Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[Br-:10].[K+].N([O-])=O.[Na+].ClCCl>S(=O)(=O)(O)O>[Br:10][CH:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[C:7]([OH:9])=[O:8]
Reactant: [Br-]
Reactant: CC(C)CC(N)C(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Product: CC(C)CC(Br)C(=O)O
Reaction time: 1 h
Yield: 84.2 %

Procedure:
D,L-Leucine (50 g, 0.38 mol) and potassium bromide (158.7 g, 1.33 mol) were dissolved in aqueous sulfuric acid (from 75 mL of H2SO4 and 250 mL of water), and sodium nitrite (34.8 g, 0.5 mol) was added portionwise wile keeping the temperature below −1° C. The mixture was kept at 0° C. for 1 h, then dichloromethane was added under stirring. The dichlomethane layer was collected and the aqueous phase was extracted twice with further portions of dichloromethane. The combined dichloromethane extracts were dried (Na2SO4) and evaporated to give the title compound as a pale yellow oil (63.4 g, 0.32 mol; 85.5%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13](=O)[CH3:14].C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>O>[CH3:1][C:2]1[NH:6][C:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[C:13](=[N:22][OH:23])[CH3:14]
Reactant: NO
Reactant: CC(=O)c1nc(-c2cccnc2)[nH]c1C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(=NO)c1nc(-c2cccnc2)[nH]c1C
Temperature: 25 °C

Procedure:
To a 20.0 g (0.0995 mole) amount of 1-[5-methyl-2-(3-pyridinyl)-1H-imidazol-4-yl]ethanone (prepared as described in Example 1) dissolved in 500 ml of boiling water were added 15.0 g (0.183 mole) of sodium acetate and 10.0 g (0.144 mole) of hydroxylamine hydrochloride. The mixture was stirred and heated for 4 hours, then cooled to room temperature. The resulting precipitate was collected by filtration and when dried at 140°-160° C. for 24 hours gave 20.3 g of the desired product as a white solid, mp 215°-216° C.
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH3:21])(=[O:10])=[O:9])[CH2:3]1.[N:22]1[N:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:25]2=[C:24]([C:31](O)=[O:32])[CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:1][C@H:2]1[CH2:3][N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:12]=2[CH3:21])(=[O:9])=[O:10])[CH2:5][CH2:6][N:7]1[C:31]([C:24]1[CH:23]=[N:22][N:26]2[CH:27]=[CH:28][CH:29]=[N:30][C:25]=12)=[O:32]
Reactant: Cc1cc(C(F)(F)F)ccc1S(=O)(=O)N1CCN[C@@H](C)C1
Reactant: O=C(O)c1cnn2cccnc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(F)(F)F)ccc1S(=O)(=O)N1CCN(C(=O)c2cnn3cccnc23)[C@@H](C)C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 74.5 %

Procedure:
To a solution of (3S)-3-methyl-1-{[2-methyl-4-(trifluoromethyl)phenyl]sulfonyl}piperazine (100 mg, 0.310 mmol) (may be prepared as described in Description 27), pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (55.7 mg, 0.341 mmol), HOBt (52.3 mg, 0.341 mmol) and DIPEA (0.081 ml, 0.465 mmol) in dry DMF (5 ml) at rt was added HBTU (129 mg, 0.341 mmol) and the resulting orange solution stirred at rt for 45 min. Concentration under vacuum left an orange oil. Purification by MDAP and concentration of the desired fractions gave the title compound (108 mg) as a clear film that became a white solid on trituration with ether.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>O1CCCC1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30]([NH:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20])=[O:31]
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2ccc(Cl)cc2Cl)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2,4-dichlorophenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 285°-287° C. (d).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].F[C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=1)[O:15][C:19]1[CH:24]=[C:23]([N:25]2[C:30](=[O:31])[CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[N:27]([CH3:36])[C:26]2=[O:37])[C:22]([F:38])=[CH:21][C:20]=1[N+:39]([O-:41])=[O:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(OCc2ccccc2)c1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(OCc4ccccc4)c3)c([N+](=O)[O-])cc2F)c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 52.9 %

