Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].CC(C)([O-])C.[NH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].[C:13]1([CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27]Cl)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CN(C)C=O>[C:13]1([CH2:19][S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:27][N:7]2[CH2:11][CH2:10][CH2:9][C:8]2=[O:12])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CCCN1
Reactant: ClCc1ccccc1SCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCCN1Cc1ccccc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1.35 g of potassium-tertbutoxide in 25 mL of dimethylformamide, cooled to 0° C., was added 0.92 mL of 2-pyrrolidinone. As a white precipitate formed, the mixture was stirred for 10 minutes, and 3.0 g of 2-phenylmethylthio chloromethyl benzene was added in one portion. The resulting solution was allowed to warm to room temperature, stirred for 1 hour, poured into water, and extracted with methylene chloride. The organic layer was washed well with water, dried over magnesium sulfate, filtered, and the filtrate evaporated to leave 3.0 g of a yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[C:14]([OH:16])=[O:15].[C:17]([C:21]1[N:22]=[C:23]([C:26]2[O:27][C:28]3[CH:34]=[CH:33][C:32]([CH2:35]Cl)=[CH:31][C:29]=3[CH:30]=2)[S:24][CH:25]=1)([CH3:20])([CH3:19])[CH3:18].O>CN(C)C=O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:35][C:32]1[CH:33]=[CH:34][C:28]3[O:27][C:26]([C:23]4[S:24][CH:25]=[C:21]([C:17]([CH3:19])([CH3:18])[CH3:20])[N:22]=4)=[CH:30][C:29]=3[CH:31]=1)[N:9]=[C:8]2[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCl)ccc3o2)n1
Reactant: COc1ccc2[nH]nc(C(=O)O)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(C(=O)O)nn2Cc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
Sodium hydride (60% in mineral oil, 7.79 g) was added into a solution of 5-methoxy-1H-indazole-3-carboxylic acid (17.0 g) in N,N-dimethylformamide (400 ml) at room temperature under nitrogen atmosphere. After 30 minutes, 4-tert-butyl-2-[5-(chloromethyl)benzofuran-2-yl]thiazole (29.76 g) was added to the solution over 5 minutes. After being stirred continuously for 3 hours at 45° C., the reaction mixture was poured into water (2 l) and the reaction vessel was washed with water (200 ml). After combining the washing mixture to the aqueous mixture, the resulting mixture was made acidic with 10% hydrochloric acid aqueous solution (500 ml) and stirred vigorously for one hour. The precipitate was collected by filtration, washed with water and air-dried for one day. The crude product was washed with a mixture of isopropyl alcohol and isopropylethyl ether (7:3) and dried in vacuo to give 5-methoxy-1-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yl]methyl}indazole-3-carboxylic acid (36.5 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])[N:6]=1)=[O:4].[OH-].[Na+].O1CCOCC1>CO>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[C:8]([C:12]([F:13])([F:14])[F:15])[CH:9]=1
Reactant: COC(=O)c1nc(-c2ccc(Cl)cc2Cl)c(C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cc(C(F)(F)F)c(-c2ccc(Cl)cc2Cl)nc1C(=O)O

Procedure:
3-Amino-6-(2,4-dichloro-phenyl)-5-trifluoromethyl-pyridine-2-carboxylic acid methyl ester (0.9 g, 2.465 mmol) was suspended in MeOH (15 ml) and NaOH 2M (2.465 ml, 4.93 mmol) was added under stirring. 1,4-Dioxane (15.00 ml) was added and the solution was left standing at RT over night. The solvent was removed in vacuo and the resulting residue was dissolved in water (10 ml) and carefully acidified to pH4 with slow addition of 2M HCl (2 ml) whilst stirring. The mixture was extracted with EtOAc (20 ml) and the organic portion was washed with brine and concentrated in vacuo. The residue was purified by reverse phase chromatography (130 g C18 column) eluting with water/MeOH to afford the title compound; LS-MS Rt=1.57 mins[M+H]+ 351.0 (Method 2 min LC_v002).
Reaction SMILES: [S:1](Cl)(=[O:4])(=[O:3])[NH2:2].[O:6]([CH2:13][CH:14]([OH:17])[CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[S:1]([O:16][CH2:15][CH:14]([O:17][S:1](=[O:4])(=[O:3])[NH2:2])[CH2:13][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: NS(=O)(=O)Cl
Reactant: OCC(O)COc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: NS(=O)(=O)OCC(COc1ccccc1)OS(N)(=O)=O
Reaction time: 0.75 h

