Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([NH:14][CH:15]2[C:40](=[O:41])[N:17]3[C:18]([C:24]([O:26]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:25])=[C:19]([CH:22]=[CH2:23])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)(=[O:4])=[O:3].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][S:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][C:12]([NH:14][CH:15]2[C:40](=[O:41])[N:17]3[C:18]([C:24]([OH:26])=[O:25])=[C:19]([CH:22]=[CH2:23])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)(=[O:3])=[O:4]
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3csc(NS(C)(=O)=O)n3)[C@H]2SC1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3csc(NS(C)(=O)=O)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To a suspension of benzhydryl 7-[2-(2-methanesulfonamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylate (4.5 g) in methylene chloride (30 ml) and anisole (4.6 g) was added 2,2,2-trifluoroacetic acid (16.8 g) under ice-cooling, and the solution was stirred at ambient temperature for an hour. After evaporation of the reaction mixture, thereto were added water and ethyl acetate, followed by adjusting to pH 7 with 1N aqueous solution of sodium hydroxide. To the separated aqueous layer were added ethyl acetate and tetrahydrofuran, followed by adjusting to pH 2 with 10% hydrochloric acid. After the organic layer was separated out, it was washed with an aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. Removal of the solvent gave a residue, which was washed with diethyl ether to obtain 7-[2-(2-methanesulfonamidothiazol-4-yl)acetamido]-3-vinyl-3-cephem-4-carboxylic acid (1.5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH2:13][CH3:14])[C:11]#[N:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)CCC.[C:20]([O:24][CH3:25])(=[O:23])[CH:21]=[CH2:22].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[C:11]([C:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([CH2:13][CH3:14])[CH2:22][CH2:21][C:20]([O:24][CH3:25])=[O:23])#[N:12]
Reactant: CCC(C#N)c1ccc([N+](=O)[O-])cc1
Reactant: C=CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: CC(C)(C)O
Product: CCC(C#N)(CCC(=O)OC)c1ccc([N+](=O)[O-])cc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
A mixture of 2-(4-nitrophenyl)butyronitrile (10.0 g), butanol (10 ml) and methyl acrylate (5.2 ml) was cooled to 10° C. in a 100 ml 3-necked round-bottomed flask, equipped with a magnetic follower. A solution of potassium tert-butoxide (0.6 g) in tert-butanol (10 ml) was added dropwise, maintaining the temperature at approximately 10° C. (solution turns purple). After addition was complete, the mixture was allowed to reach ambient temperature and then stirred for a further 2 hours. The reaction was worked-up by partitioning between diethyl ether (400 ml) and 1M KH2PO4 (400 ml). The ether layer was washed with water (50 ml), dried (MgSO4) and concentrated under reduced pressure to yield methyl 4-cyano-4-(4-nitrophenyl)hexanoate (14.1 g, 99%) as an orange oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C([BH3-])#N.[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][NH:7]2
Reactant: COc1cccc2[nH]ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cccc2c1CCN2
Yield: 54.2 %

Procedure:
4-methoxyindole (0.735 g) was dissolved in acetic acid (25 ml) and cooled in an ice bath. To this solution was added sodium cyanoborohydride (0.942 g) in portions. After the addition was complete, the solution was allowed to come to room temperature and the solution was stirred for an hour. The solvent was removed under vacuum and the residue was taken up in ethyl acetate, washed with sodium carbonate solution, water and finally with brine. The organic layer was evaporated and the resulting product was purified on a silica gel column eluting with ethyl acetate:dichloromethane (5:95) to give 0.404 g of 4-methoxyindoline.
Reaction SMILES: [CH3:1][C:2]1[C:3]([O:5][C:6](=[O:9])[C:7]=1[CH3:8])=O.S(=O)(=O)(O)O.[C:15](=[O:18])([OH:17])[O-].[Na+].[CH3:20]O>C(Cl)Cl>[CH3:1]/[C:2](=[C:7](\[CH3:8])/[C:6]([O:5][CH3:3])=[O:9])/[C:15]([O:17][CH3:20])=[O:18]
Reactant: O=C([O-])O
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)/C(C)=C(/C)C(=O)OC
Yield: 100 %

