Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:10]=[CH:11]2)=[CH:6][CH:5]=1.CS(Cl)(=O)=O.Cl.[CH3:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][NH:30]1>>[CH3:28][C@@H:29]1[CH2:33][CH2:32][CH2:31][N:30]1[CH2:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[C:9]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:10]=[CH:11]2)=[CH:6][CH:5]=1
Reactant: N#Cc1ccc(-c2cc3ccc(CCO)cc3cn2)cc1
Reactant: C[C@@H]1CCCN1
Agent: CS(=O)(=O)Cl
Agent: Cl
Product: C[C@@H]1CCCN1CCc1ccc2cc(-c3ccc(C#N)cc3)ncc2c1

Procedure:
The product from Example 74B, methanesulfonyl chloride, and (2R)-2-methylpyrrolidine hydrochloride are processed as described in Example 62F to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C@H:10]([C:22]([OH:24])=O)[NH:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13].Cl.CN(C)CCCN=C=NCC.C(OCC)(=O)C>CN(C=O)C>[C:12]([NH:11][C@H:10]1[C:22](=[O:24])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][CH2:9]1)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: Nc1ccccc1SC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(N[C@@H]1CSc2ccccc2NC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
A mixture of 13.10 g (37.9 mmol) of S-(o-aminophenyl)-N-carbobenzyloxy-D-cysteine and 7.27 g (37.9 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 82 mL of DMF was stirred at room temperature for 2 hours. To this solution was added 330 mL of ethyl acetate. The mixture was extracted 4 times with 200 mL of 1N NaOH. The ethyl acetate solution was dried with magnesium sulfate (MgSO4) and evaporated to a white amorphous residue. The residue was triturated with ether, and the resulting white crystals were filtered to yield 6.70 g (54%) of 3(S)-[(Carbobenzyloxy)amino]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one as a white solid.
Reaction SMILES: [C:1]([Si:5]([O:8][C@H:9]([CH2:13][CH3:14])/[CH:10]=[CH:11]/I)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Si:15]([O:22][C@H:23]([C:31]#[C:32]/[CH:33]=[CH:34]/[CH:35]=[CH:36]/[C@H:37]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[CH2:38][C:39]#[CH:40])[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Si:15]([O:22][C@H:23]([C:31]#[C:32]/[CH:33]=[CH:34]/[CH:35]=[CH:36]/[C@H:37]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:43])[CH3:44])[CH2:38][C:39]#[C:40]/[CH:11]=[CH:10]/[C@H:9]([O:8][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:6])[CH3:7])[CH2:13][CH3:14])[CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])([C:18]([CH3:20])([CH3:19])[CH3:21])([CH3:17])[CH3:16]
Reactant: C#CC[C@H](/C=C/C=C/C#C[C@H](CCCC(=O)OC)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: CC[C@H](/C=C/I)O[Si](C)(C)C(C)(C)C
Product: CC[C@H](/C=C/C#CC[C@H](/C=C/C=C/C#C[C@H](CCCC(=O)OC)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Yield: 80 %

