Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1.[F-:26].[Cs+]>CS(C)=O>[F:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH:5]=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cncc(Br)c23)CC1
Reactant: [F-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc3cncc(F)c23)CC1
Temperature: 150 °C
Reaction time: 8 h
Yield: 23.9 %

Procedure:
A solution of Intermediate 71 (104 mg) in dimethyl sulfoxide (2 ml) was added with cesium fluoride (284 mg, Wako Pure Chemical Industries) and stirred at 150° C. for 8 hours. The reaction mixture was cooled to room temperature and then filtered through Celite. The residue was added with water (20 ml), extracted with ethyl acetate (20 ml) and washed twice with saturated brine (10 ml for each time). The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1) to obtain the title compound (21.1 mg).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[S:26][CH:27]=[C:28]([C:30](=[N:36][O:37][CH3:38])[C:31]([O:33][CH2:34][CH3:35])=[O:32])[N:29]=1>>[CH2:34]([O:33][C:31]([C:30]([C:28]1[N:29]=[C:25]([NH:24][C:1]([C:4]23[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:10][CH2:11]3)=[O:2])[S:26][CH:27]=1)=[N:36][O:37][CH3:38])=[O:32])[CH3:35]
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CCOC(=O)C(=NOC)c1csc(N)n1
Product: CCOC(=O)C(=NOC)c1csc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)n1
Yield: 52.5 %

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and ethyl 2-amino-α-methoxyiminothiazole-4-acetate (78.0 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-[(1-ethoxycarbonyl-1-methoxyiminomethyl)thiazol-2-yl]amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (43.4 mg).
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH:10]1[CH2:14][CH:13]=[CH:12][CH:11]=1.I([O-])(=O)(=O)=O.[Na+]>CO.O>[CH:12]12[CH2:13][CH:14]([CH:10]=[CH:11]1)[N:2]([C:3]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:9])[O:1]2
Reactant: C1=CCC=C1
Reactant: CC(C)(C)OC(=O)NO
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1OC2C=CC1C2
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a solution of tert-butyl N-hydroxycarbamate (9.2 g, 69.10 mmol, 1.00 equiv) and cyclopenta-1,3-diene (20.2 g, 305.59 mmol, 4.42 equiv) in methanol (600 mL) was added of a solution of sodium periodate (17 g, 79.48 mmol, 1.15 equiv) in water (180 mL) dropwise at 0° C. with stirring in 30 min. The reaction mixture was stirred for another 30 min at 0° C. and then diluted with 600 mL of water. The solution was extracted with 3×300 mL of ethyl acetate. The combined organic layers was washed with 2×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 9.1 g (67%) of tert-butyl 2-oxa-3-azabicyclo[2.2.1]hept-5-ene-3-carboxylate as a white solid. 1HNMR (400 MHz, D2O, ppm) δ 6.42 (2H, s), 5.22 (1H, s), 4.99 (1H, s), 1.99 (1H, d, J=8.4 Hz), 1.73 (1H, d, J=8.4 Hz), 1.47 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]3[NH:33][CH:34]=[N:35][C:31]=3[CH:30]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH:17]2[C:23]([O:25]CC)=[O:24])=[O:15])(=[O:11])=[O:10])=[CH:4][C:3]=1[Cl:38].[OH-].[Na+]>>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([S:9]([NH:12][CH:13]([CH2:28][C:29]2[CH:37]=[CH:36][C:32]3[NH:33][CH:34]=[N:35][C:31]=3[CH:30]=2)[C:14]([N:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH:17]2[C:23]([OH:25])=[O:24])=[O:15])(=[O:10])=[O:11])=[CH:4][C:3]=1[Cl:38]
Reactant: CCOC(=O)C1CC(C)CCN1C(=O)C(Cc1ccc2[nH]cnc2c1)NS(=O)(=O)c1cc(Cl)c(N)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: CC1CCN(C(=O)C(Cc2ccc3[nH]cnc3c2)NS(=O)(=O)c2cc(Cl)c(N)c(Cl)c2)C(C(=O)O)C1

