Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][C:19](O)=[O:20])[C:13]1=[O:22].B.ClCCl.[OH-].[Na+]>C1COCC1>[OH:20][CH2:19][CH2:18][C:14]1[C:13](=[O:22])[N:12]([C:4]2[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=2[O:2][CH3:1])[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-n1cccc(CC(=O)O)c1=O
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])ccc1-n1cccc(CCO)c1=O
Temperature: 27 °C
Reaction time: 8 h

Procedure:
21.0 g (69.0 mmol) of [1-(2-methoxy-4-nitrophenyl)-2-oxo-1,2-dihydropyridin-3-yl]acetic acid were introduced as initial charge in 210 ml of THF, and 104 ml of 1M borane solution in THF were added dropwise at RT. The temperature increased to 27° C. during this addition. The reaction mixture was stirred overnight at RT. Following dilution with 400 ml of dichloromethane, 400 ml of 1N sodium hydroxide solution were added with cooling and the mixture was stirred for 30 min. The phases were separated, and the organic phase was washed with water, dried over sodium sulphate, filtered and evaporated to dryness on a rotary evaporator. This gave 17.0 g (85%) of crude product which were further reacted without purification.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[O:8][N:7]=1>CO.CCOCC>[CH3:1][O:2][CH2:5][C:6]1[CH:10]=[C:9]([CH3:11])[O:8][N:7]=1
Reactant: C[O-]
Reactant: Cc1cc(CCl)no1
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: COCc1cc(C)on1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.3 %

Procedure:
Sodium methoxide (30% in methanol, 7.46 mmol) was added to 3-chloromethyl-5-methyisoxazole (491 mg, 3.73 mmol) in methanol (4 mL) at room temperature under nitrogen. The reaction mixture was stirred for 15 h at room temperature then heated to reflux for 3 h. After cooling to room temperature the reaction was diluted with ether (75 mL) and washed with saturated aqueous ammonium chloride (15 mL), water (15 mL), and brine (15 mL). The organic layer was dried over magnesium sulfate, filtered, and evaporated to provide 362 mg (76% yield) of 3-methoxymethyl-5-methyl isoxazole as a clear liquid which was used in the next step without further purification: 1H NMR (300 MHz, CDCl3) δ ppm 6.02 (s, 1H), 4.48 (s, 2H), 3.38 (s, 3H), 2.42 (d, J=0.6 Hz, 3H).
Reaction SMILES: O=S(Cl)Cl.[CH3:5]O.[OH:7][C:8]1[C:9]([N+:17]([O-:19])=[O:18])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12]>C(OCC)(=O)C>[OH:7][C:8]1[C:9]([N+:17]([O-:19])=[O:18])=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([O:13][CH3:5])=[O:12]
Reactant: CO
Reactant: O=C(O)c1cccc(O)c1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(O)c1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 100 %

Procedure:
SOCl2 (0.6 mL) was added dropwise to anhydrous MeOH (10 mL) at 0° C. The mixture was stirred at this temperature for 0.5 h, then 3-hydroxy-2-nitrobenzoic acid (0.6 g, 3.2 mmol) was added to the mixture. The resulting mixture was heated at reflux for 4 h. TLC (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The resulting mixture was concentrated in vacuo to give the title compound (0.63 g 100%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.Br[CH2:26][CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[S:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][C:10]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:26][CH2:27][CH2:28][O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:20][CH:19]=1
Reactant: BrCCCOC1CCCCO1
Reactant: COC(=O)c1cc(-c2ccc(O)cc2)c(-c2ccc(F)cc2Cl)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1cc(-c2ccc(OCCCOC3CCCCO3)cc2)c(-c2ccc(F)cc2Cl)s1
Temperature: 60 °C
Yield: 92.8 %

