Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[C:3]=1[OH:10].[Cl:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][C:17]=1[Cl:18].Cl.C(NCC1C(O)=C(C2C=CC(Cl)=C(Cl)C=2)C=C(C2C=CC(Cl)=CC=2)C=1)(C)(C)C>>[Cl:11][C:12]1[CH:13]=[C:14]([C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[C:3]=2[OH:10])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: O=Cc1cccc(Br)c1O
Agent: CC(C)(C)NCc1cc(-c2ccc(Cl)cc2)cc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cl
Product: O=Cc1cccc(-c2ccc(Cl)c(Cl)c2)c1O

Procedure:
3′,4′-Dichloro-2-hydroxy-[1,1′-biphenyl]-3-carbaldehyde was prepared from 3-bromosalicylaldehyde and 3,4-dichlorophenylboronic acid using the same procedure described in Intermediate 5.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:16][CH3:17])=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:6][C@@H:5]1[CH3:18])(=O)C.[ClH:19].O1CCOCC1>CO>[ClH:19].[CH3:18][C@H:5]1[CH2:6][C:7]2[C:12](=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([O:16][CH3:17])[CH:8]=2)[NH:4]1
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)[C@@H](C)C2
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc2c(cc1[N+](=O)[O-])N[C@@H](C)C2
Temperature: 25 °C
Yield: 100 %

Procedure:
A slurry of (2S)-1-acetyl-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (5.7 g, 22.78 mmol) in MeOH (50 mL) and a 4N HCl solution in dioxane (56.9 mL, 228 mmol) was heated at 70° C. for 10 h. The resulting mixture was allowed to cool to rt and concentrated to afford (2S)-2-methyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole hydrogen chloride as a beige solid (5.55 g, 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (d, J=6.41 Hz, 3H), 2.84 (dd, J=16.94, 7.60 Hz, 1H), 3.34 (dd, J=16.85, 8.06 Hz, 1H), 3.90 (s, 3H), 4.12-4.27 (m, 1H), 7.41 (s, 1H), 7.66 (s, 1H); ESIMS (M+H)+=209.00.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:10][NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([NH:22][CH2:23][C:24]3[C:25]([NH:37][CH:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[C:26]4[CH:34]=[N:33][N:32]([CH2:35][CH3:36])[C:27]4=[N:28][C:29]=3[CH2:30][CH3:31])=[O:21])[N:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].CC1(C)C(C)(C)OB([C:52]2[CH:53]=[C:54]([CH2:58][CH:59]3[CH2:64][CH2:63][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:61][CH2:60]3)[CH:55]=[CH:56][CH:57]=2)O1.O1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH2:35]([N:32]1[C:27]2=[N:28][C:29]([CH2:30][CH3:31])=[C:24]([CH2:23][NH:22][C:20]([C:16]3[N:15]=[C:14]([C:12]([NH:11][CH2:10][C:4]4[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([C:56]5[CH:57]=[CH:52][CH:53]=[C:54]([CH2:58][CH:59]6[CH2:60][CH2:61][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:63][CH2:64]6)[CH:55]=5)[CH:3]=4)=[O:13])[CH:19]=[CH:18][CH:17]=3)=[O:21])[C:25]([NH:37][CH:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[C:26]2[CH:34]=[N:33]1)[CH3:36]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(Br)c2)n1
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: O
Solvent: C1COCCO1
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(OC)c(-c3cccc(CC4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)n1
Temperature: 100 °C
Yield: 113.2 %

