Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[NH:6][CH2:5][C:4]2([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]2)[O:3]1.C(N(CC)CC)C.[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>ClCCl>[F:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([N:6]2[CH2:5][C:4]3([CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]3)[O:3][CH:2]2[CH3:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC1NCC2(CCN(C)CC2)O1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1OC2(CCN(C)CC2)CN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C

Procedure:
2,8-Dimethyl-1-oxa-3,8-diaza-spiro[4.5]decane (1.42 g, 8.38 mmol) was dissolved in dry dichloromethane (5 ml) under argon atmosphere. Distilled triethylamine (1.75 ml, 12.57 mmol) was added and the resulted solution was cooled to 0° C. p-Fluorobenzenesulfonyl chloride (1.63 gr, 8.37 mmol) was added and the reaction flask was allowed to warm to room temperature with stirring, and a white solid started to precipitate. After 30 min of stirring, dichloromethane (90 ml) was added and the resulting solution was washed with water (2×10 ml). The organic phase was dried with anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography (silica, CH2Cl2/EtOH/NH4OH 140/10/1) to give AF715 (1.23 g, 98.7% chemical purity) as an off-white powder. 1H NMR. (CDCl3, 500 MHz) δ 7.89-7.87 (m, 2H, CHCSO2), 7.27-7.22 (m, 2H, CHCF), 5.05 (q, J=5.23, 1H, CHCH3), 3.33 (d, J=10.26 Hz, 1H, CHHNS), 3.19 (d, J=10.26 Hz, 1H, CHHNS), 2.52-2.42 (m, 114), 2.34-2.25 (m, 2H), 2.23 (s, 3H, NCH3), 2.18-2.09 (m, 1H), 1.77-1.72 (m, 2H), 1.52 (d, J=5.23 Hz, 3H, CH3CH), 1.25-1.18 (m, 1H), 1.10-1.03 (m, 1H) ppm; 13C NMR (CDCl3, 500 MHz) δ 166.45 and 164.42 (C), 134.0 (C), 130.37 (CH), 130.29 (CH), 116.68 (CH), 116.50 (CH), 86.95 (CH), 66.30 (C), 55.48 (CH2), 52.57 (CH2), 52.11 (CH2), 46.04 (CH3), 35.64 (CH2), 32.84 (CH2), 22.95 (CH3) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[NH2:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([NH:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[O:26])[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Reactant: NCCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)NCCN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 13.1 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (60 mg, 0.16 mmol) in DMF (1 mL) were added 4-(2-aminoethyl)morpholine (32 mg, 0.25 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl) (38 mg, 0.20 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified using chromatography (silica gel, gradient 10% MeOH/ethyl acetate) yielding Compound 50 as a solid (10 mg).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11](=[O:25])[CH:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[C:13](=[O:15])[CH2:14]/2)[CH2:5][CH2:4]1>[Pd].C(O)C>[CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH:10]2[CH2:14][C:13](=[O:15])[CH:12]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=3[CH3:24])[C:11]2=[O:25])[CH2:5][CH2:4]1
Reactant: COC1CCC(/C=C2\CC(=O)C(c3c(C)cc(C)cc3C)C2=O)CC1
Agent: [Pd]
Solvent: CCO
Product: COC1CCC(CC2CC(=O)C(c3c(C)cc(C)cc3C)C2=O)CC1
Reaction time: 3 h
Yield: 94.2 %

Procedure:
