Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:20]([C:23]1[CH:45]=[CH:44][C:26]([CH2:27][O:28][C:29](=[O:43])[CH:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][CH3:41])[C:33]2=[O:42])Cl)=[CH:25][CH:24]=1)([O-:22])=[O:21]>O1CCCC1.C(Cl)Cl>[N+:20]([C:23]1[CH:45]=[CH:44][C:26]([CH2:27][O:28][C:29](=[O:43])[C:30]([N:32]2[C@H:35]([S:36][C:37](=[O:39])[CH3:38])[C@@H:34]([O:40][CH3:41])[C:33]2=[O:42])=[P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:25][CH:24]=1)([O-:22])=[O:21]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CO[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(C)=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CO[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1SC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.84 g of triphenylphosphine is added to a solution of 0.63 g of 2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester in 1.8 ml of dry tetrahydrofuran, and the mixture is stirred overnight at room temperature under nitrogen. The mixture is diluted with methylene chloride and washed with a cold, saturated, aqueous sodium bicarbonate solution. Additional washing with water, drying over sodium sulphate and concentrating by evaporation in vacuo yield the crude title compound which is purified by chromatography over silica gel with toluene/ethyl acetate (19:1 to 3:1).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]#[N:22])[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[OH-:28].[K+].Cl>O1CCOCC1.OO>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([C:21]([NH2:22])=[O:28])[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(C#N)cc3[nH]c4ncc(C)cc4c23)c1
Reactant: [OH-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: C1COCCO1
Product: CCS(=O)(=O)c1cccc(-c2cc(C(N)=O)cc3[nH]c4ncc(C)cc4c23)c1
Reaction time: 18 h
Yield: 47 %

Procedure:
Compound 126 (30 mg, 0.08 mmol) stirred in dioxane (2 mL) at r.t. A solution of potassium hydroxide (25 mg, 0.44 mmol) in 30% H2O2 solution (1 mL) was added, and the reaction stirred for 18 h. The solution was neutralized with 1N HCl and concentrated in vacuo. Purification by silica gel chromatography (5 to 8% MeOH/CH2Cl2 gave 14.8 mg (47%) of the title compound as a white solid. 1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), 8.22 (s, 1H), 8.12 (s, 1H), 8.10 (d, 1H, J=7.6 Hz), 8.02 (d, 1H, J=7.6 Hz), 7.88 (t, 1H, J=7.6 Hz), 7.68 (s, 1H), 7.62 (s, 1H), 3.34 (q, 2H, J=7.2 Hz), 2.31 (s, 3H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C21H19N3O3S, 394; found 394.
Reaction SMILES: [CH2:1]([C:4]1[C:15]([OH:16])=[C:14]([CH3:17])[C:7]([C:8]([O:10]CC=C)=[O:9])=[C:6]([CH3:18])[C:5]=1[OH:19])[CH:2]=[CH2:3].P(OCC)(OCC)OCC.CN1CCCC1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:16][C:15]1[C:14]([CH3:17])=[C:7]([C:6]([CH3:18])=[C:5]([OH:19])[C:4]=1[CH2:1][CH2:2][CH3:3])[C:8]([OH:10])=[O:9]
Reactant: C=CCOC(=O)c1c(C)c(O)c(CC=C)c(O)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Product: CCCc1c(O)c(C)c(C(=O)O)c(C)c1O
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
A solution of 5.00 g of allyl 4-allyl-3,5-dihydroxy-2,6-dimethylbenzoate in 80 ml of ethyl acetate was cooled to 0° C., and then treated with 90 mg of palladium acetate and 332 mg of triethyl phosphite. After stirring for 5 minutes, 2.04 g of N-methylpyrrolidine were added, a precipitate being formed immediately. Stirring was continued at 0° C., and then, the mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residual oil was dissolved in 50 ml of ethyl acetate, and the solution was hydrogenated at atmospheric pressure for 1 hour in the presence of 100 mg of 5% palladium on charcoal. The catalyst was filtered off, and the solvent was evaporated in vacuo to yield 3.36 g of 3,5-dihydroxy-2,6-dimethyl-4-propylbenzoic acid as a coulourless oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([NH:10][C:11](=O)[CH2:12][CH:13]([CH3:15])[CH3:14])[S:4][N:3]=1>N>[CH2:12]([C:11]1[NH:9][C:7](=[O:8])[C:6]2[C:2]([CH3:1])=[N:3][S:4][C:5]=2[N:10]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: Cc1nsc(NC(=O)CC(C)C)c1C(N)=O
Agent: N
Product: Cc1nsc2nc(CC(C)C)[nH]c(=O)c12
Temperature: 140 °C
Yield: 39.4 %

