Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:67])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:25]([O:61][CH3:62])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:59][CH3:60])[C@@H:35]([CH3:58])[C:36]([NH:38][C@@H:39]([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11].C(N(CC)CC)C.[Br:75][CH2:76][C:77](Cl)=[O:78]>C1COCC1>[Br:75][CH2:76][C:77]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([CH3:67])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:63]([CH3:66])[CH2:64][CH3:65])[C@H:25]([O:61][CH3:62])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:59][CH3:60])[C@@H:35]([CH3:58])[C:36]([NH:38][C@@H:39]([CH2:48][C:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[NH:51][CH:50]=1)[C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][O:43]1)=[O:41])=[O:37])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:78]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCN)C(C)C
Reactant: O=C(Cl)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCCCCNC(=O)CBr)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
22 mg (0.023 mmol) of N-(6-aminohexyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 101) were dissolved in 9.5 ml of THF and admixed at 0° C. with 4.2 μl of triethylamine. A solution of bromoacetyl chloride in THF was added dropwise and the reaction mixture was stirred at 0° C. for 30 min. The reaction mixture was concentrated and the residue was purified by preparative HPLC. Thus, 6.9 mg (26% of theory) of the title compound were obtained as a foam.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][C:10]2[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:9]=2[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])[S:7]1(=[O:25])=[O:24].[CH3:26][NH2:27].Cl>>[F:16][C:13]1[CH:14]=[CH:15][C:9]2[N:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])[S:7](=[O:25])(=[O:24])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:27][CH3:26])[CH2:11][C:10]=2[CH:12]=1
Reactant: CN
Reactant: O=S1(=O)N(CCCCBr)Cc2cc(F)ccc2N1c1ccccc1F
Agent: Cl
Product: CNCCCCN1Cc2cc(F)ccc2N(c2ccccc2F)S1(=O)=O
Yield: 81 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(4-bromobutyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.11 g, 0.25 mmol) was reacted to methylamine and then treated with HCl to provide 4-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylbutan-1-amine (0.085 g, 81%) as a white solid:
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C1S(=O)(=O)CCC1.[C:22]([C:25]1[CH:42]=[CH:41][CH:40]=[CH:39][C:26]=1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][CH:30]=1)([OH:24])=O.[OH-].[Na+]>C(O)C>[O:24]=[C:22]1[C:25]2[CH:42]=[CH:41][CH:40]=[CH:39][C:26]=2[CH2:27][O:28][C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([OH:38])=[O:37])=[CH:31][C:30]1=2
Reactant: O=C(O)Cc1ccc(OCc2ccccc2C(=O)O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: O=S1(=O)CCCC1
Solvent: CCO
Product: O=C(O)Cc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 1 h

Procedure:
To 49 ml of absolute ethanol is added with vigorous stirring, 81 g of phosphorus pentoxide. After addition, the mixture is allowed to stir at 95°-100° C for 1 hour, 400 ml of tetramethylene sufone are added and the temperature is adjusted to 86°-90° C. Then, 38.5 g of 4-(2-carboxybenzyloxy)phenylacetic acid, Example 1, are added, the mixture is stirred for 4 hours and poured onto ice water. The aqueous mixture is made basic with sodium hydroxide and extracted with toluene. Cooling of the aqueous layer followed by acidification with concentrated hydrochloric acid gives light brown crystals. Recrystallization from acetic acid-water or from dimethoxyethane provides colorless crystals, mp 126°-128° C of 6,11-dihydro-11-oxodibenz[b,e]oxepin-2-acetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([C:13]([O:15]C)=O)[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.FC1C=C(C2C=C(C(O)=O)ON=2)C=CC=1.S(Cl)(Cl)=O.[NH2:36][NH2:37]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([C:13]([NH:36][NH2:37])=[O:15])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)c1cc(-c2cccc(F)c2)no1
Agent: O=C(O)c1cc(-c2cccc(F)c2)no1
Solvent: O=S(Cl)Cl
Solvent: CO
Product: NNC(=O)c1cc(-c2cccc(F)c2)no1