Procedure:
To the above sulfamoyl chloride solution in acetonitrile was added dropwise with stirring a solution of 8.4 g (0.05 mole) of 3-phenoxy-1,2-propanediol (95% purity obtained from Aldrich Chem. Co., Inc.) and 20.2 g (0.2 mole) of triethylamine in 50 ml of acetonitrile at such a rate that the temperature did not exceed 12° C. over a 45 min period. The cooling bath was removed and the mixture was stirred for 2 hr and treated with 100 ml of ethyl acetate and 50 ml of water. The mixture was vigorously stirred for 5 min and the layers were separated. The organic layer was washed with 50 ml of water and 100 ml of salt brine, dried over sodium sulfate and concentrated to give a gum as residue. The gum was purified by column chromatography on 350 g of silica gel. Fractions eluted with 15% acetone in methylene chloride were combined and concentrated to give a clear gum as residue. The gum was triturated with petroleum ether (b.p. 30°-60° C.) to give crystalline solid. The solid was collected by filtration and recrystallized from benzene-acetonitrile to yield 4.2 g (26% yield) of white solid title compound, mp 116°-118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([OH:10])=[O:9])[CH:6]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25]I>CCOC(C)=O>[Cl:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:7]([N:5]1[CH:6]=[C:2]([Cl:1])[CH:3]=[N:4]1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)Cn1cc(Cl)cn1
Reactant: ClCCCCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(O)C(CCCCCl)n1cc(Cl)cn1
Yield: 56.3 %

Procedure:
Step AK (1): 2-(4-Chloro-1H-pyrazol-1-yl)acetic acid (2.5 g, 15.57 mmol) was deprotonated with NaHMDS (1.0 M in THF, 31.0 mL, 31.0 mmol) and reacted with 1-chloro-4-iodobutane (1.91 mL, 15.6 mmol) using a procedure analogous to Step AC (1) to afford, after silica gel column chromatography (10-75% EtOAc/heanes), 6-chloro-2-(4-chloro-1H-pyrazol-1-yl)hexanoic acid (2.2 g, 56% yield). LC-MS (M−H)− 249.1.
Reaction SMILES: [C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[CH3:33][C:34](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:35].CCOC(C)=O.C(Cl)[Cl:64]>>[ClH:64].[C:1]([C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:12]([CH2:13][N:14]([CH2:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:34](=[O:35])[CH3:33])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: ClCCl
Reactant: N#Cc1ccc(Cn2cncc2CNCCCc2ccccc2)cc1
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)N(CCCc1ccccc1)Cc1cncn1Cc1ccc(C#N)cc1
Product: Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the amine 10 from Step 1 (41 mg, 0.125 mmol) in 2 mL of CH2Cl2 was added triethylamine (0.035 mL, 0.250 mmol). The solution was cooled to 0° C., and acetic anyhydride (0.012 mL, 0.125 mmol) was added. After 1 hour, the mixture was poured into EtOAc and washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo. This material was purified by silica gel chromatography (70% acetone/hexane), taken up in CH2Cl2 and treated with 1 M HCl/ether solution, and concentrated in vacuo. The titled product hydrochloride 9 was isolated as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:19])[C:5]([C:16]([OH:18])=[O:17])=[CH:6][NH:7]2.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][CH2:27][CH2:28][NH2:29].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:29][CH2:28][CH2:27][NH:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:19])[C:5]([C:16]([OH:18])=[O:17])=[CH:6][NH:7]2
Reactant: NCCNc1ccccn1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)c[nH]c12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)c[nH]c12
Temperature: 100 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A solution of 5-amino-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg, 1.48 mmol), N-2-pyridyl-1,2-ethanediamine (406 mg, 2.96 mmol) and triethylamine (0.410 mL, 2.94 mmol) in DMSO (2 mL) was stirred at 100° C. After 8 h, to the solution was added N-2-pyridyl-1,2-ethanediamine (102 mg, 0.744 mmol) and triethylamine (0.200 mL, 1.43 mmol) and stirred at 100° C. for another 8 h. The reaction mixture was poured into ice water and the resulting precipitate was removed by filtration, washed with ethanol. The resulting solid recrystallized by CH3CN, and dried to yield 5-amino-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (132 mg, 23%) as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:12]([CH:13]=[O:14])=[CH:11][C:5]2[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[Br:15]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:15][C:3]1[C:4]2[O:8][CH2:7][C:6]([CH3:10])([CH3:9])[C:5]=2[CH:11]=[C:12]([CH:13]=[O:14])[C:2]=1[OH:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)COc2cc(O)c(C=O)cc21
Solvent: ClCCl
Solvent: O
Product: CC1(C)COc2c1cc(C=O)c(O)c2Br
Yield: 94.2 %