Procedure:
To N-{[3-bromo-4-(methyloxy)phenyl]methyl}-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (40.46 g, 62.2 mmol) in a 2 L 3-neck flask was added 1,1-dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylate (24.96 g, 62.2 mmol) and 1,4-dioxane (700 mL). Then potassium carbonate (25.8 g, 187 mmol) and water (233 mL) were added followed by tetrakis(triphenylphosphine)palladium(0) (3.59 g, 3.11 mmol) and the mixture was then stirred at 100° C. under nitrogen with conventional heating. After 2 h the reaction was cooled and the mixture was partitioned between ethyl acetate and water and the aqueous layer extracted well with ethyl acetate. The combined organics were washed with water, brine, dried (MgSO4), filtered and evaporated to give 59.49 g (113%) of a brown foam. The crude product was purified on a 750 g Companion XL silica cartridge, eluting with 0-100% of {1% MeOH in ethyl acetate} in dichloromethane over 14 column volumes. This gave 25.38 g (48%) of a pale beige foam that the lab HPLC showed to be 97.23% pure with a retention time of 2.60 min. LC-MS m/z 845 (M+H)+, 3.02 min (ret time).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:27][C:28]([CH:30]1[CH2:34][CH2:33][CH:32]([CH2:35][N:36]([CH2:41][C:42]([OH:44])=O)[C:37]([O:39][CH3:40])=[O:38])[NH:31]1)=[O:29])[CH3:26].CN1CCOCC1>CN(C)C=O>[CH3:40][O:39][C:37]([N:36]1[CH2:41][C:42](=[O:44])[N:31]2[CH:30]([C:28]([O:27][CH2:25][CH3:26])=[O:29])[CH2:34][CH2:33][CH:32]2[CH2:35]1)=[O:38]
Reactant: CCOC(=O)C1CCC(CN(CC(=O)O)C(=O)OC)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCC2CN(C(=O)OC)CC(=O)N21
Yield: 76.5 %

Procedure:
HATU (390 mg, 1.03 mmol) was added to solution of 5-[(carboxymethyl-methoxycarbonyl-amino)-methyl]-pyrrolidine-2-carboxylic acid ethyl ester (187 mg, 0.68 mmol) and 4-methylmorpholine (375 μL, 3.4 mmol) in dimethylformamide (30 mL). After 50 minutes the solvent was removed under reduced pressure and the resulting residue was taken up in ethyl acetate (20 mL) which was washed with half saturated sodium chloride (2×10 mL), saturated sodium bicarbonate (2×10 mL) and dried over sodium sulfate. The aqueous phase also contained product. The water was removed under reduced pressure and the residue was azeotroped with toluene and then stirred with ethyl acetate (50 mL). The mixture was filtered and combined with the organic extracts. The solvent was removed under reduced pressure and the resulting residue was subjected to flash chromatography with eluent of (10% methanol in ethyl acetate) and hexane. The product-containing fractions were combined and the solvent was removed under reduced pressure to provide 4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2,6-dicarboxylic acid 6-ethyl ester 2-methyl ester (141 mg, 0.52 mmol, 76%). C12H18N2O5 calculated 270.1, observed [M+1]+271.1; rt=1.54 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.C(N(CC)CC)C.Cl[C:21](Cl)([O:23]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][C:34]=1[O:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44]>C1COCC1>[Cl:32][C:33]1[CH:39]=[CH:38][C:36]([NH:37][C:21]([NH:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:12])[CH:3]=2)=[O:23])=[CH:35][C:34]=1[O:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44]
Reactant: CN(C)CCOc1cc(N)ccc1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N)c2ccccc2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)Nc2ccc(Cl)c(OCCN(C)C)c2)c2ccccc2n1
Temperature: 0 °C
Yield: 114.2 %

Procedure:
To a solution containing 4-aminoquinaldine (74 mg, 0.46 mmol) in anhydrous THF (5.0 Ml) was added triethylamine (0.2 Ml, 1.4 mmol). The solution was cooled to 0° C. followed by the addition of triphosgene (45.0 mg, 0.18 mmol). The reaction mixture was stirred at 0° C. for 10 minutes before the addition of a solution of 4-chloro-3-(2-dimethylamino-ethoxy)aniline (100.0 mg, 0.46 mmol, for its synthsis see Steps 1-3 for Example 1) in THF (2 MI). The ice bath was removed and the mixture was heated at 65° C. for 2 hours before it was poured into a mixture of CH2Cl2/MeOH (20 Ml, 7:1 ratio). The resulting mixture was washed with 10% sodium bicarbonate (aq. 15.0 Ml). The organic layer was dried over MgSO4 and concentrated. The oily residue was chromatographed over silica gel (eluent: 20% MeOH in EtOAc) to give the desired product as an off-white solid (82.0 mg, 45% yield). The compounds of Example 15 and 16 were synthesized in the same manner as for Example 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]1[CH2:12][CH:5]2C=C1.C[N+]1([O-])[CH2:19][CH2:18][O:17]CC1.[OH:21]S([O-])=O.[Na+]>CC(C)=O.O.O=[Os](=O)(=O)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]1[CH2:12][CH:5]2[CH:18]([OH:17])[CH:19]1[OH:21]
Reactant: O=S([O-])O
Reactant: C[N+]1([O-])CCOCC1
Reactant: Fc1ccc2c(c1)C1C=CC2C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: OC1C2CC(c3cc(F)ccc32)C1O
Reaction time: 1 h

