Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=2[N+:23]([O-:25])=[O:24])[NH:19][C:18](=[O:26])[N:17]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:16]3=[O:32])[CH:12]=1)(C)(C)C.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[NH4+].[OH-]>O.C(#N)C.O>[OH:6][CH2:7][C:8]1[N:9]=[CH:10][N:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][C:22]=2[N+:23]([O-:25])=[O:24])[NH:19][C:18](=[O:26])[N:17]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[C:16]3=[O:32])[CH:12]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cn(-c2cc3c(=O)n(NS(C)(=O)=O)c(=O)[nH]c3cc2[N+](=O)[O-])cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cnc(CO)c3)cc2c1=O
Temperature: 50 °C
Reaction time: 18 h
Yield: 42.2 %

Procedure:
A mixture of 1 g (1.96 mmol) of N-{6-[4-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-1-yl]-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-methanesulfonamide, 0.738 g (2.34 mmol) of tetrabutylammonium fluoride trihydrate and 20 ml of tetrahydrofuran is stirred at 50° C. for 18 hours. The reaction mixture is concentrated to dryness and the residue fractionated by medium pressure chromatography on a RP-C18 column (20 μM material) with acetonitril/water 1:1 (containing 0.1% trifluoroacetic acid) as eluent. The residue obtained by evaporation of fractions 2-5 is dissolved in water and the pH adjusted to ˜5 with diluted NH4OH solution. The product precipitates and is collected by filtration. The residue obtained from fractions 6-13 is fractionated by medium pressure chromatography on a RP-C18 column (20 μM material) with acetonitril/water 1:2 as eluent. During concentration of the fractions the product precipitates and is collected by filtration. Crystallization of all combined product fractions from DMSO/water gives 0.328 g of N-[6-(4-hydroxymethyl-imidazol-1-yl)-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl]-methanesulfonamide as a yellow powder, m.p. >300° C.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].C(O[K])(C)(C)C.[Si:13]([O:20][CH2:21][C:22]#[C:23][C:24](=O)[CH3:25])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]>CS(C)=O>[Si:13]([O:20][CH2:21][C:22]1[CH:23]=[C:24]([CH3:25])[NH:6][C:4](=[O:5])[C:3]=1[C:1]#[N:2])([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:15])[CH3:14]
Reactant: CC(=O)C#CCO[Si](C)(C)C(C)(C)C
Reactant: N#CCC(N)=O
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Product: Cc1cc(CO[Si](C)(C)C(C)(C)C)c(C#N)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a 0° C. solution of 2-cyanoacetamide (1.74 g, 20.7 mmol) and tBuOK (2.32 g, 20.7 mmol) in DMSO (48 mL) was added 5-{[tert-butyl(dimethyl)silyl]oxy}pent-3-yn-2-one (Cpd G, 4.4 g, 21.0 mmol) dropwise. The reaction mixture turned bright orange. The reaction mixture was stirred for 2 hours at 0° C., then quenched with NH4Cl (sat., aq.) and diluted with water causing solids to precipitate out. The solids were collected via filtration and dried under vacuum to give 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (Cpd H, 5.0 g, 86%) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:18][C:19]1[C:20]([NH:25][CH2:26][CH3:27])=[N:21][CH:22]=[CH:23][CH:24]=1.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:1][C:2]1[C:3]([C:4]([NH:18][C:19]2[C:20]([NH:25][CH2:26][CH3:27])=[N:21][CH:22]=[CH:23][CH:24]=2)=[O:6])=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=1
Reactant: CCNc1ncccc1N
Reactant: O=C(O)c1cc([N+](=O)[O-])cnc1Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCNc1ncccc1NC(=O)c1cc([N+](=O)[O-])cnc1Cl

Procedure:
A solution of 2.21 g of 2-chloro-5-nitronicotinoyl chloride (obtained by nitrating 2-hydroxynicotinic acid, followed by conversion to 2-chloro-5-nitronicotinic acid, which was then treated with thionyl chloride) in 10 ml of tetrahydrofuran was slowly added over 15 minutes to a cooled, stirred mixture of 1.34 g of 3-Amino-2-ethylaminopyridine, 1.29 g of diisopropylethylamine, and 40 ml of tetrahydrofuran. The resulting mixture was allowed to stir overnight at room temperature, and then concentrated in vacuo. The title compound (2.30 g, m.p. 185°-186° C.), which precipitated out when the residue was treated with methylene chloride, was suitable for use in the next reaction.
Reaction SMILES: CNCCO.O[C:7]1[CH:17]=[CH:16][C:10]([CH:11]=[CH:12][C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1>OS([O-])=O.[Na+].O>[CH:11](=[CH:12][C:13](=[O:15])[CH3:14])[C:10]1[CH:16]=[CH:17][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)C=Cc1ccc(O)cc1
Agent: CNCCO
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: CC(=O)C=Cc1ccccc1