Procedure:
A solution of 5.27 g (27.4 mmol) of 2,3-dihydro-6-hydroxy-3,3-dimethyl-5-benzofurancarboxaldehyde and 5.86 g (32.9 mmol) of N-bromosuccinimide in 135 ml of methylene chloride was stirred at ambient temperature for 3 h. Water (400 ml) was added. The organic phase was dried and evaporated. The residue was chromatographed on silica gel (150 g) using a gradient from 20:80 (v/v) ether:hexane to 40:60 (v/v) ether:hexane eluent. There was obtained 7.0 g (25.8 mmol, 94%) of 7-bromo-2,3-dihydro-6-hydroxy-3,3-dimethyl-5-benzofurancarboxaldehyde. A sample was crystallized from toluene: mp 152°-154° C.
Reaction SMILES: [CH2:1]1[C:11]2[N:10]3[C:12]4[CH:21]=[CH:20][N:19]=[CH:18][C:13]=4[C:14]4[CH2:15][CH2:16][CH:17]=[C:8]([C:9]=43)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2]1.[Cl:22][CH:23]([CH:25]1[CH2:27][CH2:26]1)[CH3:24].C(=O)(O)[O-].[Na+].CN(C)C=O>O>[ClH:22].[CH:25]1([CH:23]([CH:3]2[CH2:4][C:5]3[CH:6]=[CH:7][C:8]4[C:9]5[N:10]([C:12]6[CH:21]=[CH:20][N:19]=[CH:18][C:13]=6[C:14]=5[CH2:15][CH2:16][CH:17]=4)[C:11]=3[CH2:1][CH2:2]2)[CH3:24])[CH2:27][CH2:26]1
Reactant: CC(Cl)C1CC1
Reactant: C1=CC2=C(CCCC2)n2c3c(c4cnccc42)CCC=C13
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C1CC1)C1CCC2=C(C=CC3=CCCc4c3n2c2ccncc42)C1
Product: Cl

Procedure:
A mixture of 5.5 g. of the product of Example 1, 2.3 g. of (1-chloroethyl)cyclopropane and 3.0 g. of sodium bicarbonate in 100 ml. of dimethylformamide is heated to 70°, with continued stirring, overnight, and the reaction mixture is then poured into water and extracted with ether. The extract is dried, evaporated to dryness, and the residue is dissolved in benzene and chromatographed. The eluate is then evaporated to dryness, the residue dissolved in absolute alcohol, treated with alcoholic hydrogen chloride, stripped down to dryness, and the glassy residue triturated with acetone to yield white crystals of the title compound, m.p. 249°-252°.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][OH:23].N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:23][CH2:22][CH2:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH3:7])[O:4][CH2:5][Cl:6]
Reactant: COCCOCCOCCOCCOCCO
Reactant: O=C(Cl)OCCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCCOCCOCCOCCOCCOC(=O)OCCl

Procedure:
In a manner similar to the method described in Example 3, chloromethyl chloroformate (Aldrich) was reacted with pentaethylene glycol monomethyl ether (TCI) and pyridine in methylene chloride at −78° C. for 3 h to give chloromethyl 2,5,8,11,14-pentaoxahexadecan-16-yl carbonate. This material was then reacted with chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid in the presence of cesium carbonate in dimethylformamide overnight to give, after flash chromatography purification (hexane/ethyl acetate, 80/20 to 20/80), chiral 3-oxo-2,4,7,10,13,16,19-heptaoxaicosyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate as a white solid. MS (ES+) m/z calcd. for C44H54Cl2F2N3O12: [(M+H)+]: 924, found: 924.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:19]=1)=[O:4].Cl>C1COCC1.[OH-].[Na+]>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[C:8]2[CH2:14][CH2:15][NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]([F:27])([F:29])[F:28])[CH:19]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc2[nH]cc(CCNCc3cccc(OCC(F)(F)F)c3)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1ccc2[nH]cc(CCNCc3cccc(OCC(F)(F)F)c3)c2c1

Procedure:
Combine N-(2-(5-methoxycarbonyl-1H-indol-3-yl)ethyl)-3-(2,2,2-trifluoroethoxy)benzylamine (200 mg, 0.5 mmol) in 50 mL THF and 1 mL 3 N NaOH. Reflux the mixture overnight, treat with 0.7 mL 5N HCl and concentrate to dryness. Chromatograph to give the title compound: ISMS 393 (M+1); Analysis for C20H19F3N2O3 CF3COOH 1.2C7H8 2.1H2O: calcd: C, 55.76; H, 5.20; N, 4.28; found: C, 55.51; H, 5.47; N, 4.50.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1B(O)O>>[CH:22]([O:21][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:27]2[CH:26]=[CH:25][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=2)[C:6]([C:4]([OH:3])=[O:5])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:23])[CH3:24]
Reactant: OB(O)c1ccc2ccccc2c1
Reactant: CCOC(=O)c1cc2cc(-c3ccc(OC(C)C)cc3)ccc2[nH]1
Product: CC(C)Oc1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc3ccccc3c2)cc1