To a mixture of 4-[1-(4-Methoxy-cyclohexyl)-meth-(E)-ylidene]-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (150 mg, 0.44 mmol) and ethanol (3.5 ml) is added 5% palladium on carbon (30 mg) and the resulting mixture hydrogenated at 3 bar pressure for 3 hours. The reaction mixture is then filtered through celite and the filtrate concentrated under reduced pressure to give 4-(4-Methoxy-cyclohexylmethyl)-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione as a pale yellow solid (142 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:33][CH2:34][CH2:35][OH:36])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([CH:32]=4)[C:28]([O:30]C)=O)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH3:37]>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:33][CH2:34][CH2:35][OH:36])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]4[CH:24]=[N:25][CH:26]=[C:27]([CH:32]=4)[C:28]([NH2:37])=[O:30])=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: N
Reactant: COC(=O)c1cncc(-c2ccc([C@H](C)N3CC[C@](CCCO)(c4ccc(F)cc4)OC3=O)cc2)c1
Solvent: CCO
Product: C[C@@H](c1ccc(-c2cncc(C(N)=O)c2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
Methyl 5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)nicotinate (30 mg, 0.1 mmol) was dissolved in anhydrous NH3 in EtOH (5 mL). Then the mixture was stirred at rt overnight. The solvent was removed in vacuo to give the crude product, which was purified by preparative HPLC to provide 5-(4-((S)-1-((R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl) nicotinamide (10 mg, 34%). LC-MS Method 2 tR=1.022 min, m/z=478; 1H NMR (CD3OD): 1.31 (m, 1H), 1.56 (m, 3H), 1.59 (m, 1H), 1.91 (m, 2H), 2.17-2.28 (m, 1H), 2.33 (m, 1H), 2.44 (m, 1H), 3.14 (m, 1H), 3.44 (m, 2H), 5.60 (m, 1H), 7.04-7.17 (m, 4H), 7.29 (m, 2H), 7.49 (m, 2H), 8.41 (m, 1H), 8.86 (m, 1H), 8.97 (m, 1H).
Reaction SMILES: CC(C)([O-])C.[K+].C1OCCOCCOCCOCCOCCOC1.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1.[Br:30][C:31]1[C:40]([CH2:41]Br)=[CH:39][C:38]2[C:37]([CH3:44])([CH3:43])[CH2:36][CH2:35][C:34]([CH3:46])([CH3:45])[C:33]=2[CH:32]=1>O1CCCC1>[Br:30][C:31]1[C:40]([CH2:41][N:25]2[CH:29]=[CH:28][CH:27]=[N:26]2)=[CH:39][C:38]2[C:37]([CH3:44])([CH3:43])[CH2:36][CH2:35][C:34]([CH3:46])([CH3:45])[C:33]=2[CH:32]=1
Reactant: c1cn[nH]c1
Reactant: CC1(C)CCC(C)(C)c2cc(CBr)c(Br)cc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(Cn3cccn3)c(Br)cc21
Yield: 48.1 %

Procedure:
To a suspension of 0.955 g (8.52 mmol) of potassium tert-butoxide and 1.877 g (7.10 mmol) 18-crown-6 ether in 35 ml tetrahydrofuran was added 0.580 g (8.52 mmol) pyrazole. After 10 minutes 2.557 g (7.10 mmol) 2-bromo-5,5,8,8-tetramethyl-3-bromomethyl-5,6,7,8-tetrahydronaphthalene was added in 15 ml THF. After 17 hours the reaction was concentrated under reduced pressure and acidified with 1M hydrochloric acid. The aqueous solution was extracted with ethyl ether, washed with saturated sodium bicarbonate, water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude material was purified by flash chromatography (gradient elution with hexane-25% ethyl acetate/hexane) to afford 1.185 g (48%) of 2-bromo-5,5,8,8,-tetramethyl-3-((pyrazol-1-yl)methyl)-5,6,7,8-tetrahydronaphthalene (M+1=348).