Procedure:
6-Fluoro-1,4-dihydro-1,4-methano-naphthalene (680 mg, 4.22 mmol) and N-methyl morpholine N-oxide (599 mg, 4 43 mmol) were stirred in acetone (50 mL) and H2O (5 mL). To this was added a solution of OsO4 (0.2 mL. 2.5% wt solution in t-BuOH, 0.02 mmol) After 72 hours, flonsil (5 g) and saturated aqueous NaHSO3 solution (3 mL) were added and stirred for 1 hour. The flonsil was filtered and the filtrate concentrated to produce a crystalline product which was triturated with acetone and filtered (524 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, J=8.0, 5.0 Hz, 1H), 6 90 (dd, J=8 0, 2.3 Hz, 1H), 6 75 (ddd, J=8 0, 8.0, 2.3 Hz, 1H), 3.79 (s, 2H), 3.18 (d, J=1 5 Hz, 2H), 2.22 (d, J=10 0 Hz, 1H), 1 92 (dd, J=10 0, 1.5 Hz, 1H) GCMS m/e 194 (M+)
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C@@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][OH:10])[CH2:5][CH2:4]1.I(C1C=CC=CC=1C(O)=O)(=O)=O.O.C(OCC)(=O)C>CS(C)=O>[F:1][C:2]([F:11])([F:12])[CH:3]1[CH2:4][CH2:5][CH:6]([CH:9]=[O:10])[CH2:7][CH2:8]1
Reactant: OC[C@H]1CC[C@@H](C(F)(F)F)CC1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: O=CC1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 125.2 %

Procedure:
After dissolving [cis-4-(trifluoromethyl)cyclohexyl]methanol (2.04 g, 10.2 mmol) in dimethylsulfoxide (30 ml), 2-iodoxybenzoic acid (4.00 g, 14.3 mmol) was added thereto and stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture, the insoluble matter was removed by filtration, and then the filtrate was separated into layers. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated to afford the title compound as a colorless oil (2.3 g, 100%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:12]=1)[C:9]([OH:11])=O)(=[O:3])[CH3:2].[F:21][C:22]([F:35])([F:34])[C:23]1[CH:24]=[C:25]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[NH2:26]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]([CH:12]=1)[C:9]([NH:26][C:25]1[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:23]([C:22]([F:21])([F:34])[F:35])[CH:24]=1)=[O:11])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 63.1 %

Procedure:
Using 5-acetyl-2-benzyloxybenzoic acid and 3,5-bis(trifluoromethyl)aniline as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: CN(C)C=O.O.[NH2:7][NH2:8].Cl([O-])(=O)(=O)=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][C:37]=1[OH:38])[CH:19]=[CH:20][CH2+:21]1[C:26]2[CH:27]=[C:28]3[O:33][CH2:32][O:31][C:29]3=[CH:30][C:25]=2[CH:24]=[C:23]([CH3:34])O1>O>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][C:37]=1[OH:38])[CH:19]=[CH:20][C:21]1[C:26]2[CH:27]=[C:28]3[O:33][CH2:32][O:31][C:29]3=[CH:30][C:25]=2[CH2:24][C:23]([CH3:34])=[N:8][N:7]=1
Reactant: COc1cc(C=C[CH2+]2OC(C)=Cc3cc4c(cc32)OCO4)ccc1O
Reactant: NN
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C=CC2=NN=C(C)Cc3cc4c(cc32)OCO4)ccc1O
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 12.5 ml of dimethylformamide and 2.1 ml (42 mM) of 100% hydrazine hydrate is cooled to 5° to 6° C. with ice-water, then 6.14 g (14 mM) of 1-(3-methoxy-4-hydroxystyryl)-3-methyl-6,7-methylenedioxy-2-benzopyrylium perchlorate (m.p. 300° C. carboniz.) are added at stirring during 15 minutes. The orange solution is stirred for a further 15 minutes, then 12.5 ml of distilled water are added at cooling which initiates the precipitation of the end-product. The crystal mash is stored for 12 hours at 5° C., filtered, washed with 3×20 ml of distilled water and dried at 80° to 100° C. Yield 4.81 g, m.p. 210° to 213° C. d. For further purification this product is refluxed with 24 ml of 99.5% ethanol, cooled, filtered, washed with 3×20 ml of ethanol and dried. Yield 4.59 g (93.7%), m.p. 214° to 216° C. (decomp.)
Reaction SMILES: [ClH:1].N[C@@H]1C(=O)N2CCCC[C@@H]2CCC1.Cl.[NH2:16][C@@H:17]1[C:24](=[O:25])[N:23]2[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:22]2[CH:21]=[CH:20][CH2:19][CH2:18]1>>[ClH:1].[NH2:16][C@@H:17]1[C:24](=[O:25])[N:23]2[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:22]2[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: N[C@H]1CCC=C[C@H]2CCCCN2C1=O
Agent: Cl
Agent: N[C@H]1CC/C=C\[C@H]2CCCCN2C1=O
Agent: N[C@H]1CCC[C@H]2CCCCN2C1=O
Product: N[C@H]1CCCC[C@H]2CCCCN2C1=O