Procedure:
It should be noted that an initial reaction of 2-methylaminoethanol (1.5 mL) with 4-hydroxybenzylideneacetone (0.68 g) in NaHSO3 (0.78 g) and H2O (1.5 mL) in a sealed vial at 140° C. for 16 hrs did not provide the necessary benzylidene acetone derivative (Scheme 1, compound (b)). Therefore, N-methyl-N-(2-hydroxyethyl)-4-aminobenzaldehyde (Scheme 1, compound (a)) was purchased and used to complete the first step of synthesis instead. When the benzylidene acetone derivative was spotted on a TLC plate the compound glowed fluorescently. The benzylidene acetone derivative reaction mixture was spotted onto preparative TLC plate for purification. Three distinct bands can be observed: a red band at the bottom of the plate, yellow band at the middle, and a faint band at the top were observed. Using mass spectra the inventors determined that the middle yellow band contained the actual benzylidene acetone derivative.
Reaction SMILES: [F:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](B3OC(C)(C)C(C)(C)O3)=[CH:8][CH:9]=2)[NH:4][N:3]=1.[C:20]([O:24][C@@H:25]([C:31]1[C:46]([CH3:47])=[CH:45][C:34]2[N:35]=[C:36]([C:38]3[CH:43]=[CH:42][N:41]=[C:40](Cl)[CH:39]=3)[S:37][C:33]=2[C:32]=1[C:48]1[CH:53]=[CH:52][C:51]([Cl:54])=[CH:50][CH:49]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[C:20]([O:24][C@@H:25]([C:31]1[C:46]([CH3:47])=[CH:45][C:34]2[N:35]=[C:36]([C:38]3[CH:43]=[CH:42][N:41]=[C:40]([C:7]4[CH:6]=[C:5]5[C:10]([C:2]([F:1])=[N:3][NH:4]5)=[CH:9][CH:8]=4)[CH:39]=3)[S:37][C:33]=2[C:32]=1[C:48]1[CH:49]=[CH:50][C:51]([Cl:54])=[CH:52][CH:53]=1)[C:26]([O:28][CH2:29][CH3:30])=[O:27])([CH3:21])([CH3:22])[CH3:23]
Reactant: CC1(C)OB(c2ccc3c(F)n[nH]c3c2)OC1(C)C
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(Cl)c3)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(-c4ccc5c(F)n[nH]c5c4)c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of 3-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (prepared according to WO201059658, 48 mg, 0.184 mmol), (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-2-(2-chloropyridin-4-yl)-5-methylbenzo[d]thiazol-6-yl)acetate (75 mg, 0.142 mmol) and 2M potassium carbonate solution (0.28 mL, 0.568 mmol) in dioxane (1.0 mL) was sparged with nitrogen for 10 minutes, Pd(PPh3)4 (16 mg, 0.014 mmol) was added and reaction mixture was heated in microwave at 100° C. for 1 h. Reaction mixture was diluted with ethyl acetate, washed with brine. The aqueous layer was back extracted with ethyl acetate and the combined organic layer was dried (MgSO4), filtered, concentrated and purified by CombiFlash (0 to 40% EtOAc/Hex) to give product. LCMS-ESI+: calc'd for C34H31ClFN4O3S: 629.2 (M+H+); Found: 629.3 (M+H+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6](F)[CH:5]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([OH:22])[CH:21]=1)[CH:17]=[O:18].Cl>CN(C=O)C.O>[Cl:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[C:6]([O:13][C:14]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:16]([CH:17]=[O:18])[CH:15]=2)[CH:5]=1
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: N#Cc1ccc(Cl)cc1F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(Cl)cc1Oc1cc(O)cc(C=O)c1
Temperature: 80 °C
Yield: 23.1 %