Procedure:
Sonogashira coupling between (R,E)-tert-butyl(1-iodopent-1-en-3-yloxy)dimethylsilane and (5S,8E,10E,12R)-methyl 5,12-bis(tert-butyldimethylsilyloxy)pentadeca-8,10-dien-6,14-diynoate (the product of Example 2 or Example 3), using a procedure analogous to that of Example 2, Step 1 gave the product in 80% yield. 1H NMR (500 MHz, C6D6): δ 6.59 (dd, J=15.2 Hz and 10.9 Hz, 1H), 6.24 (dd, J=15.2 and 11.0 Hz, 1H), 6.14 (dd, J=15.5 Hz and 5.3 Hz, 1H), 5.86 (d, J=15.4 Hz, 1H), 5.67 (dd, J=14.8 Hz and 5.6 Hz, 1H), 5.59 (d, J=15.5 Hz, 1H), 4.54 (t, J=5.7 Hz, 1H), 4.24 (q, J=5.9 Hz, 1H), 3.94 (q, J=5.6 Hz, 1H), 3.35 (s, 3H), 2.46 (m, 2H), 2.17 (t, J=7.1 Hz, 2H), 1.84 (m, 4H), 1.44 (m, 2H), 1.04 (s, 9H), 1.02 (s, 9H), 1.00 (s, 9H), 0.86 (t, J=7.5 Hz, 3H), 0.28 (s, 3H), 0.19 (s, 3H), 0.14 (s, 3H), 0.08 (s, 3H), 0.07 (s, 3H), 0.05 (s, 3H). 13C NMR (125 MHz, C6D6): δ 173.131, 145.665, 141.248, 138.411, 129.420, 111.518, 109.904, 93.989, 87.526, 84.119, 81.048, 73.998, 72.025, 63.570, 50.913, 38.321, 33.587, 31.253, 29.235, 26.014, 21.163, 18.413, 9.221, −4.207, −4.421, −4.603, −4.621, −4.772, −5.094.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])[S:15][C:14]=3[S:22]([NH2:25])(=[O:24])=[O:23])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+].[CH2:28]([S:32](Cl)(=[O:34])=[O:33])[CH2:29][CH2:30][CH3:31]>C1COCC1.C(OCC)(=O)C>[CH2:28]([S:32]([NH:25][S:22]([C:14]1[S:15][C:16]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:17][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:8][CH:9]=1)(=[O:24])=[O:23])(=[O:34])=[O:33])[CH2:29][CH2:30][CH3:31]
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(S(N)(=O)=O)s1
Reactant: CCCCS(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCS(=O)(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2ccnc2)cc1
Reaction time: 0.17 h

Procedure:
Crude 3-(4-imidazol-1-ylmethylphenyl)-5-iso-butylthiophene-2-sulfonamide (prepared according to the procedure described in Example 10(c) above) was dissolved in THF (3 mL) under N2 (g). NaOH (1.0 mL, 1M, 1.0 mmol) was added to the mixture, which was then stirred for 10 min. Butanesulfonyl chloride (45 μL, 0.35 mmol) was then added, and the mixture was stirred for 24 h at room temperature. The reaction mixture was then diluted with ethyl acetate (150 mL) and washed with water and brine. The organic phase was dried over MgSO4 and the solvent was removed in vacuo. The crude product was recrystallised from acetone to yield the title compound (31.7 mg, 0.064 mmol).
Reaction SMILES: [Na].[CH2:2]([C:9]1[O:10][C:11](=O)[C:12](=[CH:14][OH:15])[N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[CH3:18][O:19][C:20](=[NH:22])[NH2:21]>C(#N)C>[CH3:18][O:19][C:20]1[NH:22][C:14](=[O:15])[C:12]([NH:13][C:9](=[O:10])[CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:11][N:21]=1
Reactant: O=C1OC(Cc2ccccc2)=NC1=CO
Reactant: COC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC#N
Product: COc1ncc(NC(=O)Cc2ccccc2)c(=O)[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Acetonitrile (15 ml) was added to 2-benzyl-4-hydroxymethylene-5-oxazolone sodium salt (1.00 g, 4.44 mmol) and O-methylisourea hydrochloride (0.49 g, 4.44 mmol), and the mixture was stirred overnight at 80° C. The mixture was concentrated under reduced pressure, water (5 ml) was added, and the mixture was stirred at room temperature for 1 hour. Then, the precipitate was collected by filtration and vacuum dried to give 2-methoxy-6-oxo-5-phenylacetylamino-1,6-dihydropyrimidine (0.94 g, 3.64 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([NH2:14])[CH3:13]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([NH:14][CH2:12][CH3:13])=[O:6]
Reactant: O=C(O)c1cc(O)ccc1Cl
Reactant: CCN
Product: CCNC(=O)c1cc(O)ccc1Cl

