Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:11])[NH:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:12][C:13]1[C:14]([CH:19]=O)=[N:15][CH:16]=[CH:17][CH:18]=1>O.C(O)C>[OH:12][C:13]1[C:14]([CH:19]=[N:10][NH:9][C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:11])=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=Cc1ncccc1O
Reactant: NNC(=O)Nc1ccccc1
Solvent: O
Solvent: CCO
Product: O=C(NN=Cc1ncccc1O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
4-Phenyl semicarbazide (4.91 g, 33 mmol) was added to a suspension of 3-hydroxy-2-pyridine carbaldehyde (4.0 g, 33 mmol) in a mixture of ethanol water (30 mL: 40 mL). The reaction mixture was stirred at room temperature for 3 h and the yellow product was collected by filtration. The yellow precipitate was washed with EtOH/H2O 1:1 and dried under P2O5 to yield 8.22 g (99%) of product. It can be recrystallized from EtOH/H2O; m.p. 201°-2° C. (dec.). 1H NMR (d6 -DMSO) δ: 10.85 (br.s., 1H); 10.6 (br.s., 1H); 9.14 (s, 1H); 8.27 (s, 1H); 8.15 (d of d, 1H); 7.55 (d, 2H); 7.26-7.36 (m, 4H); 7.01 (t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[NH:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[S:14](Cl)(=[O:16])=[O:15].[OH:18][CH2:19][C@:20]([OH:37])([CH3:36])[C:21](=[O:35])[C@@H:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH:24]([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[NH:9][CH2:10][C:11]#[CH:12])=[CH:4][C:3]=1[S:14]([O:18][CH2:19][C@:20]([OH:37])([CH3:36])[C:21](=[O:35])[C@@H:22]([NH:27][C:28]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:34])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:15])=[O:16]
Reactant: C#CCNC(=O)c1ccc(F)c(S(=O)(=O)Cl)c1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)[C@](C)(O)CO
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C#CCNC(=O)c1ccc(F)c(S(=O)(=O)OC[C@@](C)(O)C(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
2-Fluoro-5-(prop-2-yn-1-ylcarbamoyl)benzene-1-sulfonyl chloride (3, 2.52 g, 9.14 mmol) was added dropwise to tert-butyl ((2R,4S)-1,2-dihydroxy-2,6-dimethyl-3-oxoheptan-4-yl)carbamate (2.65 g, 9.14 mmol), DIEA (1.91 mL, 10 mmol) and DMAP (0.1 g, 0.914 mmol) in DCM (30 mL) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The reaction was washed with 2N HCl and brine, dried (MgSO4) and evaporated. The residue was purified by Biotage flash column chromatography (30% EtOAc/Hep) to give product as an oil (3.62 g, 75%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][O:10]1.[C:15]1([CH:22]=[CH:21][C:19]([OH:20])=[CH:18][CH:17]=1)[OH:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CS(C)=O>[O:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]1[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:16][C:15]1[CH:22]=[CH:21][C:19]([OH:20])=[CH:18][CH:17]=1
Reactant: ClCCCCCCOC1CCCCO1
Reactant: Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Oc1ccc(OCCCCCCOC2CCCCO2)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A mixture of 10 g of 2-(6-chlorohexyloxy)tetrahydropyrane, 25 g of hydroquinone, 31 g of potassiumcarbonate, 0.752 g of potassiumiodide and 250 ml of dimethylsulfoxide was allowed to react for 4 days at 80° C. Subsequently, the reaction mixture was cooled to room temperature and after addition of water extracted with ether. The organic phase was then dried over sodium sulphate, filtered and concentrated to dryness. Chromatography on silica with 10% ethylacetate in toluene gave 11 g of product as a yellowish oil.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH2:12][N+:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:24][S:23][C:22](=[O:25])[NH:21][N:20]=3)=[CH:15][CH:14]=2)=[O:11])=[CH:6][CH:5]=1.[BH4-].[Na+].ClCCl>CO>[OH:11][CH:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)[CH2:12][N:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH2:24][S:23][C:22](=[O:25])[NH:21][N:20]=2)=[CH:15][CH2:14]1
Reactant: COc1ccc(C(=O)C[n+]2ccc(C3=NNC(=O)SC3)cc2)cc1
Agent: [BH4-]
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(O)CN2CC=C(C3=NNC(=O)SC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
1-[(4-Methoxyphenyl)carbonylmethyl]-4-(3H,6H-1,3,4-thiadiazin-2-one-5-yl)pyridinium bromide (760 mg, 1.8 mmol) was dissolved in methanol (8 ml) and gradually added with sodium borohydride (680 mg, 18 mmol) under ice-cooling and then stirred at room temperature overnight. The solvent was removed under reduced pressure. The residue obtained was added with dichloromethane, washed with water and dried over anhydrous magnesium sulfate. The residue obtained by evaporation was purified by column chromatography (dichloromethane-methanol=20:1) to obtain the titled compound (423 mg) as white crystals.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]([C:13]1[S:14][C:15]([CH3:18])=[CH:16][CH:17]=1)=[O:12]>C(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:8][CH2:18][C:15]1[S:14][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:17][CH:16]=1
Reactant: COC(=O)c1ccc(C)s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CBr)s1
Temperature: 25 °C
Yield: 100 %