Procedure:
3-Methyl-5-(3-methyl-butyrylamino)-isothiazole-4-carboxylic acid amide (method 25) (6 g, 25 mmol) was suspended in 150 mL of 30% NH3 and then was heated to 140° C. for 5 h in a pressure reactor. The mixture was cooled and neutralized to pH 7. The reaction mixture was extracted with EtOAc (3×100 mL) and the combined organic layers were washed with water (100 mL), brine (100 mL) and concentrated to get the crude product which was further purified by column (silica gel) chromatography using 30% EtOAc in hexanes as eluent. Concentration of the pure product fractions provided 6-isobutyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (2.2 g, 38%) as an off-white powder. 1H NMR (300 MHz) δ 1.05 (d, 6H), 2.32 (m, 1H), 2.69 (d, 2H), 2.82 (s, 3H).
Reaction SMILES: CS(C)(=O)=C.[CH3:6][C:7]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[O:17][CH3:18])=[O:8].[CH3:19]COCC>CS(C)=O.O>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=1[C:7]1([CH3:19])[O:8][CH2:6]1
Reactant: COc1ccc(OC)c(C(C)=O)c1
Reactant: CCOCC
Agent: C=S(C)(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(OC)c(C2(C)CO2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of dimethylsulfoxonium methylide (69.4 mM) in dimethyl sulfoxide (65 ml.) at room temperature is added solid 2,5-dimethoxyacetophenone (10 g., 55.5 mM). The reaction mixture is stirred for one hour at 25° C., for one-half hour at 50° C. and is then cooled. The mixture is diluted with water (50 ml.) and added to a mixture of ice water (200 ml.)--ether (250 ml.)--low boiling petroleum ether (25 ml.). The organic extract is washed twice with water (250 ml.), dried (MgSO4) and evaporated to an oil. Fractional distillation of the oil yields 2,5-dimethoxy-α-methylstyrene oxide.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[N:14]([CH3:36])[CH:15]=[C:16]([NH:18][C:19]([C:21]2[N:22]([CH3:35])[CH:23]=[C:24]([NH:26][C:27]([C:29]3[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=3)=[O:28])[CH:25]=2)=[O:20])[CH:17]=1)=[O:12])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>O>[NH2:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[N:14]([CH3:36])[CH:15]=[C:16]([NH:18][C:19]([C:21]2[N:22]([CH3:35])[CH:23]=[C:24]([NH:26][C:27]([C:29]3[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=3)=[O:28])[CH:25]=2)=[O:20])[CH:17]=1)=[O:12]
Reactant: Cn1cc(NC(=O)c2cc(NC(=O)c3nccn3C)cn2C)cc1C(=O)NCCNC(=O)OC(C)(C)C
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cc(NC(=O)c2cc(NC(=O)c3nccn3C)cn2C)cc1C(=O)NCCN
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Compound 6a (0.29 g, 0.06 mmol) and TFA/CH2Cl2 (1:1, 2 ml) containing H2O (40 μl) were stirred at room temperature for 1.5 hr. The solvent was removed under pressure and the residue stirred with DOWEX® 550A OH anion exchange resin (0.05 g, 0.17 mmol, washed with MeOH). The solution was decanted and evaporated. CHCl3 (5 ml) was added and the solid collected and dried under vacuum. Yield 0.02 g (90%). 1H NMR (DMSO): δ 10.49 (s, 1H, NH), 9.96 (s, 1H, NH), 8.13 (t, 1H, NH, J=6.0 Hz) 7.71 (bs, 2H, NH2), 7.40 (d, 1H, J=1.5 Hz), 7.28 (d, 1H, J=1.5 Hz), 7.18 (d, 1H, J=1.5 Hz) 7.15 (d, 1H, J=1.8 Hz), 7.04 (d, 1H, J=1.2 Hz), 6.98 (d, 1H J=1.5 Hz), 3.98 (s, 3H), 3.83 (s, 3H), 3.81 (s, 3H), 3.5-3.2 (m, 2H, CH2), 2.92 (m, 2H, CH2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:25]([O:27]C)=[O:26])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:12].[OH-].[Na+:30]>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[CH:10][C:11]([NH:13][C@H:14]([C:25]([O-:27])=[O:26])[CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1)=[O:12].[Na+:30]
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccc(F)cc1F)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)[O-]
Yield: 89 %