Procedure:
A mixture of 1.71 g of 3-benzyloxyphenol and 4.0 ml of N,N-dimethylformamide was added dropwise into a mixture of 0.34 g of sodium hydride and 8.5 ml of N,N-dimethylformamide while cooling with ice, and the mixture was stirred for 20 minutes. A mixture of 3.0 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene (described later, produced in Intermediate Production Example 4) and 7.0 ml of N,N-dimethylformamide was added dropwise at the same temperature, and stirred for 1 hour. This reaction solution was poured into ice water, and extracted with ethyl acetate. The organic layer was washed once with 1N hydrochloric acid and once with saturated saline, and dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 2.4 g of 2-(3-benzyloxyphenoxy)-5-fluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]nitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([B:7]([OH:9])[OH:8])=[CH:4][CH:3]=1.[CH3:10][C:11]([CH2:15]O)([CH2:13]O)[CH3:12]>>[Cl:1][C:2]1[S:6][C:5]([B:7]2[O:9][CH2:12][C:11]([CH3:15])([CH3:13])[CH2:10][O:8]2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)s1
Reactant: CC(C)(CO)CO
Product: CC1(C)COB(c2ccc(Cl)s2)OC1
Yield: 54 %

Procedure:
The title compound (54%, crystals) was prepared from 5-chlorothiophen-2-boronic acid and neopentylglycol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[CH2:7][CH2:8][CH2:9][CH:10]([NH2:12])[CH2:11][C:5]=2[CH:4]=1.[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([O:32][Si](CC)(CC)CC)[CH2:30]I)=[CH:25][C:24]=1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C.S([O-])(O)=O.[Na+]>CN(C)C(=O)C>[CH2:15]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C@@H:29]([OH:32])[CH2:30][NH:12][CH:10]2[CH2:9][CH2:8][CH2:7][C:6]3[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[CH2:11]2)=[CH:25][C:24]=1[NH:40][S:41]([CH3:44])(=[O:42])=[O:43])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc2c(c1)CC(N)CCC2
Reactant: CC[Si](CC)(CC)O[C@@H](CI)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1ccc2c(c1)CC(NC[C@H](O)c1ccc(OCc3ccccc3)c(NS(C)(=O)=O)c1)CCC2
Yield: 20 %

Procedure:
Under nitrogen, a solution of 3-methoxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-6-ylamine (720 mg), N-[2-benzyloxy-5-[(1R)-2-iodo-1-(triethylsilyloxy)ethyl]phenyl]-methanesulfonamide (2.1 g) and N,N-diisopropylethylamine (2.6 ml) in N,N-dimethylacetamide (10 ml) was stirred at 110° C. for 96 hours. The resulting mixture was poured into aqueous 10% sodium hydrogensulfite and extracted with ethyl acetate. The organic layer was successively washed with saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform:methanol=40:1 to 20:1) to give N-[2-benzyloxy-5-[(1R)-1-hydroxy-2-(3-methoxy-6,7,8,9-tetrahydro-5H-benzo-cyclohepten-6-ylamino)ethyl]phenyl]methanesulfonamide (381 mg).
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[NH:12][CH:13]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NN.[OH-].[K+].Cl>O.C(O)CO>[CH2:1]([C:9]1[CH:10]=[C:11]([C:14]([OH:16])=[O:15])[NH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1c[nH]c(C(=O)O)c1
Agent: Cl
Agent: NN
Agent: [K+]
Solvent: OCCO
Solvent: O
Product: O=C(O)c1cc(Cc2ccccc2)c[nH]1

Procedure:
4-Benzoylpyrrole-2-carboxylic acid (1.5 g.) was combined with 10 ml. of ethylene glycol, 4 ml. of hydrazine (97%) and 4 g. of potassium hydroxide, and heated for 2 hours in an oil bath maintained at 140°-143° C. The reaction mixture was poured into approximately 100 ml. of ice and water, acidified with conc. hydrochloric acid, and product (375 mg.) recovered by filtration. Recrystallization from ether/hexane afforded purified 4-benzoylpyrrole-2-carboxylic acid (200 mg., m.p. 183°-185° C.).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]([CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([N+:26]([O-])=O)=[CH:21][CH:22]=3)[CH2:17]2)[CH2:13][CH2:14][CH3:15])[CH2:7][CH2:6]1)(=[O:4])=[O:3]>C(O)C.[Pd]>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:12]([CH2:13][CH2:14][CH3:15])[CH:16]2[CH2:25][CH2:24][C:23]3[C:18](=[CH:19][C:20]([NH2:26])=[CH:21][CH:22]=3)[CH2:17]2)[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: CCO
Product: CCCN(CC1CCN(S(C)(=O)=O)CC1)C1CCc2ccc(N)cc2C1
Reaction time: 24 h
Yield: 87.8 %

