Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C2(C3C=CC(OC)=CC=3)O[C:13]3[C:15]4[C:20]([C:21](C5C=CC=CC=5)=[C:22]([C:23](OCCO)=[O:24])[C:12]=3C=C2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=CC=1.C(N([CH2:48][CH3:49])CC)C>C(OCC)C>[CH:12]1[C:13]2[C:15]3[C:20]([CH:21]=[CH:48][C:49]=2[O:24][CH2:23][CH:22]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3
Reactant: CCN(CC)CC
Reactant: COc1ccc(C2(c3ccc(OC)cc3)C=Cc3c(C(=O)OCCO)c(-c4ccccc4)c4ccccc4c3O2)cc1
Solvent: CCOCC
Product: C1=Cc2c(ccc3ccccc23)OC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,2-Bis(4-methoxyphenyl)-5-(2-hydroxyethoxycarbonyl)-6-phenyl-[2H]-naphtho[1,2-b]pyran (U.S. Pat. No. 6,113,814) (0.20 g, 0.34 mmol) was dissolved in anhydrous diethyl ether (20 ml) under nitrogen. To this solution was added triethylamine (0.2 ml) followed by the Acid Chloride Terminated Polydimethylsiloxane (Example 1, Step 2) (0.264 g), dropwise. The mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the crude product then purified by column chromatography (silica gel, diethyl ether/hexane, 5:1) giving the bulk product, Naphthopyran Terminated Polydimethylsiloxane, as a pink tar. Analysis by 1H NMR gave a spectrum consistent with the structure, having an average molecular weight (Mn) of 2,592 (nPDMS=14.1).
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=O)[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>O1CCOCC1>[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([C:16]3[C:17](=[S:44])[NH:18][C:19](=[O:33])[N:20]([CH2:22][C:23]4[N:28]=[C:27]([C:29]([O:31][CH3:32])=[O:30])[CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=O)[nH]c2=O)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cccc(Cn2cc(C3c4ccccc4C=Cc4ccccc43)c(=S)[nH]c2=O)n1

Procedure:
A mixture of the product from step (v) (1.84 g) and Lawesson's reagent (1.65 g) in 1,4-dioxane (30 ml) was heated at reflux for 24 hours. The mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase was dried (MgSO4) and evaporated. Purification was by chromatography eluting with 50% ethyl acetate in isohexane. Yield 1.38 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:27][C:28]1[C:35]([F:36])=[CH:34][C:31]([C:32]#[N:33])=[C:30]([F:37])[CH:29]=1.ClC1C=CC(S(N(CC2C=CC(C3OC=CN=3)=C(F)C=2F)[C@@H]2CCCC[C@H]2CO)(=O)=O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:27][C:28]2[CH:29]=[C:30]([F:37])[C:31]([C:32]#[N:33])=[CH:34][C:35]=2[F:36])[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[CH2:18][OH:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: O=S(=O)(N[C@@H]1CCCC[C@H]1CO)c1ccc(Cl)cc1
Reactant: N#Cc1cc(F)c(CBr)cc1F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(c1ccc(Cl)cc1)N(Cc1ccc(-c2ncco2)c(F)c1F)[C@@H]1CCCC[C@H]1CO
Agent: [Cs+]
Product: N#Cc1cc(F)c(CN([C@@H]2CCCC[C@H]2CO)S(=O)(=O)c2ccc(Cl)cc2)cc1F
Yield: 76.9 %

