Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[Br-].[Al+3].[Br-].[Br-].Cl>C1C=CC=CC=1>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cl
Agent: [Al+3]
Agent: [Br-]
Solvent: c1ccccc1
Product: O=C1CCc2ccc(O)cc21
Temperature: 25 °C

Procedure:
6-Hydroxyindan-1-one (16) was prepared by the demethylation of 6-methoxyindan-1-one (Rf=0.50, 30% ethyl acetate in hexane) using an approach similar to that of Gates (Gates, M.; Dickinson, C. L., Jr. J. Org. Chem. 1957, 22, 1398). Aluminum bromide (3.35 g, 12.6 mmol) was weighed under argon in an oven-dried flask and 6-methoxyindan-1-one (0.972 g, 6 mmol) was added to it. Dry benzene (40 mL) was added dropwise to this mixture and the resulting reddish-yellow solution was refluxed for four hours. The reaction mixture was cooled to room temperature after TLC showed no more starting material and 30 mL of 6N hydrochloric acid solution was added dropwise. The mixture was heated gently till the resulting solution was homogenous. The benzene layer was removed and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with water (50 mL), saturated sodium chloride solution (50 mL), dried over sodium sulfate and filtered. The filterate was removed under reduced pressure to yield 16 (3.41 g, 92%) as a grey solid (Rf=0.33, 30% ethyl acetate in hexane). White needles of compound 16 were obtained upon recrystallization from benzene. 1H NMR (acetone-d6, 200 MHz): 8.62 (s, 1H, D2O exchangeable), 7.39 (dd, J=8 Hz, 1 Hz, 1H), 7.14 (dd, J=8 Hz, 2 Hz, 1H), 7.03 (d, J=2 H z, 1H), 3.01 (m, 2H), 2.58 (m, 2H). EI-MS: 148 (M+, 100%), 120 (M+ -CO, 93%), 92 (M+ -CO--2CH2, 12%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=2)[CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].C1COCC1.C(O)(=O)C>>[C:21]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([Cl:20])[N:14]=2)[CH:3]=1)(=[O:23])[CH3:22]
Reactant: CNC(=O)c1ccc(N)cc1Nc1nc(Cl)ncc1Cl
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNC(=O)c1ccc(NC(C)=O)cc1Nc1nc(Cl)ncc1Cl

Procedure:
4-Amino-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (0.135 g, 0.000432 mol), Acetic anhydride (0.0428 mL, 0.000454 mol), THF (5 mL, 0.06 mol) and Acetic acid (0.024 mL, 0.43 mol) were stirred at rt for 16 h. Product isolated as white ppt (80 mg, 52%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:7]([C:9]1[CH:24]=[CH:23][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=2)=[CH:11][CH:10]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.CO.C(Cl)Cl>[N:1]1([CH2:7][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Oc2ccc(CN3CCCCC3)cc2)nc1
Yield: 88.6 %

