Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:22][CH2:23][O:24]C3CCCCO3)([CH2:13][CH2:14][O:15]C3CCCCO3)[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.O>O1CCOCC1>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH2:13][CH2:14][OH:15])([CH2:22][CH2:23][OH:24])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: O=C1Nc2cc(Br)ccc2C1(CCOC1CCCCO1)CCOC1CCCCO1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C1Nc2cc(Br)ccc2C1(CCO)CCO
Temperature: 60 °C
Reaction time: 2 h
Yield: 50.5 %

Procedure:
5M Aqueous hydrochloric acid (5M, 1.50 mL) was added to a stirred solution of 6-bromo-3,3-bis(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)indolin-2-one (preparation 18a, 0.62 g, 1.32 mmol) in 1,4-dioxane (3 mL) at room temperature and then mixture was stirred and heated to 60° C. After 2 hours, the mixture was cooled and water was added to the mixture. The mixture was extracted with diethyl ether and the aqueous phase was evaporated in vacuo to give the title compound (0.20 g, 50%) as a solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=3)[CH2:9]2)[CH2:4][CH2:3]1.C(O)C.[H][H]>[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)[CH2:9]2)[CH2:6][CH2:7]1
Reactant: CN1CCN(C2CCCN(c3ccc([N+](=O)[O-])cc3)C2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(C2CCCN(c3ccc(N)cc3)C2)CC1
Yield: 76.1 %

Procedure:
1-Methyl-4-[1-(4-nitro-phenyl)-piperidin-3-yl]-piperazine (1.40 g, 4.60 mmol) was dissolved in Ethanol (36.1 mL, 618 mmol) and the solution was carefully added to 10% Palladium on Carbon (0.515 g, 38.6 mmol) under nitrogen. The mixture was then placed on a Parr hydrogenation apparatus and was allowed to shake at 55 psi until uptake of hydrogen ceased. The catalyst was then filtered to afford 0.960 g of 4-[3-(4-Methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamine without further purification. (M+H)=275.7. 1H NMR (400 MHz, DMSO, d6) δ 6.67 (d, 2H, J=8.56 Hz), 6.47 (d, 2H, J=8.51 Hz), 4.54 (s, 2H), 3.39 (m, 2H), 3.20 (m, 1H), 2.62 (m, 4H), 2.33 (m, 6H), 2.12 (s, 3H), 1.85 (m, 1H), 1.74 (m, 1H), 1.52 (m, 1H), 1.18 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:40]=[CH:39][C:33]([C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:32][CH:31]=1>S(Cl)(Cl)=O.CN(C)C1C=CN=CC=1.ClCCl>[CH2:37]([O:36][C:34](=[O:35])[C:33]1[CH:39]=[CH:40][C:30]([NH:29][C:14](=[O:15])[CH:13]([N:12]2[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=[C:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:31][CH:32]=1)[CH3:38]
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
The solution of 3.0 g (7.4 mmol) [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid in 5.4 ml thionylchloride was stirred under reflux. After 1 h the volatile components were removed at a rotary evaporator, the residue taken up in toluene and evaporated (three times). The remaining oil was dissolved in 30 ml dichloromethane, cooled to 0° C. and added dropwise on a solution of ethyl 4-aminobenzoate (1.35 g, 8.1 mmol) and 2.72 g (22.2 mmol) 4-dimethylaminopyridine dissolved in 30 ml dichloromethane. The cooling bath was removed and stirring was continued for another 4 h. The reaction was poured on 25% aqueous hydrochloric acid solution, the phases separated and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel using heptane:ethyl acetate (1:0 to 1:1 v/v) as eluant to afford the title compound as a colorless solid (2.6 g, 62%). MS (ES+): 552 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23].C(=O)([O-])[O-].[K+].[K+].[Br:30][CH2:31][CH2:32][CH2:33]Br>CN(C=O)C>[Br:30][CH2:31][CH2:32][CH2:33][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:22][CH3:23]
Reactant: BrCCCBr
Reactant: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]ccc4c3)ncnc2cc1OCCCBr
Temperature: 50 °C
Yield: 65.7 %