Procedure:
4.8 g of the compound obtained in stage 16E), 3.6 g of 2-(3-bromopropoxy)tetrahydro-2H-pyran and 2.2 g of potassium carbonate are added to 30 ml of DMF and then the mixture is heated at 60° C. for 7 hours. It is poured onto ice-cold water, extraction is carried out with ether and the extract is dried and concentrated to dryness. After purifying by chromatography on silica (heptane and then heptane/AcOEt: 90/10), 6.2 g of the expected compound are obtained.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH3:18][O:1][C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1
Reactant: COC(=O)C1=COc2cc(O)ccc2O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=COc2cc(OC)ccc2O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
Stir for 15 minutes at room temperature, under argon, a solution of 0.48 mmol of methyl 6-hydroxy-1,4-benzodioxin-2-carboxylate in 5 cm3 of N,N-dimethylformamide in the presence of 0.57 mmol of 60% sodium hydride suspended in oil, and then add 0.72 mmol of methyl iodide. After being stirred for 4 hours at room temperature, the reaction mixture is concentrated under reduced pressure and then extracted with methylene chloride. After the methylene chloride phases have been concentrated to dryness, the crude product is purified by chromatography on a silica column (eluant: petroleum ether/ethyl acetate, 80:20). Methyl 6-methoxy-1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 78%.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.Cl[Sn:13]([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[CH3:6][C:7]1[S:8][C:9]([Sn:13]([CH3:16])([CH3:15])[CH3:14])=[CH:10][N:11]=1
Reactant: Cc1nccs1
Reactant: C[Sn](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ncc([Sn](C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
Butyllithium (1.6M in THF, 3.5 ml, 5.5 mmol) was added to a stirred solution of 2-methylthiazole (0.45 ml, 5.0 mmol) in THF (15 mL) at −78° C. The reaction mixture was stirred at −78° C. for 40 min. Chlorotrimethylstannane (1M in THF, 5.0 ml, 5.0 mmol) was added. Stirring was continued at −78° C. for 45 min. The reaction mixture was quenched with a satured aqueous solution of NaHCO3. The aqueous layer was extracted with Et2O. The organic extracts were dried over MgSO4, filtered and concentrated in vacuo. Used in the next step without purification (obtained 1.29 g). MS m/z=264.1. Calc'd for C7H13NSSn: 261.94.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6](=[O:33])[N:7]([CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:14][CH:15]=1)[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(Oc2ccc(N)cc2)cc1)Cc1ccccc1
Yield: 98.6 %

Procedure:
Combine benzyl-{2-[4-(4-nitro-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (2.5 g), 5% Pd/C (200 mg), and methanol (100 mL) then hydrogenated at 40 PSIG at room temperature for 2 hours. Filter off catalyst then concentrate on a rotary evaporator to yield {2-[4-(4-amino-phenoxy)-phenyl]-ethyl}-benzyl-carbamic acid tert-butyl ester (2.3 g): 1H NMR (CDCl3, 300.00 MHz): 7.42-6.70 (m, 13H), 4.41 (m, 2H), 3.39 (m, 2H), 2.77 (m, 2H), 1.52 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:10])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[F:9])[CH2:10][Br:11])#[N:2]
Reactant: Cc1ccc(F)c(C#N)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: N#Cc1cc(CBr)ccc1F
Yield: 63.1 %

Procedure:
A solution of 3-Cyano-4-fluorotoluene (1.0 g, 7.4 mmol), N-bromosuccinimide (1.3 g, 7.4 mmol) and catalytic 2,2′-azobisisobutyronitrile (AIBN) in benzene was heated to reflux for 16 hours, evaporated to dryness and flash chromatographed over silica gel eluting with 10% ethyl acetate/hexane to provide 1.0 g of 3-cyano-4-fluorobenzyl bromide.
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[F:39])[C:33](Cl)=[O:34]>>[F:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[F:39])[C:33]([NH:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=2)[CH2:7][CH2:6]1)=[O:34]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](NC(=O)c3ccc(F)c(F)c3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 3,4-difluorobenzoyl chloride: ESMS m/e: 520.3 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH:5]1[O:20][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[C:11]([CH3:19])=[CH:10]3)=[N+]=[N-].[H][H].[ClH:23]>O1CCCC1.[Pd]>[NH2:1][CH2:4][CH:5]1[O:20][C:8]2=[C:9]3[C:14](=[C:15]([CH3:17])[CH:16]=[C:7]2[CH2:6]1)[NH:13][C:12](=[O:18])[C:11]([CH3:19])=[CH:10]3.[ClH:23]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(CN=[N+]=[N-])O3
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(CN)O3
Yield: 73.4 %

