Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:6]([O:7][CH3:8])[C:4]=1[OH:5].[H-].[Na+].Cl[CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:8][O:7][C:6]1[C:4]([O:5][CH2:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:3]([CH:11]=[CH:10][CH:9]=1)[CH:2]=[O:1]
Reactant: ClCCCN1CCOCC1
Reactant: COc1cccc(C=O)c1O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cccc(C=O)c1OCCCN1CCOCC1

Procedure:
o-Vanillin (30.4 g), dissolved in 160 ml of dimethylformamide, is treated with 9.6 g of 50% sodium hydride, then with 130 ml of 2 N N-(3-chloropropyl)morpholine in toluene following the procedure described in Example 1A, yielding 42.9 g of the title compound, boiling point 178°-183° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][N:12]([CH2:20][CH:21]=O)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:15]([O:14][C:13]([N:12]([CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH2:20][CH2:21][NH:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:19])([CH3:16])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N(CC=O)CCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CNCCN(CCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-Butyl [2-(4-nitrophenyl)ethyl](2-oxoethyl)carbamate (0.52 g, 1.7 mmol) in MeOH (10 mL) was added ethyl aminoacetate hydrochloride (0.31 g, 2.2 mmol), sodium cyanoborohydride (1.1 g, 5.1 mmol), and a few drops of acetic acid. The mixture was allowed to stir at 25° C. for 16 hours. LC showed clean reaction. The product was purified by silica gel chromatography (Hexane:EtOAc) to deliver Ethyl [(2-{(tert-butoxycarbonyl) [2-(4-nitrophenyl)ethyl]amino}ethyl)amino]acetate. LC-MS (IE, m/z): 396 [M+1]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:24]([Cl:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Cl:15][C:16]1[C:24]([Cl:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: O=C1CNCCN1
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CN(C(=O)c2ccc(F)c(Cl)c2Cl)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using method analogous to those described for the synthesis of intermediates 1 to 3, the intermediate below was synthesised according to the method described below. 2-piperazinone (2.51 g, 25.07 mmol, commercially available e.g. from Sigma-Aldrich) and triethylamine (4.19 mL, 30.1 mmol) were dissolved in Dichloromethane (DCM) (50 mL). 2,3-dichloro-4-fluorobenzoyl chloride (I33)(6.28 g, 27.6 mmol) dissolved in Dichloromethane (DCM) (50 mL) was added dropwise at 0° C. and the solution allowed to stir to room temperature overnight. The mixture was diluted with Dichloromethane (200 mL) and washed with saturated sodium bicarbonate solution (100 mL). The aqueous phase was extracted with Dichloromethane (3×100 mL) and the combined extracts were washed with water (2×100 mL), brine (100 mL), dried over anhydrous sodium sulfate and concentrated to a crude solid that was triturated with hexane to afford product in 6.94 g. The product was recrystalised from ethanol (Note: slow to come out of solution) to afford the desired product in 5.08 g.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:10][N:11]([CH:13]=O)[CH3:12]>>[CH3:10][N:11]([CH3:13])[CH:12]=[CH:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C#N
Reactant: CN(C)C=O
Product: CN(C)C=Cc1cccnc1C#N
Reaction time: 120 h
Yield: 56 %