Procedure:
The title compound was prepared from 2-chloro-5-hydroxybenzoic acid and ethylamine, using a method similar to that used for preparation 52, as a colourless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:24][CH2:25][CH:26]3[CH2:28][CH2:27]3)=[N:10][CH:11]=[C:12]([CH:23]=2)[C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C:17]2=O)=[O:14])=[CH:4][CH:3]=1.Cl.[CH3:30][O:31][NH2:32]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28]3)=[N:10][CH:11]=[C:12]([CH:23]=2)[C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18]/[C:17]/2=[N:32]\[O:31][CH3:30])=[O:14])=[CH:6][CH:7]=1
Reactant: O=C(N[C@H]1CCCCC1=O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Reactant: CON
Agent: Cl
Solvent: CO
Product: CO/N=C1\CCCC[C@@H]1NC(=O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 36.4 %

Procedure:
To a solution under of 100 mg of 5-(4-chloro-phenyl)-6-cyclopropylmethoxy-N-((S)-2-oxo-cyclohexyl)-nicotinamide in 1 ml methanol was added 105 mg O-methylhydroxylamine hydrochloride and the mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between water and ethyl acetate. The phases were separated and the organic phase was purified by chromatography on silica gel using a gradient of heptane:ethyl acetate=95:5 to 50:50 to yield 0.039 g of the title compound as white foam. MS (EI): 402.3 (M+H).
Reaction SMILES: CC1C(O[C@@H]2O[C@H](C)[C@@H](O)[C@H](O[C@H]3O[C@H](C)[C@@H](O)[C@H](O)C3)C2)=C[C:5]2[C:10](C=1O)=[C:9](O)[C:8]1C([C@@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@H](O[C@H]4O[C@H](C)[C@H](O[C@H]5O[C@H](C)[C@@H](O)[C@](O)(C)C5)[C@H](O)C4)C3)[C@H:17]([C@H:19](OC)[C:20]([C@@H:22](O)[C@H:23](O)C)=O)[CH2:18][C:7]=1[CH:6]=2)=O.[OH-].[Na+].C[N:80](C)C=O>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].O>[CH:9]1[C:8]2[NH:80][C:17]3[C:18](=[CH:23][CH:22]=[CH:20][CH:19]=3)[C:7]=2[CH:6]=[CH:5][CH:10]=1
Reactant: CO[C@H](C(=O)[C@@H](O)[C@@H](C)O)[C@@H]1Cc2cc3cc(O[C@H]4C[C@@H](O[C@@H]5C[C@@H](O)[C@H](O)[C@@H](C)O5)[C@H](O)[C@@H](C)O4)c(C)c(O)c3c(O)c2C(=O)[C@H]1O[C@H]1C[C@@H](O[C@@H]2C[C@@H](O)[C@@H](O[C@@H]3C[C@](C)(O)[C@H](O)[C@@H](C)O3)[C@@H](C)O2)[C@H](O)[C@@H](C)O1
Reactant: CN(C)C=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc2c(c1)[nH]c1ccccc12

Procedure:
Heparin adipic hydrazide (70 mg) was dissolved in 6 ml of 0.1M sodium phosphate buffer, pH 5.8. Mithramycin (10 mg) was dissolved in 1 ml dimethylformamide and this solution was mixed with the heparin adipic hydrazide solution and left for 21/2% days at room temperature. The reaction mixture was then applied to a column of Sephadex G25 equilibrated in H2O whose pH had been raised to approximately 10 by the addition of dilute NaOH. The conjugate, which elated in the void volume, was collected and freeze dried. Quantitation of the drug by u.v spectrophotometric analysis and of the heparin by carbazole assay gave the composition of the conjugate as 0.54 mol mithromycin:mol heparin. The conjugate (Table III) has the structure shown in FIG. 2.
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[N:4][NH:3]1.P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:2]1[N:3]=[N:4][CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]=1[C:8]#[N:9]
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1c(-c2ccccc2)cn[nH]c1=O
Product: N#Cc1c(-c2ccccc2)cnnc1Cl
Temperature: 100 °C