Procedure:
To a solution of 2 g (0.0158 mol) of 2,3-dimethylmaleic anhydride in 40 mL of methanol was added 0.2 mL of concentrated sulfuric acid. After refluxing for 7 days, the solution was diluted with 100 mL of methylene chloride, neutralized with aqueous sodium bicarbonate solution. The methylene chloride layer was washed with 30 mL of brine, the aqueous layer was extracted with methylene chloride four times (30 mL twice and 15 mL twice). The combined methylene chloride layer and extracts were dried over anhydrous magnesium sulfate, concentrated to give 2.11 g of crude product. 1H NMR check indicated about 25% of starting material existing, the crude mixture with 0.2 mL of concentrated sulfuric acid in 40 mL of methanol was heated at reflux again for 5 days. The solution was concentrated until 30% of methanol was left, neutralized with saturated sodium bicarbonate aqueous solution, followed by addition of 30 mL of brine solution, and the mixture was extracted with ethyl acetate four times (100 mL once, 30 mL three times). The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate, concentrated to give 3.26 g of crude product 21 (˜100% yield). It was of satisfactory purity for the next step. 1H NMR (CDCl3) d 3.77 (s, 6H, OMe), 1.95 (s, 6H, Me)
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@@H:42]1[C:48](=[O:49])[N:47]2[CH2:50][CH2:51][CH2:52][CH2:53][C@@H:46]2[C:45](=[O:54])[NH:44][CH2:43]1>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[C:48](=[O:49])[N:47]2[CH2:50][CH2:51][CH2:52][CH2:53][C@@H:46]2[C:45](=[O:54])[NH:44][CH2:43]1)=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][S:22][C@H:21]2[CH2:25][CH2:26][CH2:27][C@@H:28]([C:29]([O:31][CH3:32])=[O:30])[N:20]2[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)O)Cc3ccccc3)C(=O)N21
Reactant: N[C@H]1CNC(=O)[C@H]2CCCCN2C1=O
Product: COC(=O)[C@@H]1CCC[C@@H]2SCC[C@H](NC(=O)[C@H](CC[C@H](Cc3ccccc3)C(=O)N[C@@H]3CNC(=O)[C@H]4CCCCN4C3=O)Cc3ccccc3)C(=O)N21

Procedure:
(4S,7S,10aS)-Methyl 4-((2R,5R)-2,5-dibenzyl-6-((4R,10aR)-1,5-dioxodecahydropyrido[1,2-a][1,4]diazepin-4-ylamino)-6-oxohexanamido)-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepine-7-carboxylate was synthesized as described in General Procedure H using Intermediate 23 (20 mg, 0.035 mmol) and Intermediate 39 (7.0 mg, 0.035 mmol) to give a white solid (15 mg, 56% yield). Anal. Calcd. for C40H51N5O7S m/z 745.7. found: 746.5 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.70 (m, 3H), 7.29-7.02 (m, 7H), 5.67-5.52 (m, 1H), 5.09-4.91 (m, 2H), 4.36 (d, J=13.0 Hz, 1H), 3.83-3.75 (m, 1H), 3.73-3.64 (m, 1H), 3.64-3.52 (m, 4H), 3.22-2.98 (m, 2H), 2.82-2.61 (m, 4H), 2.60-2.34 (m, 8H), 2.18 (d, J=13.8 Hz, 1H), 2.09-1.88 (m, 2H), 1.86-1.73 (m, 2H), 1.71-1.15 (m, 12H).
Reaction SMILES: I[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.O>[Cl:16][C:14]1[CH:13]=[CH:12][C:11]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)=[C:10]([CH3:9])[CH:15]=1
Reactant: Cc1cc(Cl)ccc1B(O)O
Reactant: Nc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: COCCOC
Product: Cc1cc(Cl)ccc1-c1ccc(N)cc1
Temperature: 125 °C