Procedure:
The title compound was synthesized from 4-chloro-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (300 mg, 1.0 mmol), cesium carbonate (390 mg, 1.20 mmol), and 4-(bromomethyl)-2,5-difluorobenzonitrile (278 mg, 1.20 mmol) according to the procedure described for 4-chloro-N-(2,3-difluoro-4-(oxazol-2-yl)benzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (Example 20) to give 4-chloro-N-(4-cyano-2,5-difluorobenzyl)-N-((1R,2R)-2-(hydroxymethyl)cyclohexyl)benzenesulfonamide (350 mg, 77%). 1H NMR (400 MHz, CDCl3) δ ppm 7.74 (m, 2H), 7.59 (dd, J=8.81, 5.79 Hz, 1H), 7.51 (m, 2H), 7.28 (dd, J=8.69, 4.91 Hz, 1H), 4.48 (d, J=15.80 Hz, 1H), 4.39 (d, J=15.80 Hz, 1H), 3.64 (ddd, J=14.00, 9.00, 4.00 Hz, 1H), 3.55 (ddd, J=11.83, 4.78, 3.53 Hz, 1H), 3.16 (ddd, J=11.52, 9.13, 2.27 Hz, 1H), 2.40 (br. s., 1H), 1.68 (d, J=10.58 Hz, 3H), 1.30-1.45 (m, 2H), 0.99-1.21 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[C:9]([O:13][C:14](=[O:23])[NH:15][C@H:16]1[CH2:21][CH2:20][C@@H:19](O)[CH2:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10].C1C(COC(/N=N\C(OCC2C=CC(Cl)=CC=2)=O)=O)=CC=C(Cl)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([O:8][C@H:19]2[CH2:18][CH2:17][C@H:16]([NH:15][C:14](=[O:23])[O:13][C:9]([CH3:11])([CH3:10])[CH3:12])[CH2:21][CH2:20]2)[CH:5]=[N:6][CH:7]=1
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Agent: O=C(/N=N\C(=O)OCc1ccc(Cl)cc1)OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Oc2cncc(Br)c2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate A-7, 5-bromopyridin-3-ol was reacted with (cis)-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester in presence of di-(4-chlorobenzyl)azodicarboxylate and triphenylphosphine to give the title compound as a colorless solid. MS: 371.3 and 373.3 (M+H+).
Reaction SMILES: CCCCCCC=CCCC.Br[CH2:13][CH2:14][C:15]([NH:17][CH:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:16]>C(Cl)Cl>[O:16]=[C:15]1[CH2:14][CH2:13][C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[NH:17]1
Reactant: CCOC(=O)C(NC(=O)CCBr)C(=O)OCC
Agent: CCCC=CCCCCCC
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)OCC)CCC(=O)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.3 %

Procedure:
2(b) 314 μl of 1,8-diaza[5.4.0]-7-undecene were added to a solution of 620 mg of diethyl 2-(3-bromopropionamido)malonate (prepared as described above) dissolved in methylene chloride, and the mixture was stirred at room temperature for 3 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, poured into water and then extracted with diethyl ether, The extract was washed with 5% w/v aqueous hydrochloric acid, with a 5% w/v aqueous solution of sodium bicarbonate and with water, in that order, and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to give a crude product. This was purified by column chromatography through silica gel, eluted with a 2:1 by volume mixture of cyclohexane and ethyl acetate, to give 171 mg of diethyl 2-oxopyrrolidine-5,5-dicarboxylate.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:15]O>>[CH3:1][C:2]1[S:6][C:5]([C:7]([O:9][CH3:15])=[O:8])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)O)s1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)s1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 5-methylthiophene-2-carboxylic acid (100 g, 703 mmol) in methanol (1.0 L) was added conc. sulfuric acid (10 ml) and the mixture was heated under reflux for 2 days. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. Diethyl ether (1.0 L) was added to the residue. The mixture was washed successively with water (500 ml×4) and saturated brine (500 ml), and dried over magnesium sulfate. Filtration and concentration under reduced pressure gave methyl 5-methylthiophene-2-carboxylate (109 g, yield 100%).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:36][C:37]1[CH:41]=[CH:40][NH:39][N:38]=1>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:36][C:37]3[CH:41]=[CH:40][NH:39][N:38]=3)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1cc[nH]n1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNc2cc[nH]n2)no1

