.4 g of the title product after HPLC purification on silica gel.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][CH:3]=1.C([Li])(C)(C)C.Cl[P:19]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(OCC)C>[CH:26]1([P:19]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[O:12][CH2:11][CH2:10][O:9]3)=[CH:4][CH:3]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Brc1ccc(C2OCCO2)cc1
Reactant: ClP(C1CCCCC1)C1CCCCC1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: c1cc(P(C2CCCCC2)C2CCCCC2)ccc1C1OCCO1
Temperature: 25 °C

Procedure:
This is an example of synthesis of ligand 2. 2-(4′-Dicyclohexylphosphinophenyl)-1,3-dioxolane (Ligand 2): Part I. A solution of 4-bromobenzaldehyde (5 g, 0.027 mol), ethylene glycol (7.0 g, 0.11 mmol), and p-toluenesulfonic acid (0.1 g, 0.5 mmol) in benzene was heated at reflux for 24 h using a Dean-Stark setup to remove water. The reaction was taken up in diethyl ether (100 mL) and washed with water (5×30 mL) and brine (30 mL). The organic phase was dried over magnesium sulfate and concentrated under vacuum to afford 2-(4′-bromophenyl)-1,3-dioxolane (5.95 g). Part II. 2-(4′-bromophenyl)-1,3-dioxolane (1.0 g, 4.4 mmol) was dissolved in anhydrous diethyl ether (30 mL) and the solution was cooled to −78° C. t-Butyllithium (5.14 mL, 1.7 M solution in pentane, 8.8 mmol) was added dropwise with stirring. The reaction was stirred for 2 h at −78 ° C. Chlorodicyclohexylphosphine (1.13 g, 4.8 mmol) was added dropwise via a syringe at −78 ° C. with stirring. The reaction mixture was allowed to warm up to room temperature and stirred for an additional 18 h. To the reaction mixture was added argon purged water (25 mL) slowly. The organic phase was separated under argon and the aqueous phase was washed with diethyl ether (20 mL). The combined organic phase was concentrated under vacuum to afford a colorless oil, which was crystallized from methanol to afford ligand 2 as a white crystalline solid having the structure shown below (yield: 1.4 g, 92%). 31P{1H} NMR (CDCl3): δ2.4.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.Cl[C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][N:13]=1.C(N(CC)CC)C>C(O)C>[N+:18]([C:17]1[C:12]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[N:13][CH:14]=[CH:15][CH:16]=1)([O-:20])=[O:19]
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1cccnc1-c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 69 %

Procedure:
5-Aminoindole and 2-chloro-3-nitropyridine were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was stirred at room temperature for 4 days. The resulting reaction mixture was filtered to afford the title compound (69%) as an orange solid: mp, 162.0°-163.5° C.; 13C NMR (CDCl3) δ 155.6, 150.5, 135.5, 133.5, 129.7, 127.9, 127.6, 125.9, 118.5, 115.0, 113.4, 111.2, 101.2; Anal. calcd for C13H10N4O2 : C, 61.41; H, 3.96; N, 22.04. Found: C, 61.22; H, 3.80; N, 22.08.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=[C:8]([N+:20]([O-:22])=[O:21])[C:3]=1[NH:4][CH2:5][CH2:6]O.P(Cl)(Cl)(Cl)(Cl)[Cl:24].O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:10][CH:9]=[C:8]([N+:20]([O-:22])=[O:21])[C:3]=1[NH:4][CH2:5][CH2:6][Cl:24]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)c(Cl)c1NCCO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)c(Cl)c1NCCCl
Yield: 75.9 %

Procedure:
An amount of 4.5 gm of 2-chloro-3-(4-chlorophenoxy)-6-nitro-N-2-hydroxyethylaniline was dissolved in 40 ml of toluene and mixed with 2.9 gm of PCl5, spontaneous heating and gas generation taking place. After 30 minutes the mixture was shaken with water and sodium bicarbonate solution and is evaporated. 3.6 gm of a yellowy brown oil were obtained (76% of theory).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])#[CH:12].N>>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:11]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[N:8][CH:9]=2)[CH:12]=1
Reactant: C#Cc1ccc(F)cc1F
Reactant: ON=C(Cl)c1cncnc1
Agent: N
Product: Fc1ccc(-c2cc(-c3cncnc3)no2)c(F)c1

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 1-ethynyl-2,4-difluorobenzene (Aldrich, 69 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.30-7.42 (m, 1H), 7.61 (ddd, J=11.5, 9.1, 2.4 Hz, 1H), 7.68 (d, J=3.2 Hz, 1H), 8.08 (td, J=8.6, 6.5 Hz, 1H), 9.35 (s, 1H), 9.39 (s, 2H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)=S)[CH3:2].[N:16]#[C:17][NH2:18].[Pb]>>[C:17]([NH:18][C:4]([NH:3][CH2:1][CH3:2])=[N:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[S:12][CH:13]=[CH:14][N:15]=1)#[N:16]
Reactant: CCNC(=S)NCCNCc1nccs1
Reactant: N#CN
Agent: [Pb]
Product: CCNC(=NCCNCc1nccs1)NC#N

Procedure:
Reacting N-(2-thiazolylmethyl)ethylenediamine with ethyl isothiocyanate by the procedure of Example 3(b) and then chromatographing gives N-ethyl-N'-[2-(2-thiazolylmethylamino)ethyl]thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3(b) gives N-cyano-N'-ethyl-N"-[2-(2-thiazolylmethylamino)ethyl]guanidine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]([OH:18])[C:13](OCC)=[O:14])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[OH-].[NH4+:20]>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH:12]([OH:18])[C:13]([NH2:20])=[O:14])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: CCOC(=O)C(O)c1cc(F)cc2cccnc12
Reactant: [NH4+]
Agent: [OH-]
Product: NC(=O)C(O)c1cc(F)cc2cccnc12

Procedure:
Ethyl 2-(6-fluoro-8-quinolyl)-2-hydroxyacetate (1.1 g.) was refluxed for 10 minutes in 300 ml. of conc. ammonium hydroxide. The reaction mixture was cooled slightly, clarified by filtration and evaporated to solids. Trituration of the residue with 25 ml. of toluene gave the title product (860 mg., m.p. 169°-171° C.).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]([NH:14][C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:4]=1.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C:15]([NH:14][N:5]2[N:4]=[C:3]([CH2:2][NH:1][C:32](=[O:33])[CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:13])=[O:24])=[CH:22][CH:21]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Product: O=C(Cc1ccccc1)NCc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product from Example 42 and 2-phenylacetyl chloride were processed using a method similar to that described in Example 4C to afford the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 8.42 (d, J=7.8 Hz, 1H), 8.11-8.13 (bs, 1H), 7.83-7.91 (m, 2H), 7.76-7.82 (m, 1H), 7.39 (s, 3H), 7.23-7.35 (buried m, 6H), 6.24-6.30 (bs, 1H), 4.72-4.74 (m, 2H), 3.79-3.80 (bs, 2H), 3.63-3.63 (bs, 2H); MS (ESI−) M/Z 459 (M−H)−.