Procedure:
The same procedures as in Example 60 were carried out from the compound obtained in Example 14 (4.5 g), 1 mol/L of an aqueous sodium hydroxide solution (18 mL), and methanol (180 mL), to give the captioned compound (4.1 g, 89%) as an amorphous solid product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([C:20]2[CH:25]=[CH:24][C:23](Br)=[CH:22][N:21]=2)=[O:19])[C:12]=1[F:27])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2].[OH-].[NH4+:30]>CN1C(=O)CCC1.[Cu-]=O>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([NH2:30])=[CH:22][N:21]=2)=[O:19])[C:12]=1[F:27])[CH2:9][CH3:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(Br)cn2)c1F
Reactant: [NH4+]
Agent: O=[Cu-]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(N)cn2)c1F
Temperature: 80 °C
Yield: 70 %

Procedure:
Step 2 To a solution of {(R)-1-[3-(5-bromo-pyridine-2-carbonyl)-4-chloro-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester (371 mg, 0.79 mmol) in NMP (2 mL) was added copper (I) oxide (23 mg, 0.16 mmol, 0.2 eq.) and ammonium hydroxide (˜29% in water, 2 mL) in a Reacti-vial and the mixture heated at 80° C. for 4 h. The mixture was partitioned between EtOAc (20 mL) and water (20 mL) and the organic phase extracted with further EtOAc (10 mL). Combined organic phase was washed with water (3×20 mL) and brine (10 mL) before it was dried (MgSO4), filtered and concentrated. Purified by silica column, 25 M, eluting 25-80% EtOAc in petrol to give {(R)-1-[3-(5-amino-pyridine-2-carbonyl)-4-chloro-2-fluoro-phenyl]-propyl}-carbamic acid tert-butyl ester (226 mg, 0.55 mmol, 70%). [M+H]+ 408
Reaction SMILES: C(#N)C.[CH:4]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[C:14](F)[C:15]=3[O:17][CH3:18])[C:10](=[O:21])[C:9]([C:22]([OH:24])=[O:23])=[CH:8]2)[CH2:6][CH2:5]1.Cl.Cl.[CH3:27][CH:28]1[CH2:33][NH:32][CH2:31][CH2:30][NH:29]1>C(N(CC)CC)C>[CH:4]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([F:20])=[C:14]([N:32]4[CH2:31][CH2:30][NH:29][CH:28]([CH3:27])[CH2:33]4)[C:15]=3[O:17][CH3:18])[C:10](=[O:21])[C:9]([C:22]([OH:24])=[O:23])=[CH:8]2)[CH2:6][CH2:5]1
Reactant: CC1CNCCN1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
An acetonitrile solution (30 mL) containing 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (3 g), 2-methylpiperazine dihydrochloride (1.93 g), triethylamine (1.43 mL), and boron trifluoride-tetrahydrofuran complex (2.84 g) was stirred at room temperature for one hour. Triethylamine (5.71 mL) was further added to the reaction mixture, followed by stirring at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and methanol (30 mL) was added to the residue. The mixture was refluxed for 5 hours, and the solvent was evaporated under reduced pressure. 80% Hydrated methanol (30 mL) was added to the residue, and the pH of the product was adjusted to 7 by use of 5N aqueous sodium hydroxide solution, followed by stirring at room temperature for 16 hours. The thus-produced crystals were recovered through filtration and dried, to thereby yield 3.55 g of the title compound (yield: 91%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20]([C@@H:22]1[CH2:30][C@H:29]2[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28]2)[NH:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.[C:38]([O:42][C:43]([NH:45][C@H:46]([C:48](O)=[O:49])[CH3:47])=[O:44])([CH3:41])([CH3:40])[CH3:39]>C(OCC)(=O)C>[C:38]([O:42][C:43]([NH:45][C@@H:46]([CH3:47])[C:48]([N:23]1[C@@H:24]2[C@@H:29]([CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:30][C@H:22]1[C:20]([O:19][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:21])=[O:49])=[O:44])([CH3:41])([CH3:40])[CH3:39]
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H]2CCCC[C@@H]2N1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1[C@H](C(=O)OCc2ccccc2)C[C@@H]2CCCC[C@@H]21
Temperature: 30 °C