Procedure:
Prepared by hydrolysis of 4-amino-N-[1-(1H-benzimidazol-5-yl-methyl)-2-(2-carbethoxy-4-methyl-piperidin-1-yl)-2-oxo-ethyl]-3,5-dichloro-benzenesulphonamide in the presence of 1N sodium hydroxide solution analogously to Example 24.
Reaction SMILES: [NH2:1]/[C:2](=[N:27]\[OH:28])/[C:3]([NH:9][C:10]([C:12]1[CH:17]=[C:16]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:15]([CH:24]2[CH2:26][CH2:25]2)=[CH:14][N:13]=1)=[O:11])([CH2:5][CH:6]1[CH2:8][CH2:7]1)[CH3:4].[N:29]1(C#N)CCCC[CH2:30]1>C(OCC)(=O)C>[NH2:29][C:30]1[O:28][N:27]=[C:2]([C:3]([NH:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])[C:15]([CH:24]3[CH2:25][CH2:26]3)=[CH:14][N:13]=2)=[O:11])([CH3:4])[CH2:5][CH:6]2[CH2:8][CH2:7]2)[N:1]=1
Reactant: N#CN1CCCCC1
Reactant: CC(CC1CC1)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)/C(N)=N/O
Solvent: CCOC(C)=O
Product: CC(CC1CC1)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1noc(N)n1
Temperature: 130 °C
Yield: 65.9 %

Procedure:
A mixture of N-[(2Z)-2-amino-1-(cyclopropylmethyl)-2-hydroxyimino-1-methyl-ethyl]-5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide (example 165a, 30 mg, 74.9 μmol) in piperidine-1-carbonitrile (130 mg, 130 μl, 1.18 mmol) was heated at 130° C. in a sealed tube for 2 hours. The reaction mixture was cooled to room temperature and was diluted with ethyl acetate. The organic phase was washed with water. The organic phase was collected and the aqueous phase was back-extracted with ethyl acetate. Combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (21 mg, 67%). MS (ESI, m/z): 426.6 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)=[CH:4][CH:3]=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[NH2:13][C:9]1[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([NH:1][C:23]([NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:24])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: Nc1ccc(Oc2cc(N)ncn2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Nc1cc(Oc2ccc(NC(=O)Nc3ccccc3)cc2)ncn1
Yield: 69.3 %

Procedure:
6-(4-Aminophenoxy)pyrimidin-4-ylamine (88.9 mg, 0.440 mmol) and phenyl isocyanate (52.4 mg, 0.440 mmol) were stirred together for 3 hours in dimethylformamide (2 ml) at room temperature. The reaction solution was distributed between ethyl acetate and water, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was suspended in ethyl acetate, the suspension was diluted with hexane, and the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (98.0 mg, 0.305 mmol, 69%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[N:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1>[Ni].CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:14]2[N:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]2[CH:20]=[N:21][N:22]=[C:11]2[CH2:10][NH:9]1
Reactant: Clc1ccc2c(n1)C(c1ccccc1Cl)=NCc1nncn1-2
Agent: [Ni]
Solvent: CN(C)C=O
Product: Clc1ccc2c(n1)C(c1ccccc1Cl)NCc1nncn1-2