Reaction SMILES: Cl.[NH+]1C=CC=CC=1.[C:8]([C:10]1[S:11][C:12]2[CH:18]=[C:17]([O:19]C)[CH:16]=[CH:15][C:13]=2[N:14]=1)#[N:9]>CO>[C:8]([C:10]1[S:11][C:12]2[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:13]=2[N:14]=1)#[N:9]
Reactant: COc1ccc2nc(C#N)sc2c1
Agent: Cl
Agent: c1cc[nH+]cc1
Solvent: CO
Product: N#Cc1nc2ccc(O)cc2s1
Temperature: 190 °C
Yield: 95.8 %

Procedure:
Dry pyridinium hydrochloride (34.0 g, 0.294 mol) and 2-cyano-6-methyoxy-benzothiazole (Aldrich Chemical Co., 3.0 g, 0.016 mol) were added into a 500 mL round bottom flask which was preheated in an oil bath at 100° C. The bath temperature was increased to 190° C. and the reaction mixture was refluxed at this temperature for 2 h. After the completion of reaction, it was cooled to room temperature to obtain a yellow solid which was dissolved in methanol. Silica was added to this solution and evaporated to dryness. This material was then chromatographed using 30% ethyl acetate/hexane to obtain 2.7 g of the product as a white solid (95%): mp 120° C.; 1H NMR (CD3OD) δ5.68 (bs, 1H), 8.02-8.82 (m, 3H); 13C NMR (CD3OD) δ106.96, 114.26, 119.59, 126.53, 133.83, 138.93, 147.25, 160.23; MS m/e (rel intensity) 176 (100), 151 (3), 124 (5), 96 (15), 85 (4), 69 (7), 57 (5); Exact mass: calcd 176.0044, found 176.0047. ##STR24##
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:40])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:21]=[C:20]4[C:16]([C:17]([S:30]([C:33]5[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=5)(=[O:32])=[O:31])=[N:18][N:19]4COCC[Si](C)(C)C)=[CH:15][CH:14]=3)[CH:7]=2)[CH2:3][CH2:2]1.Cl>CO>[CH:1]1([NH:4][C:5](=[O:40])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:13]3[CH:21]=[C:20]4[C:16]([C:17]([S:30]([C:33]5[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=5)(=[O:32])=[O:31])=[N:18][NH:19]4)=[CH:15][CH:14]=3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(S(=O)(=O)c3ccc(F)cc3)nn(COCC[Si](C)(C)C)c2c1
Agent: Cl
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(S(=O)(=O)c3ccc(F)cc3)n[nH]c2c1
Reaction time: 18 h
Yield: 25.8 %

Procedure:
To a solution of N-cyclopropyl-3-[3-[(4-fluorophenyl)sulfonyl]-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-indazol-6-yl]-4-methylbenzamide (Intermediate 71) (0.05 g) in methanol (1.5 ml) was added conc hydrochloric acid (0.75 ml). The solution was heated at reflux for 15 h then left at room temp. for 18 h. The solution was concentrated under vacuum then purified on a Varian Bond-Elut SPE cartridge (silica, 5 g) eluting with cyclohexane:ethyl acetate (1:1) to give the title compound (0.01 g).
Reaction SMILES: CCN(C(C)C)C(C)C.OC(C(F)(F)F)=O.[NH2:17][CH2:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:37])([F:36])[F:35])[CH2:23][CH2:22]1)=[O:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[N+:61]([C:64]1[CH:72]=[CH:71][C:67]([C:68](O)=[O:69])=[CH:66][CH:65]=1)([O-:63])=[O:62]>CN(C=O)C.O>[N+:61]([C:64]1[CH:65]=[CH:66][C:67]([C:68]([NH:17][CH2:18][C:19](=[O:20])[N:21]2[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:35])[F:36])[CH2:25][CH2:26]2)=[O:69])=[CH:71][CH:72]=1)([O-:63])=[O:62]
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 73 %

Procedure:
DIPEA (47 mg, 0.36 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone TFA salt (62 mg, 0.14 mmol) in DMF (1 mL). HOBT (19 mg, 0.14 mmol) and EDCI.HCl (28 mg, 0.14 mmol) were then added at room temperature. After 2 minutes, 4-nitrobenzoic acid (20 mg, 0.12 mmol) was added and the resulting mixture was stirred at room temperature for 4 hrs. Cold water (20 mL) was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to afford 40.7 mg (74% yield) of 4-nitro-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 88.6%, 1H NMR (CDCl3): δ 8.3 (d, 2H), 8.0 (m, 2H), 7.8-7.7 (d, 1H), 7.6 (m, 2H), 7.4-7.3 (d, 2H), 4.4-4.3 (dd, 1H), 4.3-4.2 (dd, 2H), 4.1-3.9 (2m, H), 3.8-3.6 (dd, 2H), 3.6-3.5 (m, 2H), 3.4 (t, 1H), 3.3-3.2 (m, 2H).