Procedure:
200 g of (2S,3aS,7aS)-octahydroindole-2-carboxylic acid benzyl ester para-toluene-sulphonate, 65 ml of triethylamine and 1 litre of ethyl acetate are introduced into a stirred reactor, followed, after stirring for 10 minutes at ambient temperature, by 87 g of N-[tert-butyloxycarbonyl]-(S)-alanine and 175 g of O-(benzotriazol-1-yl)-1,1,3,3-bis(tetra-methylene)uronium hexafluorophosphate. The heterogeneous mixture is then heated at 30° C. for 3 hours whilst stirring well and is then cooled to 0° C. and filtered.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][C@@H:10]([CH2:12][CH2:13][CH3:14])[N:9]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:8]2=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=[C:23]([CH3:37])[CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36].[BH3-]C#N.[Na+]>CC(O)=O.CO>[O:21]=[C:8]1[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][C@@H:10]([CH2:12][CH2:13][CH3:14])[N:9]1[CH:15]1[CH2:20][CH2:19][N:18]([CH:23]([CH3:37])[CH2:24][CH2:25][N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH2:17][CH2:16]1
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: CCC[C@@H]1CN(c2ccccc2)C(=O)N1C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCC[C@@H]1CN(c2ccccc2)C(=O)N1C1CCN(C(C)CCN2C(=O)c3ccccc3C2=O)CC1

Procedure:
Following general procedure B: a solution of (R)-1-phenyl-3-piperidin-4-yl-4-propyl-imidazolidin-2-one (152 mg, 0.53 mmol), 2-(3-oxo-butyl)-isoindole-1,3-dione (230 mg, 1.06 mmol), NaBH3CN (108 mg, 1.72 mmol) and glacial AcOH (8 drops) in MeOH (2.5 ml) was stirred at 60° C. for 16.5 hours. Standard workup and purification by flash column chromatography on silica (CH2Cl2/MeOH, 29:1) gave 2-{3-[4-((R)-2-oxo-3-phenyl-5-propyl-imidazolidin-1-yl)-piperidin-1-yl]-butyl}-isoindole-1,3-dione, contaminated with alcohol resulting from reduction of excess ketone (302 mg).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:11][CH3:12])[C:6]=2[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].CS(O)(=O)=O>O1CCOCC1>[Cl:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:7]3[CH:8]=[CH:9][N:10]([CH2:11][CH3:12])[C:6]=3[C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:4][N:3]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)c1cnc(Cl)c2ccn(CC)c12
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(Nc2cccc(Cl)c2)c2ccn(CC)c12