Procedure:
A mixture of 4-iodo-aniline (25.0 g, 114.1 mmol), 2-methyl-4-chlorophenyl-boronic acid (29.17 g, 171.1 mmol), PdCl2(P(o-tolyl)3)2 (11.66 g, 14.8 mmol), and Na2CO3 (60.49 g, 570.7 mmol) in DME/EtOH/H2O (100/50/25 mL) was heated 125° C. for 2 h. The reaction mixture was cooled to room temperature, filtered and washed with EtOAc (200 mL). The solvent was removed under reduced pressure. The crude mixture was extracted with ethyl acetate (500 mL) and the organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting crude was purified by column chromatography on silica gel, eluting with 5-30% Hexane/EtOAc to afford 4′-Chloro-2′-methyl biphenyl-4-ylamine. 1H NMR (300 MHz, CDCl3): δ 7.24-7.08 (m, 5 H), 6.72 (d. J=7.2 Hz, 2 H), 3.70 (bs, 2 H), 2.27 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][Cl:35]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH2:32][CH2:33][CH2:34][Cl:35])[CH:14]=3)=[CH:11][C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCBr
Reactant: CCOC(=O)c1cc(-c2cccc(O)c2)n(-c2cccc(Cl)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cccc(OCCCCl)c2)n(-c2cccc(Cl)c2)n1

Procedure:
100 mg (0.292 mmol) of the compound of Example 44A are provided in 3 ml of dry DMF, 76.6 mg (0.554 mmol) of potassium carbonate and 133 mg (0.846 mmol) of 1-bromo-3-chloropropane are added, and the mixture is heated under reflux for 4 h. The reaction mixture is subsequently purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with the addition of 0.1% formic acid) and 42 mg of the title compound with 49% purity (17% of theory) are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([C:10]2[C:11]([OH:19])=[C:12]([O:17][CH3:18])[CH:13]=[C:14]([CH3:16])[CH:15]=2)[C:4]=1[OH:20].[N:21]#[C:22]Br.C(=O)=O.C[CH2:28][N:29](CC)CC>CCOCC.CC(C)=O.C1COCC1>[O:19]([C:11]1[C:12]([O:17][CH3:18])=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=1[C:5]1[CH:6]=[C:7]([CH3:9])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:20][C:22]#[N:21])[C:28]#[N:29]
Reactant: COc1cc(C)cc(-c2cc(C)cc(OC)c2O)c1O
Reactant: N#CBr
Reactant: CCN(CC)CC
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(C)=O
Product: COc1cc(C)cc(-c2cc(C)cc(OC)c2OC#N)c1OC#N
Temperature: -40 °C
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A THF (30 mL) solution containing 1 (0.971 g, 3.5 mmol) and CNBr (1.032 g, 9.8 mmol) was placed in a dry ice and acetone bath at −40° C. Et3N (0.738 g, 7.30 mmol) was added and the solution was allowed to stir at −40° C. for 2 h under N2. The solution was diluted with ether (˜150 mL) and washed with water (2×200 mL), brine (50 mL), and then dried over MgSO4. Removal of the solvent under reduced pressure afforded 2 as an off-white powder (1.06 g, 94%). Further purification can be achieved by recrystallization from acetonitrile (0.96 g, 85%). 1H NMR (CDCl3) δ 6.91 (d, J=2 Hz, 2 H), 6.72 (d, J=2 Hz, 2H), 4.00 (s, 3H) 2.41 (s, 3H); 13C NMR (CDCl3) δ 150.1, 138.9, 137.8, 127.2, 123.1, 114.5, 110.2, 56.7, 21.7. Anal. Calcd for C18H16O4N2: C, 66.86; H, 4.97. Found: C, 65.77; H 5.09.
Reaction SMILES: [H][H].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([N+]([O-])=O)=[CH:7][C:6]=1[O:17][CH3:18].[CH3:19][OH:20]>O>[CH2:19]([O:20][C:8]1[CH:7]=[C:6]([O:17][CH3:18])[C:5]([O:4][CH3:3])=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: COc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1OC
Reactant: [H][H]
Reactant: CO
Solvent: O
Product: COc1cc(OCc2ccccc2)c([N+](=O)[O-])cc1OC