Procedure:
Sodium hydride (502 mg, 60% in mineral oil) was added portionwise to 4-chloro-2-fluorobenzonitrile (2.04 g) and 3,5-dihydroxybenzaldehyde (1.81 g) in DMF and the solution heated to 80° C. for 16 h. The cooled solution was diluted with water, acidified with concentrated hydrochloric acid, extracted twice with ethyl acetate, the extracts dried over sodium sulphate and evaporated. Purification by chromatography gave the sub-title compound as a white solid (0.83 g).
Reaction SMILES: C(C1OC[C@@H](C(C)(C)C)N=1)(C1OC[C@@H](C(C)(C)C)N=1)(C)C.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]=[CH2:30])=[C:25]([F:31])[CH:24]=1.[N+](=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[N-]>C(Cl)(Cl)Cl>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:30][CH:34]2[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[C:25]([F:31])[CH:24]=1
Reactant: C=Cc1ccc(Br)cc1F
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: CC(C)(C1=N[C@H](C(C)(C)C)CO1)C1=N[C@H](C(C)(C)C)CO1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1CC1c1ccc(Br)cc1F
Reaction time: 1 h

Procedure:
To a suspension of copper(I) trifluoromethanesulfonate benzene complex (0.01 eq) in chloroform (100 mL) at rt, was added (R,R)-2,2′-isopropylidene-bis(4-tert-butyl-2-oxazoline) (0.01 eq). The mixture was stirred at for 1 h then cannulated through glass wool in a solution of styrene from step 5 (1.2 eq) in chloroform (0.1M) at 4° C. To this solution was added a solution of ethyl diazoacetate (0.8 eq) in of chloroform (1M) dropwise over 3 h. The final mixture was stirred overnight at 4° C. The mixture was concentrated. Flash chromatography (Hexane, EtOAc; 95:5) afforded the desired compound. (84:16, trans:cis isomers, methodology described in Evans et al. J. Am. Chem. Soc. 1991, 113, 726)
Reaction SMILES: [C:1]1(CCCC([O-])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C[O:15][C:16]([C:18]1C=CC(O)=[CH:20][CH:19]=1)=[O:17].C(OC(C1C=CC(O)=CC=1)=O)CC.P(=O)(O)(O)O>O>[C:1]1([O:17][C:16](=[O:15])[CH2:18][CH2:19][CH3:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])CCCc1ccccc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCCOC(=O)c1ccc(O)cc1
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: O
Product: CCCC(=O)Oc1ccccc1
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
Part II: 5.739 g of sodium 4-phenylbutyrate (Triple Crown America, Inc.), 0.125 g of methylparaben (Merck), 0.075 g of propylparaben (Merck), and 149.061 g of deionized water were mixed in a beaker and heated at 70° C. Part II was slowly added into part I and continually stirred at 400 rpm for 5 minutes to form a mixture. 2% Stabileze QM™ (prepared by dissolving 2 g of Stabileze QM™ in 98 g of deionized water, heating and stirring at 70° C. to form a paste, and cooling at room temperature) was added into the mixture and stirred for 5 minutes. The pH of the mixture was adjusted to 5.34 with 0.85% phosphoric acid (Merck), and stirred at 600 rpm for 20 minutes. The mixture was cooled at room temperature.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].Br[C:28]1[CH:33]=[N:32][C:31]([CH3:34])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][N:23]([C:28]5[CH:33]=[N:32][C:31]([CH3:34])=[CH:30][N:29]=5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Reactant: Cc1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cnc(N2CCC([C@]3(C)Cc4cc(C5=CCN(S(C)(=O)=O)CC5)ncc4O3)CC2)cn1

Procedure:
The title compound is prepared from (S)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 41; the configuration of the stereocenter is arbitrarily assigned) and 2-bromo-5-methyl-pyrazine in dimethylsulfoxide at 125° C. in the presence of potassium carbonate. LC (method 4): tR=0.84 min; Mass spectrum (ESI+): m/z=470 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:21])[C:17]([O:19]C)=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4].B(Br)(Br)Br>ClCCl>[F:23][C:2]([F:1])([F:22])[C:3]([N:5]1[CH2:11][CH:10]([CH:12]([CH3:14])[CH3:13])[C:9]2[CH:15]=[C:16]([Br:21])[C:17]([OH:19])=[CH:18][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: COc1cc2c(cc1Br)C(C(C)C)CN(C(=O)C(F)(F)F)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)C1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Br)cc21
Reaction time: 8 h
Yield: 97.3 %

