Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[OH:39][C:40]1[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:39][C:40]1[C:45]([O:46][CH3:47])=[CH:44][CH:43]=[CH:42][C:41]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: COc1cccc(B(O)O)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COc1cccc(-c2cn(COCC[Si](C)(C)C)c3ncnc(N[C@@H](C)c4nn5ccc(C)c5c(=O)n4-c4ccccc4)c23)c1O
Yield: 111.3 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (60 mg, 0.10 mmol) was treated with (2-hydroxy-3-methoxyphenyl)boronic acid (41 mg, 0.24 mmol), sodium carbonate (26 mg, 0.25 mmols) and bis(triphenylphosphine)palladium(II) dichloride (7 mg, 0.01 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 50%, hexane-ethyl acetate) to give 71 mg (99% yield) of the title compound. Purity 71%.
Reaction SMILES: [O:1]=[C:2](Cl)OC(Cl)(Cl)Cl.[NH2:9][CH:10]([CH2:15][C:16]([CH3:18])=[CH2:17])[C:11]([O:13][CH3:14])=[O:12].C>O1CCOCC1>[N:9]([CH:10]([CH2:15][C:16]([CH3:18])=[CH2:17])[C:11]([O:13][CH3:14])=[O:12])=[C:2]=[O:1]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: C=C(C)CC(N)C(=O)OC
Solvent: C1COCCO1
Product: C=C(C)CC(N=C=O)C(=O)OC

Procedure:
0.35 mol diphosgene is added dropwise over 1 hour to a mixture of 0.28 mol of methyl 2-amino-4-methyl-4-pentenoate, prepared as described by D. Ferroud, J. P. Genet, and R. Kiolle in Tetrahedron Letters, 1986, 27, 23-26, and 0.4 g activated charcoal in 400 mL dioxane under N2. The reaction mixture is then heated and stirred at reflux for 21/2 hours. The reaction mixture is then cooled, filtered, and concentrated to dryness by rotary evaporator, keeping exposure to moisture to a minimum. The crude product is re-dissolved in 100 mL THF, and the pH of the solution is adjusted to 5.5-6.0 by addition of pyridine. The product mixture is again filtered, and the product is purified by fractional distillation to give methyl 2-isocyanato-4-methyl-4-pentenoate.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[OH:21])O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[OH:21]
Reactant: COCOc1ccccc1C(O)c1cccc(OC)c1O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COCOc1ccccc1Cc1cccc(OC)c1O
Temperature: 0 °C
Yield: 130.6 %

Procedure:
(2-Methoxymethoxyphenyl)(2-hydroxy-3-methoxyphenyl)methanol (15.54 g, 54 mmol) and triethylsilane (7.53 g, 0.064 mol) were dissolved in 150 ml of methylene chloride and the solution cooled to 0° C. and blanketed with nitrogen. A solution of 7.39 g (64.8 mmol) of trifluoroacetic acid in 70 ml of methylene chloride was added with stirring and cooling and the mixture was allowed to react for 2 hours. The reaction mixture was then poured into saturated aqueous sodium bicarbonate, more methylene chloride added, and the organic layer recovered. This was extracted with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure to obtain 19.34 g of orange oil. This was purified by preparative liquid chromatography eluting with a 5:95 mixture of acetone and hexane to obtain 3.95 g (27 percent of theory) of the title compound as an oil. The proton nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:29][C:30]1[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=1)[CH2:10][CH2:11][C:12]([NH:14][NH:15][C:16]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[N:23][C:22]([F:28])=[CH:21]2)=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:49])=CC=1>C1COCC1.C(Cl)Cl>[F:28][C:22]1[N:23]=[CH:24][C:25]2[C:20]([CH:21]=1)=[CH:19][C:18]([C:16]1[S:49][C:12]([CH2:11][CH2:10][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:29][C:30]3[CH:31]=[N:32][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:35]=3)=[N:14][N:15]=1)=[CH:27][CH:26]=2
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)NNC(=O)c1ccc2cnc(F)cc2c1)Cc1ccc(C(F)(F)F)nc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCc1nnc(-c2ccc3cnc(F)cc3c2)s1)Cc1ccc(C(F)(F)F)nc1
Temperature: 100 °C
Yield: 84.7 %