Procedure:
29 grams of 6-(o-chloro-phenyl)-8-chloro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine were hydrogenated in 500 ml. of dimethyl formamide in the presence of 20 grams of Raney-nickel at 50 atmospheres absolute at 60°-70° C. The filtrate was evaporated, the residue stirred with water and shaken with chloroform. The chloroform residue was stirred with methanol and the thus obtained crystalline reaction product first crystallized from dioxane-gasoline and then recrystallized from methyl ethyl ketone-gasoline. M.P. 206°-208° C.; Yield 10 grams.
Reaction SMILES: Cl.[NH2:2]O.[CH3:4][C:5]([CH3:14])([CH3:13])[C:6](=O)[CH2:7][C:8]([O:10]C)=[O:9].O>C(O)C>[C:5]([C:6]1[NH:2][O:10][C:8](=[O:9])[CH:7]=1)([CH3:14])([CH3:13])[CH3:4]
Reactant: NO
Reactant: COC(=O)CC(=O)C(C)(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc(=O)o[nH]1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A mixture of 8.8 grams (126 mmol, 1 eq) of hydroxylamine hydrochloride and 10 grams (126 mmol, 1 eq) in 40 mL of ethanol was heated to reflux and 20 grams (126 mmol, 1 eq) of methyl 4,4-dimethyl-3-oxopentanoate was added. The reaction mixture was heated for 2 hours and then allowed to cool to room temperature overnight. The mixture formed a precipitate. To this mixture was added 50 mL of water with stirring and more precipitate formed. The solid was collected by filtration and dried. This gave 13.1 grams (48% yield) of the desired product. mp 110°-15° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[N:30]=[C:29](Cl)[C:28]([Cl:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:24][C:25]1[N:30]=[C:29]([NH:1][C:2]2[CH:3]=[C:4]([C:8]#[C:9][C:10]3[CH:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[CH:13]=[CH:12][N:11]=3)[CH:5]=[CH:6][CH:7]=2)[C:28]([Cl:32])=[CH:27][N:26]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(C#Cc2cccc(N)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ccnc(C#Cc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Yield: 91.1 %

Procedure:
To a solution of tert-butyl {2-[(3-aminophenyl)ethynyl]pyridin-4-yl}carbamate (0.50 g, 1.6 mmol) and 2,4,5-trichloropyrimidine (0.19 mL, 1.7 mmol) in N,N-dimethylformamide (5.0 mL) was added potassium carbonate (0.670 g, 4.85 mmol). The resultant mixture was stirred for 40 hours at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine then dried (Na2SO4), filtered and concentrated to give the desired product as a light brown gum (0.665 g, 90%). LCMS for C22H20Cl2N5O2 (M+H)+: m/z=456.0, 458.0.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[O:34][C:33](=[O:35])[C:32]5([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[N:31]=4)=[CH:26][CH:25]=3)[N:23]=2)[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH:6][C:33]([C:32]1([NH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:22]3[N:23]=[C:19]([N:16]4[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]4)[S:20][CH:21]=3)=[CH:25][CH:26]=2)=[O:34])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)=[O:35]
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: CN1CCN(c2nc(-c3ccc(C4=NC5(CCCCC5)C(=O)O4)cc3)cs2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)C1(NC(=O)c2ccc(-c3csc(N4CCN(C)CC4)n3)cc2)CCCCC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 33.3 %