Procedure:
Method as for preparation 5 using tert-butyl (3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (500 mg, 0.99 mmol) and 3-aminopyrazole (249 mg, 2.97 mmol) as starting materials.
Reaction SMILES: [CH2:1](Br)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3].[CH2:11]([N:18]1[CH2:23][NH:22][C:21](=[S:24])[NH:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC(C)=O>[CH2:11]([N:18]1[CH2:23][N:22]2[C:2]([OH:3])([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1][S:24][C:21]2=[N:20][CH2:19]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: S=C1NCN(Cc2ccccc2)CN1
Reactant: O=C(CBr)c1ccccc1
Solvent: CC(C)=O
Product: OC1(c2ccccc2)CSC2=NCN(Cc3ccccc3)CN21
Reaction time: 2 h

Procedure:
A solution of 5.0 grams (0.025 moles) of phenacyl bromide in 40 milliliters of acetone was mixed with a solution of 5.2 grams (0.025 moles) of 5-benzyl-3,4,5,6-tetrahydro-s-triazine-2(1H)-thione in 1200 milliliters of the same solvent and left for 2 hours at room temperature. The solution was then concentrated to 300 milliliters and left overnight. 3-Benzyl-6-hydroxy-6-phenyl-3,4,6,7-tetrahydro-2H-thiazolo[3,2-a]-s-triazine hydrobromide acetonate crystallized as a pale brown solid, m.p. 97°-99° C. The yield was 9.5 grams (82%).
Reaction SMILES: C[C:2](C)([O-:4])C.[K+].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[C:9]1[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20].C(OC)=O>C1COCC1>[OH:4][CH:2]=[C:18]([CH2:17][C:9]1[N:8]([CH3:7])[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CCc1cc2ccccc2n1C
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: COC=O
Product: COC(=O)C(=CO)Cc1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a suspension of potassium tert-butoxide (300 mg, 2.67 mmol) in dry THF (5 mL) were added dropwise a solution of methyl 3-(1-methyl-1H-indol-2-yl)propanoate (322 mg, 1.482 mmol) and methyl formate (0.30 mL, 4.87 mmol) in dry THF (5 mL) over 15 min. The mixture was stirred at room temperature for 1 h. Concentration in vacuo then afforded the title compound (400 mg, 0.522 mmol, 35.2% yield). LCMS: rt=2.82 min, [M+H+]=246
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.CC1C=CC(S(O[CH2:56][C@@H:57]2[CH2:62][O:61][CH2:60][CH2:59][O:58]2)(=O)=O)=CC=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[O:58]1[CH2:59][CH2:60][O:61][CH2:62][C@@H:57]1[CH2:56][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COCCO2)cc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCCO3
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(C[C@H]2COCCO2)c2ccccc2C12COc1cc3c(cc12)OCCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using 3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]-benzodioxole-7,3′-indol]-2′(1′H)-one, and (S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, 1′-[(2S)-1,4-dioxan-2-ylmethyl]-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one was obtained (91%) as a colorless solid: mp 137-139° C. (hexanes/diethyl ether); 1H NMR (300 MHz, CDCl3) (diastereomers) δ 7.33-7.27 (m, 1H), 7.14 (d, J=7.2 Hz, 1H), 7.08-7.01 (m, 2H), 6.58 (s, 1H), 6.36, 6.33 (s, 1H), 4.91, 4.90 (d, J=9.0 Hz, 1H), 4.67, 4.66 (d, J=9.0 Hz, 1H), 4.28-4.20 (m, 1H), 4.14-4.02 (m, 2H), 3.99-3.78 (m, 5H), 3.76-3.57 (m, 4H), 3.46-3.38 (m, 1H), 2.22-2.00 (m, 2H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ177.8, 177.7, 156.8, 156.7, 153.08, 153.05, 146.38, 146.35, 142.65, 142.63, 132.3, 132.2, 129.0, 128.9, 124.0, 123.9, 123.6, 123.2, 123.1, 116.1, 116.0, 109.6, 109.4, 103.59, 103.56, 80.5, 80.4, 73.34, 73.31, 70.9, 69.4, 69.2, 66.8, 66.7, 66.52, 66.49, 57.98, 57.96, 41.9, 41.8, 32.3; MS (ES+) m/z 410.0 (M+1).
Reaction SMILES: [OH:1][CH:2]1[CH2:10][CH2:9][CH2:8][C:7]2([CH3:11])[CH:3]1[CH2:4][CH2:5][CH:6]2[CH:12]([CH3:22])[CH2:13][CH:14]1[O:18][C:17](=[O:19])[C:16]([OH:21])([CH3:20])[CH2:15]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1C1C=CC=C[NH+]=1.[Cr](Cl)([O-])(=O)=O>C(O)(C)C.C(Cl)Cl>[CH3:11][C:7]12[CH:6]([CH:12]([CH3:22])[CH2:13][CH:14]3[O:18][C:17](=[O:19])[C:16]([OH:21])([CH3:20])[CH2:15]3)[CH2:5][CH2:4][CH:3]1[C:2](=[O:1])[CH2:10][CH2:9][CH2:8]2
Reactant: CC(CC1CC(C)(O)C(=O)O1)C1CCC2C(O)CCCC12C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1ccc(-c2cccc[nH+]2)[nH+]c1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(CC1CC(C)(O)C(=O)O1)C1CCC2C(=O)CCCC21C

