Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([S:20][C:21]([F:24])([F:23])[F:22])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH2:35]([O:34][C:32]([N:11]1[C:12]([C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[CH:9]=[C:10]1[S:20][C:21]([F:23])([F:22])[F:24])=[O:33])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: Fc1ccc(-c2cc(SC(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)n1c(SC(F)(F)F)cc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C

Procedure:
A mixture of 700 mg. (2 mmoles) of 4,5-bis(4-fluorophenyl)-2-(trifluoromethylthio)pyrrole and 330 mg. (3 mmoles) of potassium tert-butoxide in 20 ml. of toluene was heated to reflux with stirring and then cooled to room temperature under nitrogen. A solution of 700 mg. (6 mmoles) of ethyl chloroformate in 15 ml. of toluene was then added dropwise and the reaction mixture stirred at room temperature for several hours. The mixture was poured onto an aqueous sodium bicarbonate solution and the product extracted into methylene chloride. The combined organic layers were dried and concentrated to give 800 mg. of a viscous oil. The oil was purified by chromatography on Silic AR CC-7 (eluted by hexane and then by mixtures of hexane/toluene), followed by recrystallization from ethanol/water to give 400 mg. of product as colorless crystals, m.p. 54°-54.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N+:14]([O-:16])=[O:15])[C:7]2[O:11][CH:10]([CH3:12])[CH2:9][C:8]=2[CH:13]=1)([O-:3])=[O:2].[CH3:17][NH2:18]>C(O)C>[CH3:17][NH:18][C:7]1[C:6]([N+:14]([O-:16])=[O:15])=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:8]=1[CH2:9][CH:10]([OH:11])[CH3:12]
Reactant: CC1Cc2cc([N+](=O)[O-])cc([N+](=O)[O-])c2O1
Reactant: CN
Solvent: CCO
Product: CNc1c(CC(C)O)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
0.056 Mole (12.5 g) of 2,3-dihydro-5,7-dinitro-2-methyl-benzofuran is suspended in 100 ml of a 33% strength solution of methylamine in ethanol. After 10 hours' stirring at room temperature in a sealed Erlenmeyer, the reaction mixture is brought for 30 minutes to the refluxing temperature of the alcohol. After the mixture is cooled, the expected product precipitates. It is drained, washed with alcohol and then recrystallized from 50 ml of 96° strength ethanol. After being dried, 0.047 mole (12 g) is obtained of a product which melts at 132° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH:16]([CH3:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CN(C=O)C>[CH2:20]([O:19][C:17](=[O:18])[CH:16]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:22])[CH3:21]
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
4-Chlorophenol (0.30 mol), Cs2CO3 (197.0 g, 0.61 mol), and ethyl 2-bromopropionate (54.3 g, 0.30 mol) were combined in anhydrous DMF (1000 mL) and stirred at 90° C. under an atmosphere of nitrogen. After 16 h, the DMF was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed twice with water and once with brine. The organic layer was dried over Na2SO4 and concentrated in vacuo to produce an oil.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(CC)CC)C>C(O)(C)C>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Cl
Temperature: 120 °C