Procedure:
A solution of N-trifluoroacetyl-8-bromo-1-isopropyl-7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine (0.041 g, 0.10 mmol) in dichloromethane (1 mL) was treated with BBr3 (0.32 ml, 1.0 M solution in CH2C12) and stirred overnight at 20 C. The excess BBr3 is quenched with water and the resulting mixture diluted with ether (50 mL), washed twice with saturated aqueous Na2CO3 (20 mL) and concentrated. Flash chromatography (20% EtOAc in hexanes, silica) resulted in 0.037 g clear oil. MS calculated for C15H17BrF3NO2+H: 380, observed: 380.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])\[CH3:4].[NH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][CH3:31]>>[CH2:30]([N:26]1[CH2:27][CH2:28][CH2:29][CH:25]1[CH2:24][NH:23][C:14](=[O:16])[C:13]1[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:12]=1[O:11][CH2:1]/[CH:2]=[C:3](/[CH2:5][CH2:6][CH:7]=[C:8]([CH3:9])[CH3:10])\[CH3:4])[CH3:31]
Reactant: COc1ccc(C(=O)O)c(OC/C=C(\C)CCC=C(C)C)c1
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)c1ccc(OC)cc1OC/C=C(\C)CCC=C(C)C
Yield: 69 %

Procedure:
In a manner identical to Example 15, 2-geranyloxy-4-methoxybenzoic acid(1.52 g) was subjected to a condensation reaction with 2-aminomethyl-1-ethylpyrrolidine (0.7 ml), thereby yielding 1.43 g(69%) of the aimed compound.
Reaction SMILES: [C:1]([C:9]1[N:13]2[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C:12]2=[C:11]([C:25]([OH:27])=O)[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][NH:29][C:30](=[O:37])[C@H:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[NH2:32]>>[C:1]([C:9]1[N:13]2[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:17][C:12]2=[C:11]([C:25](=[O:27])[NH:32][C@@H:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:30]([NH:29][CH3:28])=[O:37])[N:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(=O)c3ccccc3)nc(C(=O)O)c2C1
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)c1nc(C(=O)c2ccccc2)n2c1CN(C(=O)OC(C)(C)C)CC2)C(C)(C)C

Procedure:
Intermediate 25B was synthesized in the same manner as described above for compound 22A in Example 22 except that Intermediate 25A was used in place of 3B and L-tert-Leucine methylamide was used instead of (S)-methyl 2-amino-3,3-dimethylbutanoate. LCMS (+ESI) m/z 498.3 [M+H]+
Reaction SMILES: Cl[C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:20])[N:7](CCC3C=CC=CN=3)[C:8]2=[O:11])=[CH:4][C:3]=1S(N)(=O)=O.ClC1C=C2C(=O)NC(=O)C2=CC=1S(=O)(=O)N.NCCC1C=CC=CN=1>>[O:20]=[C:6]1[C:5]2[C:9](=[CH:10][CH:2]=[CH:3][CH:4]=2)[C:8](=[O:11])[NH:7]1
Reactant: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)N(CCc1ccccn1)C2=O
Agent: NCCc1ccccn1
Agent: NS(=O)(=O)c1cc2c(cc1Cl)C(=O)NC2=O
Product: O=C1NC(=O)c2ccccc21
Yield: 81 %

Procedure:
6-Chloro-2,3-dihydro-1,3-dioxo-2-[2-(2-pyridinyl)ethyl]-1H-isoindole-5-sulfonamide. Reaction of a mixture of 4-chloro-5-sulfamoylphthalimide and 2-(2-aminoethyl)pyridine according to the procedure of Example 1(a) afforded 81% yield of the 1,3-dioxoisoindole intermediate. Crystallization of this material from dimethylformamidemethanol provided analytically pure 6-chloro-2,3-dihydro-1,3-dioxo-2-[2-(2-pyridinyl)ethyl]-1H-isoindole-5-sulfonamide, m.p. 240°-241°.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21]C=[CH:19][CH:18]=2)([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.Br.[C:24]([OH:27])(=[O:26])[CH3:25]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.O.O.O.O.C([O-])(=O)C.[Mn+4].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C>[C:24]([C:25]1[CH:21]=[CH:22][C:17]([C:8]([C:5]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=2)([C:13]([F:14])([F:15])[F:16])[C:9]([F:11])([F:12])[F:10])=[CH:18][CH:19]=1)([OH:27])=[O:26]
Reactant: CC(=O)O
Reactant: Cc1ccc(C(c2ccccc2)(C(F)(F)F)C(F)(F)F)cc1
Agent: [Co+2]
Agent: [Mn+4]
Agent: Br
Solvent: O
Product: O=C(O)c1ccc(C(c2ccccc2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 180 °C
Reaction time: 1 h

