Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:8]([CH2:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:23]=[C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[S:21][C:20]=3[S:28]([NH:31]C(C)(C)C)(=[O:30])=[O:29])[CH:16]=[CH:17][CH:18]=2)[CH:9]=[CH:10][N:11]=1.B(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].Cl[C:47]([O:49][CH2:50][CH2:51][CH2:52][CH3:53])=[O:48]>C(Cl)Cl.O>[CH2:50]([O:49][C:47]([NH:31][S:28]([C:20]1[S:21][C:22]([CH2:24][CH:25]([CH3:27])[CH3:26])=[CH:23][C:19]=1[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][N:8]2[CH:9]=[CH:10][N:11]=[C:7]2[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH:14]=1)(=[O:29])=[O:30])=[O:48])[CH2:51][CH2:52][CH3:53]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2cccc(Cn3ccnc3-c3ccccn3)c2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: ClB(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1cccc(Cn2ccnc2-c2ccccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 3-[3-(2-pyridin-2-ylimidazol-1-ylmethyl)phenyl]-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (46.7 mg, 0.0918 mmol; see step (b)) in CH2Cl2 (1 mL) was added BCl3 (0.18 mL, 1.0 M in hexane) and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was concentrated in vacuo. Water (5 mL) was added to the residue and this was then extracted with EtOAc. The combined organic phase was washed with water and brine, dried (over anhydrous MgSO4) and concentrated in vacuo. To the crude product dissolved in CH2Cl2 (5 mL) was added Na2CO3 (43.8 mg, 0.413 mmol), water (2 mL) and butyl chloroformate (16.3 μL, 0.0129 mmol) and the reaction mixture was stirred for 23 h at ambient temperature. The reaction mixture was diluted with CH2Cl2 (30 mL) and washed with citric acid (10% aq), brine and water, dried (over anhydrous MgSO4), concentrated in vacuo, and the residue purified by flash chromatography using MeOH:CH2Cl2 (6:94) as eluent to give the title compound as a white solid in 63% yield, over two steps, (32 mg, 0.058 mmol).
Reaction SMILES: O[N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].BrCCCBr.C(N(CC)CC)C>CN(C=O)C>[C:6]1(=[O:7])[NH:2][C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]12
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: BrCCCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)c2ccccc21
Temperature: 47.5 °C
Reaction time: 5.5 h

Procedure:
A mixture of N-hydroxyphthalimide (100 mmol) and 1,3-dibromopropane (100 mmol) in dry DMF and triethyl amine (110 mmol) is stirred at 20-75° C. for 1-10 hours. After filtration, the mixture is evaporated to dryness under reduced pressure. The residue is purified by silica gel chromatography to give N-[(3-bromopropyl)oxy)]phthalimide.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[C:27]1[CH:28]=[C:29]([C:33]2[CH:38]=[C:37]([NH:39][CH:40]3[CH2:42][CH2:41]3)[N:36]=[C:35]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[CH:34]=2)[CH:30]=[N:31][CH:32]=1>COCCOC.C(Cl)Cl>[CH:40]1([NH:39][C:37]2[N:36]=[C:35]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][N:44]=3)[CH:34]=[C:33]([C:29]3[CH:30]=[N:31][CH:32]=[C:27]([C:14]4[CH:15]=[CH:16][C:11]([CH2:10][N:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:12][CH:13]=4)[CH:28]=3)[CH:38]=2)[CH2:42][CH2:41]1
Reactant: CC(C)N1CCN(Cc2ccc(B(O)O)cc2)CC1
Reactant: Brc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2ccc(-c3cncc(-c4cc(NC5CC5)nc(-c5ccccn5)c4)c3)cc2)CC1

Procedure:
To a solution of 4-((4-Isopropyl-piperazin-1-yl)methyl)-phenyl boronic acid (Intermediate B3) (3 eq, 0.408 mmol, 0.106 g) in dry DME (1 ml) under an inert atmosphere of argon is added 2M Na2CO3 (6 eq, 0.816 mmol, 0.8 ml) followed by (5″-Bromo-[2,2′;4′,3″]terpyridin-6′-yl)-cyclopropyl-amine (Example 1.26) (1 eq, 0.136 mmol, 50 mg) and PdCl2dppf (0.1 eq, 0.0136 mmol, 10 mg). The reaction mixture is heated using microwave radiation at 90° C. for 2 hours. The reaction mixture is dissolved in DCM and washed with water. The organic solvent is reduced in vacuo and the residue is purified by reverse phase column chromatography (Isolute™ C18, 0-40% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 505.
Reaction SMILES: [C:1]1([CH:11]([CH3:13])[CH3:12])[C:2](S([O-])(=O)=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+].[Mg].[OH2:16]>>[CH2:2]([OH:16])[CH2:1][CH2:6][CH2:5][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH:11]([CH3:12])[CH3:13]
Reactant: O
Reactant: CC(C)c1ccccc1S(=O)(=O)[O-]
Agent: [Mg]
Agent: [Na+]
Product: CC(C)CCCCCCCCCCO