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:11]([O-])([O-])[O:12][CH2:13][CH3:14].C(OC(=O)C)(=O)C>>[CH2:8]([O:7][C:5](=[O:6])[C:4](=[CH:11][O:12][CH2:13][CH3:14])[C:3]([CH2:2][Cl:1])=[O:10])[CH3:9]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CCOC([O-])[O-]
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)CCl)C(=O)OCC
Yield: 90.3 %

Procedure:
10 g (60.7 mM) of ethyl 4-chloroacetoacetate, 18 g (121 mM) of ethyl orthoformate and 25 g (245 mM) of acetic anhydride were stirred at 110° C. for 3 hours. Then, excessive ethyl orthoformate and acetic anhydride were distilled off under vacuum and the residue was recrystallized from hexane to obtain 12.1 g of a needle-like crystal with an yield of 90%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][S:8][CH2:9][C:10]([CH2:12][S:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=O)=[O:5])[CH3:2].[C:21]([O:25][CH2:26][CH3:27])(=[O:24])[NH:22][NH2:23].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[CH2:26]([O:25][C:21]([NH:22][N:23]=[C:10]([CH2:12][S:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:9][S:8][CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[O:24])[CH3:27]
Reactant: CCOC(=O)CCSCC(=O)CSCCC(=O)OCC
Reactant: CCOC(=O)NN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Product: CCOC(=O)CCSCC(CSCCC(=O)OCC)=NNC(=O)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 91.3 %

Procedure:
A solution of 1,3-bis[(2-ethoxycarbonylethyl)thio]acetone (6.22 g, 19.3 mmol), ethyl carbazate (2.40 g, 23.1 mmol) and a catalytic amount of p-toluenesulfonic acid in anhydrous acetonitrile (50 mL) containing molecular sieve was stirred for 2 days at room temperature. The reaction was quenched with water/ethyl acetate and filtered. The filtrate was extracted with ethyl acetate. The organic extract was washed with aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated. The residue was triturated with hexane, affording 7.2 g of 1,3-bis[(2-ethoxycarbonylethyl)thio]acetone ethoxycarbonylhydrazone. 1H NMR (CDCl3) δ2.2-2.4 (m, 9H), 2.6-2.8 (m, 8H), 3.42 (s, 2H), 3.54 (s, 2H), 4.1-4.3 (m, 6H), 8.82 (br s, 1H).
Reaction SMILES: C([O:14][C:15]([C:17]1([O:20]/[N:21]=[C:22](/[C:51]2[N:52]=[C:53]([NH:56]C(OC(C)(C)C)=O)[S:54][CH:55]=2)\[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:33])=[O:32])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]3[CH2:41][N:42](C(OC(C)(C)C)=O)[CH2:43][C:38]3=[N:37]2)=[O:24])[CH2:19][CH2:18]1)=[O:16])(C1C=CC=CC=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:56][C:53]1[S:54][CH:55]=[C:51](/[C:22](=[N:21]/[O:20][C:17]2([C:15]([OH:16])=[O:14])[CH2:18][CH2:19]2)/[C:23]([NH:25][C@@H:26]2[C:29](=[O:30])[N:28]([S:31]([OH:34])(=[O:32])=[O:33])[C@@H:27]2[CH2:35][N:36]2[N:40]=[C:39]3[CH2:41][NH:42][CH2:43][C:38]3=[N:37]2)=[O:24])[N:52]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2nc3c(n2)CN(C(=O)OC(C)(C)C)C3)cs1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(/C(=N/OC2(C(=O)O)CC2)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2nc3c(n2)CNC3)cs1
Yield: 61.3 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-((1-((benzhydryloxy)carbonyl)-cyclopropoxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-(tert-butoxycarbonyl)-5,6-dihydropyrrolo[3,4-d][1,2,3]triazol-2(4H)-yl)methyl)-4-oxoazetidine-1-sulfonic acid (20 mg, 0.022 mmol), anisole (5 μl, 0.046 mmol), DCM (300 μL) and TFA (51 μL, 0.66 mmol). The crude residue was purified by reverse phase prep HPLC (XSELECT CSH, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 60 mL/min), affording the title compound (7.3 mg, 60%) as a white powder. LCMS: Rt=0.37 min, m/z=542.1 (M+1) Method 2m_acidic_polar; 1H NMR (500 MHz, D2O) δ 7.18 (s, 1H), 5.51 (d, J=5.3 Hz, 1H), 5.01-4.92 (m, 2H), 4.87 (d, J=6.0 Hz, 1H), 4.61-4.35 (m, 4H), 1.42-1.32 (m, 2H), 1.32-1.23 (m, 2H).