Procedure:
When the formation of hydrogen had ceased (in about 30 min) 456 g (2 mole) of 1,2-dimethoxy-4,5-dinitrobenzene were added and the reaction mixture was refluxed for 2 h. To the solution, 4 l of methanol and 300 ml of water were added. Upon cooling in ice a precipitate was formed which was filtered off and dried. Yield: 369 g (64%); melting point: 141° C.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][CH2:33][N:34]4C(=O)C5=CC=CC=C5C4=O)[CH:27]=3)[C:15](=[O:25])[N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C>[NH2:34][CH2:33][CH2:32][C:28]1[CH:27]=[C:26]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Br:24])[C:15]2=[O:25])[CH:31]=[CH:30][CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCc1cccc(N2C(=O)N(c3ccccc3Br)Cc3cnc(Nc4ccccc4)nc32)c1
Yield: 28.2 %

Procedure:
A solution of 200 mg (0.31 mmol) of 7-anilino-3-(2-bromophenyl)-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one in 20 ml of ethanol was treated with 0.3 ml of hydrazine hydrate. After 20 hours the mixture was evaporated and the product purified by column chromatography on silica gel using dichloromethane/methanol/acetic acid/water (240:24:3:2) for the elution. Product-containing fractions were combined, evaporated and the residue evaporated with toluene. The residue was then dissolved in 50 ml of dichloromethane, washed with 50 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to give 45 mg (28%) of 1-[3-(2-aminoethyl)phenyl]-7-anilino-3-(2-bromophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 130° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[N:15]=[CH:14][N:13]([CH2:17][C:18](=[O:20])[CH3:19])[C:12]=2[C:11](=[O:21])[NH:10][C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:25]1([CH2:24][N:10]2[C:11](=[O:21])[C:12]3[N:13]([CH2:17][C:18](=[O:20])[CH3:19])[CH:14]=[N:15][C:16]=3[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]2=[O:22])[CH2:27][CH2:26]1
Reactant: CC(=O)Cn1cnc2c1c(=O)[nH]c(=O)n2Cc1ccccc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Cn1cnc2c1c(=O)n(CC1CC1)c(=O)n2Cc1ccccc1

Procedure:
18.1 g of 3-benzyl-7-(2-oxopropyl)xanthine were treated with 11.4 ml of bromomethylcyclopropane and 9.2 g of potassium carbonate in 150 ml of DMF for 3 hours at 70° C. The mixture was concentrated, water was added and the product was extracted with ethyl acetate. After concentration of the solution the product crystallised, m.p. 138° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[O-:9][Mn](=O)(=O)=O.[K+].N1C=CC=CC=1.[OH2:21]>O>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]([OH:9])=[O:21]
Reactant: Cc1ccnc(Br)c1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Agent: [K+]
Solvent: c1ccncc1
Product: O=C(O)c1ccnc(Br)c1
Temperature: 25 °C
Yield: 47 %