Procedure:
To a solution of 7-hydroxy-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (1 g, 3.2 mmol), (prepared as described for the starting material in Example 107), in DMF (50 ml) was added powdered potassium carbonate (1.32 g, 9.6 mmol) and 1,3-dibromopropane (6.43 g, 32 mmol). The reaction was heated at 50° C. for 2 hours. The inorganic material was filtered off and then the DMF removed. The residue was partitioned between methylene chloride/water. The organics were separated, dried over MgSO4, filtered, evaporated in vacuo and purified by flash chromatography eluting from methylene chloride to 5% methanol/95% methylene chloride. The product was concentrated in vacuo, triturated with ether and the resulting solid filtered to give 7-(3-bromopropoxy)-4-(1H-indol-5-yloxy)-6-methoxyquinazoline (900 mg, 66%) as a white solid.
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][C:11]([NH:13][C@H:14]1[CH2:18][N:17](C(OC(C)(C)C)=O)[C@H:16]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)=[O:27])[CH2:15]1)=[O:12])=O)(C)(C)C>O1CCOCC1>[ClH:40].[ClH:1].[NH2:9][CH2:10][C:11]([NH:13][C@H:14]1[CH2:18][NH:17][C@H:16]([C:26]([N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)[CH2:30][CH2:29]2)=[O:27])[CH2:15]1)=[O:12]
Reactant: CC(C)(C)OC(=O)NCC(=O)N[C@@H]1C[C@@H](C(=O)N2CCN(c3ccc(Cl)cc3)CC2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: NCC(=O)N[C@H]1CN[C@H](C(=O)N2CCN(c3ccc(Cl)cc3)CC2)C1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A solution of 4 N hydrochloric acid in 1,4-dioxane (6 mL) was added to a solution of 1-[trans-4-(N-tert-butoxycarbonylglycylamino)-N-tert-butoxycarbonyl-L-prolyl]-4-(4-chlorophenyl)piperazine (A, 210 mg) in 1,4-dioxane (6 mL) at room temperature. After stirring at room temperature for 50 min, the reaction mixture was evaporated in vacuo. The residue was washed with ether to give the titled compound (106 mg) as a white powder: 1H NMR (400 MHz, D2O) δ 2.48 (quintet, J=7.3 Hz, 1H), 2.64 (m, 1H), 3.48 (m, 5H), 3.81-3.98 (m, 5H), 3.87 (s, 2H), 4.61 (m, 1H), 5.08 (t, J=8.3 Hz, 1H), 7.32 (d, J=9.0 Hz, 2H), and 7.50 (d, J=9.0 Hz, 2H); mass spectrum (El+) m/e 365 (M).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].C([O-])(=O)C.[NH4+].C(O)(=O)C>O.C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[C:12]([C:10]#[N:11])=[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2])[CH3:17]
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)c1ccccc1
Temperature: 25 °C

Procedure:
A stirred mixture of acetophenone (180 g, 1.5 mol), ethyl cyanoacetate (170 g, 1.3 mol), ammonium acetate (23.1 g), acetic acid (72 g) and toluene (300 ml) was heated under reflux for 18 hours while water was removed from the reaction by azeotropic distillation. The mixture was allowed to cool to ambient temperature, toluene (100 ml) was added, then the mixture was washed with water (3×100 ml). The combined aqueous washings were shaken with toluene (50 ml), then the combined toluene solutions were dried (MgSO4) and the solvent was removed in vacuo. The residual oil was distilled under reduced pressure to give 2-cyano-3-phenyl-but-2-enoic acid ethyl ester as an oil which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:14]C(=O)C)[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.Cl>>[NH2:14][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[C:2]([OH:1])[CH:3]=1
Reactant: CC(=O)Nc1ccc(CN2CCCC2)c(O)c1
Agent: Cl
Product: Nc1ccc(CN2CCCC2)c(O)c1