Procedure:
A process for the preparation of solid active-ingredient concentrates, which comprises preparing a spray solution from sodium cumenesulphonate, methylhydroxyethylcellulose and water which is sprayed onto a mixture of magnesium perphthalate powder and sodium alkylbenzoate powder in a fluidized-bed drier at an air intake temperature of from about 60 to 80° C., and coating the granules formed with a melt of isotridecanol ethoxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[S:12][CH:11]=[N:10][CH:9]=2)[N:5]=[C:4]([NH:13][C@H:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[N:3]=1.[NH2:23][C:24]1[CH:29]=[N:28][CH:27]=[CH:26][N:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:14]([NH:13][C:4]2[N:3]=[C:2]([NH:23][C:24]3[CH:29]=[N:28][CH:27]=[CH:26][N:25]=3)[CH:7]=[C:6]([C:8]3[S:12][CH:11]=[N:10][CH:9]=3)[N:5]=2)[CH3:15])=[CH:17][CH:18]=1
Reactant: Nc1cnccn1
Reactant: C[C@H](Nc1nc(Cl)cc(-c2cncs2)n1)c1ccc(F)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C[C@H](Nc1nc(Nc2cnccn2)cc(-c2cncs2)n1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 57.6 %

Procedure:
To 155 mg of (S)-4-chloro-N-[1-(4-fluorophenyl)ethyl]-6-(thiazol-5-yl)pyrimidine-2-amine, 53 mg of 2-aminopyrazine, 72 mg of 4,5-bis(diphenylphosphino)-9,9′-dimethylxanthene, 196 mg of tripotassium phosphate and 81 mg of tris(dibenzylideneacetone)(chloroform)dipalladium, was added 4 ml of 1,4-dioxane, and the mixture was subjected to degassing, and substituted by argon gas, and then was stirred at 100° C. for 5 hours. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 105 mg of the objective compound as pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([OH:14])[C:11]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:10]([CH3:22])[N:9]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33]>C1COCC1>[CH2:15]([C:11]1[C:12]([OH:14])=[N:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[CH2:31][Cl:30])=[CH:3][CH:4]=2)=[N:9][C:10]=1[CH3:22])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1nc(-c2ccc(N)cn2)nc(O)c1Cc1ccccc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc(-c2ccc(NC(=O)CCl)cn2)nc(O)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a cold (0° C.) solution of compound of example 54 (0.050 g, 0.17 mmol) in THF (3 mL), was added triethylamine (0.025 g, 0.25 mmol) and chloroacetylchloride (0.029 g, 0.25 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. THF was removed under reduced pressure, and reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography (silica gel, 5% methanol in chloroform as an eluent) to obtain the title compound.
Reaction SMILES: Cl[CH2:2][CH:3]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)[OH:4].[CH3:11][NH2:12].[BH4-].[Na+]>CO.O>[CH3:11][NH:12][CH2:2][CH:3]([C:5]1[N:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1)[OH:4]
Reactant: Cn1cccc1C(O)CCl
Reactant: CN
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCC(O)c1cccn1C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-chloro-1-(1-methyl-1H-pyrrol-2-yl)ethanol (Croce, P. D.; Ferraccioli, R.; Ritieni, A. Synthesis, 1990, 212-213) (2.05 g) is dissolved in methanol (40 mL) and added dropwise to a 2.0 M solution of methylamine in methanol (65 mL) at 0° C. The reaction mixture is stirred at 0° C. for 1 h and then allowed to warm to room temperature. The reaction mixture is stirred at room temperature for 18 h and then cooled to 0° C. Sodium borohydride (0.738 g) in H2O (40 mL) is added dropwise. The reaction mixture is stirred at 0° C. for 30 min and then allowed to warm to room temperature. The reaction mixture is stirred at room temperature for 18 h. An additional 0.738 g (19.5 mmol) of sodium borohydride is added and the reaction mixture is stirred at room temperature for 18 h. The reaction is quenched with a 1 N HCl solution and then concentrated in vacuo to remove methanol. The aqueous layer is adjusted to pH 12 with a 2 N NaOH solution and extracted with CH2Cl2 (4×100 mL). The combined organic layers are dried (MgSO4), filtered, and concentrated in vacuo. The resulting yellow oil is crystallized from ethyl acetate to yield 0.772 g of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:27][CH2:28][CH2:29][CH:30]([OH:52])[CH2:31][O:32]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C=O.O>[CH2:11]([O:27][CH2:28][CH2:29][CH:30]([O:52][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:31][OH:32])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: BrCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCOCCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCCOCCC(CO)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 55.3 %