Procedure:
2,4-dichloro-5,7-difluoro-3-methylquinoline (4.90 g, 10.0 mmol), tert-butyl piperazine-1-carboxylate (3.70 g, 20.0 mmol) and triethylamine (2.80 mL, 20.0 mmol) were slurried in isopropyl alcohol (40 mL) and heated at 120° C. for 12 h. The reaction was then allowed to cool to rt and concentrated to dryness. The crude product was then purified by column chromatography (silica gel, 0 to 20% EtOAc:hexane) to give tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperazine-1-carboxylate. Mass Spectrum (ESI) m/e=398.2 (M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:16][CH2:15][CH2:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[CH:18][CH:19]=1)([O:25][CH3:26])=[O:24]
Reactant: COC(=O)c1ccc(CCCC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(CCCC2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 37 mg (0.1 mmol) of 1-t-butoxycarbonyl-4-(3-((4-carbomethoxy)phenyl)propyl)piperidine (from EXAMPLE 29, Step A) in CH2Cl2 at 0° C. was treated with 1.0 mL of TFA. The cooling bath was removed and the solution was stirred at rt for 1 h. The mixture was concentrated. The residue was dissolved in 2×5 mL of ether and concentrated to remove excess TFA. The crude product was used in Step C without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[O:6][CH2:5]1.[C:7]([CH2:10][N:11]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18][N:17]([CH2:23][C:24]([OH:26])=[O:25])[CH2:16][CH2:15][N:14]([CH2:27][C:28]([OH:30])=[O:29])[CH2:13][CH2:12]1)([OH:9])=[O:8].[OH-].[K+]>O1CCOCC1.O>[OH:6][CH:4]([CH2:3][O:2][CH3:1])[CH2:5][N:20]1[CH2:21][CH2:22][N:11]([CH2:10][C:7]([OH:9])=[O:8])[CH2:12][CH2:13][N:14]([CH2:27][C:28]([OH:30])=[O:29])[CH2:15][CH2:16][N:17]([CH2:23][C:24]([OH:26])=[O:25])[CH2:18][CH2:19]1
Reactant: COCC1CO1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COCC(O)CN1CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
7.63 g (86.58 mmol) of glycidyl methyl ether and 10 g (28.86 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane are dissolved in a mixture of 50 ml of dioxane/80 ml of water, and the pH is brought to 10 with 6 N potassium hydroxide solution. It is stirred for 24 hours at 50° C. It is evaporated to dryness, the residue is taken up with 300 ml of water/50 ml of methanol and extracted twice with 100 ml of tert-butyl methyl ether. The aqueous solution is adjusted to pH 1 with 5 N hydrochloric acid and evaporated to dryness. The residue is boiled out (extracted) with 200 ml of methanol/80 ml of methylene chloride. It is cooled in an ice bath and precipitated potassium chloride is filtered out. The filtrate is concentrated by evaporation in a vacuum, the residue is dissolved in 45 ml of water/20 ml of ethanol and then put on a column of poly-(4-vinylpyridine). The product is eluted with a solution of ethanol/water 1:3. After concentration by evaporation in a vacuum, the residue is chromatographed on a reversed-phase column (RP 18/mobile solvent =gradient of water/tetrahydrofuran). After concentration by evaporation of the main fraction, 10.38 g (77% of theory) of a greatly hygroscopic, vitreous solid is obtained.
Reaction SMILES: [N:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][C:11]3[C:12]([Cl:29])=[CH:13][C:14](OS(C(F)(F)F)(=O)=O)=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH2:32](C([Sn])=C(CCCC)CCCC)[CH2:33]CC.[Cl-].[Li+].[F-].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:1]1([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][C:11]3[C:12]([Cl:29])=[CH:13][C:14]([CH:32]=[CH2:33])=[C:15]([CH:20]=3)[C:16]([O:18][CH3:19])=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(Cl)cc1OS(=O)(=O)C(F)(F)F
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [F-]
Solvent: CN(C)C=O
Product: C=Cc1cc(Cl)c(Cc2ccc(-n3cccn3)cc2)cc1C(=O)OC
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-(((trifluoromethyl)sulfonyl)oxy)benzoate (0.18 g) in DMF (3.50 mL) were added tributylvinyltin (0.17 mL), trans-dichlorobis(triphenylphosphine)palladium(II) (0.01 g) and lithium chloride (0.12 g), and the mixture was stirred at 90° C. for 1 hr under argon atmosphere. To the reaction mixture was added aqueous potassium fluoride solution, and the precipitated insoluble substance was removed by filtration through Celite. The filtrate was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.13 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1)C#N.[H-].[Na+].[O:19]1CCCC1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:11]1[N:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[O:19]
Reactant: N#CC(c1ncccn1)c1ccccc1Cl
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: O=C(c1ncccn1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
A mixture of 2-chlorophenyl(2-pyrimidinyl)acetonitile (3.25 g, 0.0142 mol), sodium hydride (60% in mineral oil, 1.07 g, 0.016 mol) and anhydrous tetrahydrofuran is stirred two hours at reflux and cooled to room temperature. Dry air is bubbled into the mixture while stirring three days. The mixture is quenched by dropwise addition of a 3:1 water:methanol mixture and then water. The tetrahydrofuran is removed in vacuo and the aqueous residue filtered to afford the title compound as a brown solid (2.00 g, 64.7%) which is identified by NMR spectral analysis.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([CH3:22])[C:5](=[O:21])[C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[CH:10][C:9]([CH3:19])=[C:8]([CH3:20])[CH:7]=2.C(N(CC)CC)C.C(Cl)(Cl)Cl>CS(C)=O>[CH3:22][N:4]1[C:3]([CH:2]=[O:1])=[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:11]2[C:6](=[CH:7][C:8]([CH3:20])=[C:9]([CH3:19])[CH:10]=2)[C:5]1=[O:21]
Reactant: Cc1cc2c(-c3ccccc3)c(CO)n(C)c(=O)c2cc1C
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc2c(-c3ccccc3)c(C=O)n(C)c(=O)c2cc1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
To a solution 1,2-dihydro-3-hydroxymethyl-2,6,7-trimethyl-1-oxo-4-phenylisoquinoline(Reference Example 1) (1.44 g) in DMSO (30 ml) were added triethylamine (2.25 ml) and sulfur trioxide pyridine complex (2.5 g). The mixture was stirred for 15 minutes at room temperature. To the reaction mixture was added chloroform, which was washed with 2N-HCl and water, followed by drying (MgSO4). The solvent was distilled off to leave 1,2-dihydro-2,6,7-trimethyl-1-oxo-4-phenyl-3-isoquinolinecarboaldehyde as colorless crystals (1.03 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[C:5]#[N:6].[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6]
Reactant: [H][H]
Reactant: N#Cc1ccc([N+](=O)[O-])c(N)c1
Agent: [Pd]
Solvent: CCO
Product: N#Cc1ccc(N)c(N)c1
Yield: 203.9 %