Procedure:
Using a method similar to Example 345, using piperidine (0.041 mL, 0.414 mmol), 6-(4-formyl-phenoxy)-nicotinamide (compound of example 332, step 1) (0.100 g, 0.413 mmol), sodium triacetoxyborohydride (0.131 g, 0.618 mmol), and acetic acid (0.036 mL, 0.629 mmol) in 1,2-dichloroethane (8.0 mL) provides, after silica gel chromatography (10:1→3:1 methylene chloride:methanol), 0.114 g (88%) of the title compound as a white foam: high resolution mass spectrum (electrospray): m/z calc for C18H22N3O2 312.1712, found 312.1722, 1H NMR (DMSO-d6): 8.63 (d, 1H, J=2.0 Hz), 8.27 (dd, 1H, J=2.4, 8.8 Hz), 8.06 (s br, 1H), 7.50 (s br, 1H), 7.35 (a, 2H, J=8.3 Hz), 7.15-7.06 (m, 3H), 3.44 (s, 2H), 2.35 (s, 4H), 1.57-1.48 (m, 4H), 1.46-1.36 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5]C=1N.C([O-])([O-])=O.[K+].[K+].CI.[CH3:26][N:27]([CH:29]=O)[CH3:28]>>[F:1][C:2]1[CH:8]=[C:7]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)[CH:6]=[CH:5][C:29]=1[N:27]([CH3:26])[CH3:28]
Reactant: CN(C)C=O
Reactant: CC1(C)OB(c2ccc(N)c(F)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CN(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
The mixture of 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (474 mg, 2 mmol), K2CO3 (828 mg, 6 mmol), and MeI (710 mg, 5 mmol) in DMF (10 mL), was stirred at 100° C. overnight. Then it was cooled and extracted by EA/H2O, the organic layer was combined, washed by brine, dried over anhydrous Na2SO4, and concentrated to give the crude compound in 93% yield. MS (m/z): 266 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][CH:6]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]2)[CH2:5][C:4]([CH3:24])([CH3:23])[NH:3]1.C(N(C1CC(C)(C)NC(C)(C)C1)[P:31]1[O:36][CH2:35][C:34]([CH3:38])([CH3:37])[CH2:33][O:32]1)CCC>>[CH3:37][C:34]1([CH3:38])[CH2:35][O:36][P:31]([N:8]([CH:6]2[CH2:7][C:2]([CH3:25])([CH3:1])[NH:3][C:4]([CH3:24])([CH3:23])[CH2:5]2)[CH2:9][CH2:10][CH2:11][N:12]([P:31]2[O:32][CH2:33][C:34]([CH3:37])([CH3:38])[CH2:35][O:36]2)[CH:13]2[CH2:14][C:15]([CH3:22])([CH3:21])[NH:16][C:17]([CH3:20])([CH3:19])[CH2:18]2)[O:32][CH2:33]1
Reactant: CC1(C)CC(NCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: CCCCN(C1CC(C)(C)NC(C)(C)C1)P1OCC(C)(C)CO1
Product: CC1(C)COP(N(CCCN(C2CC(C)(C)NC(C)(C)C2)P2OCC(C)(C)CO2)C2CC(C)(C)NC(C)(C)C2)OC1

Procedure:
If N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)trimethylenediamine is used as the amine in an analogous procedure, N,N'-bis(5,5-dimethyl-1,3,2-dioxaphosphorinan-2-yl)-N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)trimethylenediamine is obtained, which melts at 102° (Compound No. 4).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([NH2:22])=[N:18][C:19]=1[O:20][CH3:21].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[C:19]([O:20][CH3:21])[N:18]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2ncsc2n1
Reactant: COc1ccc(N)nc1OC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccc(Nc2nc(Cl)nc3scnc23)nc1OC
Yield: 73.3 %

Procedure:
A solution of 5,7-dichlorothiazolo[5,4-d]pyrimidine (300 mg, 1.45 mmol), 5,6-dimethoxypyridin-2-amine (269 mg, 1.74 mmol) and DIEA (281 mg, 2.17 mmol) in 5 mL of DMSO was stirred at room temperature for 24 hours. Then the mixture was poured into 30 mL of water, and the formed solid was filtered and washed with water. The obtained crude product was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with ethyl acetate) to give 5-chloro-N-(5,6-dimethoxypyridin-2-yl)thiazolo[5,4-d]pyrimidin-7-amine (344 mg, 73%) as an off-white solid. LC-MS: 324.1 [M+H]+, tR=1.69 min.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][N:14]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:13](=[O:20])[CH:12]=2)=[CH:7][CH:6]=1.[Li+].[OH-]>C1COCC1.CO.[OH-].[Na+]>[C:16]([N:14]1[C:13](=[O:20])[CH:12]=[C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][C:3]([OH:21])=[O:2])=[CH:10][CH:9]=2)[S:15]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COC(=O)Cc1ccc(-c2cc(=O)n(C(C)(C)C)s2)cc1
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)n1sc(-c2ccc(CC(=O)O)cc2)cc1=O