Procedure:
A solution of 3-methyl-2-cyanopyridine (20.0 g, 0.17 m), DMF (200 mL) and DMF acetal (30 mL, 0.25 m) was heated at 120° with stirring under N2 for 5 days. Additional acetal was periodically added in 5 mL aliquots (total 45 mL, 0.38 m). The solution was then evaporated to dryness to give a crude oil which solidified on standing. The solid was crystallized from ligroin to yield 16.5 g (56%) of N,N-dimethyl-2-(2-cyano-3-pyridyl)ethenamine. An analytical sample was prepared by recrystallization from ligroin, mp 71.5°-72°.
Reaction SMILES: [H-].[Na+].[Br-].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH2:9][PH3+].[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH:29]=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[CH2:18]([O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)/[CH:29]=[CH:9]\[C:8]1[CH:7]=[C:6]([O:5][CH3:4])[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: COc1cc(C[PH3+])cc(OC)c1OC
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COc1cc(/C=C\c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a stirred suspension of sodium hydride (0.75, 31.4 mmol) in N,N-dimethylimidazolidinone (10 ml) was added 3,4,5-trimethoxy-benzyl-phosphonium bromide (8.26 g 15.71 mmol) under argon. The aldehyde (4.0 g, 1258 mmol) from Example 40 was added to the deep red solution followed by 2 ml of N,N-dimethylimidazolidinone. Before adding ice (10 g)-water (75 ml) the mixture was stirred overnight. Upon extraction with ethyl acetate (3×100 ml), the organic phase was washed with water (3×75 ml), dried and evaporated to a dark colored mass (9.0 g). The crude product in hexane-ethyl acetate (9:1) was chromatographed on a column of SILICA GEL (200 g) to afford a mixture of E- and Z-isomers (3.70 g, 61% yield). A 1.1 g sample of the mixture was rechromatographed on a column of SILICA GEL and eluted with hexane-ethyl acetate (19:1) to furnish Z-isomer (0.25 g) and E-isomer (0.32 g). The Z-isomer was further purified by preparative TLC (hexane-ethyl acetate, 7:3) to yield 3', 4'-Dibenzyloxy-3,4,5-trimethoxy-(Z)-stilbene as a chromatographically homogeneous and viscous oil: IR νmax 1581, 1509, 1462, 1454, 1412, 1265, 1237, 1128, 1007 cm-1 ; 1H-NMR (400 MHz) 3.731 (6H, s, 2×OCH3), 3.856 (3H, s, OCH3), 4.856 (2H, s, ArCH2), 5.121 (2H, s, ARCH2), 6.589 (2H, s, ArH), 6.600 (3H, m, ArH), 6.747 (1H, d, J=8.6 Hz, ArH), 6.758 (1H, brs, ArH), 7,273-7,407 (10H, ArH).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[CH2:18][C:19](=[CH2:21])[CH3:20].C(O)(=O)C>CO.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: C=C(C)Cc1cc(C(C(=O)OC)C2CCCC2)ccc1O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)C(c1ccc(O)c(CC(C)C)c1)C1CCCC1

Procedure:
4 g (0.014 mol) of the compound from Example V are dissolved in 30 ml of methanol and 10 ml of acetic acid and hydrogenated at 5.3 bar using Pd/C as a catalyst. Reaction time: 2.5 h. After filtering off the catalyst, the solvent is evaporated in vacuo and a slightly yellowish oil is obtained.
Reaction SMILES: [NH2:1][C@H:2]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:20]([O:19][C:17]([C@@H:2]([NH:1][S:31]([C:28]1[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][CH:27]=1)(=[O:33])=[O:32])[CH2:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1)=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(OCCCC(=O)O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
200 mg of 4-[4-((2S)-2-amino-2-tert-butoxycarbonyl-ethyl)-phenoxy]-butyric acid were dissolved in 2 ml of DMF and cooled to 0° C. 220 mg of 4-chlorobenzenesulfonyl chloride and 270 mg of diisopropylethylamine were added and the reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was cooled to −25° C. for 16 hours and then warmed to room temperature. The reaction was quenched by the addition of water, and the mixture was extracted three times with dichloromethane. The combined organic phases were dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with dichloromethane/methanol/water/acetic acid (9/1/0.1/0.1). Yield 84 mg. MS (ES+): m/e=498.1 (M+H)+; 442.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH2:18][C:19]#[N:20])[CH2:15][CH3:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCN(CC#N)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 65.5 %

Procedure:
To a solution of 150 mg 1-t-butyloxycarbonyl-4-ethylamino-piperidine (from Step A) in 3 ml DCE were added 60 mg of chloroacetonitrile, 109 mg of potassium carbonate, and 11 mg of potassium iodide. The reaction was stirred at 60° C. overnight. Methylene chloride was added, and the solution was washed with 2×20 ml water, and 20 ml brine. The solvent was then evaporated under reduced pressure. The residue was purified by flash chromatography with 20% EtOAc in hexane to give 115 mg of the title compound.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[C:25]([Br:30])[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:32][C:33]([O:35]C)=[O:34]>>[CH2:1]([C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:32][C:33]([OH:35])=[O:34])=[C:25]([Br:30])[CH:24]=2)=[CH:19][CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br
Reactant: COC(=O)CBr
Product: O=C(O)COc1ccc(-c2ccc(-c3c(Cc4ccccc4)sc4ccccc34)cc2)cc1Br