Procedure:
To a suspension of 6.17 g of 50% sodium hydride (washed with hexanes) in 245 ml of dry dimethylformamide was added 19.45 g of benzyl bromide at 0° C. A solution of 56.65 g of 4-(hexadecyloxy)-1-(triphenylmethoxy)-2-butanol in 60 ml of dimethylformamide was added dropwise with stirring at 0° C. under argon. The mixture was stirred overnight at room temperature, then poured into 1000 ml of iced water and extracted with petroleum ether. The organic phase was dried, the solvent removed and the residue dissolved in a mixture of 235 ml of methanol and 125 ml of tetrahydrofuran. A 500 mg portion of p-toluene sulfonic acid was added, the mixture was allowed to stand overnight and then the solvent was removed. The residue was dissolved in petroleum ether, washed with saturated aqueous sodium bicarbonate, dried and the solvent removed giving an oil. This oil was again subjected to treatment with p-toluenesulfonic acid in the solvent system described above, again giving an oil which was purified by HPLC, giving 23 g of the desired compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1.[H][H]>O1CCCC1.[Pd].C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: [H][H]
Reactant: O=C(O)C=Cc1cc(F)cc(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)CCc1cc(F)cc(F)c1
Yield: 98.8 %

Procedure:
A solution of 3-(3,5-difluorophenyl)propenoic acid (0.0435 mol) in tetrahydrofuran (100 ml) and a slurry of 10% palladium on carbon (1.5 g) in ethyl acetate were shaken together under 50 psi hydrogen for 4 hours. The mixture was filtered and concentrated to yield 8 g (99%) of a yellow oil.
Reaction SMILES: [C:1]([BH3-])#N.[Na+].[CH2:5]([CH:13]1[CH2:17][CH2:16][CH2:15][NH:14]1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C=O.C(O)(=O)C>C(#N)C>[CH3:1][N:14]1[CH2:15][CH2:16][CH2:17][CH:13]1[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [BH3-]C#N
Reactant: c1ccc(CCC2CCCN2)cc1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCCC1CCc1ccccc1
Reaction time: 0.25 h
Yield: 55 %

Procedure:
Sodium cyanoborohydride (17.4 mg, 0.27 mmol) was added portion-wise to a stirred solution of 2-phenethyl pyrrolidine (30 mg, 0.17 mmol) and 37% aqueous formaldehyde (0.07 mL, 0.87 mmol) in 1.5 mL acetonitrile at 25° C. The mixture was stirred for 15 min, acetic acid was added dropwise until the reaction was neutral, and the mixture was stirred for an additional 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in 10 mL diethyl ether and the ethereal solution was washed with 10 mL of saturated Na2CO3 and extracted twice with 5 mL of 1N HCl. The combined HCl solutions were then basicified with saturated Na2CO3 to obtain a pH=10 and extracted three times with 10 mL dichloromethane. The combined dichloromethane layers were washed with 10 mL of saturated NaCl, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified on thin layer chromatography to give 1-methyl-2-phenethyl pyrrolidine free base; 18 mg, 55% yield.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:24]=[CH:23][C:8]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[CH:7][CH:6]=1.[CH2:25]([O:27][C:28]1[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][NH:30][N:29]=1)[CH3:26].O>CN(C)C=O>[CH2:25]([O:27][C:28]1[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][N:30]([CH2:4][C:5]2[CH:24]=[CH:23][C:8]([O:9][CH2:10][C:11]3[N:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[O:14][C:15]=3[CH3:16])=[CH:7][CH:6]=2)[N:29]=1)[CH3:26]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Reactant: CCOC(=O)Cc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (549 mg), ethyl 3-ethoxy-1H-pyrazol-4-ylacetate (347 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-ylacetate (618 mg, yield: 74%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: C12(COC3C(I)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[CH:34]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][C:36]=1[Cl:44])[CH2:31]2.N1(S(N)(=O)=O)CCC1.[CH3:61][S:62]([NH2:65])(=[O:64])=[O:63]>>[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[CH:34]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:35]1[CH:43]=[CH:42][C:38]([C:39]([NH:65][S:62]([CH3:61])(=[O:64])=[O:63])=[O:40])=[CH:37][C:36]=1[Cl:44])[CH2:31]2
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1ccc(C(OCc2ccccc2)C2C3CC4CC(C3)CC2C4)c(Cl)c1
Agent: NS(=O)(=O)N1CCC1
Agent: O=C(O)c1cc(I)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: CS(=O)(=O)NC(=O)c1ccc(C(OCc2ccccc2)C2C3CC4CC(C3)CC2C4)c(Cl)c1