Procedure:
A mixture of ethyl 4-chloro-1-ethyl-1H-pyrrolo[3,2-c]pyridine-7-carboxylate (0.095 g), 3-chloroaniline (0.079 ml) and methanesulfonic acid (0.049 ml) in 1,4-dioxan (2.5 ml) was irradiated at 180° C. for 30 minutes with microwaves. The residue was partitioned between ethyl acetate and water, the aqueous was separated, basified with an aqueous 2M sodium bicarbonate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to afford the title compound as a brown oil (0.160 g).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[S:12][C:11]([C:13]([O:15]CC)=[O:14])=[N:10][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[CH:19]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1.[Cl-].[NH4+]>COCCOC.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>[Cl:24][C:20]1[CH:19]=[C:18]([C:9]2[N:10]=[C:11]([C:13]([OH:15])=[O:14])[S:12][C:8]=2[C:30]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:25])[CH:31]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CCOC(=O)c1nc(-c2cccc(Cl)c2)c(Br)s1
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: [Cl-]
Solvent: COCCOC
Product: O=C(O)c1nc(-c2cccc(Cl)c2)c(-c2cccc(Cl)c2)s1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
At room temperature, 7.2 ml of an aqueous 2M sodium carbonate solution and 167 mg (0.144 mmol) of tetrakis(triphenylphosphine)palladium are added to 1.00 g (2.88 mmol) of the compound from Example 5A and 677 mg (4.33 mmol) of (3-chlorophenyl)boronic acid in 40 ml of DME, and the mixture is subsequently stirred at 80° C. overnight. A saturated aqueous ammonium chloride solution is added, and the reaction mixture is subsequently extracted with dichloromethane. The organic phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient). 173 mg (17% of theory) of the title compound are obtained.
Reaction SMILES: C1(C(=[N:14][CH:15]([C:21]2[CH:33]=[CH:32][C:24]([C:25]([O:27]C(C)(C)C)=[O:26])=[CH:23][CH:22]=2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.Cl>C(OCC)C>[NH2:14][CH:15]([C:21]1[CH:33]=[CH:32][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=O)C(N)c1ccc(C(=O)O)cc1

Procedure:
Tert-butyl 4-{1-[(diphenylmethylene)amino]-2-ethoxy-2-oxoethyl}benzoate (17.4 g, 39.2 mmol) and 2N HCl (200 mL, 400 mmol) were stirred in diethyl ether (200 mL) at room temperature overnight. The aqueous phase was separated and concentrated in vacuo. The HCl salt was dissolved in water and 35 mL of 2N NaOH was added. The volume was reduced in vacuo and the resulting precipitate collected by filtration to give to give the desired product as a white solid. 1H NMR (DMSO-d6, 600 MHz) δ 7.88 (d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 4.60 (s, 1H), 4.04 (m, 2H), 1.09 (t, J=7.2 Hz, 3H). MS: cal'd 224 (MH+), exp 224 (MH+).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].N([O-])=O.[Na+].[I-:16].[K+]>OS(O)(=O)=O.O>[I:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9]
Reactant: Nc1ccccc1S(N)(=O)=O
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: NS(=O)(=O)c1ccccc1I
Temperature: 0 °C
Reaction time: 3 h
Yield: 69.5 %

Procedure:
2-aminobenzene sulfonamide (3.5 g) in conc. H2SO4, 98% (25 ml) are heated at 60° to give a clear solution. 20 g of ice is then added and the solution is cooled to 0° C. NaNO2 (1.45 g) in water (4 ml) is added dropwise very carefully without exceeding 5°-6° C. The reaction mixture is stirred at 5°-6° C. for 3 hours. A solution of potassium iodide (3.75 g) in H2O (25 ml) is then introduced dropwise and the obtained red mixture is stirred for 18 hours. H2O (50 ml) is added and the obtained precipitate is filtered, washed several times in water. The obtained solid is dissolved in ethyl acetate, washed once with 0.2N sodiumthiosulfate solution and twice with water, evaporated to dryness to give 4 g of a light yellow compound (62% yield).
Reaction SMILES: [OH:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:22]5[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]5)=[N:19][C:18]4=[O:29])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[CH3:28][N:25]1[CH2:26][CH2:27][N:22]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:30]=[CH:31][C:2]([O:1][S:46]([CH3:45])(=[O:48])=[O:47])=[CH:3][C:4]=3[C:32]([F:35])([F:34])[F:33])[N:8]=[CH:9]4)[C:18](=[O:29])[N:19]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)Cl
Reactant: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(O)cc4C(F)(F)F)c3)S2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(OS(C)(=O)=O)cc4C(F)(F)F)c3)S2)CC1
Reaction time: 1 h