Procedure:
A solution of 1-C (0.35 g, 1.2 mmol) and 10% LiOH (0.8 mL, 3.5 mmol) in THF (4 mL) and methanol (1 mL) was stirred at 25° C. for 2 h. The reaction mixture was diluted with 1 N NaOH (75 mL) and extracted with CH2Cl2 (3×25 mL). The aqueous layer was adjusted to pH˜2 with 10% HCl and extracted with EtOAc (3×50 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated in vacuo to yield 1-D as a brown solid (quantitative) which was used in the next step without further purification. 1H NMR (400 MHz, CD3OD): δ 7.57 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 6.51 (s, 1H), 3.67 (s, 2H), 1.68 (s, 9H); LCMS found for C15H16NO3S (M−H)−: m/z=290.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][C:9](C(O)=O)=[N:10][C:4]2=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:10]1[C:4]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)c1ccc2ccccc2n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: c1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 319.5 %

Procedure:
A 100 ml RBF equipped with magnetic stir bar and N2 inlet was charged with 356 mg (2.06 mmol, 1 eq) 2-quinaldic acid in 10 ml dry DMF. The solution was cooled to 0° C. and 415 mg (3.07 mmol, 1.5 eq) HOBt was added followed by 415 mg EDCl (2.16 mmol, 1.05 eq). The reaction was stirred 2 hours at 0° C. when 1.1 g (2.06 mmol, 1 eq) of free asparagine amine in 10 ml dry DMF was added. The reaction was stirred at 0° C. for 2 hours then room temperature overnight. The reaction was poured into sat. bicarb and extracted with 2×65 mL ethyl acetate. The combined organics were washed with 5% aq. citric acid, brine, dried and concentrated to 1.4 g crude foam. Purification by flash chromatography on silica gel (100% EA) yielded 850 mg (61%) of quinoline adduct.
Reaction SMILES: [CH3:1]/[CH:2]=[CH:3]/C(C1C(C)(C)CC=CC=1C)=O.CC1OC=CC(=O)C=1O.[CH3:24][CH2:25][C:26]1O[CH:31]=[CH:30][C:28](=O)[C:27]=1O>>[CH3:24][C:25]1[CH2:26][CH2:27][CH:28]([C:2]([CH3:3])=[CH2:1])[CH2:30][CH:31]=1
Reactant: CCc1occc(=O)c1O
Reactant: C/C=C/C(=O)C1=C(C)C=CCC1(C)C
Agent: Cc1occc(=O)c1O
Product: C=C(C)C1CC=C(C)CC1

Procedure:
Beta-damascenone (having the structure: ##STR12## Maltol; Ethyl maltol;
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)=[CH2:2].C(N(CC)CC)C.[C:17]([Si:21]([CH3:24])([CH3:23])Cl)([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[O:9]([C:6]1[CH:7]=[CH:8][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1)[Si:21]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:24])[CH3:23]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=Cc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
The concentrated 4-vinylphenol solution above and 10 mL (7.3 g, 0,072 mol) of triethylamine (TEA) were transferred to a 1 L 3 neck round-bottomed flask fitted with a mechanical stirrer, pressure-equalized addition funnel, reflux condenser, and argon inlet tube. A solution of 75 g (0.5 mol) Of t-butyldimethylchlorosilane and 75 mL (55 9, 0.54 mol) of dry TEA in 50 mL of methylene chloride was added through the addition funnel over 45 minutes. The reaction mixture turned pink and remained clear for quite some time. Considerable heat was evolved, particularly in the early stages of the addition, necessitating cooling the mixture in ice occasionally. The mixture was stirred at room temperature for 10 hrs., being stored in the freezer if necessary to complete the following day.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][NH2:5].O=[C:7]([CH2:13][C:14](=O)[CH3:15])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N1C(CC)=CC(C(O)=O)=N1)C>C(Cl)Cl>[OH:1][CH2:2][CH2:3][N:4]1[C:14]([CH3:15])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5]1
Reactant: CCOC(=O)C(=O)CC(C)=O
Reactant: NNCCO
Agent: CCc1cc(C(=O)O)nn1CC
Solvent: ClCCl
Product: CCOC(=O)c1cc(C)n(CCO)n1