Procedure:
N-[3-hydroxy-4-(pyrrolidin-1-ylmethyl)phenyl]acetamide (0.14 g, 0.61 mmol), hydrochloric acid 20% (1 mL). The mixture was refluxed 6 h, evaporated and used for the next step.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH:24]4[CH2:26][CH2:25]4)=[CH:19][N:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:27][CH:28]1[NH:32][C:31](=[O:33])[CH2:30][CH2:29]1>>[CH:24]1([C:20]2[CH:21]=[C:22]([CH3:23])[C:17]([N:14]3[CH2:15][CH2:16][N:11]([C:9]([C:5]4[CH:4]=[CH:3][C:2]([N:32]5[CH:28]([CH3:27])[CH2:29][CH2:30][C:31]5=[O:33])=[N:7][C:6]=4[CH3:8])=[O:10])[CH2:12][CH2:13]3)=[N:18][CH:19]=2)[CH2:26][CH2:25]1
Reactant: CC1CCC(=O)N1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)nc2C)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C(=O)CCC3C)nc2C)CC1
Yield: 88.1 %

Procedure:
Using (6-bromo-2-methylpyridin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 249 and 5-methylpyrrolidin-2-one (54 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (138 mg) was obtained.
Reaction SMILES: O1[C:7]2([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:14])[CH:2]1[C:3]([CH2:28][F:29])([CH2:26][F:27])[O:4][C:5]1[CH:18]=[CH:17][C:16]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[CH:15][C:6]=12>[C].[Pd].CO>[F:25][C:19]([F:24])([C:16]1[CH:17]=[CH:18][C:5]2[O:4][C:3]([CH2:28][F:29])([CH2:26][F:27])[CH:2]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:14])[C:6]=2[CH:15]=1)[C:20]([F:23])([F:22])[F:21]
Reactant: [O-][n+]1ccccc1C12OC1C(CF)(CF)Oc1ccc(C(F)(F)C(F)(F)F)cc12
Agent: [Pd]
Solvent: CO
Product: [O-][n+]1ccccc1C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Temperature: 25 °C
Yield: 37.4 %

Procedure:
A mixture of 0.50 g of 2-(3,4-epoxy-6-pentafluoroethyl-2,2-bisfluoromethyl-3,4-dihydro-2H-1-benzopyran-4-yl)pyridine N-oxide, 0.10 g of 10% palladium carbon and 15 ml of methanol was stirred at room temperature under hydrogen stream. The-reaction mixture was subjected to vacuum filtration to remove the catalyst and the mother liquor was distilled off. The resultant residue was dissolved in 10 ml of dioxane and 0.82 g of soda talc was added thereto. The mixture was refluxed with heating for 1 hour and subjected to vacuum filtration to remove insoluble materials. Water was added to the mother liquor and the mixture was extracted with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.18 g of 2-(6-pentafluoroethyl-2,2-bisfluoromethyl-2H-1-benzopyran-4-yl)pyridine N-oxide.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C1COCC1>[CH3:24][S:25]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:16])(=[O:27])=[O:26]
Reactant: O=C(NCCCCO)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCNC(=O)OCc1ccccc1
Temperature: 22.5 °C
Reaction time: 6 h
Yield: 81.3 %

Procedure:
To a solution of benzyl 4-hydroxybutylcarbamate (1.1 g, 4.9 mmol) and triethylamine (1.7 mL, 9.8 mmol) in THF was added methanesulfonyl chloride (0.67 g, 5.9 mmol) at 0° C. The reaction was stirred at 20-25° C. for 6 hours and concentrated. The residue was partitioned between ethyl acetate and water. The phases were separated, and the organic layer was washed with hydrochloride solution (1 N), saturated sodium bicarbonate solution, and saline. The separated organic layer was dried and concentrated to give 4-(benzyloxycarbonylamino)butyl methanesulfonate (1.2 g).
Reaction SMILES: [CH3:1][C:2]1[O:26][C:5]2=[CH:6][C:7]3[S:8][C:9]4[C:14]([C:15]=3[C:16]([C:17]3[CH:22]=[C:21]([I:23])[C:20]([OH:24])=[C:19]([I:25])[CH:18]=3)=[C:4]2[C:3]=1[CH3:27])=[CH:13][CH:12]=[CH:11][CH:10]=4.O[C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32]C)=[O:31]>>[CH3:1][C:2]1[O:26][C:5]2=[CH:6][C:7]3[S:8][C:9]4[C:14]([C:15]=3[C:16]([C:17]3[CH:18]=[C:19]([I:25])[C:20]([O:24][C@H:29]([CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:30]([OH:32])=[O:31])=[C:21]([I:23])[CH:22]=3)=[C:4]2[C:3]=1[CH3:27])=[CH:13][CH:12]=[CH:11][CH:10]=4
Reactant: Cc1oc2cc3sc4ccccc4c3c(-c3cc(I)c(O)c(I)c3)c2c1C
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Product: Cc1oc2cc3sc4ccccc4c3c(-c3cc(I)c(O[C@H](Cc4ccccc4)C(=O)O)c(I)c3)c2c1C