Procedure:
Add freshly recrystallised NBS (323.8 g, 1.81 mol) to a solution of methyl-5-methylthiophene-2-carboxylate (258 g, 1.65 mol) in chloroform (2.6 L) at room temperature, and stir. Add benzoyl peroxide (3.99 g, 0.016 mol) and heat the reaction mixture to reflux for 7 hours. Cool the reaction mixture to ambient temperature and filter through diatomaceous earth. Wash the filter cake with chloroform (250 ml). Collect the organic layers and remove the solvent to give the title compound (388 g, 100%), which is used without further purification. ESI (m/z) 236(M+H).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[CH:4]=1.[Br-].[C:12](#[N:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[NH2:15].[C:21](=O)(OCC)[O:22]CC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[F:10][C:5]1[CH:4]=[C:3]([C:12]2[C:13]3[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:15][C:21](=[O:22])[N:20]=2)[CH:8]=[CH:7][C:6]=1[F:9]
Reactant: Fc1ccc(Br)cc1F
Reactant: N#Cc1ccccc1N
Reactant: CCOC(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Br-]
Agent: [Mg]
Solvent: C1CCOC1
Product: O=c1nc(-c2ccc(F)c(F)c2)c2ccccc2[nH]1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
An oven dried round-bottom flask was charged with magnesium turnings (3.55 g, 146 mmol) in THF (100 mL) under argon. 1-Bromo-3,4-difluorobenzene (4.0 mL, 35.3 mmol) was added to the suspension in one portion. The solution was heated to 40° C. Once the temperature had stabilized at 50° C., the remainder of the bromide (13.52 mL, 155 mmol total) was added dropwise. After complete addition, the solution was stirred for 1 hour at 65° C. A solution of anthranilonitrile (4.95 g, 41.9 mmol) in THF (25 mL) was added dropwise while keeping the internal temperature constant. After stirring or two hours at 65° C., diethyl carbonate (16.3 mL, 135 mmol) was added dropwise to the brownish-red solution . This solution was stirred for an additional 30 minutes at 65° C. and then cooled to room temperature. The solution was poured into a mixture of 250 mL of 1 M citric acid and ice. The mixture was extracted three times with CHCl3 (50 mL) and the combined extracts were washed with a 10% Na2CO3 solution. The organics were dried over Na2SO4, concentrated, and triturated with Et2O to afford the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][C:12]([NH:14][CH3:15])=[O:13])[CH:8]=2)[CH:3]=[CH:2]1.N1C2C(=CC=CC=2C(C2C=CC=CC=2)CC(NC)=O)C=C1>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:10]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH2:11][C:12]([NH:14][CH3:15])=[O:13])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: CNC(=O)C=C(c1ccc2cc[nH]c2c1)c1ccccn1
Agent: CNC(=O)CC(c1ccccc1)c1cccc2cc[nH]c12
Product: CNC(=O)CC(c1ccc2cc[nH]c2c1)c1ccccn1