Procedure:
The title compound was prepared from hydroxyethyl hydrazine (3.64 g, 50 mM) and ethyl 2,4-dioxovalerate (8.5 g, 50 mM) as described in Example 1 Preparation 1 as a colourless oil (9.39 g, 95%); νmax (CH2Cl2) 1700 cm-1 ; δH (CDCl3) 1.39 (3H, t, J7 Hz), 2.40 (3H, s), 2.98 (2H, t, J7 Hz), 4.33-4.48 (4H,m), and 6.39 (1H, s); E.I. m/e 198 (95% ).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12](OS(C(F)(F)F)(=O)=O)[CH:13]=2)[N:8]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:7]=1[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:5])[CH3:2].[F:38][C:39]([F:50])([F:49])[C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:43]3[CH:44]=[CH:45][C:40]([C:39]([F:50])([F:49])[F:38])=[CH:41][CH:42]=3)[CH:13]=2)[N:8]([C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:27][CH:28]=2)[C:7]=1[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(OS(=O)(=O)C(F)(F)F)ccc2n1-c1ccc(C(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(-c3ccc(C(F)(F)F)cc3)ccc2n1-c1ccc(C(C)C)cc1

Procedure:
A mixture 2-ethoxycarbonylmethyl-1-(4-isopropylphenyl)-5-trifluoromethane-sulfonyloxyindole-3-carboxylic acid ethyl ester (133 mg, 0.25 mmol, see step (a) above), 4-trifluoromethylphenylboronic acid (142 mg, 0.75 mmol), K2CO3 (276 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (78 mg, 0.067 mmol) and anhydrous dioxane (10 mL) was stirred at 90° C. for 4 h. The mixture was diluted with EtOAc (30 mL), washed with saturated NaHCO3 (aq, sat) dried (Na2SO4), concentrated and purified by chromatography to give the sub-title compound. Yield 102 mg (76%).
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH2:5])[CH3:2].[Br:6][CH:7]([CH3:17])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)=[O:9]>C1(C)C=CC=CC=1.C(O)(C(F)(F)F)=O>[Br:6][CH:7]([CH3:17])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:1]([O:3][CH2:4][CH3:5])[CH3:2])=[CH:12][CH:11]=1)=[O:9]
Reactant: CC(Br)C(=O)c1ccc(O)cc1
Reactant: C=COCC
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CCOC(C)Oc1ccc(C(=O)C(C)Br)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 103.9 %

Procedure:
Ethoxyethene (3.148 g, 43.655 mmol) and TFA (0.249 g, 2.183 mmol) was added to a suspension of 2-bromo-1-(4-hydroxyphenyl)propan-1-one (5.000 g, 21.827 mmol) in toluene (50 ml) at rt. The reaction mixture was stirred at 30° C. for 2 h and 30 min. The solvent was evaporated to yield the product as an oil (6.83 g, 100%).
Reaction SMILES: CO.[CH:3]1([C:9]2[CH:18]=[C:17]3[C:12]([C:13]([CH3:47])=[CH:14][C:15](=[O:46])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([N:27]([CH2:35][C:36]4[CH:45]=[CH:44][C:39]5[O:40][CH2:41][CH2:42][O:43][C:38]=5[CH:37]=4)C(=O)OC(C)(C)C)[CH2:23][CH2:22]3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[ClH:48].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:48].[CH:3]1([C:9]2[CH:18]=[C:17]3[C:12]([C:13]([CH3:47])=[CH:14][C:15](=[O:46])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([NH:27][CH2:35][C:36]4[CH:45]=[CH:44][C:39]5[O:40][CH2:41][CH2:42][O:43][C:38]=5[CH:37]=4)[CH2:23][CH2:22]3)=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(C3CCCCC3)ccc12
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(=O)n(CCN2CCC(NCc3ccc4c(c3)OCCO4)CC2)c2cc(C3CCCCC3)ccc12
Reaction time: 1.5 h