Procedure:
3-Oxo-5-phenyl-2,3-dihydro-pyridazine-4-carbonitrile (70 mg) was suspended in 1 mL phosphorous oxychloride and heated to 100° C. for 6 hours. The mixture was then cooled and poured onto ice. The resulting brown solid product was filtered and air dried and used in the next step without further purification.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH3:17])[C:9]=1[SH:18].I[CH2:20][CH3:21].Cl>C(#N)C.O>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[C:10]([CH3:17])[C:9]=1[S:18][CH2:20][CH3:21]
Reactant: Cc1c(C(=O)O)ccc(Cl)c1S
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCSc1c(Cl)ccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
3.71 g (11.3 mmol) of cesium carbonate were added to 1.10 g (5.42 mmol) of 4-chloro-3-mercapto-2-methylbenzoic acid in 20 ml of acetonitrile. The reaction mixture was stirred at RT for 10 min, and 1.02 g (6.51 mmol) of iodoethane were then slowly added dropwise. The reaction mixture was then stirred at RT for 16 h. The solvent was then removed, and a mixture of 20 ml of methanol and 2 ml of 20% strength aqueous sodium hydroxide solution was then added to the reaction mixture. For the hydrolysis of the ethyl ester formed, the mixture was stirred at RT for 16 h and then freed from the solvents. The residue was taken up in water and acidified with diluted HCl, and the mixture was stirred at RT for 10 min and then filtered. The residue was washed with water and sucked dry. 1.15 g of clean product were isolated.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=3)[CH:14]=2)=[C:5]([C:25]([O:27]CC)=[O:26])[CH:4]=[N:3]1.O.[OH-].[Li+]>CO.O>[CH3:1][N:2]1[C:6]([C:7](=[O:24])[NH:8][C:9]2[CH:10]=[CH:11][C:12]3[N:13]([N:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=3)[CH:14]=2)=[C:5]([C:25]([OH:27])=[O:26])[CH:4]=[N:3]1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(-c3ccccc3)nn2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3ccccc3)nn2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.6 %

Procedure:
A mixture of ethyl 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylate (480 mg, 1.23 mmol) and lithium hydroxide hydrate (155 mg, 3.69 mmol) in methanol (10 ml) and water (3.0 ml) was stirred for 18 hours at 25° C. The solvent was evaporated, the residue was diluted with water and the solution was acidified with hydrochloric acid to pH=0, the precipitated solid was collected, washed with water and dried in vacuo affording 1-methyl-5-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid (435 mg, 98%) as light brown solid. Mp.: 259° C. MS: m/z=361.2 (M−H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[F:22][C:23]([F:32])([F:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1I.C(N(CC)CC)C>[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:10]([NH:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[C:2][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[C:23]([F:32])([F:31])[F:22])[CH:4]=2)=[O:21])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: C#Cc1cccc(NC(=O)Cc2ccc(O)c(OC)c2)c1
Reactant: FC(F)(F)c1ccccc1I
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc(CC(=O)Nc2cccc(C#Cc3ccccc3C(F)(F)F)c2)ccc1O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A mixture of N-(3-ethynylphenyl)-4-hydroxy-3-methoxypheny-acetamide (the compound of Example 19) (200 mg), 1-trifluoromethyl-2-iodobenzene (280 mg), copper (I) iodide (19 mg), bis(triphenylphosphine)palladium (II) dichloride (70 mg), triethylamine (1 g) and acetonitrile (3 ml) is heated with stirring at 50° C. under argon atmosphere for 18 hours. The solvent is evaporated under reduced pressure, and the residue is purified by silica gel column chromatography (eluent: gradient from 0% to 100% hexane/ethyl acetate) to give the desired compound (120 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([O:26]C)=O)=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:40])([F:39])[F:38])[CH3:30])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH3:41]>CO>[Si:1]([O:8][CH2:9][C:10]1[N:15]=[CH:14][C:13]2[N:16]([C:19]3[S:23][C:22]([C:24]([NH2:41])=[O:26])=[C:21]([O:28][CH:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=4[C:37]([F:40])([F:39])[F:38])[CH3:30])[CH:20]=3)[CH:17]=[N:18][C:12]=2[CH:11]=1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)c1sc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)cc1OC(C)c1ccccc1C(F)(F)F
Reactant: N
Solvent: CO
Product: CC(Oc1cc(-n2cnc3cc(CO[Si](C)(C)C(C)(C)C)ncc32)sc1C(N)=O)c1ccccc1C(F)(F)F