Procedure:
The title compound was prepared in accordance with Example 8(c) from 5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (see step (a) above) and 2-naphthylboronic acid followed by hydrolysis in accordance with the procedure described in Example 1(c).
Reaction SMILES: C([O:8][C:9](=[O:20])[NH:10][C:11]([CH3:19])([CH2:13][CH:14](O)[CH2:15][CH2:16][OH:17])[CH3:12])C1C=CC=CC=1.[H-].[Na+].C(O)(=O)C>C1COCC1>[OH:17][CH2:16][CH2:15][CH:14]1[O:20][C:9](=[O:8])[NH:10][C:11]([CH3:12])([CH3:19])[CH2:13]1
Reactant: CC(C)(CC(O)CCO)NC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC1(C)CC(CCO)OC(=O)N1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.8 %

Procedure:
To a cold (0° C.) solution of benzyl(4,6-dihydroxy-2-methylhexan-2-yl)carbamate (460 mg, 1.6 mmol) in 30 mL of anhydrous THF was added sodium hydride (60% dispersion in oil, 128 mg, 3.2 mmol). The reaction was stirred at 0° C. for 15 min then allowed to warm to room temperature and stirred for an additional 4 hours. Acetic acid (ca 3.5 mmol) was added and the mixture was concentrated under reduced pressure. The crude residue was purified by column chromatography (5 to 12% methanol in dichloromethane) to give a white solid (219 mg, 1.26 mmol, 77%). 1H NMR (d6-DMSO, 400 MHz) δ 1.17 (s, 6H), 1.41-1.48 (dd, J=12.3, 13.4 Hz, 1H), 1.64-1.71 (m, 2H), 1.79-1.83 (dt, J=1.8, 13.7 Hz, 1H), 3.49-3.55 (m, 2H), 4.37-4.41 m, 1H), 4.54-4.57 (t, J=5.0 Hz, 1H), 7.2 (br s, 1H). LRMS (ESI/APCI) m/z 174 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:13]=2)=[N:5]S(=O)[N:3]=1.[ClH:26]>CO.C(O)C>[ClH:26].[ClH:26].[ClH:26].[N:19]1([CH2:18][C:14]2[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=2)[O:11][CH2:10][CH2:9][CH2:8][NH:7][C:6](=[NH:5])[C:2](=[NH:1])[NH2:3])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: NC1=NS(=O)N=C1NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: N=C(N)C(=N)NCCCOc1cccc(CN2CCCCC2)c1
Yield: 82.6 %

Procedure:
A suspension of 3-amino-4-[3-(3-piperidinomethylphenoxy)propylamino]-1,2,5-thiadiazole 1-oxide (17.1 g; 47.0 mmoles) [prepared according to published United Kingdom Patent Application No. 2,067,987] in 450 mL of methanol was treated with 38 mL of concentrated HCl. The resultant solution was stirred for 3 hours at ambient temperature. Concentration of the solution followed by azeotropic removal of water with absolute ethanol gave colorless crystals. These were suspended in 200 mL of absolute ethanol, filtered and dried under vacuum to give 16.6 g (82.6%) of the title compound, m.p. 205°-222° C. (dec.). Recrystallization from 50% methanolethyl acetate gave an analytical sample, m.p. 206°-216° C. (dec.).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.O.O=[CH:17]C(O)=O.C(=O)([O-])[O-].[K+].[K+].[N+:27]([CH:29]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)S(C1C=CC(C)=CC=1)(=O)=O)#[C-:28]>CN(C=O)C>[C:40]1([C:29]2[N:27]=[CH:28][N:1]([CH:2]3[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]3)[CH:17]=2)[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: O=CC(=O)O
Reactant: [C-]#[N+]C(c1ccccc1)S(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2cnc(-c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.4 %