Procedure:
A mixture of (R)—N′-(4-(tert-butyloxycarbonylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pentanoyl)-3-fluoroisoquinoline-6-carbohydrazide (108 mg, 207 μmol) and Lawesson's reagent (101 mg, 249 μmol) in THF (2 mL) was heated in a Biotage® microwave reactor at 100° C. for 10 minutes. The mixture was diluted with DCM, absorbed onto silica gel, and purified by flash chromatography (silica gel, 2-8% MeOH/DCM) providing tert-butyl (R)-4-(5-(3-fluoroisoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)-1-(6-(trifluoromethyl)pyridin-3-yl)butan-2-ylcarbamate (96 mg, 88%) as a white solid. LCMS (API-ES) m/z: 548.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CO[C:16](=O)[C:17]1C=C(N(CCC)CCC)C=CC=1N.S(Cl)(Cl)=O>C(O)C>[CH2:16]([O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:17]
Reactant: O=C(O)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: CCCN(CCC)c1ccc(N)c(C(=O)OC)c1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 48 h

Procedure:
5-Chloro-2-nitro-benzoic acid (compound A′) (10.0 g) was dissolved in ethanol (100 ml). Thionyl chloride (20 ml) was added dropwise to the solution at 0° C., and the mixture was then heated under reflux with stirring for 48 hr. After the completion of the reaction, the reaction solution was concentrated under the reduced pressure. Distilled water was added to the residue, and the mixture was neutralized with a saturated aqueous sodium hydrogencarbonate solution under ice cooling. The cooled solution was subjected to separatory extraction with ethyl acetate. The organic layer was dried over sodium sulfate and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 5-chloro-2-nitro-benzoic acid ethyl ester as a useful intermediate (11.0 g, yield 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]=[O:20])=[CH:15][CH:14]=1)[O:8][CH:7]([C:21]([F:24])([F:23])[F:22])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2.[BH4-].[Na+]>CO.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][OH:20])=[CH:17][CH:18]=1)[O:8][CH:7]([C:21]([F:24])([F:22])[F:23])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2
Reactant: O=Cc1ccc(Cc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1=Cc2cc(Cl)c(Cc3ccc(CO)cc3)cc2OC1C(F)(F)F
Reaction time: 0.25 h

Procedure:
The 6-chloro-7-(4-formylbenzyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid (Example 604 g) (210 mg, 0.49 mmole) was dissolved in MeOH:THF (1:1) (3 mL). NaBH4 (20 mg, 0.49 mmole) was added to the above solution portionwise. After stiring for 15 min, the reaction was finished. The reaction was quenched with (sat.) NH4Cl, the organic layer was extracted with EtOAc and dried over MgSO4 and filtered. The filtrate was concentrated to give the title compound as an oil, which solidify upon standing as a white solid 200 mg (95% yield): ESHRMS m/z 397.0457 (M−H, C19H13O4F3Cl, Calc'd 397.0449). 1H NMR (acetone-d6/400 MHz) 7.87 (s, 1H), 7.57 (s, 1H), 7.31 (d, 2H, J=8.2 Hz), 7.22 (d, 2H, J=8.2 Hz), 6.92 (s, 1H), 5.80 (q, 1H, J=7.2 Hz), 4.59 (s, 2H), 4.09 (d, 2H, J=4.3 Hz).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH3:29][N:30]1[CH2:34][CH2:33][CH2:32][CH:31]1[CH2:35][CH2:36][N:37]1[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42](B3OC(C)(C)C(C)(C)O3)[CH:43]=2)[C:38]1=[O:55]>>[F:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:42]3[CH:43]=[C:44]4[C:39](=[CH:40][CH:41]=3)[C:38](=[O:55])[N:37]([CH2:36][CH2:35][CH:31]3[CH2:32][CH2:33][CH2:34][N:30]3[CH3:29])[CH2:45]4)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Reactant: CN1CCCC1CCN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Product: COc1cc(OC)c(F)c(-c2cc3[nH]nc(-c4ccc5c(c4)CN(CCC4CCCN4C)C5=O)c3cn2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and 2-[2-(1-methylpyrrolidin-2-yl)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=534.3.
Reaction SMILES: [CH:1]1([NH:7][C:8](=[O:29])[C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14](=[O:28])[C@H:15]([CH3:27])[NH:16]C(OCC2C=CC=CC=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOCC.[BrH:35]>C(O)(=O)C>[BrH:35].[CH:1]1([NH:7][C:8](=[O:29])[C@@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14](=[O:28])[C@H:15]([CH3:27])[NH2:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NC1CCCCC1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)NC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
2 g (0.005 mol) of N-benzyloxycarbonyl-L-alanyl-L-proline cyclohexylamide were dissolved in 10 ml of 4-N hydrogen bromide in acetic acid and the mixture was stirred at room temperature for 1 hour. 100 ml of dry ether were then added. An oil precipitated and was allowed to settle. The solution was decanted off, the oil washed with 100 ml of ether, dissolved in the minimum volume of methanol and an excess of ethyl acetate added. Crystallisation soon took place and there were obtained 1.75 g (100%) of L-alanyl-L-proline cyclohexylamide hydrobromide of melting point 233°-236° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[C:9]([O:16][CH3:17])=[C:8]2[C:4]=1[CH:5]=[C:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:7]2>[C].[Pd].C(O)C>[CH3:17][O:16][C:9]1[C:10]([O:14][CH3:15])=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[C:4]2[C:8]=1[CH2:7][CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:5]2
Reactant: CCOC(=O)CCCCCCCC1=Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCCCCCC1Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.5 %