Procedure:
Prepared from 4-(2,3-dimethyl-1-oxa-9-thia-cyclopenta[b]fluoren-4-yl)-2,6-diiodo-phenol and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester according to the procedure in Example 8 to provide the title compound as a white solid: mp 215-217: NMR (DMSO-d6): δ 8.17 (s, 1H), 7.94 (d, J=8 Hz, 1H), 7.85 (d, J=4 Hz, 2H), 7.39-7.30 (m, 5H), 7.22 (dd, J=7 Hz, 1H), 7.16 (dd, J=7, 1 Hz, 1H), 6.87 (d, J=8 Hz, 1H), 5.41 (s, 1H), 3.43 (dd, J=6, 1 Hz, 2H), 2.36 (s, 3H), 1.56 (s, 3H); MS (+FAB): [M+H]+, 745; Anal. Calc. for C31H22I2O4S: C, 50.02, H, 2.98, N, 0.00. Found: C, 47.59, H, 2.98, N, 0.13.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[C:10]([C:18]4[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=4)=[C:11]4[C:16](=[CH:17][C:7]=3[S:6][C:5]=2[CH:4]=[CH:3][CH:2]=1)[CH:15]=[CH:14][CH:13]=[CH:12]4.S(Cl)([Cl:32])(=O)=O.O>C(Cl)(Cl)Cl>[Cl:32][C:17]1[C:7]2[S:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:9]=3[C:8]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:20][CH:19]=2)=[C:11]2[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]2
Reactant: O=S(=O)(Cl)Cl
Reactant: CS(=O)(=O)Oc1ccc(-c2c3ccccc3cc3sc4ccccc4c23)cc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)Oc1ccc(-c2c3ccccc3c(Cl)c3sc4ccccc4c23)cc1
Reaction time: 19 h
Yield: 88.3 %