Procedure:
3-Amino-4-nitrobenzonitrile (20.00 g, 0.042 mol) was hydrogenated under 50 psi of hydrogen gas in 250 mL of anhydrous ethanol with 1.00 g of 10% Pd/C for 5 hours. The mixture was then filtered through a pad of celite and the filtrate concentrated. Trituration of the resulting solid with diethyl ether afforded 11.40 g of the desired product as a tan solid (70%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]2[C:3]=1[C:4]([S:12]([CH2:15][C:16]([NH:18][C:19]1[CH:23]=[C:22]([CH3:24])[O:21][N:20]=1)=[O:17])(=[O:14])=[O:13])=[CH:5][NH:6]2.[H-].[Na+].[Br:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br>CN(C=O)C>[Br:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][N:6]1[C:7]2[C:3](=[C:2]([F:1])[CH:10]=[C:9]([F:11])[CH:8]=2)[C:4]([S:12]([CH2:15][C:16]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[O:21][N:20]=2)=[O:17])(=[O:14])=[O:13])=[CH:5]1
Reactant: BrCc1cccc(Br)c1
Reactant: Cc1cc(NC(=O)CS(=O)(=O)c2c[nH]c3cc(F)cc(F)c23)no1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)CS(=O)(=O)c2cn(Cc3cccc(Br)c3)c3cc(F)cc(F)c23)no1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
In a 5 mL microwave vial, 2-((4,6-difluoro-1H-indol-3-yl)sulfonyl)-N-(5-methylisoxazol-3-yl)acetamide (62.0 mg, 0.174 mmol) from Step C was dissolved in DMF (3 mL) and cooled to 0° C. Sodium hydride (60% by weight, 8.0 mg, 0.35 mmol) was then added in one portion and the reaction mixture was vigorously stirred at 0° C. for 15 minutes. 3-bromo-benzylbromide (44.0 mg, 0.174 mmol) was added in one portion and the reaction mixture was stirred while being allowed to warm to ambient temperature over 3 hours. The reaction mixture was quenched with water (2 mL) and the solution was extracted with ethyl acetate (3×4 mL). The organics were combined, dried over magnesium sulfate, and concentrated in vacuo to give an oily residue which was purified on a silica gel column (0-50% ethyl acetate:hexanes over 19 min) to yield the title compound (45 mg, 0.09 mmol, 50% yield). LCMS>98% 220 nm, RT=0.84 min, m/z=524 ([79Br]m+1), 526 ([81Br]m+1). 1H NMR (400 MHz, DMSOD6) 11.32 (s, 1H), 8.39 (s, 1H), 7.59 (s, 1H), 7.52 (m, 2H), 7.29 (t, J=7.6 Hz, 1H), 7.17-7.24 (m, 2H), 6.52 (s, 1H), 5.53 (s, 2H), 4.47 (s, 2H), 2.36 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].[C:12](O)(=O)[CH3:13]>>[CH3:12][C:13]1[O:11][C:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: CC(=O)O
Reactant: Nc1ccc(C(=O)O)cc1O
Product: Cc1nc2ccc(C(=O)O)cc2o1
Temperature: 130 °C
Reaction time: 72 h
Yield: 62 %