Procedure:
To a solution of (1-methanesulfonyl-piperidin-4-ylmethyl)-(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine (490 mg, 1.20 mmol) in ethanol (30 mL) was added 10% palladium on charcoal (50 mg). The solution was shaken on a Parr shaker for 24 h at 55 psi of H2. The solution was filtered through Celite® and concentrated to afford N-(1-methanesulfonyl-piperidin-4-ylmethyl)-N-propyl-1,2,3,4-tetrahydro-naphthalene-2,7-diamine (400 mg) 85, [M+H]+=380, which was used directly in the next step.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[C:8]([Cl:21])[C:7]=1[CH2:22][CH3:23])(=[O:4])[CH2:2][CH3:3].[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>>[C:1]([O:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])=[CH:16][CH:15]=2)=[C:8]([Cl:21])[C:7]=1[CH2:22][CH3:23])(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Oc1cc(Cl)c(Oc2ccc(N)cc2)c(Cl)c1CC
Reactant: CC(C)C(=O)Cl
Product: CCC(=O)Oc1cc(Cl)c(Oc2ccc(NC(=O)C(C)C)cc2)c(Cl)c1CC
Yield: 83.5 %

Procedure:
Ethyl(3,5-dichloro-4-[4-aminophenoxy]phenyl) propionate (80 mg) was coupled with isobutyryl chloride (30 mg), using the method described in Example 1(h). After recrystallization (ethyl acetate/petrolium ether), 80 mg of ethyl(3,5-dichloro-4-[4-isobutyr-amidophenoxy]phenyl) propionate was obtained, which was hydrolysed using the method described in Example 1(i). This gave 50 mg of 3,5-dichloro-4-(4-isobutyramidophenoxy)-phenylpropionic acid, m/z 382.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12]O.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][Br:15]
Reactant: OCCc1c[nH]c2ccc(F)cc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Fc1ccc2[nH]cc(CCBr)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of 5-fluoro-3-(2-hydroxyethyl)indole (10.3 g, 0.056 mole) and CBr4 (24.8 g, 0.073 mole) in 100 mL of dry acetonitrile at 0° C. under Ar was added a solution of triphenylphosphine (19.6 g, 0.073 mole) in 200 mL of dry acetonitrile. The mixture was stirred at 0° C. for 1 h and then at room temperature for 2 h. The resulting mixture was evaporated and the residue was chromatographed (SiO2 /ethyl acetate-hexane=1:4) to give the product (8.50 g, 61%) as a brown solid; IR (neat) 3440 cm-1 ; 1Hnmr (80 MHz, CDCl3) δ: 7.75 (br s, 1H), 7.15-6.57 (m, 4H), 3.53-3.32 (m, 2H), 3.17-2.94 (m, 2H).
Reaction SMILES: [C:1]([OH:24])(=O)[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[CH2:25]([CH2:27][NH2:28])[OH:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC#N.CCOC(C)=O>[OH:26][CH2:25][CH2:27][NH:28][C:1](=[O:24])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)O
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenoic acid (DHA, 1.2 g, 3.66 mmol) was taken up in 20 mL of CH3CN along with ethanolamine (220 μL, 3.66 mmol), HATU (1.5 g, 4.0 mmol) and DIEA (950 μL, 5.49 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and then diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3, brine, dried (Na2SO4) and concentrated under reduced pressure to afford crude (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-hydroxyethyl)docosa-4,7,10,13,16,19-hexaenamide. This material was taken up in 15 mL of CH2Cl2 along with (E)-methyl 4-chloro-4-oxobut-2-enoate (3.66 mmol) and triethylamine (765 μL, 5.49 mmol). The resulting reaction mixture was stirred at room temperature for 18 h. It was then diluted with CH2Cl2 and washed with brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (60% EtOAc, 40% pentane) afforded 380 mg of 2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl methyl fumarate (21% yield). MS (EI) calcd for C29H41NO5: 483.3. found: 484 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH:6](C)[CH2:5][C:4]([CH3:10])([CH3:9])[C:3]=1[C:11](=[O:16])/[C:12](/[CH3:15])=[CH:13]/[CH3:14].O1CCOC[CH2:18]1>>[CH3:1][C:2]12[C:13]([CH3:14])=[C:12]([CH3:15])[C:11](=[O:16])[CH:3]1[C:4]([CH3:10])([CH3:9])[CH:5]([CH3:18])[CH2:6][CH2:7]2
Reactant: C/C=C(\C)C(=O)C1=C(C)CC(C)CC1(C)C
Reactant: C1COCCO1
Product: CC1=C(C)C2(C)CCC(C)C(C)(C)C2C1=O