Procedure:
The title compound was prepared from 4′-(2-benzyl-benzo[b]thiophen-3-yl)-3-bromo-biphenyl-4-ol, and methyl bromoacetate, in substantially the same manner, as described in Example 2 step g , and was obtained as a white solid, mp 150-152° C.; MS m/e 528 (M+);
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[CH:6]=[N:7][OH:8].[Cl:14]N1C(=O)CCC1=O>C(Cl)Cl.O>[OH:8][N:7]=[C:6]([Cl:14])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: ON=Cc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: ClCCl
Product: ON=C(Cl)c1cccc(C(F)(F)F)c1
Temperature: 45 °C
Yield: 85.2 %

Procedure:
To a dried flask containing 3-(trifluoromethyl)benzaldehyde oxime (1.89 g, 10 mol) in methylene chloride (100 mL) was added N-chlorosuccinimide (1.40 g, 10.5 mmol) slowly at 0° C. The reaction mixture was warmed to 45° C. for 2 h, poured over ice, diluted with H2O (20 mL), and extracted with EtOAc (100 mL). The organic phase was washed with H2O (2×25 mL) and saline solution (25 mL), dried over sodium sulfate, concentrated in vacuo to give N-hydroxy-3-(trifluoromethyl)benzenecarboximidoyl chloride (2 g, 90%). LCMS: 224.4 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[NH:24]1[C:32]2[C:27](=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][N:31]=2)[CH:26]=[CH:25]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:29]5[CH:28]=[C:27]6[CH:26]=[CH:25][NH:24][C:32]6=[N:31][CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnc5[nH]ccc5c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 39 mg, 0.105 mmol) and 7-azaindole-5-boronic acid pinacol ester (ABCR, Karlsruhe, Germany, 31 mg, 0.127 mmol) to give the title compound as a white solid. (HPLC: tR 2.35 min (Method A); M+H=410 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 11.75 (s, br, 1H), 8.95 (s, 1H), 8.38-8.28 (m, 1H), 8.22-8.15 (m, 1H), 8.13-8.03 (m, 2H), 8.01-7.95 (m, 1H), 7.59-7.51 (m, 2H), 6.55-6.47 (m, 1H), 3.93 (s, 3H), 3.58 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]=[C:4]([CH3:9])[O:3]1.[Cl:11][CH2:12][C:13](Cl)=[O:14].[Li+].CC([N-]C(C)C)C.Cl>C(OCC)(=O)C.CCOCC>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH:5]=[C:4]([CH2:9][C:13](=[O:14])[CH2:12][Cl:11])[O:3]1
Reactant: O=C(Cl)CCl
Reactant: CC1=CC(=O)OC(C)(C)O1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)C=C(CC(=O)CCl)O1
Reaction time: 0.5 h
Yield: 68.9 %

Procedure:
In an argon gas stream, 20.6 ml of n-butyl lithium (1.6M solution in hexane) were added to 60 ml of an ether solution containing 3.53 g (0.033 mol) of diisopropylamine at -20° C. to form LDA. After stirring for 30 minutes, a mixture of 4.26 g (0.03 mol) of 2,2-dimethyl-6-methyl-1,3-dioxin-4-one and 60 ml of ether as well as 60 ml of an ether solution containing 1.69 g (0.015 mol) of chloroacetyl chloride were added to LDA. After the temperature was gradually returned to room temperature, 10% hydrochloric acid was added thereto to neutralize the solution, and extraction was then carried out with ether. The resultant organic layer was dried over anhydrous magnesium sulfate. Next, the solvent was distilled off, and the residue was then subjected to column chromatography (an eluent of hexane:ethyl acetate =4:1), thereby obtaining 2.26 g (yield 69%) of 2,2-dimethyl-6-(3-chloro-2-oxopropyl)-1, 3-dioxin-4 -one.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:28]([C:31]1[CH:36]=[CH:35][C:34]([S:37]([NH2:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1)([O-:30])=[O:29]>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:40][S:37]([C:34]3[CH:33]=[CH:32][C:31]([N+:28]([O-:30])=[O:29])=[CH:36][CH:35]=3)(=[O:38])=[O:39])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and 4-nitrobenzenesulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (32%); 1H NMR (d6-DMSO) δ 8.33 (d, J=8.8 Hz, 2H), 8.08 (d, J=8.8 Hz, 2H), 7.38-7.07 (m, 13H), 6.82 (d, J=8.0 Hz, 2H), 6.35 (d, J=15.7 Hz, 1H), 2.35 (q, J=7.3 Hz, 2H), 0.81 (t, J=7.3 Hz, 3H); APCI m/z: 538 (M+).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][N:12]([C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=1)[C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:14]Cl.O>CC(C)=O>[CH2:1]([N:8]1[CH2:10][CH2:11][N:12]([C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)c1cccc(N(CCCl)CCCl)c1
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cccc(N2CCN(Cc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 41 h
Yield: 51 %