Procedure:
298 g of 2-(4-methylphenyl)-2-phenylhexafluoropropane, 2.49 g of cobalt(II) acetate tetrahydrate, 2.45 g of manganese(IV) acetate tetrahydrate and 0.41 g of hydrogen bromide (corresponding to 4.1 g of a 10% strength HBr solution in glacial acetic acid) were initially introduced into a 1 l glass autoclave. The mixture was heated to about 180° C. under an oxygen pressure of 6.5 bar and under an exothermic reaction and was left at 170°-180° C. for 1 hour. The reaction solution was cooled to about 100° C. and 200 g of acetic acid were then distilled off. 275 g of water were slowly added to the solution remaining in the flask (about 600 g) at the boiling point. The carboxylic acid which had crystallized out was filtered off with suction, washed twice with 75 ml of 50% strength aqueous acetic acid each time and five times with 85 ml of water each time and dried at 60° C./60 mbar. Yield: 311 g (95.5% of theory) melting point: 153°-155° C., small colorless crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]CCC.C(OCC(F)(F)[F:31])(=O)CCCCCCCCC#C.C(OCC(F)(F)F)(=O)CCCCCCCCC=C.C(O)(=O)CCCCCCCCC#C.C(O)(=O)CCCCCCCCC=C.FC(F)(F)CO.C1(N=C=NC2CCCCC2)CCCCC1>CS(C)=O.CN(C)C1C=CN=CC=1>[F:31][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: C#CCCCCCCCCC(=O)OCC(F)(F)F
Reactant: CCCCCCCCCCCCCCBr
Agent: C#CCCCCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C=CCCCCCCCCC(=O)O
Solvent: CS(C)=O
Solvent: OCC(F)(F)F
Product: C=CCCCCCCCCCF

Procedure:
Glassware used for surface modification was cleaned with organic solvents and etched overnight in basic detergent solution. Prior to use, it was rinsed with ultrapure water and dried at 120° C. 1-Hexadecene (98%, Sigma-Aldrich) was purified by column chromatography and vacuum distillation. 1-Hexadecyne was obtained by reacting 1-bromotetradecane with lithium acetylide ethylenediamine complex in dimethylsulfoxide. 11-Fluoroundec-1-ene was synthesized as described elsewhere.14 2,2,2-Trifluoroethyl undec-10-ynoate and 2,2,2-trifluoroethyl undec-10-enoate were synthesized by esterification of 10-undecynoic acid, respectively 10-undecenoic acid, with 2,2,2-trifluoroethanol using N,N′-dicyclohexylcarbodiimide as a coupling reagent and 4-dimethylaminopyridine as a catalyst. Solvents used were either of analytical grade or distilled prior to use.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH2:12][CH3:13])[C:5](OC)=[O:6].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][C:11]=1[CH2:12][CH3:13]
Reactant: CCc1ccc(C(=O)OC)cc1Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(CO)cc1Cl
Reaction time: 1 h
Yield: 97.6 %

Procedure:
To a solution of methyl 3-chloro-4-ethylbenzoate (367 mg, 1.85 mmol) in THF (5 mL) that cooled to −50° C., LiAlH4 (141 mg, 2.70 mmol) was added in portions. After which, the mixture was stirred at this temperature for 1 h. Added water (0.2 mL) slowly, followed by NaOH (aq, 10%, 0.2 mL) and water (0.6 mL), the resulted mixture was filtered and washed with THF, concentrated the filtrate to give 308 mg of the title compound (98%). 1H NMR (400 MHz, CDCl3): δ 1.22 (3H, t, J=7.6 Hz), 2.74 (2H, q, J=7.6 Hz), 4.63 (2H, d, J=5.2 Hz), 7.17-7.23 (2H, m), 7.35 (1H, s).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20]C)=O)[CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1.O.[NH2:23][NH2:24]>C(O)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([NH:23][NH2:24])=[O:20])[CH:16]=3)[CH:11]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc2ccn(-c3ccc(SC)cc3)c2c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CSc1ccc(-n2ccc3ccc(C(=O)NN)cc32)cc1