Procedure:
(7S,11aS)-7-Aminooctahydro-1H-pyrido[1,2-a]azocin-6(2H)-one hydrogen chloride (273 mg, 1.17 mmol) was synthesized as described for the preparation of Intermediate 54 using (7S,11aR,Z)-7-amino-3,4,7,8,9,11a-hexahydro-1H-pyrido[1,2-a]azocin-6(2H)-one hydrochloride. Anal. Calcd. for C11H20N2O m/z 196.2. found: 197.0 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:12][S:11][C:10]=2[CH:21]=1.[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][O:29][CH3:30]>>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:26]([CH2:27][CH2:28][O:29][CH3:30])[CH2:25][CH2:24][O:23][CH3:22])=[CH:21][C:10]=3[S:11][CH:12]=2)=[CH:15][CH:16]=1
Reactant: Fc1ccc(-c2csc3cc(OCCCBr)ccc23)cc1
Reactant: COCCNCCOC
Product: COCCN(CCCOc1ccc2c(-c3ccc(F)cc3)csc2c1)CCOC

Procedure:
In analogy to example 3.1, 6-(3-Bromo-propoxy)-3-(4-fluoro-phenyl)-benzo[b]thiophene and bis(2-methoxyethyl)amine were converted to yield {3-[3-(4-Fluoro-phenyl)-benzo[b]thiophen-6-yloxy]-propyl}-bis-(2-methoxy-ethyl)-amine as colorless oil, MS: 418 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[C:4]([C:14](=O)[C:15](Cl)=[O:16])=[CH:3]1.Cl.C([O:23][C:24](=[NH:38])[CH2:25][C:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][CH3:36])=[CH:32][CH:33]=2)[N:28]([CH3:37])[CH:27]=1)(C)C.CCN(CC)CC>C(Cl)Cl>[CH3:36][O:35][C:31]1[CH:30]=[C:29]2[C:34]([C:26]([C:25]3[C:24](=[O:23])[NH:38][C:15](=[O:16])[C:14]=3[C:4]3[C:5]4[C:10](=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=4)[N:2]([CH3:1])[CH:3]=3)=[CH:27][N:28]2[CH3:37])=[CH:33][CH:32]=1
Reactant: Cn1cc(C(=O)C(=O)Cl)c2ccc([N+](=O)[O-])cc21
Reactant: COc1ccc2c(CC(=N)OC(C)C)cn(C)c2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(C3=C(c4cn(C)c5cc([N+](=O)[O-])ccc45)C(=O)NC3=O)cn(C)c2c1
Temperature: 0 °C
Yield: 31 %

Procedure:
A suspension of (1-methyl-6-nitro-1H-indol-3-yl)-oxo-acetyl chloride (251 mg, 0.94 mm) and 2-(6-methoxy-1-methyl-1H-indol-3-yl)-acetimidic acid isopropyl ester hydrochloride (280 mg, 0.94 mm) in CH2Cl2(25 mL) was cooled to 0° C., treated with Et3N (0.53 mL, 3.7 mm), and stirred at room temperature while allowing to warm to room temperature overnight. The mixture was then diluted with CH2Cl2 (25 mL), washed with H2O (20 mL), and 0.5 N HCl (20 mL). The combined organic layers were dried over MgSO4, filtered and evaporated. The residue was then combined with toluene (4 mL), cooled to 0° C., treated with pTsOH (197 mg, 1 mm), and stirred for 3 hours. The red solids which precipitated were collected and partitioned between CH2Cl2 (50 mL), and H2O (25 mL). The organic fraction was washed with saturated NaHCO3 solution (25 mL), then dried over MgSO4, filtered and evaporated. Rinsing the residue with tetrahydrofuran (THF) afforded 3-(6-methoxy-1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3yl)-pyrrole-2,5-dione; mp=308-310° C.; in 31% yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[Na+].[I-].[SH:9][C:10]1[N:14]=[CH:13][NH:12][N:11]=1>CO>[CH2:2]([S:9][C:10]1[N:14]=[CH:13][NH:12][N:11]=1)[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: Sc1nc[nH]n1
Reactant: C=CCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: C=CCCCSc1nc[nH]n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.9 %