Procedure:
To a solution of methanesulfonic acid 4-benzo[b]naphtho[2,3-d]thiophen-11-yl-phenyl ester (1.00 g, 2.47 mmol) in chloroform (10 mL) was added sulfuryl chloride (0.21 mL, 2.60 mmol, 1.05 eq) dropwise at room temperature under a dry nitrogen atmosphere. After stirring 19 hours the reaction mixture was added to water (100 mL) and the organics were extracted with ether (2×100 mL). The extracts were combined, washed with brine, combined with silica gel and the solvent was removed. The adsorbate was flash chromatrographed (85/15 petroleum ether/ethyl acetate) to give the title compound as a white solid (0.957 g, 88%): mp 155-158° C.; NMR (CDCl3); δ 8.41 (ddd, J=8, 1, 1 Hz, 1H), 7.82 (ddd, J=8, 1, 1 Hz, 1H), 7.67 (ddd, J=8, 7, 1 Hz, 1H), 7.61-7.56 (m, 3H), 7.51-7.45 (m, 3H), 7.42-7.38 (ddd, J=8, 7, 1 Hz, 1H), 7.10 (ddd, J=8, 7, 1 Hz, 1H), 6.64 (d, J=8 Hz, 1H), 3.34 (s, 3H); MS (+EI) : [M+], 1 chlorine isotope pattern, 438 (100%), 440 (40%); Anal. Calc. for C23H15ClO3S2: C, 62.93, H, 3.49, N, 0.00. Found: C, 62.72, H, 3.25, N, 0.03.
Reaction SMILES: [ClH:1].[CH:2]1[C:19]2[CH:18]=[CH:17][C:16]3[C:7](=[CH:8][C:9]([CH2:20][NH:21][C:22]([CH3:27])([CH2:25][OH:26])[CH2:23][OH:24])=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1.C1C2C=CC3C(=CC(C=[O:47])=C4C=3C=CC=C4)C=2C=CC=1.C(O)C(N)(CO)CO>CO.CCOCC>[ClH:1].[CH:2]1[C:19]2[CH:18]=[CH:17][C:16]3[C:7](=[CH:8][C:9]([CH2:20][NH:21][C:22]([CH2:27][OH:47])([CH2:23][OH:24])[CH2:25][OH:26])=[C:10]4[C:15]=3[CH:14]=[CH:13][CH:12]=[CH:11]4)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cc2c3ccccc3ccc2c2ccccc12
Reactant: CC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12
Agent: Cl
Agent: NC(CO)(CO)CO
Solvent: CO
Solvent: CCOCC
Product: OCC(CO)(CO)NCc1cc2c3ccccc3ccc2c2ccccc12

Procedure:
Using the reductive amination procedure described in 1B, 6-chrysenecarbaldehyde (1A) and tris(hydroxymethyl)aminomethane (Aldrich) gave 2-((6-chrysenylmethyl)amino)-2-hydroxymethyl-1,3-propanediol hydrochloride, mp 238°-239° (dec), (CH3OH/Et2O), (C, H, Cl, N).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3](=[O:11])[C:2]1=[O:12].[S:13](=O)(=[O:16])([OH:15])[OH:14]>>[O:12]=[C:2]1[C:3](=[O:11])[NH:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([S:13]([OH:16])(=[O:15])=[O:14])[CH:6]=2)[NH:1]1
Reactant: O=S(=O)(O)O
Reactant: O=c1[nH]c2ccccc2[nH]c1=O
Product: O=c1[nH]c2ccc(S(=O)(=O)O)cc2[nH]c1=O
Reaction time: 0.5 h

Procedure:
2,3(1H, 4H)-Quinoxalinedione (10 g) was added portionwise to a stirred mixture of 65% fuming sulphuric acid (10 ml) and conc. sulphuric acid (40 ml) at room temperature. After stirring for 30 minutes at 55°-60°, the mixture was worked up as in example 1 to give the hydrated crystalline product (15.3 g, mp. >300°).
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29].C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([C:28](=[O:29])[C:27]5[CH:31]=[CH:32][CH:33]=[C:25]([C:24]([F:23])([F:34])[F:35])[CH:26]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=C1CCNC[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccc(C(F)(F)F)c1)N1CCC(=O)N2C[C@H](Oc3cnc(C4CC4)cn3)C[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.9 %