Procedure:
Following the procedure as described in Example 299 Step 2 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-2-fluoro-5-iodobenzoic acid with 4-(adamantan-2-yl(benzyloxy)methyl)-3-chlorobenzoic acid and to replace azetidine-1-sulfonamide with methanesulfonamide, the title compound was obtained as a colorless solid (0.312 g, 61%): 1H NMR (300 MHz, DMSO-d6) δ 12.24 (br s, 1H), 8.04 (d, J=1.7 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.37-7.22 (m, 5H), 5.08 (d, J=9.9 Hz, 1H), 4.27 (d, J=11.8 Hz, 1H), 4.16 (d, J=11.8 Hz, 1H), 3.37 (s, 3H), 2.38-2.31 (m, 1H), 2.09-1.34 (m, 13H), 1.08-1.02 (m, 1H); MS (ES−) m/z 486.2, 488.2 (M−1).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=O)C.C(OCC)(=O)C.ClCCl.[OH-].[Na+]>Cl>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N2CCCCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Nc1ccc(S(=O)(=O)N2CCCCC2)cc1
Yield: 70.62 %

Procedure:
N-[4-(Acetylamino)phenylsulfonyl]piperidine (Example 5) was heated at 100° C. in 20% hydrochloric acid (5 mL) for one hour (TLC ethyl acetate/dichloromethane 8:2). The solution is neutralized at 0° C. with NaOH. The precipitate that forms is filtered and recrystallized from methanol/diethyl ether to afford the desired N-[4-(amino)phenylsulfonyl]piperidine. 70.62% yield; white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][N:3]=1.[N-:11]=[N+:12]=[N-:13].[Na+].Cl>C(O)C.O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]2[N:3]([N:11]=[N:12][N:13]=2)[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)c1ccc2nnnn2c1

Procedure:
To a stirred solution of 8.4 gm. (51.6 mmoles) of 2-chloro-5-acetylpyridine and 8.4 gm. (129 mmoles) of sodium azide in 150 ml of ethanol and 150 ml of water was added 75 ml of 10% HCl over a period of 20 minutes. The reaction mixture was then heated to reflux for 18 hours, cooled in an ice bath and the resulting crystals filtered off to give a first crop of 6.0 gm. A second crop of 1.0 gm. was obtained for a total of 7.0 gm. of A, (84.% yield), m.p. 159°-160° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([CH3:25])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:12])=[CH:4][CH:3]=1.[Br:26][CH2:27][CH2:28][CH2:29]Cl.O>CC(C)=O>[Br:26][CH2:27][CH2:28][CH2:29][O:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]([CH3:25])([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:10][C:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Cc1cc(C(C)(CC(=O)c2ccccc2)c2ccccc2)ccc1O
Solvent: CC(C)=O
Solvent: O
Product: Cc1cc(C(C)(CC(=O)c2ccccc2)c2ccccc2)ccc1OCCCBr
Yield: 85.5 %