Procedure:
An ethanol (6.0 ml) suspension of ethyl 8-(4,5,6,7-tetramethoxyinden-2-yl)octanoate (310 mg, 0.763 mmols)and 10% palladium-carbon (60 mg) was stirred under a hydrogen atmosphere at room temperature for 4 hours. The palladium-carbon was removed by filtration, and the filtrate was concentrated in vacuo to obtain the entitled compound (310 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:6][CH2:5]1.[CH2:7]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[CH3:8]>C(O)C>[OH:6][CH:4]([CH2:3][O:2][CH3:1])[CH2:5][NH:12][CH2:11][C:10]([O:9][CH2:7][CH3:8])=[O:13]
Reactant: CCOC(=O)CN
Reactant: COCC1CO1
Solvent: CCO
Product: CCOC(=O)CNCC(O)COC
Yield: 100 %

Procedure:
A solution of glycidyl methyl ether (1.00 g) and glycine ethyl ester (5.91 g) in ethanol was stirred overnight, and concentrated under reduced pressure to obtain the title compound (2.17 g).
Reaction SMILES: C[Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=1.[C:21](O)(=O)C>CO.C1(C)C=CC=CC=1>[CH3:21][O:17][C:16](=[O:18])[CH2:15][C:13]1[CH:14]=[C:9]([Br:8])[CH:10]=[CH:11][C:12]=1[O:19][CH3:20]
Reactant: COc1ccc(Br)cc1CC(=O)O
Reactant: CC(=O)O
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cc1cc(Br)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
Trimethylsilyldiazomethane (2 M solution in diethyl ether, 0.306 mL, 0.612 mmol) was added to a solution of (5-bromo-2-methoxy-phenyl)-acetic acid (100 mg, 0408 mmol) in methanol (1 mL) and toluene (4 mL), and the mixture was stirred at room temperature for 30 minutes. Acetic acid was added to the reaction mixture to terminate the reaction, and then the mixture was concentrated under reduced pressure to give the target compound as a colorless oil (103.7 mg, 98%).
Reaction SMILES: N[C:2]1[CH:12]=[N:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(=O)(=O)(O)[OH:14].N([O-])=O.[Na+].C(=O)([O-])O.[Na+]>O>[OH:14][C:2]1[CH:12]=[N:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)c1ccncc1N
Agent: O=C([O-])O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1ccncc1O
Reaction time: 1.33 h

Procedure:
Ethyl 3-aminoisonicotinate (5.55 g) is suspended in water (70 ml), and thereto added conc. sulfuric acid (4.0 ml). The reaction solution is cooled with ice, and a solution of sodium nitrite (2.79 g) in water (30 ml) is added dropwise thereto. The reaction solution is stirred under the same cooling conditions for 20 minutes and then at 90° C. for 80 minutes. The reaction solution is diluted with water (100 ml) and the solution is adjusted to pH 8 to 9 by addition of saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer is dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1) to give ethyl 3-hydroxyisonicotinate (2.64 g).
Reaction SMILES: C[O:2][C:3](=[O:40])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:10]([OH:39])=[C:11]2[C:16](=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:18]=1)[N:15]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:14](=[O:32])[C:13]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[CH:12]2)=[O:8].[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:25]([N:15]1[C:16]2[C:11](=[C:10]([OH:39])[C:9]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:40])=[O:2])=[O:8])=[N:18][C:17]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:12]=[C:13]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:14]1=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)CCNC(=O)c1nc(-c2ccccn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)c1nc(-c2ccccn2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 29.8 %

