Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)[CH2:17][N:18]([CH3:27])[C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:43](OC(=O)C)(=[O:45])[CH3:44]>ClCCl>[CH:1]1([N:7]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=3)[CH2:17][N:18]([CH3:27])[C:19](=[O:26])[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:10][CH2:9]2)[C:43](=[O:45])[CH3:44])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(=O)OC(C)=O
Reactant: CN(CC(CCN1CCC(NC2CCCCC2)CC1)c1ccc(Cl)c(Cl)c1)C(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N(C1CCCCC1)C1CCN(CCC(CN(C)C(=O)c2ccccc2)c2ccc(Cl)c(Cl)c2)CC1
Reaction time: 2 h

Procedure:
N-[4-(4-cyclohexylaminopiperidino)-2-(3,4-dichlorophenyl)-butyl]-N-methylbenzamide was dissolved in dichloromethane (4.0 mL), and triethylamine (1.0 mL) and acetic anhydride (0.65 mL) were added. After being stirred for 2 hours, the mixture was washed with aqueous sodium bicarbonate, dried, and evaporated. The resulting material was chromatographed, with dichloromethane:methanol (95:5) as the eluent, to give the title compound (0.60 g) as a white solid; MS: m/z=558(M+1). Analysis for C31H41Cl2N3O2 ·0.6 CH2Cl2 : Calculated: C, 62.26; H, 6.98; N, 6.89. Found: C, 62.15; H, 6.99; N, 7.30
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[CH2:5][N:6]([CH3:8])[CH3:7].Br[C:14]1[CH:23]=[N:22][CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>>[CH3:7][N:6]([CH2:5][C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[CH2:2][NH:1][C:20]1[CH:21]=[N:22][CH:23]=[CH:14][C:15]=1[C:16]([O:18][CH3:19])=[O:17])[CH3:8]
Reactant: COC(=O)c1ccncc1Br
Reactant: CN(C)Cc1ccccc1CN
Product: COC(=O)c1ccncc1NCc1ccccc1CN(C)C
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from N-[2-(aminomethyl)benzyl]-N,N-dimethylamine and methyl 3-bromoisonicotinate according to the procedure for Preparation 4A. 1H NMR (400 MHz, CDCl3): δ 8.27 (s, 1H), 7.88 (d, 1H, J=5.1 Hz), 7.82 (br s, 1H), 7.61 (d, 1H, J=5.1 Hz), 7.20-7.36 (m, 4H), 4.68 (d, 2H, J=5.8 Hz), 3.87 (s, 3H), 3.46 (s, 2H), 2.22 (s, 6H). [M+H] calc'd for C17H21N3O2, 300; found 300.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH2:16])=[O:10])[CH:5]=[CH:4][N:3]=1.[F:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23](F)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH:16][C:23]2[CH:22]=[N:21][CH:20]=[C:19]([F:18])[CH:24]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Fc1cncc(F)c1
Reactant: Cc1cc(NC(=O)c2nc(C)sc2N)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(NC(=O)c2nc(C)sc2Nc2cncc(F)c2)ccn1
Yield: 65 %