Procedure:
To 0.7 mL of methanol solution containing 73 mg of tert-butyl (1-(2-(7-cyclohexyl-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 0.7 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added at room temperature, and stirred for 1.5 hours. Ethyl acetate was added, and the resulting solid was filtered to give 43 mg of 7-cyclohexyl-1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-4-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: C[O-].[Na+].[CH2:4]([SH:6])[CH3:5].[CH3:7][C:8]1([CH3:31])[CH:17](OS(C)(=O)=O)[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:24]([O:26]CC)=[O:25])[C:15]=2[CH3:23])[S:10](=[O:30])(=[O:29])[CH2:9]1>CO.C(OCC)(=O)C>[CH3:7][C:8]1([CH3:31])[CH:17]([S:6][CH2:4][CH3:5])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:24]([OH:26])=[O:25])[C:15]=2[CH3:23])[S:10](=[O:29])(=[O:30])[CH2:9]1
Reactant: CCOC(=O)c1ccc2c(c1C)C(OS(C)(=O)=O)C(C)(C)CS2(=O)=O
Reactant: CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCSC1c2c(ccc(C(=O)O)c2C)S(=O)(=O)CC1(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
A methanolic solution of 0.8 g (4 mmol, 3 eq.) containing about 28 wt % sodium methoxide was diluted with 5 ml of anhydrous methanol, and 0.5 ml (6.8 mmol, 1.5 eq.) of ethanethiol was added. The mixture was stirred at room temperature for 5 minutes, and then 0.5 g (1.3 mmol) of 3,3,5-trimethyl-4-methanesulfonyloxy-6-ethoxycarbonylthiochroman-1,1-dioxide was added. The mixture was refluxed for 8 hours, and allowed to stand at room temperature for 5 days. The reaction mixture was diluted with 100 ml of ethyl acetate and washed with 50 ml of water twice, and an aqueous layer was separated and cooled in an ice bath. The aqueous layer was acidified with 5 wt % hydrochloric acid and extracted with 100 ml of ethyl acetate, and an organic layer was dried over sodium sulfate. The solvent was distilled off, and the residue was dried under reduced pressure to give 0.32 g (yield 75%) of a yellowish solid.
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].NC1C=C(Cl)C(Cl)=CC=1O.C(OC1C(C(Cl)=O)=CSC=1)C.[Cl:30][C:31]1[C:47]([Cl:48])=[CH:46][C:34]([NH:35][C:36]([C:38]2[C:42](OCC)=[CH:41][S:40][CH:39]=2)=[O:37])=[C:33]([OH:49])[CH:32]=1>C(Cl)Cl.C(N(CC)CC)C.O.CC(C)=O>[Cl:30][C:31]1[C:47]([Cl:48])=[CH:46][C:34]2[NH:35][C:36](=[O:37])[C:38]3[C:42](=[CH:41][S:40][CH:39]=3)[O:49][C:33]=2[CH:32]=1
Reactant: CCOc1cscc1C(=O)Nc1cc(Cl)c(Cl)cc1O
Agent: CCOc1cscc1C(=O)Cl
Agent: Nc1cc(Cl)c(Cl)cc1O
Agent: O=S([O-])S(=O)[O-]
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1Nc2cc(Cl)c(Cl)cc2Oc2cscc21