Procedure:
4-Amino-3-hydroxybenzoic acid (4.9 g) was added to acetic acid (250 ml) and stirred for 3 days at 130° C. The solution was concentrated under reduced pressure, and precipitates were collected by filtration. The precipitates were dissolved in methanol and chloroform. The solution was concentrated under reduced pressure, and precipitates were collected by filtration, washed with methanol and dried under reduced pressure to give the title compound (3.5 g, Y.:62%).
Reaction SMILES: N1C=CC(NS(C2C=C3C(=CC=2)C(C2C=CC(C(F)(F)F)=CC=2[C:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=2)=CC=C3)(=O)=O)=NC=1.Cl[C:45]1[CH:50]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:48]=[CH:47][C:46]=1[C:55]1[CH:64]=[CH:63][CH:62]=[C:61]2[C:56]=1[CH:57]=[CH:58][C:59]([S:65]([N:68]([CH2:74][C:75]1[CH:80]=[CH:79][C:78]([O:81][CH3:82])=[CH:77][CH:76]=1)[C:69]1[S:70][CH:71]=[CH:72][N:73]=1)(=[O:67])=[O:66])=[CH:60]2>>[CH3:82][O:81][C:78]1[CH:77]=[CH:76][C:75]([CH2:74][N:68]([C:69]2[S:70][CH:71]=[CH:72][N:73]=2)[S:65]([C:59]2[CH:60]=[C:61]3[C:56](=[CH:57][CH:58]=2)[C:55]([C:46]2[CH:47]=[CH:48][C:49]([C:51]([F:52])([F:53])[F:54])=[CH:50][C:45]=2[C:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH:32]=2)=[CH:64][CH:63]=[CH:62]3)(=[O:67])=[O:66])=[CH:80][CH:79]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2-c2cccc3cc(S(=O)(=O)Nc4ccncn4)ccc23)CC1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4Cl)cccc3c2)cc1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4C4=CCN(C(=O)OC(C)(C)C)CC4)cccc3c2)cc1

Procedure:
The title compound was prepared in an analogous manner to that of intermediate Y, except that 5-(2-chloro-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide was used instead of 5-(2-chloro-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)naphthalene-2-sulfonamide.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)(=[O:14])=[O:13])[CH:9]=2)[NH:4][N:3]=1.[C:23](Cl)(=[O:25])[CH3:24]>N1C=CC=CC=1>[F:21][C:19]1[CH:20]=[C:15]([S:12]([NH:11][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[NH:1][C:23](=[O:25])[CH3:24])(=[O:14])=[O:13])[CH:16]=[C:17]([F:22])[CH:18]=1
Reactant: Nc1n[nH]c2ccc(NS(=O)(=O)c3cc(F)cc(F)c3)cc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1n[nH]c2ccc(NS(=O)(=O)c3cc(F)cc(F)c3)cc12

Procedure:
N-[5-(3,5-Difluorobenzenesulfonylamino)-1H-indazol-3-yl]acetamide can be obtained as described in Example 28 from 0.1 g of N-(3-amino-1H-indazol-5-yl)-3,5-difluorobenzenesulfonamide, 9 ml of pyridine and 0.024 ml of acetyl chloride. 338 mg of N-[5-(3,5-difluorobenzenesulfonylamino)-1H-indazol-3-yl)acetamide are thus obtained in the form of a cream solid melting at 268° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][CH:6]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:26]=1[O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>ClCCl>[OH:5][CH:6]([O:24][C:25]1[CH:30]=[C:29]([N+:1]([O-:4])=[O:2])[CH:28]=[C:27]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:26]=1[O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH3:68])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=[N+]([O-])O
Reactant: CCCCCCCCCCCCCCCCCCOc1cccc(OC(O)CCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOc1cc([N+](=O)[O-])cc(OC(O)CCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Reaction time: 0.25 h
Yield: 76.2 %

Procedure:
Dispersed was 63 g of silica gel into 21 g of nitric acid and 150 ml of dichloromethane was added. Into the resulting dispersion, added was a solution dissolving 5.0 g of 1-(1′-hydroxyoctadecyloxy)-2,3-dioctadecyloxybenzene in 30 ml of dichloromethane. After stirring for 15 minutes, silica gel was filtered off. After the filtrate was concentrated under reduced pressure, 300 ml of methanol was added and stirred. Resulting precipitant was filtered off to obtain 4.0 g of 3-(1′-hydroxyoctadecyloxy)-4,5-dioctadecyloxy nitrobenzene (yield: 76%).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:19]([N:21]3[CH2:26][CH2:25][C:24]4([C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[CH2:28][O:27]4)[CH2:23][CH2:22]3)=[O:20])=[CH:9][N:10]2[CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)=[CH:6][CH:5]=1.[CH2:35](N(CC)CC)C.C=O.C([BH3-])#N.[Na+]>CO>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:19]([N:21]3[CH2:26][CH2:25][C:24]4([C:34]5[C:29](=[N:30][CH:31]=[CH:32][CH:33]=5)[CH2:28][O:27]4)[CH2:23][CH2:22]3)=[O:20])=[CH:9][N:10]2[CH2:13][C@@H:14]2[CH2:18][CH2:17][CH2:16][N:15]2[CH3:35])=[CH:6][CH:5]=1
Reactant: O=C(c1cn(C[C@@H]2CCCN2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ncccc12
Reactant: CCN(CC)CC
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: CN1CCC[C@H]1Cn1cc(C(=O)N2CCC3(CC2)OCc2ncccc23)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 74.2 %