Procedure:
In a similar manner as described for example A7, 14.1 g of methyl 5-[6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3H-imidazo[4,5-c]pyridin-3-yl]-3-{1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylate and 1.6 l of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1([C:20]#[CH:21])[CH2:19][CH2:18][C:13]2([O:17][CH2:16][CH2:15][O:14]2)[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH3:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[CH:30][CH:29]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:1]([O:8][CH2:9][C:10]1([C:20]#[C:21][CH:32]([C:31]2[CH:34]=[CH:35][C:28]([CH3:27])=[CH:29][CH:30]=2)[OH:33])[CH2:19][CH2:18][C:13]2([O:14][CH2:15][CH2:16][O:17]2)[CH2:12][CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: C#CC1(COCc2ccccc2)CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1ccc(C(O)C#CC2(COCc3ccccc3)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 82.5 %

Procedure:
To a solution of 8-(benzyloxymethyl)-8-ethynyl-1,4-dioxaspiro[4.5]decane (Reference Example 87) (393 mg, 1.37 mmol) in tetrahydrofuran (4.6 mL), 2.6 M n-butyllithium (solution in hexane, 0.555 mL, 1.44 mmol) was added at −78° C., and the obtained solution was stirred for 10 minutes. Further, 4-methylbenzaldehyde (0.178 mL, 1.51 mmol) was added, and the obtained solution was allowed to warm gradually to room temperature and stirred for 1 hour. Saturated aqueous ammonium chloride solution was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (459 mg, 1.13 mmol, 82%) as a colorless oily compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[F:40][C:41]1[CH:54]=[CH:53][CH:52]=[CH:51][C:42]=1[O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH:46]([NH2:50])[CH2:45]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:40][C:41]1[CH:54]=[CH:53][CH:52]=[CH:51][C:42]=1[O:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH:46]([NH:50][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:45]1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Reactant: NC1CCCC(Oc2ccccc2F)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NC4CCCC(Oc5ccccc5F)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.15 mmol, 74.3 mg), HCl salt of 3-(2-fluorophenoxy)cyclohexanamine (0.15 mmol, 37 mg), HATU (0.15 mmol, 57 mg) and DIEA in DMA was stirred at room temperature for overnight. The product, N-(3-(2-fluorophenoxy)cyclohexyl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after evaporation of solvent.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:25][C:26]3[N:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:28]=[C:29]([CH3:31])[CH:30]=3)=[N:9][N:10]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O>[Pd].CO.C1COCC1>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:25][C:26]3[N:27]([C:32]([CH3:35])([CH3:34])[CH3:33])[N:28]=[C:29]([CH3:31])[CH:30]=3)=[N:9][N:10]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:19][CH:20]=3)[C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3cc([N+](=O)[O-])ccc23)n(C(C)(C)C)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Nc2nn(-c3ccc(C(C)(C)C)cc3)c(=O)c3cc(N)ccc23)n(C(C)(C)C)n1
Yield: 66.7 %