Procedure:
A 20.87 g. portion of the preceding product (prepared as described above) is stirred in 210 ml. of acetone and 210 ml. of water, then 87.0 g. of sodium dithionite is added portionwise with stirring at room temperature as described in J. Chem. Soc., 4727 (1956). The resulting colorless mixture is heated on a steam bath for 1/2 hour, then is cooled and extracted four times with ether. The ether layer is washed 3 times with brine, then is dried over anhydrous sodium sulfate and evaporated to provide yellow crystals. This material is recrystallized from methylene chloride/hexane to yield 3.63 g. of 2-amino-4,5-dichlorophenol as buff colored crystals. A 4.81 g. amount of this product (prepared as described) is dissolved in 35 ml. of methylene chloride then a 3.51 ml. portion of triethylamine is added and the mixture is stirred. To this is added dropwise with stirring 48 ml. of a solution of 9.90 g. of 4-ethoxy-3-thiophenecarbonyl chloride (prepared as described in Example 1 ) dissolved in 100 ml. of methylene chloride. The mixture is allowed to stir overnight then the precipitate is collected, air dried, triturated with water, collected and dried to yield 4.95 g. of 4',5'-dichloro-4-ethoxy-2'-hydroxy-3-thiophenecarboxanilide.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N+:13]([O-])=O)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]>C1COCC1.[Pd]>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([NH2:13])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(=O)N1CCc2ccc(N)cc21
Yield: 94.9 %

Procedure:
A stirred suspension of 1-acetyl-2,3-dihydro-6-nitro-1H-indole (D9, 125 g, 0.61 mole) in THF (5500 ml) was hydrogenated over 10% Pd-C (20 g) at 50 psi for 20 h. The catalyst was removed by filtration through a plug of kieselguhr and the filtrate concentrated in vacuo to afford the title compound as a beige solid (102 g, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CN)o1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1

Procedure:
The title compound, MS: m/e=254.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-nitro-2-chloroquinoline and 5-methyl-2-furanmethanamine.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]([O:35]C)=[O:34])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:24]=[CH:25][C:26]([C:29]([F:32])([F:30])[F:31])=[CH:27][CH:28]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:33]([OH:35])=[O:34])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccc(C(F)(F)F)cc4)CC3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCC(c4ccc(C(F)(F)F)cc4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 52.4 %

Procedure:
A solution of methyl 2-phenyl-3-(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)quinoxaline-6-carboxylate (50 mg, 0.10 mmol, 1.00 equiv) and sodium hydroxide (20 mg, 0.50 mmol, 5.00 equiv) in methanol (10 mL) was placed in a 50-mL round bottom flask and stirred for 2 h at 50° C. in an oil bath. The pH value of the solution was adjusted to 4-5 with aqueous sodium hydroxide (1 M). The resulting solution was extracted with 3×10 mL of dichloromethane, and the organic layers combined, concentrated under vacuum, and purified by prep-TLC (DCM:CH3OH 10:1) yielding 25 mg (51%) of 2-phenyl-3-(4-(4-(trifluoromethyl)phenyl)piperidin-1-yl)quinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:20][CH:19]=[C:18]([C:21](O)=[O:22])[CH:17]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH:37]1[CH2:41][CH2:40][N:39]=[C:38]1[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][NH2:49])=[CH:44][CH:43]=1>ClCCCl>[NH:39]1[CH2:40][CH2:41][N:37]=[C:38]1[C:42]1[CH:43]=[CH:44][C:45]([CH2:48][NH:49][C:21]([C:18]2[CH:17]=[C:16]([CH2:15][N:13]([S:10]([C:6]3[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH3:24])(=[O:11])=[O:12])[CH3:14])[O:20][CH:19]=2)=[O:22])=[CH:46][CH:47]=1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)O)co2)c(C)c1
Reactant: NCc1ccc(C2=NCCN2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2cc(C(=O)NCc3ccc(C4=NCCN4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure AA using 5-({[(4-Methoxy-2,6-dimethylphenyl)sulfonyl](methyl)amino}methyl)furan-3-carboxylic acid (100 mg, 0.3 mmol), CDI (195 mg, 0.6 mmol) and 1-[4-(4,5-dihydro-1H-imidazol-2-yl)phenyl]methanamine (52 mg, 0.3 mmol) in DCE (6 mL).