Procedure:
Fifty grams (0.15 mol) of 4-hydroxy-3,5-dimethyl-β,β-diphenylpropiophenone (prepared as in Example 5), dissolved in 200 mls of acetone, are added, with stirring, to a reaction mixture consisting of 29 grams (0.184 mol) of 1-bromo-3-chloropropane in 300 mls of acetone and 42 grams (0.304 mol) of water-free potash. The preparation is boiled under reflux for one day and the precipitate is sucked off. The acetone is evaporated, the residue taken up with ether and a little acetone and, subsequently, washed with water. The ethereal phase is dried over sodium sulfate. The solvent is evaporated in vacuo. The residue is crystallized from acetone/petroleum ether. Fifty-two and five-tenths grams [85.5%] of 4-(3-bromopropoxy)-3,5-dimethyl-β,β-diphenylpropiophenone are obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=1.C(N(CC)CC)C.O.[NH2:20][NH2:21]>O>[NH:20]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][N:3]=1)[NH2:21]
Reactant: NN
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(NN)nc1
Temperature: 70 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
A suspension of 2-bromo-5-(methanesulfonyl)-pyridine (7.3 g, 116 mmol), triethylamine (14.7 g, 145 mmol), and hydrazine hydrate (7.26 g, 145 mmol) in water (205 mL) was heated to 70° C. The reaction mixture became homogenous before the product started to precipitate out of this mixture (after 90 minutes). The reaction mixture was stirred at 70° C. for total of 5 hours and then was allowed to cool to room temperature and stirred for 18 hours. The precipitated product was collected by filtration, dried and recrystallized from hot ethanol to afford 2-hydrazinyl-5-(methanesulfonyl)-pyridine in 86% yield. Analytical data: 1H NMR (300 MHz, CDCl3) δ 3.12 (s, 3H), 4.44 (br s, 2H), 6.80 (br d, J=8.7 Hz, 1H), 7.81 (dd, J1=9.0 Hz, J2=2.4 Hz, 1H), 8.38 (d, 2.3 Hz, 1H), 8.57 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7](O)[C:6]=2[CH:17]=1.S(Cl)([Cl:20])=O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([Cl:20])[C:6]=2[CH:17]=1
Reactant: O=S(Cl)Cl
Reactant: OC1c2ccccc2C=Cc2ccc(Br)cc21
Solvent: c1ccccc1
Product: ClC1c2ccccc2C=Cc2ccc(Br)cc21

Procedure:
663 milligrams (2.31 millimoles) of 3-bromo-5H-dibenzo[a,d]cyclohepten-5-ol, 825 milligrams (6.94 millimoles) of thionyl chloride and 10 milliliters of benzene were mixed together and refluxed for 1.5 hours and the solvent removed in vacuo to obtain a 3-bromo-5-chloro-5H-dibenzo[a,d]-cycloheptene product as residue. The residue was dissolved in 10 milliliters of dimethylformamide and 1.74 milliliters (1.29 grams, 10.0 millimoles) of ethyl diisopropyl amine and 500 milligrams (2.31 millimoles) of cinnamoylpiperazine added thereto and the resulting mixture stirred overnight to obtain a 1-(3-bromo-5H-dibenzo[a,d]cyclohepten-5-yl)-4-cinnamoylpiperazine compound in the reaction mixture. It was recovered as residue by vaporizing the solvent in vacuo, the residue then was dissolved in ethyl acetate, the ethyl acetate solution washed with three 50 milliliter portions of water and with one 100 milliliter portion of brine, and then dried over potassium carbonate. After removing the drying agent, the solvent was evaporated in vacuo from the dried solution to obtain 1.07 grams (95 percent yield) of the cinnamoylpiperazine compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:23])=[C:14]([C:20](O)=[O:21])[N:15]=[C:16]2[Cl:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:30])[C@@H:27]([CH3:29])[NH2:28]>>[CH3:24][O:25][C:26](=[O:30])[C@H:27]([NH:28][C:20]([C:14]1[N:15]=[C:16]([Cl:19])[C:17]2[C:12]([C:13]=1[OH:23])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2)=[O:21])[CH3:29]
Reactant: COC(=O)[C@@H](C)N
Reactant: O=C(O)c1nc(Cl)c2cc(OCc3ccccc3)ccc2c1O
Product: COC(=O)[C@@H](C)NC(=O)c1nc(Cl)c2cc(OCc3ccccc3)ccc2c1O

Procedure:
7-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.33 g, was coupled with D-Alanine methyl ester analogously to Example A-1 a). 0.246 g of off-white solid were obtained: MS-(+)-ion, M+1=415.0 amu.