Procedure:
To a mixture of 2-bromo-4-picoline (300 g, 1.74 mol) in pyridine/water (1 L each) at 95° C. was added KMnO4 (200 g) dissolved in water (IL). Further, added KMnO4 (2 Kg) in portions (app. 20 mg each time) over a period of 4 days. The reaction mixture was cooled to RT and filtered off the solid MnO2. The filtrate was evaporated completely under reduce pressure and acidified with 6N HCl. The solid product obtained was filtered, washed with water and dried to give 2-bromoisonicotinic acid (166 g, 47%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.Br[CH2:14][CH2:15][C:16]([O:18]C)=[O:17]>CS(C)=O.O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:8]=[CH:7]2
Reactant: COC(=O)CCBr
Reactant: Clc1ccc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)CCn1ccc2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
Under an N2 atmosphere, crushed KOH was added to a solution of 5-chloro-1H-indole (2.0 g, 13.2 mmol) in DMSO (19 mL, 0.7 M), and the mixture was stirred for 2 h at RT. Methyl 3-bromopropanoate (1.9 mL, 17.2 mmol) was added dropwise, and the reaction was continued to stir at RT overnight. After diluting with H2O, the reaction was cleared with a 4.5 N aqueous KOH solution and washed 3 times with CH2Cl2. The aqueous layer was acidified with a 2N HCl solution to pH 3 and extracted 3 times with CH2Cl2. The organic fractions were combined, dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 0-8% MeOH in CH2Cl2 gave 3-(5-chloro-1H-indol-1-yl)propanoic acid (2 g, 68%). 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J=2.0 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.44 (d, J=3.1 Hz, 1H), 7.13 (dd, J=8.7, 2.1 Hz, 1H), 6.42 (dd, J=3.2, 0.7 Hz, 1H), 4.40 (t, J=6.8 Hz, 2H), 2.75 (t, J=6.8 Hz, 2H). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=224.5; tR=2.74 min.
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.[NH2:10][C@H:11]([C:13]([OH:15])=[O:14])[CH3:12].[NH2:16][C@H:17]([C:28](O)=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1>>[NH2:16][C@H:17]([C:28]([NH:10][C@@H:11]([C:13]([OH:15])=[O:14])[CH3:12])=[O:29])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1
Reactant: C[C@H](N)C(=O)O
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: c1ccc2[nH]ccc2c1
Product: C[C@@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
NMR (1H) in DMSO-d6 10.88 (1H, s) NH indole, 8.20 (1H, broad s) NH Ala, 7.58 (1H, d) H4 indole, 7.32 (1H, d) H7 indole, 7.16 (1H, s) H2 indole, 7.05 (1H, t) H6 indole, 6.97 (1H, t) H5 indole, 4.05 (1H, broad q) Hα Ala, 3.73 (1H, dd) Hα Trp, 3.12 (1H, dd) HβA Trp, 2.88 (1H, dd) HβB Trp, 1.12 (1H, t) CH3 Ala
Reaction SMILES: [CH:1]([N:4]1[C:8]2=[N:9][C:10]3[C:15]([CH:16]=[C:7]2[C:6](N)=[N:5]1)=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[CH:11]=3)([CH3:3])[CH3:2].[BrH:20]>>[Br:20][C:6]1[C:7]2[C:8](=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[CH:11]=3)[N:4]([CH:1]([CH3:3])[CH3:2])[N:5]=1
Reactant: Br
Reactant: COc1ccc2cc3c(N)nn(C(C)C)c3nc2c1
Product: COc1ccc2cc3c(Br)nn(C(C)C)c3nc2c1