Procedure:
Benzylamine (1.2 mL, 11 mmol), 120b (1.0 g, 3.6 mmol), water (50 mL), and acetone (50 mL) were heated an reflux for 28 h, then stirred at room temperature an additional 41 h. After evaporation of the acetone, the mixture was extracted with EtOAc (2×). The organic phase was extracted further with water and brine, then dried (Na2SO4), filtered and concentrated. The product was purified by chromatography on silica gel, eluting with 30% to 50% EtOAc in hexanes, then evaporated to yield a yellow oil (0.57 g). IR(neat): cm-1 1722. 1H NMR(300 MHz, CDCl3): 7.57-7.08 (m, 9H), 3.88 (s, 3H), 3.56 (s, 2H), 3.24 (m, 4H), 2.61 (m, 4H). HR-MS: Calc'd. 311.1760, Found 311.1764.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.N[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>C(#N)C>[C:9]1([C:3]2=[CH:2][C:1]([O:6][C:4]2=[O:5])=[O:7])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccccc1
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Solvent: CC#N
Product: O=C1C=C(c2ccccc2)C(=O)O1
Yield: 29.2 %

Procedure:
Following the general procedure of Example I, 150 mmols of maleic anhydride were reacted with 25 mmols of distilled aniline in 60 mL of acetonitrile and in the presence of 38 mmols of concentrated HCl and 2.5 mmols of cuprous oxide. The process resulted in a 29.2% yield of 3-phenylmaleic anhydride.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]([C:12]3[CH:29]=[CH:28][C:15]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:14][CH:13]=3)[N:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1.[CH3:30]OC(OC)(N(C)C)C>>[CH3:30][C:9]1[N:8]=[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[N:11]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[CH:28][CH:29]=2)[N:10]=1
Reactant: c1ccc2nc(COc3ccc(-n4ncnc4-c4ccncc4)cc3)ccc2c1
Reactant: COC(C)(OC)N(C)C
Product: Cc1nc(-c2ccncc2)n(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1

Procedure:
Following the procedure for the preparation of 2-[4-(5-Pyridin-4-yl-[1,2,4]triazol-1-yl)-phenoxymethyl]-quinoline but substituting N,N-dimethylacetamide dimethyl acetal provided the title compound. 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=6.2 Hz, 2H), 8.22 (d, J=8.3 Hz, 1H), 8.08 (d, J=8.3 Hz, 1H), 7.84 (d, J=7.7 Hz, 1H), 7.74 (m, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.56 (m, 1H), 7.36 (d, J=6.2 Hz, 2H), 7.25 (d, J=9.1 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 5.41 (s, 2H), 2.48 (s, 3H); MS: (M+H m/z=394.4).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])CC(O)=O.CN(C)C=O>C(Cl)Cl>[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:1][C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCC(CC(=O)O)c1ccc(OC)cc1OC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCC(CC(=O)Cl)c1ccc(OC)cc1OC