Procedure:
3-(1H-Indol-6-yl)-N-methyl-3-pyridin-2-yl-propionamide CLXIII was prepared from 3-(1H-indol-6-yl)-N-methyl-3-pyridin-2-yl-acrylamide using the procedure described for preparation of 3-(1H-Indol-7-yl)-N-methyl-3-phenyl-propionamide XIX using.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:18]=[C:17]([CH2:19][OH:20])[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=1)[C:12]#[N:13].Cl[C:22]1[CH:23]=[C:24]2[N:31]([CH3:32])[CH2:30][CH2:29][N:25]2[C:26](=[O:28])[N:27]=1>C1COCC1>[F:3][C:4]1[CH:18]=[C:17]([CH2:19][O:20][C:22]2[CH:23]=[C:24]3[N:31]([CH3:32])[CH2:30][CH2:29][N:25]3[C:26](=[O:28])[N:27]=2)[CH:16]=[CH:15][C:5]=1[O:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([CH:14]=1)[C:12]#[N:13]
Reactant: N#Cc1cncc(Oc2ccc(CO)cc2F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3cncc(C#N)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using NaH (5.90 mg, 0.246 mmol) in THF (5 mL) was added 5-(2-fluoro-4-(hydroxymethyl)phenoxy)n-icotinonitrile (30 mg, 0.12 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyr-imidin-5(1H)-one (22.8 mg, 0.123 mmol).
Reaction SMILES: [Mg].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7]Br.[CH3:12][N:13]([CH3:32])[CH:14]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=[O:21].[Cl-:33].[NH4+]>CCOCC>[ClH:33].[CH3:32][N:13]([CH:14]([C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C:16]1([CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([O:3][CH3:2])[CH:5]=1)[OH:21])[CH3:12]
Reactant: CN(C)C(c1ccc(C(F)(F)F)cc1)C1CCCCC1=O
Reactant: COc1cccc(CBr)c1
Reactant: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: COc1cccc(CC2(O)CCCCC2C(c2ccc(C(F)(F)F)cc2)N(C)C)c1
Product: Cl
Temperature: 25 °C
Yield: 70.9 %

Procedure:
0.29 g (12.0 mmole) of magnesium turnings was stirred in 5 ml of ether of analysis purity. 2.42 g (12.0 mmole) of 3-methoxybenzyl bromide dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for a further hour at RT. 3.0 g (10.0 mmole) of the 2-[dimethyl-amino-(4-trifluoromethylphenyl)methyl]cyclohexanone prepared according to stage 2 were dissolved in 5 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction solution was worked up by adding 30 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT, each time with 50 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 5.60 g of crude base (133% of theory) were obtained. 3.26 g of 2-[dimethylamino-(4-trifluoromethyl-phenyl)methyl]-1-(3-methoxybenzyl)cyclohexanol, hydrochloride (70.9% of theory) were obtained from the crude base according to the procedure described in Example 1 (3rd stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 133° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.[CH3:11][N:12](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)[CH3:13].F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CNC>CN(C=O)C.O>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:13])[CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc(I)cc1
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)c1ccc(I)cc1
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A solution of 4-iodobenzoic acid (2.0 g, 8.0 mmol), HATU (4.6 g, 12.0 mmol) and DIPEA (1.6 g, 12.0 mmol) in DMF (30 mL) was stirred for 1 h. Then, dimethylamine hydrochloride (0.98 mg, 12.0 mmol) was added. The resulting solution was stirred overnight. The reaction was monitored by TLC (petroleum ether/EtOAc 2:1). The reaction mixture was poured into water (30 mL) and extracted with EtOAc (40 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified by silica gel column chromatography using petroleum ether/EtOAc (4:1) to afford the desired compound (1.5 g, 60%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 7.75 (d, 2H), 7.16 (d, 2H), 3.15-2.97 (d, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:21]([CH2:36][CH:37]([CH3:39])[CH3:38])[C:22]([NH:24][N:25]([S:32]([CH3:35])(=[O:34])=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH2:9][N:10]1C(=O)C2=CC=CC=C2C1=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN.[CH3:43]O>>[NH2:10][CH2:9][C@@H:8]([C@@H:21]([CH2:36][C:37]([CH3:38])([CH3:43])[CH3:39])[C:22]([NH:24][N:25]([S:32]([CH3:35])(=[O:33])=[O:34])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: CO
Reactant: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](CN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: NN
Solvent: O
Product: CC(C)(C)C[C@@H](C(=O)NN(c1ccccc1)S(C)(=O)=O)[C@H](CN)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 0.705 g of 2(R)-[1(R)-(tert-butoxycarbonyl)-2-phthalimidoethyl]-2′-(methanesulphonyl)-4-methyl-2′-phenylvalerohydrazide in 15 ml of methanol was treated with 0.51 ml of hydrazine hydrate. The mixture was stirred under nitrogen overnight and then evaporated. The residue was stirred with 25 ml of dichloromethane/methanol/acetic acid/water (120:15:3:2). After 2 hours the precipitated solid was removed by filtration and the filtrate was evaporated. The residue was purified by chromatography on Kieselgel 60 using dichlormethane/methanol/acetic acid/water (240:24:3:2) for the elution. Fractions containing the amine product were combined and evaporated, and the residue was dissolved in 30 ml of dichloromethane and washed with three 10 ml portions of saturated sodium hydrogen carbonate solution. After drying over anhydrous magnesium sulphate the solution was evaporated to give 0.42 g of 2(R)-[2-amino-1(R)-(tert-butoxycarbonyl)ethyl]-2′-(methanesulphonyl)-4methyl-4-methyl-2′-phenylvalerohydrazide in the form of a pale yellow foam.
Reaction SMILES: C=O.[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:22]=2)[CH:17]=1.[Na].[C:31](#N)C>CO.C(Cl)Cl>[S:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:13]([NH2:29])=[N:14][CH:15]=[C:16]([C:18]2[CH:19]=[N:20][N:21]([CH:23]3[CH2:24][CH2:25][N:26]([CH3:31])[CH2:27][CH2:28]3)[CH:22]=2)[CH:17]=1
Reactant: CC#N
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccccc2s1
Agent: C=O
Agent: [Na]
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(n2cc(-c3cnc(N)c(-c4nc5ccccc5s4)c3)cn2)CC1
Reaction time: 0.5 h