Procedure:
3-Bromo-1-isopropyl-7-methoxy-1H-pyrazolo[3,4-b]quinoline was prepared from 1-isopropyl-7-methoxy-1H-pyrazolo[3,4-b]quinolin-3-amine by preparation of the diazonium salt in hydrobromic acid followed by reaction with cuprous bromide. The product was recrystallized from ether/hexane and obtained in the form of a brown solid, m.p. 130°-131° C.
Reaction SMILES: CO[C:3]1[CH:10]=[C:9](OC)[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[CH:13]1([C:18]([CH3:20])=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.[OH-].[Na+].[CH2:23](O)C>>[C:13]1([CH:18]=[CH:20][C:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:3]=2)=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:23]=1
Reactant: CCO
Reactant: CC(=O)C1CCCC1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C(C=Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2,4-dimethoxybenzaldehyde (10.27 g, 45 mmol) and methyl cyclopentyl ketone (6.06 g, 54 mmol) in anhydrous ethanol (81 mL) was treated with 5 M NaOH (aq) (18 mL, 90 mmol) and the mixture stirred at room temperature for 18 h. The volatiles were removed in vacuo. The residue was extracted with ether (100 mL) and the extract washed with water (3×60 mL), then with brine. The ethereal solution was dried over MgSO4, filtered, and concentrated in vacuo, affording the intermediate chalcone in a crude yield of 14.63 g. The crude intermediate (14.52 g) was dissolved in 110 mL ethyl acetate, treated with platinum oxide (5 mole %) and stirred over 1 atm of H2 at room temperature overnight. The Pt was filtered through a fine fritted funnel and the black residue washed with ethyl acetate. The filtrate was concentrated in vacuo to give a yellowish resin. The resin was chromatographed using silica gel and 6:1 hexanes/ethyl acetate, yielding 6.02 g (41%) of the ketone as a colorless oil. 1H NMR (CDCl3): δ 1.48–1.81 (m, 8H), 2.67 (m, 2H), 2.80 (m, 3H), 3.76 (s, 3H), 3.75 (s, 3H), 6.37 (dd, J=8.1, 2.1 Hz, 1H), 6.41 (d, J=2.1 Hz, 1H), 7.00 (d, J=8.1 Hz, 1H). MS(APCI) calcd for C16H22O3: 262.2; found (M+H+): 263.1.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[CH2:3][C:4]([N:6]([C@H:15]1[CH2:19][NH:18][C@H:17]([C:20]([O:22][CH3:23])=[O:21])[CH2:16]1)C1C=CC=C(OC)C=1)=[O:5].[CH:26]1[C:31]([CH:32]=O)=[CH:30][C:29]2[O:34][CH2:35][O:36][C:28]=2[CH:27]=1.C([BH3-])#N.[Na+]>C(O)(=O)C.ClCCCl>[O:36]1[C:28]2[CH:27]=[CH:26][C:31]([CH2:32][N:18]3[CH2:19][C@H:15]([N:6]([C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:25])[CH3:24])[CH2:32][C:31]4[CH:26]=[CH:27][CH:28]=[C:29]([O:34][CH3:35])[CH:30]=4)[CH2:16][C@H:17]3[C:20]([O:22][CH3:23])=[O:21])=[CH:30][C:29]=2[O:34][CH2:35]1
Reactant: COC(=O)[C@@H]1C[C@@H](N(C(=O)CC(C)(C)C)c2cccc(OC)c2)CN1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1C[C@@H](N(Cc2cccc(OC)c2)C(=O)CC(C)(C)C)CN1Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
A solution of the crude amine (9b) (140 mg) prepared above, piperonal (74 mg, 0.49 rmnol) and glacial acetic acid (2 drops) in 1,2-dichloroethane (0.5 mL) was stirred for 30 min at room temperature. 95% Sodium cyanoborohydride (32 mg, 0.48 mmol) was added in small portions and stirring was continued for 1 h. The reaction was quenched with saturated aqueous sodium bicarbonate solution (2 mL), extracted with dichloromethane, dried (MgSO4) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography eluting with dichloromethane-ethyl acetate (90:10-75:25) to give the title pyrrole (10) (115 mg, 71.4%) as a pale yellow oil:
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>CN(C=O)C>[OH:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[O:4][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCCBr
Reactant: Oc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1ccccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 55 %

Procedure:
To a solution of pyrocatechol (5.51 g, 50 mmol) in dry DMF (30 mL) was slowly added sodium hydride (1.2 g, 50 mmol) at 0° C. After stirring at 25° C. for 4 hours, the reaction mixture was heated at 65-70° C. for 1 hour followed by an addition of ethyl 4-bromobutyrate (10.7 mL, 75 mmol). The reaction mixture was then left stirring at this temperature for 6 hours. Upon quenching with water, extraction with dichloromethane, and evaporation gave the crude product which was purified by column chromatography, eluting with 87% hexane:10% CH2Cl2:3% EtOAc. Crystallization with hexane afforded a white solid in 55% yield (6.17 g, mp. 37.2-38.4° C.). 1H NMR (400 MHz, CDCl3): 1.26 (3H, t, J=7.1 Hz), 2.17 (2H, m), 2.52 (2H, t, J=7.0 Hz), 4.09 (2H, t, J=6.0 Hz), 4.16 (2H, q, J=7.1 Hz), 6.81-6.89 (3H, m), 6.92-6.94 (1H, m).
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])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.[C:23]1([CH3:32])[C:24]([N:29]=[C:30]=[O:31])=[CH:25][CH:26]=[CH:27][CH:28]=1.CO>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])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:30]([NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[CH3:32])=[O:31])=[CH:18][CH:17]=1
Reactant: Cc1ccccc1N=C=O
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc2ncnc(Oc3ccc(NC(=O)Nc4ccccc4C)cc3)c2cc1OC
Yield: 41 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in chloroform (3 ml), and o-toluyl isocyanate (0.25 μl) was then added to the solution. The mixture was heated under reflux overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 30 mg (yield 41%) of the title compound.