Procedure:
200 mg (1.00 mmol) of L-methionine methyl ester hydrochloride was added to a solution of 411 mg (1.00 mmol) of 2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one and 258 mg (2.00 mmol) of N,N-diisopropylethylamine in 20 ml of dimethylformamide. After the mixture was stirred at 80° C. for 15 hours, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography to obtain 191 mg (33%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([OH:13])=[O:12])[NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Li+].[Li+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>CN(C)C=O>[OH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:12])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2ccc(O)cc2[nH]1
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1cc2ccc(O)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-hydroxy-1H-indole-2-carboxylic acid (2.66 g) in N,N-dimethylformamide (25.0 mL) was added lithium carbonate (1.22 g), followed by stirring at room temperature for 10 minutes. Benzyl bromide (2.14 mL) was added thereto, followed by stirring at 100° C. for 2 hours. The reaction mixture was lowered to 60° C., and 1 M hydrochloric acid (40.0 mL) was added thereto, followed by leaving to be cooled and extracting with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate), and the crude purified product was washed with cold ethanol (5.00 mL) to obtain benzyl 6-hydroxy-1H-indole-2-carboxylate (1.95 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][CH2:8][C:5]2([O:7][CH2:6]2)[CH2:4][O:3]1.[NH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])[NH:18][C:19]2=[O:22])=[CH:14][CH:13]=1>C(O)C.[Br-].[Li+]>[OH:7][C:5]1([CH2:6][NH:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[C:17]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:30])[F:31])[NH:18][C:19]3=[O:22])=[CH:14][CH:13]=2)[CH2:8][O:9][C:2]([CH3:10])([CH3:1])[O:3][CH2:4]1
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: CC1(C)OCC2(CO2)CO1
Agent: [Br-]
Agent: [Li+]
Solvent: CCO
Product: CC1(C)OCC(O)(CNc2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)CO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
6,6-Dimethyl-1,5,7-trioxaspiro[2.5]octane (292 mg, 2.03 mmol) prepared according to a known method described in publications (EP227338, for example) and the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (154 mg, 0.506 mmol) obtained in step C of Example 1-1 were dissolved in ethanol (4 ml). The obtained mixture was stirred at a room temperature for 4 hours and then stirred under heating to reflux for 18 hours. Thereafter, lithium bromide (0.2 mg, mmol) was added to the reaction solution at a room temperature, and the obtained mixture was then stirred for 3 hours. Thereafter, the reaction solution was concentrated, and water was then added thereto, followed by extraction with ethyl acetate. The extract was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=40:1 to 20:1), so as to obtain 7-[(5-hydroxy-2,2-dimethyl-[1,3]dioxan-5-ylmethyl)amino]-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (163 mg, 72%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4([N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:25])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[C:10](=[O:33])[C:9]=2[N:8]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[N:7]=1)=O)C.[OH-].[Na+]>CCO>[C:29]([O:28][C:26](=[O:27])[N:24]([C:21]1([C:18]2[CH:17]=[CH:16][C:15]([N:11]3[CH2:12][CH2:13][C:14]4[C:6]([CH:4]=[O:3])=[N:7][N:8]([C:34]5[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=5)[C:9]=4[C:10]3=[O:33])=[CH:20][CH:19]=2)[CH2:22][CH2:23]1)[CH3:25])([CH3:32])([CH3:30])[CH3:31]
Reactant: CCOC(=O)c1nn(-c2ccc(OC)cc2)c2c1CCN(c1ccc(C3(N(C)C(=O)OC(C)(C)C)CC3)cc1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-n2nc(C=O)c3c2C(=O)N(c2ccc(C4(N(C)C(=O)OC(C)(C)C)CC4)cc2)CC3)cc1
Yield: 99 %

Procedure:
Part A. 6-{4-[1-(tert-Butoxycarbonyl-methyl-amino)-cyclopropyl]-phenyl}-1-(4-methoxy-phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (0.59 g, 1.79 mmol) was stirred in EtOH (15 mL) and 1N NaOH (3 mL) at rt for 1 h. After evaporation, the mixture was acidified with citric acid. The mixture was extracted with EtOAc (2×), washed with H2O and brine, dried over MgSO4, filtered, and concentrated to dryness in vacuo. This acid underwent a series of reactions similar to those used in Part E of Example 1 to afford (1-{4-[3-formyl-1-(4-methoxy-phenyl)-7-oxo-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-phenyl}-cyclopropyl)-methyl-carbamic acid tert-butyl ester (yield: 99%). LC/MS (ESI+) 461.6 (M+H−t-Bu)+, tR=1.2.97 min (10–90% CH3CN/H2O in a 4-min run).
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>ClC(Cl)C.O1CCCC1>[CH3:20][O:19][C:16]1[C:17]2[N:18]=[C:10]([NH:9][C:8]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:27])[S:11][C:12]=2[C:13]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[N:14][CH:15]=1
Reactant: C1COCCN1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N3CCOCC3)nc12
Reaction time: 16 h
Yield: 33.3 %