Procedure:
2.00 g of 7-Nitro-4-(2-tert-butyl-5-methyl-2H-pyrazol-3-ylamino)-2-(4-tert-butyl-phenyl)-2H-phthalazin-1-one were hydrogenated over palladium on charcoal in methanol/THF 1:1 at room temperature. After completion of the reaction the catalyst was filtered off and the filtrate evaporated. The residue was dissolved in 50 ml dichloromethane and extracted three times with a 3:1 mixture of water/conc. HCl. The combined aqueous phases were brought to pH 8 by addition of sodium bicarbonate and extracted with dichloromethane. Removal of the solvent yielded 1.25 g of the title product.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].[Cl:18][C:19]1[CH:20]=[C:21](O)[CH:22]=[CH:23][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>COC(C)(C)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:18])[CH:24]=2)[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4]
Reactant: Oc1cccc(Cl)c1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COC(C)(C)C
Product: COC(=O)[C@@H]1C[C@H](Oc2cccc(Cl)c2)CN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 86 %

Procedure:
To a stirred solution of (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (CAS Reg 74844-91-0) (6.1 kg, 24.87 mol), 3-chlorophenol (3.52 kg, 27.39 mol) & triphenylphosphine (7.18 kg, 27.37 mol) in tert-butyl methyl ether (30.5L) at 0′C. was added diisopropylazodicarboxylate (5.53 kg, 27.35 mol) in tert-butyl methyl ether (15L) dropwise. The mixture was stirred overnight at 20′C. The reaction was filtered and the liquors washed with 0.5M sodium hydroxide (aq) (2×12.5L) & water (12.2L). The tert-butyl methyl ether solvent was replaced with n-heptane (42.7L) by atmospheric pressure distillation & cooled to crystallise crude product, which was collected by filtration (11.1 kg, 125% contaminated with ca 35% reduced diisopropyl dicarboxylate & triphenylphosphine oxide-corrected yield=86%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[C:5]([C:7]1[C:8](=[O:15])[N:9]([CH2:13][CH3:14])[CH:10]=[CH:11][CH:12]=1)=O.[NH2:20][C:21]1[CH:25]=[C:24]([NH:26]C(=O)OC(C)(C)C)[NH:23][N:22]=1.C([O-])(=O)C.[NH4+]>>[NH2:26][C:24]1[C:25]2[C:12]3[CH:11]=[CH:10][N:9]([CH2:13][CH3:14])[C:8](=[O:15])[C:7]=3[C:5]([C:4]3[CH:3]=[C:2]([F:1])[CH:18]=[C:17]([F:19])[CH:16]=3)=[N:20][C:21]=2[NH:22][N:23]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(N)n[nH]1
Reactant: CCn1cccc(C(=O)c2cc(F)cc(F)c2)c1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CCn1ccc2c(c(-c3cc(F)cc(F)c3)nc3[nH]nc(N)c32)c1=O
Yield: 27.1 %

Procedure:
91 mg (0.346 mmol) of 3-(3,5-difluorobenzoyl)-1-ethylpyridin-2(1H)-one with 69 mg (0.346 mmol) of tert-butyl 3-amino-1H-pyrazol-5-ylcarbamate and 533 mg (6.91 mmol) of ammonium acetate are added to a boiling flask. The mixture is carried at 200° C. dry (i.e., without solvent) for 15 minutes. The solution is placed at room temperature, and then the solid is dissolved in a water/ethyl acetate mixture. The phases are separated and the aqueous phase is extracted several times with ethyl acetate. The organic phases are mixed, dried on magnesium sulfate and concentrated. The product is purified by silica gel chromatography (eluent: 10:1 dichloromethane/methanol) to yield 32 mg (27%) of 1-amino-5-(3,5-difluorophenyl)-7-ethyl-3H-pyrazolo[3,4-c][2,7]naphthyridin-6(7H)-one.