Procedure:
A mixture of methyl 3-(3-fluorophenyl)isoxazole-5-carboxylate (prepared according to the literature method: T. T. Dang, U. Albrecht and P. Langer, Preparation 2006, No. 15, 2515-252; or treatment of 3-(3-fluorophenyl)isoxazole-5-carboxylic acid with thionyl chloride and methanol) (5.55 g, 25 mmol, 1.0 equiv.), hydrazine (960 mg, 30 mmol) and MeOH (100 mL) was refluxed for 1 h and concentrated. The residue was washed with dichloromethane and dried in vacuum to give 3-(3-fluorophenyl)isoxazole-5-carbohydrazide (5.6 g, quant.). LRMS (M+H+) m/z 222.0
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10](O)[CH2:11][CH3:12])=[CH:6][CH:5]=1.C(Br)(Br)(Br)[Br:17].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[Br:17][CH:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][C:2]([F:15])([F:14])[F:1])=[CH:5][CH:6]=1)[CH2:11][CH3:12]
Reactant: CCC(O)c1ccc(OC(F)(F)F)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCC(Br)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 1-(4-(trifluoromethoxy)phenyl)propan-1-ol (300 mg; 1.36 mmol) in anh. DCM (10 ml) was treated at rt with CBr4 (451 mg; 1.36 mmol), and with PPh3 (357 mg; 1.36 mmol). The resulting mixture was further stirred at rt, under nitrogen, for 17 h. Concentration to dryness under reduced pressure, and subsequent purification by FC (DCM) afforded 1-(1-bromopropyl)-4-(trifluoromethoxy)benzene as a slightly yellow oil which was directly used for the next reaction. LC-MS (conditions A): tR=1.01 min.; no ionisation.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:20][CH2:21][CH2:22][CH3:23])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NOCc1ccccc1
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCN(OCc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a stirred solution at 0° C. of N--t-Butoxycarbonyl-O-benzylhydroxylamine, prepared as in Example 1175A, in anhydrous THF was added portionwise a 60% dispersion of sodium hydride (1.2 equiv.) in mineral oil. Mixture stirred 30 minutes ar 0° C., and then, 1-iodobutane (1.2 equiv.) was added dropwise. Reaction stirred one hour at 0° C., and than, overnight at room temperature. Reaction concentrated in vacuo. Residue taken up in EtOAc and washed with water, 1.0M NaHCO3, 1N H3PO4, and brine. Organic layer dried with Na2SO4, filtered, and evaporated.
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22]C(=O)N(C)C)=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[CH2:29][CH2:30][CH2:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[N:34](C(C)=C)[C:33]1=[O:44]>CO>[C:3]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[C:17]([S:22][CH2:29][CH2:30][CH2:31][N:32]3[C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[NH:34][C:33]3=[O:44])=[C:18]([Cl:21])[CH:19]=[CH:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: C=C(C)n1c(=O)n(CCCBr)c2ccccc21
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCCCn3c(=O)[nH]c4ccccc43)c2CC1
Temperature: 25 °C
Yield: 82.4 %

Procedure:
Add potassium hydroxide (933 mg, 16.6 mmol) in one portion to a solution of 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (200 mg, 0:52 mmol) in methanol (10 mL). Heat the reaction at reflux under nitrogen 4 h. Then cool to room temperature and add 1-(3-bromo-propyl)-3-isopropenyl-1,3-dihydro-benzoimidazol-2-one (142 mg, 0.52 mmol). Stir the reaction at room temperature overnight. Remove solvents in vacuo, extract into diethyl ether (2×50 mL), wash with water (2×50 mL) and brine (50 mL). Dry over MgSO4, filtrate and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-[3-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-propylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as an oil (209 mg, 76%). MS (ES+) m/z: 550 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([OH:23])=[CH:18][C:17]=3[CH3:24])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].[CH3:32][S:33](Cl)(=[O:35])=[O:34].O>N1C=CC=CC=1>[CH3:22][C:21]1[CH:20]=[C:19]([O:23][S:33]([CH3:32])(=[O:35])=[O:34])[CH:18]=[C:17]([CH3:24])[C:16]=1[C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][C:3]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:2]([F:1])[CH:7]=2)[CH:11]=1
Reactant: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)CCc1ccc(OCc2cccc(-c3c(C)cc(OS(C)(=O)=O)cc3C)c2)cc1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 86.9 %

Procedure:
To an ice-cooled solution of ethyl 3-{2-fluoro-4-[(4′-hydroxy-2′,6′-dimethylbiphenyl-3-yl)methoxy]phenyl}propanoate (310 mg, 0.736 mmol) in pyridine (8 mL) was added dropwise methanesulfonyl chloride (168 mg, 1.47 mmol). The mixture was stirred at room temperature for 2 days. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-1/1) to give the title compound (320 mg, yield 87%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[CH:38][C:6]([CH2:7][O:8][C:9](=[O:37])[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[C:28](C)(C)[O:29][SiH2]C(C)(C)C)=[O:22])=[CH:5][CH:4]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].CCOC(C)=O.C(Cl)(Cl)Cl>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9](=[O:37])[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=2[C:21]([N:23]2[CH2:27][CH2:26][CH2:25][CH:24]2[CH2:28][OH:29])=[O:22])=[CH:38][CH:39]=1
Reactant: COc1ccc(COC(=O)Nc2cc(OC)c(OC)cc2C(=O)N2CCCC2C(C)(C)O[SiH2]C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1ccc(COC(=O)Nc2cc(OC)c(OC)cc2C(=O)N2CCCC2CO)cc1