Procedure:
(8R,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (27.6 mg, 0.085 mmol, 1 equivalent, prepared as described in Example 55, Part B) was suspended in dichloromethane (1.0 mL) in a 4-mL scintillation vial. 3-(Trifluoromethyl)benzoyl chloride (23.05 mg, 0.111 mmol, 1.3 equivalents) was added as a solution in dichloromethane (0.1 mL) followed by the addition of triethylamine (0.059 mL, 0.425 mmol, 5.0 equiv) and 4-(dimethylamino)pyridine (1.0 mg, 0.0085 mmol, 0.1 equivalent). The resulting solution was stirred at room temperature for an additional 30 minutes. The reaction was loaded directly onto a 4 g silica gel column eluted with 50:50 to 100:0 ethyl acetate:heptanes (flow rate=18 mL/minute) over 20 minutes to give the title compound as a white solid (25 mg, 64%). 1H NMR (400 MHz, pyridine-d5, 90° C.) δ ppm 8.06 (s, 1H), 7.97 (d, J=1.3 Hz, 1H), 7.89 (s, 1H), 7.68 (dd, J=18.2, 7.8 Hz, 2H), 7.47 (t, J=7.8 Hz, 1H), 5.40 (dq, J=8.0, 4.0 Hz, 1H), 4.53-4.10 (m, 1H), 4.13 (td, J=8.8, 3.6 Hz, 2H), 3.96 (d, J=4.1 Hz, 2H), 3.41 (dd, J=13.9, 10.0 Hz, 1H), 3.32-3.17 (m, 1H), 2.90-2.67 (m, 2H), 2.55 (ddd, J=14.2, 8.8, 5.5 Hz, 1H), 2.07-1.91 (m, 2H), 1.06-0.97 (m, 2H), 0.92-0.79 (m, 2H); MS (ESI+) m/z 461.1 (M+H)+; [α]D23.7=0.10 (c=0.12, CH3OH).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[N:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]2[CH:18]=1)=[O:5])C.O.[OH-].[Li+]>O1CCCC1.O>[F:17][C:14]([F:15])([F:16])[C:11]1[N:12]=[CH:13][C:8]2[N:9]([CH:18]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=2)[CH:10]=1
Reactant: CCOC(=O)c1cn2cc(C(F)(F)F)ncc2n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn2cc(C(F)(F)F)ncc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Step A was dissolved in tetrahydrofuran (10 mL) and a solution of lithium hydroxide monohydrate (97 mg, 8.3 mmol) in water (5 mL) was added. The reaction mixture was stirred at room temperature for one hour, after which time the tetrahydrofuran was removed on a rotary evaporator under reduced pressure, and water was added (5 mL), followed by the addition of 1 N HCl (5 mL). The resulting suspension was filtered through a glass-fritted filter funnel, and the isolated solid was washed with water and dried over nitrogen to afford 451 mg of the title compound as a solid. 1H NMR ((CD3)2SO) δ 9.33 (s, 1H), 9.30 (s, 1H), 8.69 (s, 1H).
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([CH3:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:31][C:32]1[CH:37]=[CH:36]C(B(O)O)=[CH:34][CH:33]=1>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:20]([C:23]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)=[C:21]([CH3:22])[C:12]=2[CH:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[C:7]([OH:9])=[O:8])=[CH:25][CH:26]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C)c2ccccc2c1-c1ccc(Cl)cc1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1-c1ccc(Cl)cc1

Procedure:
2-(1,4-bis(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetic acid (140) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using 4-chlorobenzene boronic acid in the Suzuki reaction, giving the title compound (mono trifluoroacetic acid salt). 1H-NMR: (400 MHz, DMSO-d6): δ 12.82 (s, 1H), 7.75-7.63 (m, 4H), 7.55 (dd, J=8.2, 2.4 Hz, 1H), 7.46-7.31 (m, 5H), 7.26-7.21 (m, 2H), 5.14 (s, 1H), 2.24 (s, 3H), 0.96 (s, 9H). LCMS-ESI− (m/z): [2M-2H+Na]− calcd for C58H50Cl4NaO6: 1007.2; Found: 1007.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH2:36]>>[Cl:32][C:33]1[CH:40]=[CH:39][CH:38]=[CH:37][C:34]=1[CH2:35][NH:36][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([C:16]2[CH:15]=[N:14][C:10]3[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]4[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:28]([F:29])([F:31])[F:30])[C:9]=3[CH:17]=2)=[CH:26][CH:25]=1
Reactant: NCc1ccccc1Cl
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NCc1ccccc1Cl)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 2-chlorobenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=570.90 (M+H+); retention time=0.98 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[SH:23].CN(C=O)C>CS(C)=O>[Cl:9][C:6]1[CH:5]=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:23][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:13]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: Sc1ccc2ccccc2c1
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1

Procedure:
2-(2,6-Dichloro-4-nitro-phenylsulfanyl)-napthalene was synthesized (100%) from 3,4,5-trichloronitrobenzene (Acros) and napthalene-2-thiol (Avocado) in a similar manner as described in example 1 using DMSO as solvent instead of DMF.