Procedure:
2-Azidomethyl-5,8-dimethyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (2.76 g, 10.2 mmol) was dissolved in tetrahydrofuran (200 ml), to which 10% palladium-on-carbon (2.76 g) was added. The mixture was stirred at room temperature for 2 hours in the atmospher of hydrogen. The catalyst was filtered off, and the filtrate was condensed. The residue was converted to a hydrochloric acid salt, and then subjected to recrystallization (methanol-ether) to obtain 2.10 g of the title compound as yellow crystals (73.4%).
Reaction SMILES: [CH3:1][CH:2]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]([C:13]1[C:14]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:15][CH:16]=[C:17]([O:19]C(=O)C)[CH:18]=1)=[O:12])[CH2:3][CH2:4][CH3:5].[NH4+].[OH-]>CO>[CH3:1][CH:2]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]([C:13]1[C:14]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:15][CH:16]=[C:17]([OH:19])[CH:18]=1)=[O:12])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)OCCCOC(=O)c1cc(OC(C)=O)ccc1-c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C)OCCCOC(=O)c1cc(O)ccc1-c1ccccc1

Procedure:
After the p-acetyloxybiphenylcarboxylic acid (2-pentyloxy)propyl ester was diluted with 50 ml of methanol, a mixture of methanol: NH4OH (28%)=1:1 was added under stirring to carry out hydrolysis. Then, the rection mixture was extracted with anhydrous sodium sulfate (×3), the ether layer was washed with 50 ml of water (×3) and dried over anhydrous sodium sulfate, followed by evaporation of the solvent to obtain an oily product. The product was purified by silica gel chromatography to obtain 2.6 g of p-hydroxybiphenylcarboxylic acid (2-pentyloxy)propyl ester.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:30]=[CH:29][C:12]2[NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]3)=[N:15][C:11]=2[CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:30]=[CH:29][C:12]2[NH:13][C:14]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:15][C:11]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc3cc(Cl)ccc3[nH]2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2[nH]c(N3CCNCC3)nc2c1
Reaction time: 1 h

Procedure:
TFA (2 mL) was added to a solution of tert-butyl 4-(5-chloro-1H-benzimidazol-2-yl)piperazine-1-carboxylate (72 mg) in DCM (2 mL) and the reaction was stirred for 1 h. The solvent was then evaporated under high vacuum for 1 h to afford the title compound as a gum which was used without further analysis.
Reaction SMILES: [Cl-].[NH4+].[N+:3]([C:6]1[CH:28]=[CH:27][C:9]2[N:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:11](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:12][C:8]=2[CH:7]=1)([O-])=O>C(O)C.O.[Fe]>[NH2:3][C:6]1[CH:28]=[CH:27][C:9]2[N:10]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:11](/[CH:13]=[CH:14]/[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:12][C:8]=2[CH:7]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)nc(/C=C/c1ccccc1)n2-c1ccccn1
Yield: 70.4 %

Procedure:
Iron powder (1.95 g, 35 mmol) and ammonium chloride (200 mg, 3.7 mmol) was added to a solution of (E)-5-nitro-1-(2-pyridyl)-2-styryl-1H-benzimidazole (2.41 g, 7.0 mmol) in ethanol (50 ml) and water (25 ml). After the reaction mixture was refluxed for 3 h, the hot reaction mixture was filtered through a pad of celite and the filtrate was evaporated under reduced pressure. The obtained residue was partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate solution (200 ml). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (200 ml). The combined extracts were washed with brine (20 ml), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 200 g; n-hexane/ethyl acetate (1/2)) and obtained solids (1.54 g, 70%) were recrystallized from ethyl acetate to afford the titled compound as brown solids. MW: 312.38; mp: 146.0-148.0° C.; 1H-NMR (CDCl3) δ: 8.75 (1H. ddd, J=4.8, 1.8, 1.1 Hz), 8.01-7.91 (1H, m), 7.95 (1H, d, J=16.0 Hz), 7.56-7.23 (8H, m), 7.13 (1H, d, J=16.0 Hz), 7.11 (1H, d, J=2.2 Hz), 6.69 (1H, dd, J=8.8, 2.2 Hz), 3.70 (2H, br.s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12](I)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:24]1[CH2:25][CH2:26][O:27][CH2:28][CH:29]=1)CCC>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:24]3[CH2:29][CH2:28][O:27][CH2:26][CH:25]=3)=[C:13]([Cl:17])[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(I)cc2C1
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CCOCC1
Product: CC(C)(C)OC(=O)N1Cc2cc(Cl)c(C3=CCOCC3)cc2C1