Procedure:
The TBDMS ether 10 (0.37 g, 0.66 mmol) in THF (20 mL) was deprotected (Method A: Bu4NF (0.8 ml, 0.8 mmol)) to give the product (flash column chromatography 80% EtOAc/20% n-hexane, then EtOAc) as a colourless oil (0.29 g, 97%). [α]D22.1−69.6° (c=0.23, CHCl3), 1H NMR (CDCl3) δ 8.72 (s, 1H), 7.76 (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 6./90 (d, J=8.6 Hz, 2H), 6.80 (s, 1H), 5.10 (m, 2H), 4.40 (m, 1H), 4.30 (m, 1H), 3.92 (s, 3H), 3.83 (s, 3H), 3.80 (m, 4H), 3.7 (m, 1H), 3.58 (m, 1H), 3.45 (m, 1H), 2.15 (m, 1H), 1.90 (m, 1H), 1.70 (m, 2H). IR (neat) 3338, 2958, 2837, 1726, 1599 cm−1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=2[OH:24])[CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33]>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([C:16](=[O:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:28][C:29]3[CH:36]=[CH:35][CH:34]=[C:31]([C:32]#[N:33])[CH:30]=3)=[CH:19][C:18]=2[O:24][CH2:28][C:29]2[CH:36]=[CH:35][CH:34]=[C:31]([C:32]#[N:33])[CH:30]=2)[CH2:14][CH2:15]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(O)cc2O)CC1
Reactant: N#Cc1cccc(CBr)c1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(OCc3cccc(C#N)c3)cc2OCc2cccc(C#N)c2)CC1
Yield: 67.1 %

Procedure:
{2-[1-(2,4-Dihydroxy benzoyl)piperidin-4-yl]ethyl}carbamic acid tert-butyl ester (1.05 g, 2.88 mmol) and 3-bromomethyl-benzonitrile (2.25 g, 11.5 mmol) and other reagents as described in Example 75(a) were used to afford 1.15 g of the required product. 1H NMR (DMSO-d6): δ 1.4 (9H, s), 2.1 (2H, d), 2.6 (1H, m), 2.95 (4H, m), 3.45 (1H, m), 4.5 (2H, m), 5.2 (4H, s), 6.7 (2H, d), 6.84 (1H, d), 7.14 (1H, dd), 7.52 (1H, m), 7.62 (3H, d), 7.7 (2H, d), 7.8 (5H, m), 7.95 (1H, s).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.C(Cl)Cl.[OH:14][CH2:15][CH:16]1[CH2:19][C:18]([CH2:42][C:43]#[N:44])([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:17]1.C(N(CC)CC)C>>[CH:15]([CH:16]1[CH2:17][C:18]([CH2:42][C:43]#[N:44])([N:20]2[CH:24]=[C:23]([C:25]3[C:26]4[CH:33]=[CH:32][N:31]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:41])[CH3:40])[C:27]=4[N:28]=[CH:29][N:30]=3)[CH:22]=[N:21]2)[CH2:19]1)=[O:14]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(CO)C4)c3)ncnc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(C=O)C4)c3)ncnc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
Dimethyl sulfoxide (0.194 mL, 0.00274 mol) was added to a solution of oxalyl chloride (0.145 mL, 0.00171 mol) in methylene chloride (6.384 mL, 0.09959 mol) at −78° C. After 10 min, 3-(hydroxymethyl)-1-[4-(7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]cyclobutylacetonitrile (0.500 g, 0.00114 mol) in methylene chloride (12.77 mL, 0.1992 mol) was added and the resultant mixture was stirred at −78° C. for 30 min. Triethylamine (0.794 mL, 0.00570 mol) was then added and the mixture was stirred for 5 h with the temperature allowed to gradually warm up to rt. After quenching with water, the mixture was extracted with methylene chloride. The organic layers were combined, washed with brine, dried and evaporated to dry. The residue was purified on silica gel, eluting with 0 to 100% EtOAc in hexane, to give the desired aldehyde (430 mg, 86%). LCMS calculated for C22H29N6O2Si(M+H)+: 437.2; Found: 437.4.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:43])[NH:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:42])NOC3C=CC([N+]([O-])=O)=CC=3)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:44]([NH2:53])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52].C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:43])[NH:25][CH2:26][CH2:27][CH2:28][O:29][C:30](=[O:42])[NH:53][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCN
Reactant: O=C(NOc1ccc([N+](=O)[O-])cc1)OCCCNC(=O)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCNC(=O)OCCCNC(=O)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Reaction time: 2 h
Yield: 97.8 %