Procedure:
37% Aqueous formaldehyde (0.060 ml) was added to a stirred solution of 3-(1,3-benzothiazol-2-yl)-5-[1-(4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.250 g) dissolved in methanol (2.5 ml) and DCM (2.5 ml). Sodium triacetoxyhydroborate (0.141 g) was added and the resulting solution was for 30 minutes. The mixture was concentrated. DCM and 7N methanol/ammonia were added. The mixture was concentrated on silica gel and the residue was purified by flash chromatography on silica gel eluting with 2 to 10% methanolic ammonia (7 N) in DCM. The solvent was evaporated to dryness to afford a solid. Acetonitrile (4 ml) was added and the solution was stirred overnight. The solid was filtered, and dried under vacuum. There was thus obtained 3-(1,3-benzothiazol-2-yl)-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridin-2-amine (0.198 g); Mass Spectrum: M+H+ 391; NMR Spectrum (DMSOd6): 8.48 (d, 1H), 8.33 (s, 1H), 8.16 (d, 1H), 8.15 (d, 1H), 8.10 (d, 1H), 7.93 (s, 1H), 7.88 (bs, 2H), 7.57 (dd, 1H), 7.49 (dd, 1H), 4.08-4.18 (m, 1H), 2.84-2.92 (m, 2H), 2.22 (s, 3H), 1.94-2.12 (m, 6H).
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH:6]([N:16]([CH3:27])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](O)=[O:4].S(Cl)([Cl:31])=O>C1C=CC=CC=1>[CH3:1][C:2]([CH3:28])([CH:6]([N:16]([CH3:27])[S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([Cl:31])=[O:4]
Reactant: COc1ccc(CC(N(C)S(=O)(=O)c2ccc(C)cc2)C(C)(C)C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ccc(CC(N(C)S(=O)(=O)c2ccc(C)cc2)C(C)(C)C(=O)Cl)cc1
Reaction time: 3 h

Procedure:
A mixture of 283 g of 2,2-dimethyl-4-(p-methoxyphenyl)-3-(N-methyl-p-toluenesulfonamido)butyric acid, 1500 ml of dry benzene and 430 ml of thionyl chloride is boiled for 3 hours. After removal of volatile material by evaporation in vacuo, the residue is taken up in toluene and the solvent is evaporated in vacuo. This procedure is repeated twice whereafter crystallization of the initially oily product is accomplished by treatment with ether, melting point 110°-111° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1([CH2:9][Cl:10])[CH2:7][O:6][C:5](=[O:8])[NH:4]1.C(O[Cl:16])(C)(C)C>CO>[Cl:16][N:4]1[C:3]([CH2:9][Cl:10])([CH2:2][Cl:1])[CH2:7][O:6][C:5]1=[O:8]
Reactant: O=C1NC(CCl)(CCl)CO1
Reactant: CC(C)(C)OCl
Solvent: CO
Product: O=C1OCC(CCl)(CCl)N1Cl
Reaction time: 1 h
Yield: 78.9 %

Procedure:
To a solution of 4,4-bis(chloromethyl)oxazolidin-2-one (1.11 g, 6.03 mmol) in MeOH (10 ml) was added tert-butylhypochlorite (1.0 ml, 8.4 mmol). The solution was stirred for 1 h, concentrated in vacuo, and the residue purified by flash chromatography (30% to 80% EtOAc in hexanes) to afford the title compound as a white solid (1.04 g, 4.76 mmol, 79%). 1H NMR (CDCl3, 400 MHz) δ 3.78 (d, J=12.0 Hz, 2H), 3.84 (d, J=12.4 Hz, 2H), 4.55 (s, 2H). LRMS (ESI/APCI): 228 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:14](=[O:16])[CH3:15])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1O)([O-:3])=[O:2].C1(C)C=CC(S([Cl:26])(=O)=O)=CC=1.CCN(C1C=CC=CC=1)CC.[N+](C1C=CC=CC=1)([O-])=O>Cl>[Cl:26][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([C:14](=[O:16])[CH3:15])=[CH:7][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)c1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Temperature: 95 °C
Yield: 87.5 %