Procedure:
A solution of 90.0 mg (0.290 mmol) of [3R-[3 beta,5S,(5beta,(R*)-1R*-(1 beta,3a alpha,4alpha,7a beta)]]-dihydro-5-[2-(octahydro-4-hydroxy-7a-methyl-1H-inden-1-yl)-2-methylethyl]-3-hydroxy-3-methyl-2(3H)-furanone in 4 ml. of dry methylene chloride was treated at room temperature with 340.0 mg (1.162 mmol) of 2,2'-bipyridinium chlorochromate for 5.5 hours. A few drops of isopropyl alcohol were then added and the resulting mixture diluted with 50 ml of methylene chloride, filtered through Celite® filter aid. After evaporation of the solvent, the residue was dissolved in 100 ml. of ethyl acetate, extracted with 3×20 ml. of 1N hydrochloric acid and then with 3×30 ml of brine. The organic phases were combined, dried and evaporated to give 89.0 mg (quantitative yield) of [3R-[3 beta,5S,(5 beta,(R*)-1R*-(1 beta,3a alpha,7a beta)]]-dihydro-5-[2-(octahydro-7a-methyl-1H-inden-4-one-1-yl)-2-methylethyl]-3-hydroxy-3-methyl-2(3H)-furanone.
Reaction SMILES: Cl[C:2]1[C:3](=[O:26])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([F:25])[F:24])=[CH:18][CH:17]=2)[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1>>[F:24][CH:23]([F:25])[O:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:4]2[C:3](=[O:26])[C:2]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([O:28][CH3:27])=[CH:30][CH:31]=3)=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:5]2(=[O:14])=[O:13])=[CH:17][CH:18]=1
Reactant: COc1ccc(N)cc1
Reactant: O=C1C(Cl)=C(c2ccccc2)S(=O)(=O)N1Cc1ccc(OC(F)F)cc1
Product: COc1ccc(NC2=C(c3ccccc3)S(=O)(=O)N(Cc3ccc(OC(F)F)cc3)C2=O)cc1

Procedure:
The title compound was prepared from 4-chloro-2-[4-(difluoromethoxy)benzyl]-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 4-methoxyaniline in a similar manner as described for e.g. Examples 14 and 30. H NMR (400 MHz, CDCl3): δ 3.67 (s, 3H), 4.86 (s, 2H), 6.48-6.52 (m, 2H), 6.50 (t, J=74 Hz, 1H), 6.60-6.64 (m, 2H), 7.09-7.14 (m, 7H), 7.52-7.56 (m, 2H); 13C NMR (100 MHz, CDCl3): δ 42.8, 55.5, 109.9, 113.6, 115.8 (t, J=259 Hz), 119.6, 123.8, 124.6, 128.0, 128.7, 129.0, 129.3, 130.6, 131.3, 131.4, 151.2, 157.3, 159.3; Mass Spectrum: M−H+ 485.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[F:24][C:21]([F:22])([F:23])[C:18]1[CH:19]=[CH:20][C:15]([O:14][C:9]2[C:8]3[C:13](=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=3)[N:12]=[CH:11][CH:10]=2)=[CH:16][CH:17]=1
Reactant: O=[N+]([O-])c1cccc2c(Oc3ccc(C(F)(F)F)cc3)ccnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1cccc2c(Oc3ccc(C(F)(F)F)cc3)ccnc12
Yield: 70.2 %