Procedure:
Prepared in analogy to Example A49(a) from 5-chloro-6-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A3(c)) and tributyl-(3,6-dihydro-2H-pyran-4-yl)-stannane. Yellow solid. MS (m/e): 282.3 ({37Cl}[M+H−Me2C═CH2]+, 49%), 280.3 ({35Cl}[M+H−Me2C═CH2]+, 100%).
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:20][C:19]([NH:21][C:22](=[O:24])[CH3:23])=[N:18][C:17]=2[CH3:25])=[CH:12][CH:11]=1>CS(C)=O.O>[NH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[S:20][C:19]([NH:21][C:22](=[O:24])[CH3:23])=[N:18][C:17]=2[CH3:25])=[CH:14][C:15]=1[Br:8]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(N)cc2)s1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(N)c(Br)c2)s1

Procedure:
NBS (2.52 g, 14.7 mmol) is added to a stirred solution of N-[5-(4-amino-phenyl)-4-methyl-thiazol-2-yl]-acetamide (Example 1a) (3.5 g, 14.7 mmol) in dry dimethylsulphoxide (50 ml) at 10° C. After 10 minutes the solution is diluted with water (200 ml) and the resulting precipitate is removed by filtration. Crystallisation from ethyl acetate—methanol affords the title compound. MH+ (TOF, MS ES+): 325.9, 328.9
Reaction SMILES: [H-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].[C:18]([O:21][CH2:22][CH2:23][CH2:24][CH2:25]Br)(=[O:20])[CH3:19]>CN(C)C=O>[C:3]([NH:6][C:7]([CH2:25][CH2:24][CH2:23][CH2:22][O:21][C:18](=[O:20])[CH3:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: CC(=O)OCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(CCCCOC(C)=O)(NC(C)=O)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
A stirred suspension of 95% sodium hydride (60.8 g, 2.532 mol) in anhydrous dimethylformamide (500 ml) under an atmosphere of argon was cooled to 0° C. (ice bath). A solution of diethyl acetamido-malonate (500 g, 2.302 mol) in anhydrous dimethyl-formamide (1.2 1) was added over a period of 45 minutes while keeping the reaction temperature below 18° C. After the addition was complete, the turbid solution was gradually warmed to room temperature. After stirring for one hour at room temperature, 4-bromobutyl acetate (471.5 g, 2.417 mol) was added. The mixture was then stirred at 59°-60° C. for 18 hours. The resulting slurry was cooled to room temperature, quenched with absolute ethanol (40 ml) and glacial acetic acid (4 ml), stirred for about 15 minutes, poured into a 10% lithium chloride solution and extracted with ethyl acetate (2×3 l). The combined ethyl acetate extracts were washed with 10% lithium chloride (3×3 l), dried (anhydrous sodium sulfate), and evaporated in vacuo to give 750 g of title product as an oil.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[N:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14](=[O:36])[CH2:15][C@H:16]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].C(N(CC)C(C)C)(C)C>ClCCl>[CH3:6][O:7][C:8]1[N:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:14](=[O:36])[CH2:15][C@H:16]([C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[CH2:31][CH2:32][N:33]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:34][CH2:35]2)=[CH:28][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: COc1nnccc1C(=O)C[C@H](c1ccc(C2CCNCC2)cc1)c1ccccc1C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1nnccc1C(=O)C[C@H](c1ccc(C2CCN(S(C)(=O)=O)CC2)cc1)c1ccccc1C
Yield: 78.9 %

Procedure:
Methanesulfonyl chloride (35 mg, 0.31 mmol) was added at 0° C. to a solution of (R)-1-(3-methoxypyridazin-4-yl)-3-(4-(piperidin-4-yl)phenyl)-3-o-tolylpropan-1-one (64 mg, 154 μmol) and N,N-diisopropylethylamine (79.6 mg, 0.62 mmol) in dichlormethane (2.5 mL). The ice bath was removed, then after 1 h the reaction mixture was partitioned between sat. aq. ammonium chloride solution and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2, heptane/ethyl acetate gradient) produced the title compound (60 mg, 79%). Light yellow gum, MS: 494.3 [M+H]+.
Reaction SMILES: [N:1]([C:4]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21]C3C=CC=CC=3)=[CH:16][CH:15]=2)=[N:12][C:11]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7])=[N+]=[N-].Cl[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1Cl>>[CH2:21]([O:20][C:17]1[CH:18]=[CH:19][C:14]2[C:13]3[N:12]=[C:11]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=3[NH:1][C:15]=2[CH:16]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Clc1ccccc1Cl
Reactant: COC(=O)c1cc(-c2ccc(OC)cc2)nc(-c2ccc(OCc3ccccc3)cc2)c1N=[N+]=[N-]
Product: COC(=O)c1cc(-c2ccc(OC)cc2)nc2c1[nH]c1cc(OCc3ccccc3)ccc12