Procedure:
To a solution of 5-[1-(4-hydroxy-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(4-methyl-piperazin-1-yl)-thiazol-4-one (10 mg, 0.02 mmol) in 1 mL CH2Cl2 was added DIEA (7.7 mg, 0.06 mmol) and methanesulfonyl chloride (4 mg, 0.03 mmol). The mixture was stirred for 1 h and loaded onto a silica gel-packed column. The desired product was eluted with 0-100% gradient of CH2Cl2/EtOAc, followed by 10% MeOH/EtOAc (8.6 mg, 74%).
Reaction SMILES: O.[NH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1>C(O)(=O)C.C(Cl)(Cl)Cl>[CH:6]1[CH:5]=[CH:4][C:3]([N:2]([C:6]2[CH:5]=[CH:4][C:3]([NH2:2])=[CH:8][CH:7]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:8][CH:7]=1
Reactant: Nc1cccc(B(O)O)c1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1ccc(N(c2ccccc2)c2ccccc2)cc1

Procedure:
(N,N′-Bis(m-(boronic acid)phenyl)-1,5-bis(phenyl)anthracene-2,3,6,7-tetracarboxyl diimide (47): A mixture of 1,5-bis(phenyl)anthracene-2,3,6,7-tetracarboxyl bisanhydride (0.10 g, 0.22 mmol), 3-aminophenyl boronic acid monohydrate (0.99 g, 0.64 mmol) in 5 ml of acetic acid was reacted and worked up according to the procedure for coupling yielding a yellow solid. Product was dissolved in and heated slightly in chloroform. The chloroform was removed by vacuum filtration and the final product, a yellow solid, was dried in a vacuum oven. 1H NMR (300 MHz, CDCl3): δ 7.31-7.63 (m, 9H), 8.52 (s, 1H), 8.63 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2cccc3c2OCC3)CC1
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)Cn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-N,N-dimethyl-acetamide gave the title compound.
Reaction SMILES: [C:1]([CH:4]([OH:22])[C@H:5]1[O:9][C@@H:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[NH:13][C:11]2=[O:12])[CH2:7][C@@H:6]1[N:19]=[N+:20]=[N-:21])(=[O:3])[CH3:2].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>N1C=CC=CC=1>[C:1]([CH:4]([OH:22])[C@H:5]1[O:9][C@@H:8]([N:10]2[CH:18]=[C:16]([CH3:17])[C:14](=[O:15])[N:13]([C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:11]2=[O:12])[CH2:7][C@@H:6]1[N:19]=[N+:20]=[N-:21])(=[O:3])[CH3:2]
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1N=[N+]=[N-]
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)C(O)[C@H]1O[C@@H](n2cc(C)c(=O)n(C(=O)c3ccccc3)c2=O)C[C@@H]1N=[N+]=[N-]
Reaction time: 8 h

Procedure:
5'-Acetyl-3'-azido-3'-deoxythymidine (0.75 g, 2.4 mMol) was dissolved in pyridine (5 mL) and benzoyl chloride (1.4 mL, 12 mMol, 5 eq.) was added at room temperature. The reaction was stirred overnight then poured onto ice water (250 mL). The pH of the aqueous solution was adjusted to 1. The product was extracted with chloroform. The organic phase was washed with water, dried with MgSO4 and filtered. The chloroform was removed and the oily product was flash chromatographed on silica gel eluted with chloroform. The product was collected as an oil.