Procedure:
A mixture of 22.6 grams (0.1 mole) of 3',5'-dinitro-4'-hydroxyacetophenone, 19.0 grams of p-toluenesulfonyl chloride (0.1 mole), 16.0 grams (0.107 mole) of diethylaniline, and 18.0 grams of nitrobenzene was heated at about 95° C. for 8 hours. The reaction mixture was poured into 200 milliliters of 10 percent aqueous hydrochloric acid and the nitrobenzene steam distilled from the mixture. The residue was cooled to room temperature, the aqueous layer decanted, and the dark oil which slowly solidified (yield 87.5 percent) recrystallized from ethanol (charcoal) to give a pale yellow crystalline compound, melting point 86°-86.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Oc1ccc(F)cc1
Reactant: BrCCCCOCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(OCCCCOCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 69.6 %

Procedure:
4-Fluorophenol (500 mg) and benzyl 4-bromobutyl ether (1.1 g) were dissolved in DMF (20 mL), and potassium carbonate (1.0 g) was added thereto at room temperature, followed by stirring at 100° C. for 18 hours. The reaction mixture was allowed to cool to room temperature, and water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=90/10) to obtain 1-[4-(benzyloxy)butoxy]-4-fluorobenzene (851 mg).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][O:13][C:14]1[CH:19]=[C:18]([S:20][CH3:21])[CH:17]=[CH:16][C:15]=1[C:22]1[NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[N:30]=1>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([S:20]([CH3:21])=[O:6])[CH:17]=[CH:16][C:15]=1[C:22]1[NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][C:25]=2[N:30]=1
Reactant: COc1cc(SC)ccc1-c1nc2cnccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: COc1cc(S(C)=O)ccc1-c1nc2cnccc2[nH]1
Temperature: 0 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
A solution of 911 mg. (4.22 mmoles) of m-chloroperoxybenzoic acid in 50 ml. of chloroform was added in a dropwise fashion to a solution of 1.15 gm. (4.23 mmoles) 2-(2-methoxy-4-methylmercaptophenyl)imidazo[4,5-c]pyridine in 150 ml. of chloroform at 0° C. The reaction was stirred overnight at 0° C., washed with dilute aqueous sodium bicarbonate, and the solvent removed in vacuo. The residue was flash chromatographed over silica gel using dichloromethane/methanol (9:1) affording 620 mg. (51% yield) of the title product, m.p. about 143°-146° C. (decomposition).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[I-:22].[Na+].O>CC(=O)CC>[I:22][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:21])[CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1
Reactant: [I-]
Reactant: O=C(CCCCc1ccccc1)c1ccc(CCBr)cc1
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: O=C(CCCCc1ccccc1)c1ccc(CCI)cc1
Yield: 83.2 %

Procedure:
A solution of 1-[4-(2-bromoethyl)phenyl]-5-phenylpentan-1-one (18.2 g) and sodium iodide (9.5 g) in 2-butanone (180 ml) was stirred at 60° C. for 3.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and the solvent was distilled away under reduced pressure to give a brown oily substance (19.2 g). The obtained brown oily substance was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=20:1) to give 1-[4-(2-iodoethyl)phenyl]-5-phenylpentan-1-one (17.2 g) as a yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:21]([N:24]1[CH2:29][CH2:28][CH:27]([C:30](Cl)=[O:31])[CH2:26][CH2:25]1)(=[O:23])[CH3:22].C(N(CC)CC)C>C(Cl)Cl>[C:21]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]([N:18]2[CH2:17][CH2:16][N:15]([C:9]3[C:10]([C:12](=[O:14])[CH3:13])=[CH:11][C:2]([Cl:1])=[C:3]4[C:8]=3[N:7]=[CH:6][CH:5]=[CH:4]4)[CH2:20][CH2:19]2)=[O:31])[CH2:28][CH2:29]1)(=[O:23])[CH3:22]
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(C(=O)C2CCN(C(C)=O)CC2)CC1
Reaction time: 2 h
Yield: 67.7 %

Procedure:
1-(5-Chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) was combined with 1-acetylpiperidine-4-carbonyl chloride (0.029 g, 0.16 mmol) and triethylamine (0.043 mL, 0.31 mmol) in methylene chloride (1.0 mL) at room temperature and stirred for 2 hours. The reaction was diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (30 mg, 65%). LCMS calculated for C23H28ClN4O3 (M+H)+: m/z=443.2; Found: 443.2.