Procedure:
A solution of 0.15 g (0.29 mmol) 1′-({6-chloro-1-[(2S)-pyrrolidin-2-ylmethyl]-1H-indol-3-yl}carbonyl)-7H-spiro[furo[3,4-b]pyridine-5,4′-piperidine]dihydrochloride, 0.10 ml (0.72 mmol) triethylamine and 0.070 g (2.3 mmol) paraformaldehyde in 3 ml methanol was heated at reflux for 2 h. Cooling the reaction mixture to 0° C. using an ice-water bath was followed by addition of 0.030 g (0.43 mmol) sodium cyanoborohydride. The reaction mixture was stirred at room temperature for 16 h, quenched with water and diluted with 1 M aqueous sodium hydroxide solution. The aqueous layer was extracted with three portions of ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography (aminopropyl-modified silica gel) to give the title compound (0.10 g; 77%) as an off-white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH2:5]([OH:16])[C@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14]O)[OH:13])[OH:11])[OH:9])[OH:7].I>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:4])[O:13][CH:12]([CH:10]2[O:11][C:6]([CH3:8])([CH3:5])[O:9][CH:8]2[CH:6]2[O:7][C:12]([CH3:14])([CH3:10])[O:16][CH2:5]2)[CH2:14][O:3]1
Reactant: CC(C)=O
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: I
Solvent: c1ccncc1
Product: CC1(C)OCC(C2OC(C)(C)OC2C2COC(C)(C)O2)O1
Temperature: 60 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To 200 ml of acetone were added 10.0 g of D-mannitol and 175 mg of hydriodic acid (57%) and the mixture was refluxed with stirring in a water bath at 60° C. for 5 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. After completion of the reaction, a small amount of pyridine was added. The acetone was then distilled off under reduced pressure and the residue was dissolved in chloroform. The solution was washed with aqueous sodium bicarbonate and water and dried over anhydrous magnesium sulfate. The chloroform was distilled off under reduced pressure to give 15.0 g (90%) of 1,2:3,4:5,6-tri-O-isopropylidene-D-mannitol. After recrystallization from 70% ethanol, it melted at 68.5°-70.5° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.[I:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:21](O)=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CC(O)=O>[I:17][C:18]1[CH:19]=[C:20]([C:21]2[NH:1][C:2]3[CH:3]=[C:4]([CH2:5][N:6]4[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]4)[CH:13]=[CH:14][C:15]=3[N:16]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: CN1CCN(Cc2ccc(N)c(N)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.2 %

Procedure:
A mixture of 1-(3,4-diaminobenzyl)-4-methylpiperazine (10 mmol), 3-iodo-4-methylbenzoic acid (2.6 g, 10 mmol), EDCI (11 mmol), and HOBt (11 mmol) in dry DMF (25 mL) was stirred at ambient temperature for 24 hrs. The mixture was then evaporated in vacuo and the crude residue was dissolved in CH2Cl2 (100 mL) was washed with water (100 mL), brine (100 mL) and then dried by Na2SO4, filtered and concentrated. The residue obtained was dissolved in AcOH (30 mL) and heated at reflux for 3 hrs. The reaction mixture was eavporated in vacuo and the residue was purified by silica gel chromatography (eluent: 10% MeOH in CH2Cl2, MeOH was added 0.5% Et3N) to give a yellow solid (1.35 g, 30.3%). 1H NMR (300 MHz, CDCl3) δ: 8.50 (1 H, s), 7.94-7.97 (1 H, d, J=9.0 Hz), 7.53-7.56 (1 H, d, J=9.0 Hz), 7.52-7.55 (1 H, d, J=9.0 Hz), 7.30 (1 H, s), 7.20-7.23 (1 H, d, J=9.0 Hz), 3.60 (2 H, s), 2.54 (8 H, brs), 2.45 (3 H, s), 2.32 (3 H, s).