Procedure:
A solution of methyl 3-azido-2-(4-(benzyloxy)phenyl)-6-(4-methoxyphenyl)isonicotinate (Example 205C, 356 mg, 0.763 mmol) in 1,2-dichlorobenzene (10 mL) was heated at 165° C. for 20 min. The solvent was removed under a stream of nitrogen to leave crude methyl 7-(benzyloxy)-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxylate as a yellow solid: 1H NMR (CDCl3) δ ppm 9.37 (1H, s), 8.29 (1H, d, J=8.85 Hz), 8.13 (1H, s), 8.07-8.12 (2H, m), 7.47-7.51 (2H, m), 7.38-7.44 (2H, m), 7.31-7.37 (1H, m), 7.00-7.05 (3H, m), 5.19 (2H, s), 4.07 (3H, s), 3.88 (3H, s). This was suspended in a solution of 7 N ammonia in methanol (12 mL) and heated in a sealed microwave vial at 60° C. for 36 hr. The solvent was removed and the residue was dissolved in methylene chloride. An equal volume of hexane was added and the precipitate was collected by filtration. This gave 160 mg of 7-(benzyloxy)-2-(4-methoxyphenyl)-5H-pyrido[3,2-b]indole-4-carboxamide as a yellow solid. MS (ESI) m/z 424.1 (M+H). 1H NMR (DMSO-d6) δ ppm 11.38 (1H, s), 8.55 (1H, br. s.), 8.28 (1H, s), 8.23 (2H, d, J=8.85 Hz), 8.12 (1H, d, J=8.55 Hz), 7.83 (1H, br. s.), 7.49-7.57 (2H, m), 7.44 (2H, t, J=7.48 Hz), 7.31-7.40 (2H, m), 7.10 (2H, d, J=8.85 Hz), 6.97 (1H, dd, J=8.70, 2.29 Hz), 5.22 (2H, s), 3.85 (3H, s).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([NH:14][C:15]([CH:17]1[CH2:22][CH:21]([OH:23])[CH:20]=[CH:19][CH2:18]1)=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([NH:14][CH2:15][CH:17]1[CH2:22][CH:21]([OH:23])[CH:20]=[CH:19][CH2:18]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(NCc1ccccc1)C1CC=CC(O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1C=CCC(CNCc2ccccc2)C1
Reaction time: 0.75 h

Procedure:
To a suspension of lithium aluminum hydride (1.50 g, 40.5 mmol) in dry THF (100 ml), cooled in an ice bath, was added drop-wise a solution of N-benzyl-5-hydroxycyclohex-3-enecarboxamide (4.6 g, 20 mmol) in THF (60 ml) over 30 min. The cold bath was removed and the reaction was heated under reflux for 16 h. Then the mixture was cooled in an ice bath and diluted with ether (200 ml), then carefully quenched with water (1.5 ml), 1N sodium hydroxide (4 ml) and water (1.5 ml), successively. After stirring for 45 min, the white suspension was filtered through a glass frit, and the residue was washed with ether. Removal of solvents by rotary evaporation gave the alcohol as a clear, colorless oil (3.8 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:36])=[C:4]([CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=2)[CH:10]=1)[C:5]([OH:7])=[O:6].Cl(O)(=O)(=O)=O.O>C(O)(=O)C>[Cl:1][C:2]1[C:3]([OH:36])=[C:4]([CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(Cl)c(O)c(C(=O)O)c3)cc12
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: CC(=O)O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cc(Cl)c(O)c(C(=O)O)c3)cc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 63 %

Procedure:
240 mg (0.46 mmol) of 3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid was dissolved in 5 mL of glacial acetic acid. 500 μL of 70% perchloric acid was added and the mixture stirred at ambient temperature for 24 h. 50 mL of water was added and the resulting precipitate filtered off and dried by suction to afford 117 mg (0.29 mmol, 64%) of 3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ 8.83 (d, 1H), 8.34 (d, 1H), 8.14 (d, 1H), 8.07 (d, 1H), 7.66 (dd, 1H), 7.47 (ddd, 1H), 7.22 (d(d), 1H), 7.10 (ddd, 1H), 3.84 (s, 3H), MS: m/z 394.0 (M−H+).