Procedure:
0.64 ml (7.4 mmol) of oxalyl chloride was added to a solution of 1.03 g (3.7 mmol) of 3-(2,4-dimethoxyphenyl)octanoic acid (prepared as described in Preparation 3) and a catalytic amount of dimethylformamide in 10 ml of methylene chloride, and the resulting mixture was stirred for 1 hour. The solvent and an excess of the reagent were removed by distillation under reduced pressure, to give 3-(2,4-dimethoxyphenyl)octanoyl chloride. A solution of this acid chloride in 9 ml of methylene chloride was then added dropwise to an ice-cooled solution of 772 mg (3.7 mmol) of 2-t-butyl-5-methoxycarbonylaniline (prepared as described in Preparation 5) and 2 ml of pyridine in 5 ml of methylene chloride over a period of 2 minutes. The temperature of the mixture was allowed to rise to room temperature, and then the mixture was stirred for 20 minutes. At the end of this time, the reaction was quenched by adding water, the reaction mixture was diluted with a 1:1 by volume mixture of ethyl acetate and hexane and the diluted solution was washed with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 100 g of silica gel, using a 2:3 by volume mixture of ethyl acetate and hexane as the eluent, to give 1.66 g (yield 96%) of the title compound as an oily substance.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Br.[Br:12][CH2:13][CH2:14][NH2:15].[OH-].[Na+]>>[Br:12][CH2:13][CH2:14][NH:15][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NCCBr
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCBr)c1ccc(F)cc1
Yield: 68.9 %

Procedure:
4-fluoro-benzoyl chloride (3 ml; 0.026 mol) was added dropwise to a cold (~0° C.). Stirring mixture of 2-bromo-ethyl-amine hydrobromide (5 g; 0.0236 mol) and 10% aqueous sodium hydroxide (21 ml; 0.052 mol). Crystalline product started to precipitate out of the reaction mixture almost immediately. After 15 minutes of stirring, the product was collected by filtration, triturated with diethyl ether and dried under vacuum giving the desired compound as a white solid (4 g).
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=[O:10])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1>CC(O)C>[CH2:1]1[CH2:2][C:3]2[C:8](=[CH:7][CH:6]=[CH:5][CH:4]=2)[C@H:9]([OH:10])[CH2:11]1
Reactant: O=C1CCCc2ccccc21
Solvent: CC(C)O
Product: O[C@@H]1CCCc2ccccc21
Temperature: 35 °C
Reaction time: 2 h
Yield: 98.4 %

Procedure:
Sodium 2-propoxide (0.38 ml of 0.1M solution in 2-propanol) was charged to the catalyst solution followed by the α-tetralone (0.5 ml, 3.76 mmol). The mixture was stirred under vacuum (80 mmHg) at 35° C. for 2 h, after the first hour the flask was back filled with nitrogen and sufficient 2-propanol charged to compensate for the volume removed by distillation. This gave (R)-1-tetralol Yield 98.4%, ee 95.7%. The turnover number, integrated over 1 h, was 185 h−1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([O:29]CC)=[O:28].[OH-].[K+]>CCO.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]([C:18]2[CH:23]=[CH:22][C:21]3[O:24][CH2:25][O:26][C:20]=3[CH:19]=2)[CH:10]1[C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)C1C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccccc1OC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccccc1C1c2ccccc2C(c2ccc3c(c2)OCO3)C1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
To a solution of ethyl(1RS,2RS,3RS)-1-(2-methoxyphenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate (90 mg, 0.22 mmol) in EtOH (2 ml) containing a few drops of THF was added 6M KOH (0.22 ml, 1.32 mmol). The resulting mixture was allowed to stir at room temperature overnight, then was concentrated under reduced pressure. The residue was partitioned between H2O and Et2O. The aqueous phase was acidified with 3M HCl and extracted with EtOAc. The EtOAc extract was washed successively with H2O and saturated aqueous NaCl and dried (MgSO4). The solvent was removed in vacuo to afford the title compound (40 mg, 49%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.II.[Cl:13]Cl>>[Cl:13][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: ClCl
Agent: II
Product: O=[N+]([O-])c1ccc(F)c(Cl)c1

Procedure:
141 G of 4-fluoronitrobenzene, 11.5 g of ferric chloride and 0.6 g of iodine were charged and then heated. At a temperature of 50° to 55° C., 80 g of chlorine was blown into the liquid over 12 hours to complete the reaction. The same succeeding procedures as in Example 1 were repeated to obtain 174 g of 3-chloro-4-fluoronitrobenzene. Analytical value thereof by gas chromatography was as follows: