Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C(=O)[S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:6]=1[NH2:18].[OH-].[K+].O>C(O)CO>[NH2:18][C:6]1[CH:7]=[C:8]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:9]=[CH:10][C:5]=1[S:4][S:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][C:6]=1[NH2:18]
Reactant: CN(C)C(=O)Sc1ccc(Cc2ccccc2)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Nc1cc(Cc2ccccc2)ccc1SSc1ccc(Cc2ccccc2)cc1N
Temperature: 60 °C

Procedure:
To a slurry of S-2-amino-4-benzylphenyl dimethylcarbamothioate (1.43 g, 4.99 mmol) in 15 mL ethylene glycol was added potassium hydroxide (0.840 g, 15.0 mmol) (solid, finely crushed). The reaction was heated to 60° C. under nitrogen. 10 mL 2-BuOH was added as cosolvent and the resulting solution was heated for 2 h. The reaction was fitted with a water-cooled reflux condensor and heated to 90° C. for 3 h. The reaction was cooled, and concentrated in vacuo. The material was partitioned between Et2O and water. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give an oil, which was purified by silica gel chromatography, ISCO, 0-30% EtOAc/hexanes to give 2-(2-(2-amino-4-benzylphenyl)disulfanyl)-5-benzylbenzenamine as a brown oil. MS (ESI) m/z: Calculated: 428.1; Observed: 429.0 (M++1).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[C:27]([C:28]2[CH2:32][CH2:31][O:30][N:29]=2)=[C:26]([S:33]([CH3:36])(=[O:35])=[O:34])[CH:25]=[CH:24][C:13]=1[C:14]([C:16]1[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=1[OH:21])=[O:15]>O1CCOCC1>[CH2:3]([O:21][C:20]1[N:19]([CH2:22][CH3:23])[N:18]=[CH:17][C:16]=1[C:14](=[O:15])[C:13]1[CH:24]=[CH:25][C:26]([S:33]([CH3:36])(=[O:35])=[O:34])=[C:27]([C:28]2[CH2:32][CH2:31][O:30][N:29]=2)[C:12]=1[Cl:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1ccccc1
Reactant: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2Cl)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCn1ncc(C(=O)c2ccc(S(C)(=O)=O)c(C3=NOCC3)c2Cl)c1OCc1ccccc1
Yield: 20.5 %

Procedure:
1.44 g (60 mmol) of sodium hydride and 10.40 g (60 mmol) of benzyl bromide were added a little at a time to a solution of 6.00 g (15 mmol) of 4-[2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl]-1-ethyl-5-hydroxy-1H-pyrazole in 300 ml of dry dioxane. The mixture was stirred under reflux for 24 hours, the solvent was removed under reduced pressure and the residue was taken up in dichloromethane and washed three times with water. The organic phase was dried and concentrated and the residue was chromatographed over silica gel (eluent: N-pentane/ethyl acetate). 1.5 g (20% of theory) of 5-benzyloxy-4-[2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylsulfonylbenzoyl]-1-ethyl-1H-pyrazole were obtained (mp.: 70-75° C.).
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[N:4]([CH2:10][CH2:11][C:12](O)=[O:13])[C:3]1=[O:15].C(Cl)(=O)C([Cl:19])=O.C(Cl)Cl>CN(C)C=O>[CH3:1][N:2]1[C:6](=[O:7])[C:5]([CH3:9])([CH3:8])[N:4]([CH2:10][CH2:11][C:12]([Cl:19])=[O:13])[C:3]1=[O:15]
Reactant: CN1C(=O)N(CCC(=O)O)C(C)(C)C1=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C(=O)N(CCC(=O)Cl)C(C)(C)C1=O
Temperature: 24 °C
Reaction time: 0.92 h
Yield: 97.7 %

Procedure:
A mixture of 10.71 g (50 mmol) 3-(3,5,5-trimethyl-2,4-dioxo-imidazolidin-1yl)-propionic acid (synthetized according to example 15), 31.73 g oxalyl chloride, 25 ml methylenechloride and 0.5 ml dimethylformamide is stirred for 1 h and 55 minutes at 24° C., thereafter evaporated in a rotary evaporator at 70° C. in vacuo, stripped 3 times with about 50 ml of toluene, evaporated completely do dryness and dried at 70° C./10.1 mbar. 11.36 g (97.6% of theory) of crystalline 3-(3,5,5-trimethyl-2,4-dioxo-imidazolidin-1yl)-propionylchloride are obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=3)[N:12]=2)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:6]=1)=[O:4].[O:33]=[C:34]([N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[CH2:35][C:36]#[N:37].N1CCCCC1>CO>[CH3:1][C:2]([CH3:32])([CH3:31])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([NH:14][C:15]3[CH:22]=[CH:21][C:18]([CH:19]=[C:35]([C:34]([N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)=[O:33])[C:36]#[N:37])=[CH:17][CH:16]=3)[N:12]=2)[N:7]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:28])[CH3:29])[CH:6]=1)=[O:4]
Reactant: N#CCC(=O)N1CCCCC1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=C(C#N)C(=O)N4CCCCC4)cc3)nc12
Reaction time: 5 h
Yield: 59.6 %

Procedure:
To a 20 ml vial 4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxymethyl)-pyrrolo[2,3-b]pyrazin-2-yl]amino]benzaldehyde (35 mg, 0.0800 mmol), 3-oxo-3-(1-piperidyl)propanenitrile (18.01 mg, 0.1200 mmol), piperdine (0.02 ml, 0.15 mmol) and 3-oxo-3-(1-piperidyl)propanenitrile (18.01 mg, 0.12 mmol), were taken in methanol (5 ml). To this reaction mixture, piperdine (0.02 ml, 0.15 mmol) was added drop wise at RT. After completion of the addition, the reaction mixture was stirred for 5 hrs. Ethanol was evaporated, the residue was loaded on silica gel column and elution with CH2Cl2 to MeOH 0-2, 3% yielded 28 mg of 3-[4-[[7-(2,2-dimethylpropanoyl)-5-(2-trimethylsilylethoxymethyl)pyrrolo[2,3-b]pyrazin-2-yl]amino]phenyl]-2-(piperidine-1-carbonyl)prop-2-enenitrile.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1.[C-:11]#[N:12].[K+]>C(#N)C.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[N:8]1[CH:9]=[CH:10][C:5]([CH2:4][CH2:3][CH2:2][C:11]#[N:12])=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: ClCCCc1ccncc1
Agent: [K+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CC#N
Product: N#CCCCc1ccncc1
Temperature: 25 °C
Yield: 84.5 %

Procedure:
To the product of Example 21 (6.7 g, 42.9 mmol) in 300 mL of acetonitrile (CH3CN), was added potassium cyanide (KCN, 11.2 g, 171.7 mmol) and dibenzo-18-crown-6 (1.0 g, 2.8 mmol). After the reaction had been refluxed for 18 hours, it was cooled to room temperature, and stripped of all solvent under reduced pressure. The residue was partitioned between 100 mL each of water and CH2C2 and the aqueous phase was washed with 3×100 mL of CH2Cl2. The combined organic phase was dried (Na2SO4), filtered, and stripped of solvent to yield 6.7 g of crude product. This material was purified by HPLC on silica gel to yield 5.3 g of the title material as a yellow oil.
Reaction SMILES: [C:1]([CH2:5][OH:6])([F:4])([F:3])[F:2].N1C=CC=CC=1.[CH2:13]([S:15](Cl)(=[O:17])=[O:16])[CH3:14].Cl.N1C=CC=CC=1>>[C:1]([CH2:5][O:6][S:15]([CH2:13][CH3:14])(=[O:17])=[O:16])([F:4])([F:3])[F:2]
Reactant: CCS(=O)(=O)Cl
Reactant: OCC(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)OCC(F)(F)F

Procedure:
A 10-L four-neck flask was equipped with a refluxing pipe and a dropping funnel to serve as a reactor. To the flask were added CF3CH2OH (337.1 g; 3.37 mol) and pyridine (306.31 g; 3.88 mol) in an ice bath, and the mixture was stirred. Using the dropping funnel, ethanesulfonyl chloride (364.15 g; 3.20 mol) was dropped, with care for heat generation. The reaction solution changed its color gradually to milky white as pyridine hydrochloride was produced. After the end of the reaction, the reaction solution was washed with a 1 N HCl aqueous solution. The washed solution was separated to collect an organic layer.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18](O)=[O:19])[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[CH2:54]([O:56][C:57](=[O:65])[C:58]1[CH:63]=[CH:62][C:61]([NH2:64])=[CH:60][CH:59]=1)[CH3:55]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18](=[O:19])[NH:64][C:61]3[CH:62]=[CH:63][C:58]([C:57]([O:56][CH2:54][CH3:55])=[O:65])=[CH:59][CH:60]=3)[CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(C(=O)O)cc21
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(C(=O)OC(C)(C)C)CCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3,4-dihydro-2H-quinoline-1,7-dicarboxylic acid 1-tert-butyl ester (1.0 g, 3.61 mmol) in dimethylformamide (20 ml) was treated with diisopropyl ethyl amine (0.51 g, 3.97 mmol, 1.1 equiv.), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (1.27 g, 3.97 mmol, 1.1 equiv.) and 4-amino-benzoic acid ethyl ester (0.65 g, 3.97 mmol, 1.1 equiv.). The mixture was stirred at room temperature overnight, then the solvent was evaporated and the residue purified by flash chromatography (heptane/ethyl acetate gradient) to afford 7-(4-ethoxycarbonyl-phenylcarbamoyl)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester as a white solid, 1.1 g (70%). MS (ISP): m/e=423.1 (M−H).
Reaction SMILES: [Cl-].[NH4+].[B-](F)(F)(F)F.CCOC(C(C#N)=[N:14]OC(N(C)C)=[N+](C)C)=O.C(N(CC)C(C)C)(C)C.[CH3:34][C:35]1[N:44]([CH2:45][CH2:46][CH3:47])[C:43](=[O:48])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:49]([C:51]3[N:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]4=[C:53]([C:60]4[CH:61]=[C:62]([CH:66]=[CH:67][CH:68]=4)[C:63]([OH:65])=O)[N:52]=3)=[O:50])[CH:41]=2)[N:36]=1>CN(C=O)C>[CH3:34][C:35]1[N:44]([CH2:45][CH2:46][CH3:47])[C:43](=[O:48])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:49]([C:51]3[N:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]4=[C:53]([C:60]4[CH:61]=[C:62]([CH:66]=[CH:67][CH:68]=4)[C:63]([NH2:14])=[O:65])[N:52]=3)=[O:50])[CH:41]=2)[N:36]=1
Reactant: CCCn1c(C)nc2ccc(C(=O)c3nc(-c4cccc(C(=O)O)c4)c4ccccn34)cc2c1=O
Reactant: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCn1c(C)nc2ccc(C(=O)c3nc(-c4cccc(C(N)=O)c4)c4ccccn34)cc2c1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.4 %

Procedure:
0.107 g (2 mmol) of ammonium chloride, 0.328 g (1 mmol) of TOTU and 0.517 g (4 mmol) of N,N-diisopropylethylamine are added, at ambient temperature under an inert atmosphere, to 0.233 g (0.5 mol) of 3-{3-[(2-methyl-4-oxo-3-propyl-3,4-dihydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic acid in 30 ml of DMF. The reaction medium is stirred for 5 hours at ambient temperature and then concentrated under reduced pressure. 50 ml of a saturated solution of sodium hydrogen carbonate are added to the residue. The precipitate obtained is filtered off, and then dried under reduced pressure at 50° C. overnight. 0.230 g of a yellow solid is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:18]([CH3:31])=[CH:19][C:20]([CH:27]4[CH2:30][CH2:29][CH2:28]4)=[C:21]([CH:26]=3)[C:22]([NH:24][NH2:25])=[O:23])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].CS(O)(=O)=O.C(O[C:40](OCC)(OCC)[CH2:41][CH3:42])C>O1CCOCC1.C(OCC)(=O)C>[CH:27]1([C:20]2[C:21]([C:22]3[O:23][C:40]([CH2:41][CH3:42])=[N:25][N:24]=3)=[CH:26][C:17]([C:15]([N:12]3[CH2:11][CH2:10][CH:9]([C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)[CH2:14][CH2:13]3)=[O:16])=[C:18]([CH3:31])[CH:19]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: Cc1cc(C2CCC2)c(C(=O)NN)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: CCOC(CC)(OCC)OCC
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)o1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 78.8 %

Procedure:
To a round-bottom flask was added a solution of 5-(4-(4-cyanophenyl)piperidine-1-carbonyl)-2-cyclobutyl-4-methylbenzohydrazide (compound 230.4, 150 mg, 0.360 mmol, 1.00 equiv) in dioxane (5 mL). MeSO3H (7 mg, 0.07 mmol, 0.20 equiv), and 1,1,1-triethoxypropane (190 mg, 1.08 mmol, 3.00 equiv) were added to the reaction. The resulting solution was stirred for 20 min at 110° C., then cooled to room temperature and diluted with 50 mL of ethyl acetate. The organic layer was washed with 2×20 mL of water, dried over anhydrous sodium sulfate and concentrated in vacuo. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (64.0% CH3CN up to 76.0% in 6 min, up to 100.0% in 4 min, down to 64.0% in 1 min); Detector, Waters 2489 254&220 nm. The fractions containing pure compound were combined and lyophilized to yield 129 mg (79%) of the title compound as a white solid. m/z (ES+) 455 (M+H)+. 1H-NMR (300 MHz, CD3OD, ppm): δ 7.73-7.67 (m, 3H), 7.52-7.48 (m, 3H), 5-4.94 (m, 1H), 4.25-4.20 (m, 1H), 3.60-3.58 (m, 1H), 3.33-3.24 (m, 1H), 3.05-2.97 (m, 4H), 2.49 and 2.30 (2 singlets, amide rotamers, CH3, 3H), 2.39-2.34 (m, 2H), 2.19-1.91 (m, 4H), 1.88-1.66 (m, 4H), 1.49-1.42 (t, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)C1C=CC=CC=1.[F:15][C:16]([F:48])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:39][CH2:38][C:25]2([N:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:28]([CH3:36])[NH:27][C:26]2=[O:37])[CH2:24][CH2:23]1)=[O:21].ClCCN1CCCC1>>[F:48][C:16]([F:15])([F:47])[C:17]1[CH:18]=[C:19]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[C:20]([N:22]1[CH2:23][CH2:24][C:25]2([N:29]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:28]([CH3:36])[N:27]([CH2:12][CH2:13][N:8]3[CH2:1][CH2:11][CH2:10][CH2:9]3)[C:26]2=[O:37])[CH2:38][CH2:39]1)=[O:21]
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: CC1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1
Agent: ClCCN1CCCC1
Product: CC1N(CCN2CCCC2)C(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)N1c1ccccc1

Procedure:
The title compound, MS: m/e=583.2 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one 1-benzyl-piperidin-4-one and 1-(2-chloroethyl)pyrrolidine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([Cl:12])=[CH:5]2.C([Sn](CCCC)(CCCC)[C:18]1[S:22][CH:21]=[N:20][CH:19]=1)CCC>COCCOC.CO.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>[Cl:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[CH:11][CH:10]=2
Reactant: Clc1cc2cc(Br)ccc2cn1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Solvent: CO
Product: Clc1cc2cc(-c3cncs3)ccc2cn1
Temperature: 120 °C
Reaction time: 1 h
Yield: 27.9 %

Procedure:
A suspension of 6-bromo-3-chloroisoquinoline (39 mg, 0.16 mmol), 5-(tributylstannyl)-thiazole (72 mg, 0.19 mmol) and Pd(PPh3)4 (18.6 mg, 0.016 mmol) in DME/MeOH (3/1 mL) was stirred at 120° C. under microwave irradiation for 60 minutes. The reaction mixture was filtered and concentrated in vacuo. The residue was purified using Biotage silica gel column chromatography eluting with 25% EtOAc in cyclohexane to afford the title compound (11 mg, 28%).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([NH2:30])=[O:29]>CN(C)C=O.ClCCl>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:27][C:28]([NH2:30])=[O:29])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: NC(=O)CBr
Reactant: Oc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: NC(=O)COc1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reaction time: 216 h

Procedure:
A mixture of 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenol (0.28 g, Example 30), potassium carbonate (0.16 g) and 2-bromoacetamide (0.16 g) was stirred together at ambient temperature in dry dimethyl formamide (5 ml) for 4 days and then allowed to stand at ambient temperature for 9 days. The mixture was diluted with dichloromethane (50 ml) and washed with 1M aqueous sodium hydroxide solution and then with water. Some insoluble material which remained throughout the extractions was collected by filtration. The solid was purified by flash column chromatography on silica using ethyl acetate as the mobile phase. Appropriate fractions were collected, combined and evaporated to give 2-[4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy]acetamide, m.p. 247-248° C.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[NH2:13].O>C1(C)C=CC=CC=1>[CH:1](=[N:13]/[C:12]1[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=1[O:10][CH3:9])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COc1ccccc1N
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccccc1/N=C/c1ccccc1
Yield: 99.8 %

Procedure:
To benzaldehyde (26.1 g, 25.0 mL, 0.246 mol, 1.21 equiv) in toluene (100 mL) was added 2-methoxyaniline (25.1 g, 23.0 mL, 0.204 mol, 1.00 equiv). The reaction mixture was heated to reflux with azeotropic removal of water with a Dean-Stark trap for 12 h. The reaction mixture was concentrated and dried under high vacuum to afford (E)-N-benzylidene-2-methoxyaniline as a yellow oil (43.0 g, >99% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:18]=[CH:19][CH:20]=1)[CH2:12]OS(C)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21]([O-:24])([O-:23])=[O:22].[Na+:25].[Na+].C(OCC)(=O)C>O>[Na+:25].[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][S:21]([O-:24])(=[O:23])=[O:22])[CH:18]=[CH:19][CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCc1cccc(OCc2ccccc2)c1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=S(=O)([O-])Cc1cccc(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 5 h
Yield: 39.8 %

Procedure:
5.80 g of methanesulfonic acid 3-benzyloxybenzyl ester and 5.21 g of sodium sulfite were dissolved in 50 ml of water and stirred at 90° C. for 5 hours. The mixture was allowed to cool to room temperature overnight, then 30 ml of ethyl acetate were added and the mixture was stirred in an ice bath for 1 hour. The precipitate was filtered off with suction, washed twice with 10 ml of ice-water and twice with 10 ml of ice-cold ethyl acetate, and dried in a vacuum drying cabinet at 40° C. overnight. This gave the product (2.37 g) with a molecular weight of 300.3 g/mol (C14H13O4S.Na); MS (ESI): m/e=296 (M−Na++H2O+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]=[CH:6][C:7]1([CH3:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)[CH3:2].[H][H]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH2:6][C:7]1([CH3:17])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)C=CC1(C)CCCc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1(C)CCCc2ccccc21

Procedure:
A solution of 21 g of 4 in 200 ml ethanol was hydrogenated in the presence of 2 g 5% Pd on carbon. After the take-up of hydrogen was complete, the catalyst was filtered off and the filtrate evaporated. This yielded 21 g of colourless oil; Rf =0.42 (hexane/ethyl acetate 9/1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[CH2:5][N:6]1[S:10](=[O:12])(=[O:11])[NH:9][C:8](=[O:13])[CH2:7]1.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>C(O)(=O)C>[O:11]=[S:10]1(=[O:12])[NH:9][C:8](=[O:13])[CH2:7][N:6]1[CH2:5][C:4]1[CH:3]=[C:2]([NH:1][C:17](=[O:19])[CH3:18])[CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc(CN2CC(=O)NS2(=O)=O)c1
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(CN2CC(=O)NS2(=O)=O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of the title compound of Example 6, 5-(3-aminobenzyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (10 mg, 0.041 mmol) in acetic acid (AcOH, 5 mL) is treated with acetic anhydride (85 mg, 0.83 mmol) and stirred at RT for 72 h. The mixture is stirred with water for 2 h, then concentrated to dryness. The crude mixture is purified by LC/MS to afford N-[3-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-ylmethyl)phenyl]acetamide: [M−1]−=282.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:37]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:6]>C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:35]=[C:36]([N:38]2[CH2:39][CH2:40][O:41][CH2:42][CH2:43]2)[CH:37]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[SH:15])=[O:6]
Reactant: O=C(NCc1ccccc1SC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cc(F)cc(N2CCOCC2)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccccc1S)c1cc(F)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.8 %

Procedure:
3-Fluoro-5-(morpholin-4-yl)-N-[2-(tritylsulfanyl)benzyl]benzamide (517 mg, 0.88 mmol) was treated with a solution of triethylsilane/TFA/DCM (10 mL, 1/9/10). The reaction mixture was stirred at RT for 20 min and concentrated under reduced pressure. Purification of the residue by flash column chromatography (DCM:MeOH 98:2) afforded the title compound (219 mg, 72%) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.36-7.31 (2H, m), 7.21-7.15 (3H, m), 6.85 (1H, ddd, J 8.5, 2.2, 1.4), 6.69 (1H, dt, J 11.6, 2.3), 6.57 (1H, br t, J 5.7), 5.39 (1H, br s), 4.66 (2H, d, J 5.7), 3.84 (4H, t, J 4.9), 3.20 (4H, t, J 4.9).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[O:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)([O-:4])=[O:3].C(N(CC)CC)C.Br[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([OH:42])([C:38]([F:41])([F:40])[F:39])[C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=1>ClCCl>[F:35][C:34]([F:36])([F:37])[C:33]([C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][CH:17]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[CH2:14][CH2:13]2)=[CH:28][CH:29]=1)([OH:42])[C:38]([F:39])([F:41])[F:40]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1cccc(OC2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(OC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Reaction time: 20 h
Yield: 70.4 %

Procedure:
To a stirred mixture of 4-(3-nitrophenoxy)piperidine hydrochloride (11.87 mmol, 3.07 g) and triethylamine (35.6 mmol, 4.96 mL, 3.60 g) in dichloromethane was added 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (11.87 mmol, 4.00 g). The reaction was stirred for 20 hours then was filtered. The filtrate was chromatographed on silica (eluting with a gradient of dichloromethane to ethyl acetate) to give the title compound (4 g). MS (ESI) m/z 479.0 [M+H]+
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([S:19](Cl)(=[O:21])=[O:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[NH2:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)=[O:28].Cl>O>[CH2:7]([S:19]([NH:23][C:24]1[CH:25]=[C:26]([CH:38]=[CH:39][C:40]=1[O:41][CH3:42])[C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=1)=[O:28])(=[O:21])=[O:20])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)c(Cl)c2)cc1N
Reactant: CCCCCCCCCCCCS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCS(=O)(=O)Nc1cc(C(=O)Nc2ccc(Cl)c(Cl)c2)ccc1OC
Temperature: 25 °C
Yield: 79.7 %

Procedure:
Pyridine (5 mL) was added to a mixture of 1-dodecane-sulfonyl chloride (Maybridge) (0.8 g, 3.0 mmol) and 3-amino-4-methoxy-N-(3,4-dichloro-phenyl)-benzamide from Example 4 (0.73 g, 3.0 mmol) and stirred at room temperature. After 5 days the mixture was heated on a steambath for 1.5 hours, allowed to cool, and added to water (150 mL), acidified with 4N HCl, and stirred for an hour. The precipitate was filtered off, rinsed with water then with ethanol and dried to afford the product (1.3 g); m.p. 15-152° C. after recrystallization from ethanol and chromatography on silica gel in CHCl3/EtOAc (9:1).