Procedure:
According to the same procedure described in Example 49, a solution of 2,4,6,6-tetramethyl-1-[2-methyl-crotonoyl]-1-cyclohexene (1.0 g.) in 10 ml. of dioxan was heated at 100° under nitrogen with acidic diatomaceous earth (0.2 g.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1[CH3:17].Cl[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[N+:29]([O-:31])=[O:30].C(N(CC)CC)C>C(O)C>[CH3:17][N:13]1[CH2:14][CH2:15][CH2:16][CH:12]1[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:21][C:20]=3[N+:29]([O-:31])=[O:30])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: CN1CCC[C@@H]1Cc1c[nH]c2ccc(N)cc12
Solvent: CCO
Solvent: CCN(CC)CC
Product: CN1CCCC1Cc1c[nH]c2ccc(Nc3ccc(C(F)(F)F)cc3[N+](=O)[O-])cc12
Yield: 38 %

Procedure:
(R)-5-Amino-3-(N-methylpyrrolidin-2-ylmethyl)-1H-indole and 4-chloro-3-nitrobenzotrifluoride were used. Triethylamine was used as base, absolute ethanol was used as solvent, and the reaction was heated at reflux for 4.5 hours. Column chromatography afforded the title compound (38%) as a red foam: Rf =0.30 in 9:1:0.1 [methylene chloride/methanol/ammonium hydroxide]; 13C NMR (CDCl3) δ147.0, 139.7, 135.1, 131.6, 131.0, 129.2, 128.5, 124.7, 124.2, 120.7, 118.6, 116.8, 116.6, 113.6, 112.6, 67.1, 57.4, 40.8, 31.3, 29.2, 21.9. FAB LRMS 419 [MH+]. Anal. calcd for C21H21N4O2.0.6 CH2Cl2 : C, 55.27; H, 4.77; N, 11.94. Found: C, 55.44; H 4.58; N 11.52.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH:8]=[CH:9][N+:10]([O-])=O)=[CH:5][C:6]=1[CH3:7].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:7][C:6]1[CH:5]=[C:4]([CH2:8][CH2:9][NH2:10])[S:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C=C[N+](=O)[O-])sc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(CCN)sc1C
Yield: 55 %

Procedure:
In close analogy to the procedure described above, 2,3-Dimethyl-5-(2-nitro-vinyl)-thiophene is reacted with lithium aluminium hydride to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([OH:39])[C@@H:14]([NH:16][CH2:17][C:18]2[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:19]=2[C:28]2[CH:33]=[C:32]([CH:34]([CH3:36])[CH3:35])[CH:31]=[CH:30][C:29]=2[O:37][CH3:38])[CH3:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[O:42](C(OC(C)(C)C)=O)[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=O>C(Cl)Cl>[C:46]([O:45][C:43](=[O:42])[N:16]([C@@H:14]([CH3:15])[C@H:13]([C:5]1[CH:4]=[C:3]([C:2]([F:40])([F:41])[F:1])[CH:8]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:6]=1)[OH:39])[CH2:17][C:18]1[CH:23]=[C:22]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:20][C:19]=1[C:28]1[CH:33]=[C:32]([CH:34]([CH3:35])[CH3:36])[CH:31]=[CH:30][C:29]=1[O:37][CH3:38])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN[C@@H](C)[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(C(=O)OC(C)(C)C)[C@@H](C)[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (1S,2S)-1-[3,5-bis(trifluoromethyl)phenyl]-2-({[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}amino)propan-1-ol (135.5 mg, 0.228 mmol) in CH2Cl2 (5 mL) was added BOC2O (49.7 mg, 0.228 mmol). The reaction was stirred at room temperature for 2 days; during this time, 2 additional portions of BOC2O (25 mg each) were added. After 2 days, the reaction was concentrated, and the residue was purified by flash chromatography with 20% EtOAc/hexanes to afford tert-butyl{(1S,2S)-2-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-1-methylethyl}{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.41 (40% EtOAc/hexanes). LCMS=594.2 (M+1−BOC)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].[CH3:11]I.[H-].[Na+].O>CS(C)=O>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(C)cc(C)c1C
Reaction time: 10 h