Procedure:
To a stirred solution of 145 mg (0.38 mmol) (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester in 6 ml dichloroethane and 2 ml tetrahydrofuran at room temperature was added 0.16 ml (1.88 mmol) morpholine and stirring continued at 50° C. for 16 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (ethyl acetate/heptane) followed by trituration in ether afforded 48 mg (34%) morpholine-4-carboxylic acid (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-amide as a white crystalline solid. ES-MS m/e (%): 380 (M+H+, 100).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:49]([N:51]([CH2:66][CH3:67])[S:52](C1C=CC(CS(Cl)(=O)=O)=CC=1)(=[O:54])=[O:53])[CH3:50]>>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:28]=[CH:29][C:30]([C:31]([OH:33])=[O:32])=[CH:34][CH:35]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([CH2:42][C:43]1[CH:44]=[CH:45][C:46]([S:52](=[O:54])(=[O:53])[N:51]([CH2:66][CH3:67])[CH2:49][CH3:50])=[CH:47][CH:48]=1)(=[O:41])=[O:40])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: CCN(CC)S(=O)(=O)c1ccc(CS(=O)(=O)Cl)cc1
Product: CCN(CC)S(=O)(=O)c1ccc(CS(=O)(=O)NCCc2c(CCOc3ccc(C(=O)O)cc3)c3cc(Cl)ccc3n2C(c2ccccc2)c2ccccc2)cc1

Procedure:
The title compound was prepared from 4-{2-[2-(2-amino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic acid methyl ester (Step 6, Example 1) and (4-Diethylsulfamoyl-phenyl)-methanesulfonyl chloride according to Example 1 Step 7.
Reaction SMILES: C([Li])CCC.[C:6](=[O:8])=[O:7].CC(C)=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[C:24]([CH3:34])[O:23][N:22]=2)=[CH:17][CH:16]=1.C(=O)=O>C1COCC1>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[C:24]([CH2:34][C:6]([OH:8])=[O:7])[O:23][N:22]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(-c2noc(C)c2-c2ccc(OC)cc2)cc1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1ccc(-c2noc(CC(=O)O)c2-c2ccc(OC)cc2)cc1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
n-Butyllithium (50 ml of 1.6 molar solution, 80 mmole) is added dropwise to a stirred, cold (dry-ice-acetone bath), solution of 3,4-di(p-methoxyphenyl)-5-methylisoxazol (21.72 g., 73.6 mmole, Ex. 2) in THF (220 ml) under a nitrogen atmosphere. After stirring for 1 hour at -75° C., the red coloured mixture is poured into crushed dry-ice and stirred. The stirred mixture is allowed to warm to room temperature, concentrated, and the residue dissolved in water. The resulting solution is twice extracted with ether, layered with ethyl acetate, cooled in ice and acidified with concentrated hydrochloric acid. The layers are separated and the aqueous layer extracted with ethyl acetate. The combined ethyl acetate layers are dried (MgSO4) and concentrated to give a sticky foam residue. Recrystallization from benzene gives the title compound as a colourless solid, m.p. 142°-143° C. The nmr (CDCl3) spectrum τ 6.2 (8H, s, d, CH3O and --CH2 --), 3.28 to 2.52 (8H, m, aryl H's), 0.45 (1H, broad, COOH) agrees with the assignment.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1.[C:28](Cl)(=[O:38])[O:29][C@@H:30]1[CH:35]2[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]2)[CH2:31]1.O>N1C=CC=CC=1>[C:22]1([C@H:3]([NH:2][C:28]([O:29][C@@H:30]2[CH:35]3[CH2:36][CH2:37][N:32]([CH2:33][CH2:34]3)[CH2:31]2)=[O:38])[C:4]2[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=2)[O:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(Cl)O[C@H]1CN2CCC1CC2
Reactant: COC(=O)c1ccc(COc2cccc([C@@H](N)c3ccccc3)c2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1ccc(COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
To a stirred solution of (S)-methyl 4-((3-(amino(phenyl)methyl)phenoxy)-methyl)benzoate hydrochloride (12.0 g, 31.3 mmol) in pyridine (100 mL) at 0° C. was added portion-wise (R)-quinuclidin-3-yl carbonochloridate (8.50 g, 37.5 mmol). The reaction was stirred at 0° C. for 1 hour and then allowed to warm to RT for 16 hours. Water was added to the reaction mixture and extracted with ethyl acetate (×3). The combined extracts were washed with brine, dried (sodium sulfate), filtered and the solvent evaporated at reduced pressure. The crude material was purified by chromatography on a KP-NH Biotage cartridge eluting with 0-20% methanol in ethyl acetate to afford the title compound (10.3 g, 66%).