Procedure:
A solution of the carbonate (2.0 g, 3.4 mmol) produced in Example 17 in 20 mL of anhydrous dimethylformamide was added dropwise under nitrogen to a solution of nonylamine (760 μl, 4.1 mmol) and triethylamine (2.4 mL, 17 mmol) in 20 mL of anhydrous dimethylformamide at ice bath temperature. After the addition the solution was stirred at ice bath temperature for 2 hrs and at room temperature overnight. The reaction was diluted with ethyl acetate, extracted five times with water, one time with 1N HCl, five times with saturated Na2CO3, dried (MgSO4) and the solvent removed under reduced pressure to give 1.94 g of an off-white solid. Recrystallization from diisopropyl ether gave 1.55 g (77%) of the title compound as a white crystalline solid, mp 89-91° C.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:11]=[C:10]([O:12][CH3:13])[C:9]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)=[CH:8][C:6]=1[NH2:7])([O-:4])=[O:3].[CH:23]([C:25]([CH3:27])=O)=[CH2:24]>P(=O)(O)(O)O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[Cl:21])[O:14][C:9]1[C:10]([O:12][CH3:13])=[CH:11][C:5]([N+:2]([O-:4])=[O:3])=[C:6]2[C:8]=1[C:25]([CH3:27])=[CH:23][CH:24]=[N:7]2
Reactant: COc1cc([N+](=O)[O-])c(N)cc1Oc1ccc(Cl)c(Cl)c1
Reactant: C=CC(C)=O
Agent: Cl
Agent: O=P(O)(O)O
Product: COc1cc([N+](=O)[O-])c2nccc(C)c2c1Oc1ccc(Cl)c(Cl)c1
Temperature: 115 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
A mixture of 83 g of 2-nitro-4-methoxy-5-(3,4-dichlorophenoxy)aniline hydrochloride (0.22 mole) polyphosphoric acid in 250 ml of 85% phosphoric acid was heated in a nitrogen atmosphere at 110-120° C. and 32.17 g of methyl vinyl ketone (0.46 mole) was added dropwise under vigorous stirring. After the addition was complete, the mixture was stirred and maintained at 110-120° C. for a further 4 hours. An additional 14 g of methyl vinyl ketone (0.2 mole) was added and the mixture was heated for a further 4 hours. The reaction mixture was poured into ice cold sodium hydroxide solution (pH 10-12) and left over night. The resulting precipitate was separated by filtration and dried. The solid was dissolved in chloroform and mixed with activated charcoal and filtered through a celite bed. The celite bed was washed with chloroform and the filtrate was concentrated to 400 ml under vacuum and diluted with methanol until a turbidity appeared and left overnight. The crystalline product formed was separated by decantation and crystallized from chloroform to give 8 g of pure product, 5-(3,4-dichlorophenoxy)-6-methoxy-4-methyl-8-nitroquinoline. The combined filtrates were evaporated to dryness and the residue was chromatographed over silica gel with 30% chloroform in hexane to yield a fraction from which the product which was crystallized (chloroform/methanol) to give 13 g of product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([CH2:18][C:19]([OH:21])=O)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.C(N(CC)CC)C.C(Cl)CCl.OC1C2N=NNC=2C=CC=1>ClCCl>[O:25]1[CH2:26][CH2:27][N:22]([C:19](=[O:21])[CH2:18][C@@H:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:23][CH2:24]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1CC(=O)O
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1CC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 3 g (10.30 mmol) of [(3S)-2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-3-yl]acetic acid in 100 mL of dichloromethane, there are added dropwise 1.10 mL (11.32 mmol) of morpholine, still dropwise 4.3 mL (30.9 mmol) of triethylamine, 2.20 g (12.40 mmol) of EDC and 1.70 g (1.68 mmol) of HOBt (hydroxybenzotriazole). The batch is stirred at ambient temperature for 15 hours. The reaction mixture is then diluted with dichloromethane, successively washed with 1M HCl solution, saturated aqueous NaHCO3 solution and then brine until neutral. The organic phase is then dried over MgSO4, filtered and concentrated to dryness. After purification by chromatography over silica gel using dichloromethane and methanol as eluants, the title product is obtained in the form of an oil.
Reaction SMILES: [I:1]([O-])(=O)=O.[K+].[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].C(OC(=O)C)(=O)C.[OH:33][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:36])=[O:35]>CC(C)=O>[F:38][C:37]([F:40])([F:39])[S:34]([O-:36])(=[O:35])=[O:33].[C:22]([C:19]1[CH:20]=[CH:21][C:16]2[C:13]3[CH:14]=[CH:15][C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:11][C:12]=3[I+:1][C:17]=2[CH:18]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1ccc(-c2ccc(C(C)(C)C)cc2)cc1
Reactant: [O-][I+2]([O-])[O-]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)c1ccc2c(c1)[I+]c1cc(C(C)(C)C)ccc1-2
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 0 °C
Reaction time: 14 h
Yield: 2 %