Procedure:
A suspension of tert-butyl 4-aminopiperidine-1-carboxylate (3.88 g), oxoacetic acid hydrate (1.48 g), and potassium carbonate (4.46 g) in DMF (60 mL) was stirred at room temperature for 3 hours. Then, 1-{[isocyano(phenyl)methyl]sulfonyl}-4-methylbenzene (3.5 g) was added thereto, followed by stirring at room temperature for 14 hours. The solvent was evaporated under reduced pressure, to the residue were added ethyl acetate and water, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate, the combined organic phase was washed with water and saturated brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 90/10) to obtain tert-butyl 4-(4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate (3.1 g).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:5]=[C:4]([NH:18][CH2:19][CH2:20][OH:21])[N:3]=1.Cl.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:31][CH2:32][N:33]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][C:12]4[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=4)[N:5]=[C:4]([NH:18][CH2:19][CH2:20][OH:21])[N:3]=3)[CH2:34][CH2:35]2)=[CH:26][CH:25]=1
Reactant: N#Cc1c(Cl)nc(NCCO)nc1NCc1cccnc1
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCc2cccnc2)nc(NCCO)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 20b, 4-chloro-2-(2-hydroxy-ethyl-amino)-6-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile was treated with 4-(4-fluorophenyl)-piperidine hydrochloride in dioxane in the presence of N-ethyl-diisopropyl-amine at 80° C. to yield the 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-2-(2-hydroxy-ethyl-amino)-6-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=448.
Reaction SMILES: Cl[O-].[Na+].[CH2:4]([O:6][P:7]([O:17][CH2:18][CH3:19])([CH2:9][C:10]([O:12][CH:13]([CH3:16])[CH2:14][CH3:15])=[O:11])=[O:8])[CH3:5].[ClH:20].C(Cl)(Cl)(Cl)[Cl:22]>>[Cl:20][C:9]([Cl:22])([P:7]([O:6][CH2:4][CH3:5])([O:17][CH2:18][CH3:19])=[O:8])[C:10]([O:12][CH:13]([CH3:16])[CH2:14][CH3:15])=[O:11]
Reactant: ClC(Cl)(Cl)Cl
Reactant: Cl
Reactant: CCOP(=O)(CC(=O)OC(C)CC)OCC
Agent: [Na+]
Agent: [O-]Cl
Product: CCOP(=O)(OCC)C(Cl)(Cl)C(=O)OC(C)CC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of 185 ml of 5.25% commercial grade sodium hypochlorite solution (Clorox®) and 100 ml of carbon tetrachloride was cooled to 0° C. To this mixture, with vigorous stirring, was added a solution of 12.6 g of 1-methylpropyl 2-(diethoxyphosphinyl)-acetate in 50 ml of carbon tetrachloride over a 1/2 hour period. During this addition the temperature was kept at 0°-5° and the pH at 9.0-9.5 by the simultaneous addition of 1 N hydrochloric acid. The reaction mixture was stirred an additional 15 minutes at 0°-5° C. The carbon tetrachloride layer was washed with water, dried over magnesium sulfate and stripped at 60° C./1 mm pressure to yield 16.0 g of 1-methylpropyl 2,2-dichloro-2-(diethoxyphosphinyl)acetate as a pale yellow oil ND27 =1.4524.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[CH3:10].C(=O)([O-])[O-].[K+].[K+].C1(=O)[O:21][CH2:20][CH2:19][O:18]1>CN(C=O)C.C(OCC)(=O)C.O>[OH:18][CH2:19][CH2:20][O:21][C:4]1[C:3]([CH3:10])=[CH:2][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]
Reactant: Cc1cc(C=O)ccc1O
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccc(C=O)c1OCCO
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
To a stirred solution of 4-hydroxy-3-methyl-benzaldehyde (0.545 g, 4.00 mmol) in DMF (10 mL) was added potassium carbonate (1.10 g, 7.97 mmol). The reaction mixture was stirred at RT for 5 minutes and then a solution of ethylene carbonate (0.705 g, 8.00 mmol) in DMF (2 mL) was added. The resultant mixture was heated at 80° C. for 90 hours. The reaction mixture was allowed to cool and diluted with ethyl acetate and water. The organic phase was removed, washed with brine (×2), dried (magnesium sulfate), filtered and the solvent evaporated at reduced pressure to afford the title compound (0.677 g, 94%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([O:29]C)=[O:28])[CH:25]=3)[NH:20][CH:19]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[OH2:28].[CH2:1]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]([OH:29])=[O:28])[CH:25]=3)[NH:20][CH:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2[nH]cc(CCCCN3CCCC(Cc4ccccc4)C3)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O
Product: O=C(O)c1ccc2[nH]cc(CCCCN3CCCC(Cc4ccccc4)C3)c2c1

Procedure:
A mixture of methyl 3-[4-(3-benzylpiperidin-1-yl)butyl]indole-5-carboxylate and KOH is heated under reflux in ethanol. After customary work-up, 3-[4-(3-benzylpiperidin-1-yl)butyl]-5-carboxyindole, hydrate, m.p. 144-147°, is obtained.