Procedure:
In 100 ml of dimethyl sulfoxide were dissolved 10 g of 2,3,5-trimethylphenol and 10.4 ml of methyl iodide and the solution was ice-cooled. To this solution was added 5.6 g of 60% oily sodium hydride and the mixture was stirred for 10 hours. Water was added and the resulting mixture was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. The solvent was then distilled off to give an oily substance. Yield 12.9 g (quantitative).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22][CH3:23])[CH:17]=1)[C:7]([C:24]([O:26][CH3:27])=[O:25])=[C:6]2[C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1.ClC1C=CC=C(C(OO)=[O:48])C=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[N:8]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:23])=[O:48])[CH:17]=1)[C:7]([C:24]([O:26][CH3:27])=[O:25])=[C:6]2[C:28]1[CH:29]=[C:30]([O:38][CH3:39])[C:31]([O:36][CH3:37])=[C:32]([O:34][CH3:35])[CH:33]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1-c1cccc(SC)c1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OC)cc2c(=O)n1-c1cccc(S(C)=O)c1
Reaction time: 1 h
Yield: 850.3 %

Procedure:
To a solution of the compound obtained in Example 121 (200 mg) in chloroform (15 ml) is added a solution of m-chloroperbenzoic acid (78 mg) in chloroform (10 ml) at room temperature, and the mixture is stirred for one hour. The reaction mixture is washed with a 5% aqueous sodium hydroxide solution, dried, and concentrated under reduced pressure to give 6,7-dimethoxy-3-methoxycarbonyl-2-(3-methylsulfinylphenyl)-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone (1750 mg) as listed in Table 11.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH2:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(CN)C(=O)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ccccc1[N+](=O)[O-])C(=O)O
Temperature: 80 °C
Yield: 79.3 %

Procedure:
2-tert-Butoxycarbonylamino-3-aminopropionic acid (10 g, 49 mmol), 2-fluoronitrobenzene (5.7 ml, 54 mmol), and sodium bicarbonate (8.25 g, 98 mmol) was taken into 130 ml of dimethylformamide and heated at 80° C. for 18 hours. The reaction was evaporated in vacuo to give a viscous orange residue that was dissolved in 300 ml of water and extracted with diethyl ether (3×150 ml). The aqueous solution was acidified to pH 5 with 10% sodium hydrogen sulfate and extracted with ethyl acetate (3×250 ml). The combined extracts were dried over anhydrous sodium sulfate, filtered, and evaporated to give 12.64 g (83%) of the title compound as an orange amorphous solid. 1H NMR (CD3OD) δ8.15-8.10 (1H,d), 7.54-7.48 (1H,t), 7.13-7.08 (1H, d), 6.73-6.65 (1H, t), 4.45-4.35 (1H, m), 3.9-3.8 (1H, dd), 3.65-3.55 (1H, dd), 1.45 (9H, s).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-].[CH3:13][O:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[CH:17]=[N+:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH3:13][O:14][C:15]1[CH:26]=[CH:25][CH:24]=[CH:23][C:16]=1[CH:17]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: c1ccc(-n2cccc2)cc1
Reactant: COc1ccccc1C=[N+]1CCCC1
Agent: [Cl-]
Product: COc1ccccc1C(c1cccn1-c1ccccc1)N1CCCC1

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-phenyl-1H-pyrrole and 1-(2-methoxy-benzylidene)pyrrolidinium chloride.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]3[CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[O:20][C:15]=3[C:14]=2[CH2:29][CH2:30][CH3:31])=[C:6]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:5]=1[O:38][CH3:39])=[O:3]>C(OCC)(=O)C.CO.C(O)(=O)C>[NH2:1][C:2]([C:4]1[CH:33]=[CH:32][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:28]=[CH:27][C:16]3[CH2:17][CH2:18][CH:19]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[O:20][C:15]=3[C:14]=2[CH2:29][CH2:30][CH3:31])=[C:6]([CH2:34][CH:35]2[CH2:37][CH2:36]2)[C:5]=1[O:38][CH3:39])=[O:3]
Reactant: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)ccc2c1OC(CCC(=O)OC)CC2
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(C(N)=O)c(OC)c2CC2CC2)ccc2c1OC(CCC(=O)O)CC2

Procedure:
The compound of Example 74 is saponified as described in Example 62. Chromatography on silica gel with ethyl acetate/methanol/acetic acid (95:4.5:0.5) as eluant gives the product.