Procedure:
The title compound was prepared following the procedure described in Intermediate-11, step-4 using 8-nitro-4-(4-(trifluoromethyl)phenoxy)quinoline (200 mg, 0.59 mmol), iron powder (335 mg, 5.98 mmol), and NH4Cl (260 mg, 4.70 mmol) in EtOH (5 mL) and water (1 mL) to afford 126 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 8.60 (d, J=4.8 Hz, 1H), 7.85 (d, J=8.7 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H), 7.31 (d, J=7.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 6.92 (d, J=7.2 Hz, 1H), 6.85 (d, J=5.4 Hz, 1H), 6.01 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[Cu](C#N)[C:13]#[N:14]>CN(C=O)C.C(OCC)(=O)C>[O:9]=[C:7]1[NH:6][C:5]2[CH:10]=[CH:11][C:2]([C:13]#[N:14])=[CH:3][C:4]=2[O:8]1
Reactant: O=c1[nH]c2ccc(Br)cc2o1
Reactant: N#C[Cu]C#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(=O)oc2c1

Procedure:
A mixture of 6-bromo-3H-benzooxazol-2-one (47) (400 mg, 1.87 mmol, 1 eq), copper cyanide (3.3 g, 37 mmol, 20 eq), in DMF (10 ml) was stirred at 175° C. for 3 hours. The reaction mixture was diluted with ethyl acetate, filtered to remove the precipitated solid material, and the organic phase was washed with water, purified by flash chromatography to give 2-oxo-2,3-dihydro-benzooxazole-6-carbonitrile (48).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:37])[NH:23][CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:38]([CH:41]4[CH2:46][CH2:45][N:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:43][CH2:42]4)[N:39]=[CH:40][C:10]=13)[CH2:2]2>C(Cl)Cl.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>[CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:23][CH:24]4[CH2:25][CH2:26][NH:27][CH2:28][CH2:29]4)=[O:37])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:38]([CH:41]4[CH2:46][CH2:45][N:44]([C:47]([O:49][CH2:50][CH3:51])=[O:48])[CH2:43][CH2:42]4)[N:39]=[CH:40][C:10]=13)[CH2:2]2
Reactant: CCOC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)NC5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc32)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)NC5CCNCC5)cc4)nc32)CC1
Yield: 88 %