Reaction SMILES: C([O:5][C:6]1[N:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:16][N:15]([C:17]3[C:18]([F:25])=[C:19]([CH2:23][OH:24])[CH:20]=[CH:21][CH:22]=3)[CH2:14]2)=[CH:8][CH:7]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:25][C:18]1[C:19]([CH2:23][OH:24])=[CH:20][CH:21]=[CH:22][C:17]=1[N:15]1[CH2:14][CH:13]([O:12][C:9]2[CH:8]=[CH:7][C:6](=[O:5])[NH:11][CH:10]=2)[CH2:16]1
Reactant: CC(C)(C)Oc1ccc(OC2CN(c3cccc(CO)c3F)C2)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1ccc(OC2CN(c3cccc(CO)c3F)C2)c[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
(3-{3-[(6-tert-Butoxypyridin-3-yl)oxy]azetidin-1-yl}-2-fluorophenyl)methanol (760 mg) was mixed with dichloromethane (5 ml), and TFA (2 ml) was added thereto, followed by stirring at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and a 1 M aqueous NaOH solution and CHCl3 were added thereto. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (CHCl3/MeOH) to obtain 5-({1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}oxy)pyridin-2(1H)-one (428 mg).
Reaction SMILES: C([NH:4][OH:5])(=O)C.C([O-])([O-])=O.[K+].[K+].F[C:13]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]3[C:26](=[O:43])[N:27]([C:30]4[CH:35]=[CH:34][C:33]([N:36]5[CH2:41][CH2:40][CH2:39][CH2:38][C:37]5=[O:42])=[CH:32][CH:31]=4)[CH2:28][CH2:29][C:24]=3[C:23]([C:44]([F:47])([F:46])[F:45])=[N:22]2)=[CH:17][C:14]=1[C:15]#[N:16].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[NH2:16][C:15]1[C:14]2[CH:17]=[C:18]([N:21]3[C:25]4[C:26](=[O:43])[N:27]([C:30]5[CH:35]=[CH:34][C:33]([N:36]6[CH2:41][CH2:40][CH2:39][CH2:38][C:37]6=[O:42])=[CH:32][CH:31]=5)[CH2:28][CH2:29][C:24]=4[C:23]([C:44]([F:46])([F:45])[F:47])=[N:22]3)[CH:19]=[CH:20][C:13]=2[O:5][N:4]=1
Reactant: CC(=O)NO
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)c3c2C(=O)N(c2ccc(N4CCCCC4=O)cc2)CC3)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Nc1noc2ccc(-n3nc(C(F)(F)F)c4c3C(=O)N(c3ccc(N5CCCCC5=O)cc3)CC4)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
Acetohydroxamic acid (54 mg, 0.72 mmol) and K2CO3 (0.2 g, 1.45 mmol) were added to 8 mL of DMF and 4 mL of H2O. The mixture was stirred at rt for 15 min, followed by addition of a solution of 2-fluoro-5-[7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-1-yl]benzonitrile (0.12 g, 0.24 mmol) in DMF(2 mL). The mixture was stirred at rt overnight. The mixture was then partitioned between ethylacetate (40 mL) and water (20 mL), washed with H2O (20 mL×3) and brine (20 mL), dried over Na2SO4, filtered, and concentrated. HPLC (C18 RP., 0.5% TFA, H2O/MeCN gradient) purification gave 100 mg (67% yield) of the title compound as its TFA salt. LRMS (ESI−): 623.4 (M+TFA−H)−. 1H NMR (CDCl3) δ 7.80 (s, 1H), 7.72 (d, 1H), 7.44 (d, 1H), 7.34–7.24 (m, 4H), 4.16 (t, 2H), 3.98 (br, 2H), 3.61 (br, 2H), 3.20 (t, 2H), 2.60 (br, 2H), 1.98–1.89 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:32])[CH:12]2[CH2:31][N:16]3[C:17]4[C:22]([C:23](/[CH:24]=[CH:25]/[C:26]([O:28]CC)=[O:27])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+].CC(O)=O>C1COCC1.