Procedure:
5-bromopent-1-ene (10 mmol) and NaI were dissolved in 30 ml MeOH and stirred at room temperature for 12 h. 10 mmol 3-mercapto-1H-1,2,4-triazole (potassium salt) in 10 ml MeOH was added to above solution and further stirred for 24 hours. After the solvent MeOH was evaporated in vacuum, a mixture of hexane and ethyl acetate (1/1 in volume) 100 ml was added and stirred for 5 minutes. The precipitate was removed by filtration. The solvent in the filtrate was removed in vacuum. The residual was separated with a Si gel column (solvents: 1 ethyl acetate/1 hexane in volume). 1.2 g product was obtained as colorless oil. Yield: 71%. 1H NMR (CDCl3): 10.83 (1H, brs.), 8.17 (1H, s), 5.75 (1H, m), 4.99 (2H, m), 3.16 (2H, t), 2.19 (2H, m), 1.82 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.O[C@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][C@@H:11]([CH3:16])[C:12]([O:14][CH3:15])=[O:13]
Reactant: Cc1cc(O)cc(Cl)c1
Reactant: COC(=O)[C@@H](C)O
Product: COC(=O)[C@H](C)Oc1cc(C)cc(Cl)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 42, using the 3-chloro-5-methylphenol instead of the m-cresol and the (R)-methyl 2-hydroxypropanoate instead of the (S)-methyl 2-hydroxypropanoate.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH:12]=[CH:13][CH3:14]>>[CH2:1]([NH:8][CH2:14][CH2:13][CH:12]=[CH:11][CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC=CCCBr
Reactant: NCc1ccccc1
Product: CC=CCCNCc1ccccc1

Procedure:
Reaction of benzylamine with 5-bromopent-2-ene gives 5-benzylamino-2-pentene, which can be condensed with the half-ester of malonic acid, as described in Section XXVIII. Subsequent diazo transfer and cycloaddition, according to Section XXVIII, provides ethyl 3-benzyloxycarbonyl-7-methyl-2-oxo-3-azabicyclo[4.1.0]heptane-1-carboxylate. Processing of this compound as in Section XXXVIII provides the desired trisubstituted compound.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:13])[C:3]=1[C:14]([O:16]CC1C=CC=CC=1)=[O:15].C[Al](C)C.[CH3:28][C@H:29]1[CH2:31][O:30]1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.ClC1C=CC=CC=1>[OH:30][C@@H:29]([CH3:31])[CH2:28][N:6]1[C:2]([CH3:1])=[C:3]([C:14]([OH:16])=[O:15])[C:4](=[O:13])[N:5]1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C[C@H]1CO1
Reactant: Cc1[nH]n(-c2ccccc2)c(=O)c1C(=O)OCc1ccccc1
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Clc1ccccc1
Solvent: O
Product: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C[C@H](C)O
Reaction time: 1 h
Yield: 54.3 %