Procedure:
A solution of tert-butyl 4-(3-(4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1-(ethoxycarbonyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)phenyl)ureido)piperidine-1-carboxylate (0.054 mmol) in CH2Cl2 (1 mL) and trifluoroacetic acid (0.2 mL) is stirred at room temperature for 2 hours, diluted with saturated sodium bicarbonate, extracted with CH2Cl2, washed with brine, dried and concentrated. Purification by HPLC provides ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-piperidin-4-ylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate (88%). (HRMS=604.3356 (M+H, obs.), 604.3354 (M+H, calc.))
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH2:25])[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][CH:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([NH:25][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:20]=3)(=[O:18])=[O:17])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(N)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cccc(NC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of [4-(3-amino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (30 mg, 0.079 mmol) and benzoyl chloride (16.4 mg, 0.119 mmol) in tetrahydrofuran (3 mL) was added triethylamine (16 mg, 0.158 mmol) at 0° C. After being stirred at room temperature overnight, the mixture was concentrated in vacuo. The residue was purified by flash column (gradient elution, 0-5% methanol in dichloromethane) to afford [4-(3-benzoylamino-benzenesulfonylamino)-4,5,6,7-tetrahydro-indazol-1-yl]-acetic acid ethyl ester (27.4 mg, 72%) as a white solid. MS cald. for C24H26N4O5S 482, obsd. (ESI+) [(M+H)+] 483.
Reaction SMILES: [C:1]([O:4][CH2:5][C@H:6]1[NH:9][C:8](=[O:10])[C@H:7]1[NH2:11])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].[Cl:17][CH2:18][C:19]([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:31][O:32][CH3:33])[C:28](Cl)=[O:29])[N:26]=1)=[O:20].O>O1CCCC1>[C:1]([O:4][CH2:5][C@H:6]1[NH:9][C:8](=[O:10])[C@H:7]1[NH:11][C:28](=[O:29])[C:27]([C:25]1[N:26]=[C:22]([NH:21][C:19](=[O:20])[CH2:18][Cl:17])[S:23][CH:24]=1)=[N:31][O:32][CH3:33])(=[O:3])[CH3:2]
Reactant: CON=C(C(=O)Cl)c1csc(NC(=O)CCl)n1
Reactant: CC(=O)OC[C@H]1NC(=O)[C@H]1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON=C(C(=O)N[C@@H]1C(=O)N[C@@H]1COC(C)=O)c1csc(NC(=O)CCl)n1

Procedure:
Under ice-cooling and stirring, 12 ml of an aqueous solution containing 632 mg of cis-4-acetoxymethyl-3-amino-2-oxoazetidine and 1.122 g of sodium hydrogen carbonate is added to a suspension of 2.36 g of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl chloride (syn-isomer) in 20 ml of tetrahydrofuran. The mixture is stirred for 2 hours at room temperature and the solvent is then distilled off in vacuo to leave the residue, which solidifies. Water is added to the solidified residue, followed by filtration. The collected crystals are washed successively with an aqueous sodium hydrogen carbonate solution, water and ether and dried to give cis-4-acetoxymethyl-3-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-2-oxoazetidine (syn-isomer), m.p. 180°-190° C. (dec.).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[C:7](Cl)(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>O1CCCC1>[C:7]([N:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6])(=[O:12])[C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)C(=O)Cl
Reactant: O=C1NCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)N1CCNC1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A suspension, cooled to 0°C, of imidazolidin-2-one (17.2 parts by weight) in tetrahydrofurane (200 parts by volume) was treated dropwise over the course of one hour, with pivaloyl chloride (24.2 parts by weight) at the same temperature. The mixture was then stirred for a further 3 hours at 0°C, triethylamine (27.8 parts by volume) was subsequently added dropwise while cooling with ice water, and the mixture was then left to stand overnight at room temperature. The triethylamine hydrochloride which had separated out was then filtered off, the filtrate was completely concentrated in vacuo by means of a rotary evaporator and the residue was further warmed for 1 hour, in vacuo, in a bath at 60°C. The oily product (crude yield: 32.8 parts by weight) was further processed, as it was. When an attempt was made to distill the substance in vacuo, severe decomposition occurred.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([F:21])[CH:20]=1)[NH2:17].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[N:7]=[C:6]([C:8]#[N:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=2)[CH:18]=[C:19]([F:21])[CH:20]=1
Reactant: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1cc(F)cc(F)c1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1nc(Nc2cc(F)cc(F)c2)ccc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 29.4 %

Procedure:
A mixture of 6.5 g of 6-chloro-3-nitropicolinonitrile (0.065 mol) and 6.2 g of 3,5-difluoroaniline (0.048 mol) in 100 ml of toluene is heated at 70° C. for 5 hours. The crude reaction product is diluted in an ethyl acetate fraction and washed using saturated NaCl solution. The organic phase is dried with sodium sulfate and the residue purified by silica gel chromatography (AcOEt/petroleum ether) to yield 3.9 g (33%) of a yellow solid.