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:32])[CH:12]2[CH2:31][N:16]3[C:17]4[C:22]([C:23](/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27])=[C:15]3[CH2:14][CH2:13]2)=[CH:21][CH:20]=[CH:19][CH:18]=4)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1c2n(c3ccccc13)CC(N(C)S(=O)(=O)c1ccc(F)cc1)CC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CN(C1CCc2c(/C=C/C(=O)O)c3ccccc3n2C1)S(=O)(=O)c1ccc(F)cc1
Temperature: 50 °C
Yield: 11.3 %

Procedure:
A solution of 85 mg of the product from Step 2 in 2 mL of THF and 3 mL of MeOH was added 0.5 mL of 2N NaOH. The mixture was heated at 50° C. for 8 h and 1 mL of AcOH was then added, and concentrated. The residue was suspended in 5 mL of water and the solid was collected by filtration, and then purified by Combiflash eluted with a gradient up to 70% EtOAc/hexane containing 5% of AcOH to give 9 mg of the title compound (eluted first). 1H NMR (500 MHz, acetone-d6) d 8.12 (m, 2H), 7.87 (d, 1H), 7.87 (m, 1H), 7.48 (t, 1H), 7.42 (m, 1H), 7.28 (m, 2H), 6.28 (d, 1H), 4.65 (m, 1H), 4.27 (m, 1H), 4.04 (t, 1H), 3.49 (m, 1H), 3.10 (m, 1H), 3.02 (s, 3H), 2.10 (m, 1H), 1.78 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21](Br)[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[CH3:31][C:32](C)([O-])[CH3:33].[K+].C(B1OC(C)(C)C(C)(C)O1)(C)=C.[Cl-].[NH4+]>CN(C)C=O.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>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:15][S:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:32]([CH3:33])=[CH2:31])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)Cn1ncc2c1CCC[C@H]2NS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C=C(C)c1cc(C(F)(F)F)cc(S(=O)(=O)N[C@@H]2CCCc3c2cnn3CC(=O)OCC)c1
Temperature: 130 °C
Yield: 36.8 %

Procedure:
To a solution of [(R)-4-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (Example 1-1, 100 mg, 0.196 mmol) in N,N-dimethylformamide (2 mL) in a microwave vial (5 mL), tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.19 mmol), potassium tert-butoxide (45 mg, 0.4 mmol) and isopropenyl boronic acid pinacol ester (55 μl, 0.294 mmol) were added. After being heated in a microwave oven (130° C., 15 min.), the mixture was poured into aq. ammonium chloride (10 mL) and extracted with dichloromethane (20 mL×3). The combined organic layers were washed with water (10 mL×3) and brine (20 mL), dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (gradient elution, 0-5% methanol in dichloromethane) to afford [(R)-4-(3-isopropenyl-5-trifluoromethyl-benzene-sulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (34 mg, 36.8%) as a white solid, MS calcd. for C21H24F3N3O4S 471, obsd. (ESI+) [(M+H)+] 472.