Procedure:
A mixture of 3-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-8-pyridin-2-yl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-propionic acid methyl ester (62 mg, 0.116 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added until pH was about 3-4, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The crude product was purified twice by silica gel chromatography (100% EtOAc, then 10-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3-4, and the resulting precipitate was isolated by filtration to give 18 mg of the title compound. MS: (+) m/z 521.41 (M+1).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:39])[CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH:12]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:11]2[CH:12]=[C:7]([CH2:6][C:5]([OH:39])=[O:4])[CH:8]=[N:9][CH:10]=2)=[CH:18][CH:17]=1)([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:33])([CH3:34])[CH3:32])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(-c2cncc(CC(=O)OC)c2)cc1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(-c2cncc(CC(=O)O)c2)cc1)c1ccc(OCC(O)C(C)(C)C)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.6 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.183 mL, 0.183 mmol) was added to a solution of [5-(4-{1-ethyl-1-[4-(2-hydroxy-3,3-dimethyl-butoxy)-3-methyl-phenyl]-propyl}-phenyl)-pyridin-3-yl]-acetic acid methyl ester (Example 146-(2); 30.8 mg, 0.061 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at 60° C. for one hour. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (20.5 mg, 69%).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:20]=1>>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:19]1[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:13][CH2:1][O:2][C:3]=3[CH:4]=2)[C:16]2[C:29]([Cl:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=1
Reactant: NCCc1ccc2c(c1)OCCO2
Reactant: Cc1sc2nc(-c3ccccn3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccccn3)nc(NCCc3ccc4c(c3)OCCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-2-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-2-yl)-4-(3,4-ethylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][N:5]([CH2:7][C:8]2[CH:9]=NC(C)=N[CH:13]=2)[CH2:4][C@H:3]1[C:15]1[NH:16][C:17](=[O:30])[C:18]2[CH:23]=[N:22][N:21]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:19]=2[N:20]=1.C([BH3-])#N.[Na+].[F:35][C:36]1C=C(C=[CH:42][CH:43]=1)C=O>>[F:35][C:36]1[CH:13]=[C:8]([CH:9]=[CH:42][CH:43]=1)[CH2:7][N:5]1[CH2:6][C@@H:2]([CH3:1])[C@H:3]([C:15]2[NH:16][C:17](=[O:30])[C:18]3[CH:23]=[N:22][N:21]([CH:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)[C:19]=3[N:20]=2)[CH2:4]1
Reactant: Cc1ncc(CN2C[C@@H](C)[C@H](c3nc4c(cnn4C4CCOCC4)c(=O)[nH]3)C2)cn1
Reactant: O=Cc1cccc(F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(Cc2cccc(F)c2)C[C@H]1c1nc2c(cnn2C2CCOCC2)c(=O)[nH]1

Procedure:
Following the procedure for the preparation of 6-{(3S,4S)-4-methyl-1-[(2-methylpyrimidin-5-yl)methyl]pyrrolidin-3-yl}-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one but substituting sodium cyanoborohydride and 3-fluorobenzaldehyde provided the title compound. 400 MHz 1H NMR (CDCl3) δ 8.02 (s,1H), 7.35-7.30 (m, 1H), 7.21-7.20 (m, 1H), 7.05 (d, J=9.5 Hz, 1H), 6.98-6.93 (m, 1H), 4.83-4.77 (m, 1H), 4.14-4.08 (m, 2H), 3.80-3.77 (m, 1H), 3.64-3.54 (m, 3H), 3.36 (t, J=8.8 Hz, 1H), 3.01 (d, J=9.9 Hz, 1H), 2.84-2.83 (m, 1H), 2.57 (m, 1H), 2.44-2.27 (m, 3H), 1.95-1.83 (m, 3H), 1.20 (d, J=7.1 Hz, 3H). MS: (M+H m/z 412.4).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:34]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>>[CH2:34]([N:41]1[CH2:42][CH2:43][N:44]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:33])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][CH2:22][C:23]4[CH:28]=[CH:27][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:25][CH:24]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:45][CH2:46]1)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: CCCCCCCN1CCNCC1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccc(S(N)(=O)=O)cc3)cc2)c1
Product: CCCCCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 10 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylbenzyl)benzenesulfonamide following procedure C and using 1.5 equivalents of n-heptylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:11]=[C:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[CH2:1]([N:8]([C:9]1[N:10]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[N:11]=[C:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)[C:32]([NH:31][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C=NC1CCCCC1
Reactant: Clc1ccc(-n2nc3ccccc3c2NCc2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)N(Cc1ccccc1)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, benzyl-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in toluene for 48 h under reflux conditions to give the title compound as yellow solid. MS: m/e=459.4 [M+H+].
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[N+:11]([O-])([O-:13])=[O:12].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:11]([C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=1[OH:10])([O-:13])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)c1cccc(O)c1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)c1ccc([N+](=O)[O-])c(O)c1
Reaction time: 24 h
Yield: 27.3 %

Procedure:
3-isopropylphenol (3.00 g, 22 mmol) was dissolved in methylene chloride(40 ml) followed by the addition of sodium nitrate (2.06 g, 24 mmol). The addition of sulfuric acid (25 mL/3M) is then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 h, the reaction mixture is diluted with methylene chloride and extracted with water. The organic layer is dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.09 g, 27%). 1H NMR (CD3COCD3): d 7.95 (d,1H), 7.62 (d,1H), 7.11 (d, 1H), 2.95 (m, 1H), 1.24 (d, 6H).