Procedure:
Into a 250 ml 3-neck round bottom flask equipped with a mechanical stirrer, thermometer, and inlet was charged with agitation, 4.0 grams (18.8 mmol, 1.0 eq) of potassium iodate, 5.0 grams (18.8 mmol, 1.0 eq) of 4,4'-di-t-butylbiphenyl, and 20 mL of acetic anhydride to form a mixture which was cooled to 0° C. To the mixture was added 5.63 grams (3.32 mL, 37.5 mmol, 2.0 eq) of triflic acid dropwise at such a rate that the reaction temperature did not exceed 10° C. The temperature was kept below 10° C. during the addition by the use of a cooling bath. The reaction mixture was never homogeneous and the 4,4'-di-t-butylbiphenyl did not appear very soluble in the reaction mixture. The reaction mixture turned dark almost immediately upon addition of the triflic acid. The mixture was stirred for about 14 hours at room temperature. The reaction was quenched with approximately 60 mL of water and extracted with methylene chloride. The methylene chloride layer was washed with saturated aqueous sodium bicarbonate solution and concentrated in vacuo. The residue was a dark viscous oil. This material was soluble in ether and could be precipitated with hexanes; however, the precipitate was a brown amorphous powder. Titration with acetone gave a tan solid 0.2 gram (2% yield). Melting point=233°-234° C.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4](S(N=C=O)(=O)=O)=[CH:3][CH:2]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=O.C1CCC=CC=1>C1(C)C=CC=CC=1>[CH2:19]([O:18][C:14](=[O:17])[CH3:15])[CH3:20].[CH3:5][CH2:6][CH2:1][CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CCOC(=O)C=O
Solvent: Cc1ccccc1
Solvent: C1=CCCC=C1
Product: CCCCCC
Product: CCOC(C)=O
Yield: 50 %

Procedure:
Following the method of Scheme AC, a mixture of 15.25 g of p-toluenesulfonyl isocyanate and 20 mL 50% solution of ethyl glyoxalate in toluene with 50 mL of toluene was heated under reflux for 36 h, then 10 mL of 1,3-cyclohexadiene were added as one portion. The reaction was heated for an additional 8 h and cooled down. The product was ppt from toluene, and was recrystallized from hexane ethyl acetate providing 13.0 g (50% yield) of the cycloadduct (see Scheme AC, Compound AC4) as white crystals: mp. 140-142° C.). The cycloadduct was mixed with 200 mg of 10% Pd/C, 150 mL of ethyl acetate and 150 mL of ethanol and was hydrogenated for 24 h at rt. The reaction mixture was filtered through celite and evaporated. The residual material was recrystallized from hexane ethyl acetate providing 12.0 g of the tosylate as white crystals (see Compound AC5, Scheme AC). NMR (CDCl3) 7.88 (d, J=8, 2H), 7.28 (d, J=8, 2H), 4.34 (d, J=2,1H), 4.22 (q, J=6, 2H), 3.62 (m, 1H), 2.42 (s, 3H), 2.22 (m, 1H), 2.00 (m, 1H), 1.80 (m, 1H), 1.70-1.30 (m, 6H), 1.28 (t, J=7, 3H). The tosylate (2.0 g) was dissolved in 50 mL EtOAc containing phenol (6.0 g), then 100 mL of 30% solution of HBr in AcOH was added dropwise. The reaction was allowed to stir 48 h, then EtOAc and most of the AcOH was evaporated under reduced pressure. The residue was dissolved in water, neutralized with Na2CO3 and extracted with Et2O. The organic solution was saturated using HCl and evaporated providing 0.85 g of a yellow solidified oil (see Compound AC6, Scheme AC).