Procedure:
A mixture of methyl 1-[4-(methylthio)phenyl]-1H-indole-6-carboxylate (2.50 g, 8.41 mmol), hydrazine monohydrate (4.08 mL, 84.1 mmol) and ethanol (40 mL) was heated under reflux overnight. After cooling, the precipitate was collected by filtration and washed with ethanol to give crude 1-[4-(methylthio)phenyl]-1H-indole-6-carbohydrazide.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:15](=[S:17])[NH2:16])=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH3:14])=[O:10])=[N:6][CH:7]=1.Br[CH2:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22]>C(#N)C>[Br:1][C:2]1[C:3]([C:15]2[S:17][CH2:19][C:20]([OH:25])([C:21]([F:24])([F:23])[F:22])[N:16]=2)=[CH:4][C:5]([NH:8][C:9]([NH:11][CH2:12][CH2:13][CH3:14])=[O:10])=[N:6][CH:7]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: CCCNC(=O)Nc1cc(C(N)=S)c(Br)cn1
Solvent: CC#N
Product: CCCNC(=O)Nc1cc(C2=NC(O)(C(F)(F)F)CS2)c(Br)cn1
Temperature: 80 °C

Procedure:
A suspension of 5-bromo-2-(3-propylureido)pyridine-4-carbothioamide (Intermediate 44, 100 g, 315 mmol), 3-bromo-1,1,1-trifluoroacetone (64 mL, 630 mmol) in acetonitrile (1.5 L) was heated at 80° C. for 20 hours. The solution was then cooled down and was concentrated under reduced pressure. This gave an orange oil that was carried on without further purification.
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]3[CH2:17][N:16]([CH2:18][CH3:19])[CH2:15][CH2:14][C:12]=3[S:13][C:7]=2[N:6]=[CH:5]1.S(Cl)([Cl:22])=O>ClCCCl>[Cl:22][CH2:2][CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]3[CH2:17][N:16]([CH2:18][CH3:19])[CH2:15][CH2:14][C:12]=3[S:13][C:7]=2[N:6]=[CH:5]1
Reactant: CCN1CCc2sc3ncn(CCO)c(=O)c3c2C1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: CCN1CCc2sc3ncn(CCCl)c(=O)c3c2C1
Yield: 83 %

Procedure:
10.5 g (37.6 mM [sic]) of 3-(2-hydroxyethyl)-6-ethyl-3,4, 5,6,7,8-hexahydropyrido[3',4':4,5]thieno-[2,3-d]pyrimidin-4-one in 100 ml of 1,2-dichloroethane were heated to reflux (slow dissolution) and then 3.5 ml (48 mM [sic]) of thionyl chloride in 20 ml of 1,2-dichloroethane were added dropwise. After refluxing for 1 h, the reaction mixture was allowed to cool, and the solid was filtered off with suction and washed with 1,2-dichloroethane. The crude product was partitioned between methylene chloride and water at pH=9. The organic phase was dried and concentrated to isolate 9.3 g (83%) of product as a dark oil which slowly crystallized and is sufficiently pure for further reactions, melting point 94-96° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:24]>[Pd]>[ClH:24].[ClH:24].[NH2:13][C:11]1[C:10]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:12]=1
Reactant: O=[N+]([O-])c1cn(Cc2ccccc2)nc1NCc1ccccc1
Agent: [Pd]
Agent: Cl
Product: Nc1cn(Cc2ccccc2)nc1NCc1ccccc1
Reaction time: 17 h

Procedure:
500 mg (1.62 mmoles) of 1-benzyl-3-benzylamino-4-nitropyrazol (Example 1, Step I, Fraction 1) are hydrated in 20 ml 5-normal methanolic hydrochloric acid with catalytic quantities of palladium/carbon at room temperature and 50 bar. After 17 hours, the hydration is concluded and hydrogen chloride gas is guided through the solution for 5 minutes. The solution is reduced in the rotary evaporator in a vacuum to half of the original volume and then mixed with acetic acid until a colorless precipitate is formed which is recrystallized from acetic acid/methanol.