Procedure:
To a 500 mL round-bottomed flask was added benzyl 5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylate (3.1 g, 10 mmol), chlorobenzene (30 mL) and the mixture cooled in an ice bath. The trimethylaluminum (25 ml, 50 mmol) was added and the ice bath removed followed by the addition of (S)-2-methyloxirane (0.87 g, 15 mmol). The mixture stirred 1 h and cooled in an ice bath with the addition of THF (60 mL). Sodium sulfate decahydrate (3g) was added to the mixture cautiously (foaming) and the mixture stirred 1 h. Sodium sulfate (10 g) was added and stirred 1 h. The mixture was filtered through celite, washed with 4:1 chloroform/isopropanol and the filtrate concentrated, diluted with chloroform, washed with 1 N HCl and sat. sodium bicarbonate. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified by silica gel chromatography eluting with methanol/chloroform to afford the title compound as a foam (1.5 g). MS (ESI pos. ion) m/z: 367 (MH+). Calc'd exact mass for C21H22N2O4: 366.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[N:12]2[CH:13]=[C:14]([O:17][C@H:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[C@@H:21]([NH2:28])[CH2:20][CH2:19]3)[CH:15]=[CH:16][C:11]2=[N:10][N:9]=1.C1([O:35][C:36](=[O:60])[NH:37][C:38]2[N:39]([C:47]3[CH:52]=[CH:51][CH:50]=[C:49]([N:53]([CH2:55][CH2:56][N:57]([CH3:59])[CH3:58])[CH3:54])[CH:48]=3)[N:40]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:42]=2)C=CC=CC=1.CCN(C(C)C)C(C)C.CCOCC>O1CCOCC1>[CH:36]([OH:60])=[O:35].[C:43]([C:41]1[CH:42]=[C:38]([NH:37][C:36]([NH:28][C@@H:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[C@H:18]([O:17][C:14]3[CH:15]=[CH:16][C:11]4[N:12]([C:8]([N:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]5[CH3:1])=[N:9][N:10]=4)[CH:13]=3)[CH2:19][CH2:20]2)=[O:35])[N:39]([C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([N:53]([CH2:55][CH2:56][N:57]([CH3:58])[CH3:59])[CH3:54])[CH:48]=2)[N:40]=1)([CH3:46])([CH3:44])[CH3:45]
Reactant: CN(C)CCN(C)c1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(N(C)CCN(C)C)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A solution of Intermediate 81d (26 mg, 0.07 mmol) in 1,4-dioxane (2 mL) was treated with Intermediate 150c (30 mg, 0.07 mmol) and DIPEA (24 μL, 0.13 mmol) and the mixture was stirred at 70° C. for 18 h. After cooling to RT the mixture was concentrated in vacuo. The residue was purified by FCC, using 0-20% MeOH in DCM, then by prep HPLC (C18 column, 10-98% MeCN in H2O, 0.1% HCO2H) over 20 mins. Concentration of the fractions in vacuo gave pale yellow glass. Trituration with Et2O gave the title compound as an off white solid (20 mg, 40%). LCMS (Method 5): Rt 3.70 min, m/z 719.6 [MH+]. NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.4 Hz), 1.27 (9H, s), 1.47-1.53 (2H, m), 1.64-1.71 (2H, m), 1.77-1.97 (4H, m), 2.00-2.15 (2H, m), 2.16 (3H, s), 2.39 (2H, t, J=7.2 Hz), 2.87-2.92 (1H, m), 2.93 (3H, s), 3.13-3.21 (4H, m), 3.35-3.46 (4H, m), 4.80-4.87 (1H, m), 5.52 (1H, t, J=4.3 Hz), 6.32 (1H, s), 6.68-6.72 (3H, m), 7.13 (1H, d, J=8.6 Hz), 7.19 (1H, dd, J=9.7, 2.2 Hz), 7.24-7.38 (5H, m), 7.64 (1H, d, J=9.7 Hz), 7.69 (1H, m), 8.11 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][NH:16][CH:15]([CH3:19])[CH2:14]1)=[O:12])=[CH:5]2.[CH2:20]=O.[Na]>ClCCl.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:20])[CH:15]([CH3:19])[CH2:14]1)=[O:12])=[CH:5]2
Reactant: C=O
Reactant: CC1CN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1CN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The product of Example 64, (5-Chloro-1H-indol-2-yl)-(3-methyl-piperazin-1-yl)-methanone (0.19 g) was dissolved in dichloromethane (10 mL). At room temperature, paraformaldehyde (0.031 g) was added, followed by acetic acid (1 drop). The reaction mixture was stirred at ambient temperature for 5 h. Sodium triacetoxybrohydride (0.318 g) was added. The reaction mixture was stirred at ambient temperature for 16 h and poured into dichloromethane (20 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% methanol/dichloromethane) to give the title compound (0.22 g). 1H NMR (400 MHz, CDCl3): δ 10.69 (br s, 1H), 7.56 (d, J=1.76 Hz, 1H), 7.33 (d, J=8.80 Hz, 1H), 7.16 (dd, J=1.96, 6.66 (d, J=1.57 Hz, 1H), 4.63-4.36 (m, 2H), 3.63-2.67 (m, 3H), 2.30 (s, 3H), 2.30-2.20 (m, 1H), 2.18-2.09 (m, 1H), 1.12 (d, J=5.87 Hz, 1H). MS (electrospray): exact mass calculated for C15H18ClN3O, 291.11; m/z found, 292.1 [M+H]+.