Procedure:
5-Amino-2-methyl-thiazole-4-carboxylic acid (2-methyl-pyridin-4-yl)-amide (0.15 g, 0.605 mmol) was dissolved in 5 mL fry DMF. 3,5-Difluoropyridine (0.213 g, 1.85 mmol) and cesium carbonate (0.59 g, 1.85 mmol) were added. The reaction mixture was irradiated in the microwave at 150° C. for 45 min, diluted with 100 mL water and extracted three times with ethyl acetate (50 mL each). The organic phases were pooled, dried with sodium sulfate and evaporated. The crude product was flash-chromatographed on silica gel with heptane/ethyl acetate 100:0→0:100 gradient to yield the title compound as an off-white solid (0.135 g, 65%), MS (ISP): m/e=344.1 (M+H+).
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:42])[CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([OH:41])([O:39][CH3:40])=[O:38])[CH2:8][C:9]([CH3:32])=[CH:10][CH2:11][C:12]1[C:13]([O:25]CC[Si](C)(C)C)=[C:14]2[C:18](=[C:19]([CH3:23])[C:20]=1[O:21][CH3:22])[CH2:17][O:16][C:15]2=[O:24].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:25][C:13]1[C:12]([CH2:11][CH:10]=[C:9]([CH3:32])[CH2:8][CH:7]([CH2:33][CH:34]=[CH:35][CH2:36][P:37]([OH:41])([O:39][CH3:40])=[O:38])[C:6]([OH:42])=[O:5])=[C:20]([O:21][CH3:22])[C:19]([CH3:23])=[C:18]2[C:14]=1[C:15](=[O:24])[O:16][CH2:17]2
Reactant: COc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CC(CC=CCP(=O)(O)OC)C(=O)OCC[Si](C)(C)C)C(=O)OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1c(C)c2c(c(O)c1CC=C(C)CC(CC=CCP(=O)(O)OC)C(=O)O)C(=O)OC2
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 2-[4-(hydroxy-methoxy-phosphoryl)-but-2-enyl]-6-[6-methoxy-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-4-methyl-hex-4-enoic acid 2-trimethylsilanylethyl ester (11 mg, 0.016 mmol) in THF (1 mL) was added TBAF (50 μL, 1 M solution in THF) at room temperature. The solution was stirred for 16 hours and concentrated. The solution was dried under reduced pressure and re-suspended in DMF (0.8 mL) and water (0.25 mL). The solution was filtered through Acrodisc (13 mm syringe filter with a 0.45 μm Nylon membrane) and purified by RP HPLC using a Phenomenex Synergi 5 μ Hydro RP 80A column (50×21.2 mm) with eluents of H2O, 0.1% TFA-CH3CN, 0.1% TFA. The product from the column was subjected to ion exchange chromatography (Sodium salt form of Dowex 50WX8-400) using a 2×4.5 cm column eluting with H2O-MeOH (1:1) to provide 7.5 mg of the desired product as an oil. 1H NMR (300 MHz, CDCl3) δ 1.80 (s, 3H), 2.01-2.29 (m, 5H), 2.11 (s, 3H), 2.35 (d, 2H, J=22 Hz), 3.38 (d, 2H, J=7 Hz), 3.53 (d, 3H, J=11 Hz), 3.75 (s, 3H), 5.19 (s, 2H), 5.26 (t, 1H, J=6 Hz), 5.43-5.54 (m, 2H) ppm; 31P (121.4 MHz, CDCl3) δ 23.5 ppm; MS (m/z) 469.2 [M+H]+, 491.3 [M+Na]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:6]=[CH:7][C:8]#[N:9].[ClH:15].C[CH2:17][OH:18]>>[ClH:15].[CH3:17][O:18][C:8](=[NH:9])[CH:7]=[CH:6][C:5]1[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(C=CC#N)cc1OC
Reactant: CCO
Agent: Cl
Product: COC(=N)C=Cc1ccc(OC)c(OC)c1
Reaction time: 18 h
Yield: 60 %

Procedure:
A suspension of 3,4-dimethoxycinnamonitrile (10 g; 52 mmol) in EtOH (150 mL) was cooled in an ice bath. The cold mixture was then saturated with hydrogen chloride. The reaction solution was refrigerated for 18 hours. The precipitate formed was collected by filtration. The colorless solid gave 8.0 g (60% yield) of methyl-(3,4-dimethoxy)-cinnamoimidate hydrochloride which was used in the next reaction, 1H-NMR (DMSO-d6; 200 MHz) δ11.8 (broad s, 1H), 10.9 (broad s, 1H), 7.82-7.9 (d, 1H), 7.3 (d, 2H), 7.02-7.12 (d, 1H), 6.81-6.9 (d, 1H), 4.2 (s, 3H), and 3.76 (s, 3H), 3.82 ppm (s, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>O1CCOCC1>[ClH:25].[ClH:25].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccnc3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2c(NC3CCNCC3)ccnc2c1

Procedure:
A solution of 4-(quinolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.77 g, 5.41 mmol) in dioxane (20 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 228.6 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1([NH:20][C:21]([C:23]2[C:31]3[CH:30]=[C:29]([C:32]4[C:37]([Cl:38])=[CH:36][N:35]=[C:34](Cl)[N:33]=4)[S:28][C:27]=3[CH:26]=[CH:25][CH:24]=2)=[O:22])[CH2:19][CH2:18]1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:34]2[N:33]=[C:32]([C:29]3[S:28][C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([C:21](=[O:22])[NH:20][CH:17]5[CH2:18][CH2:19]5)[C:31]=4[CH:30]=3)[C:37]([Cl:38])=[CH:36][N:35]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(CCN)CC1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(CCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Temperature: 25 °C

Procedure:
4-(2-aminoethyl)-piperidine-1-carboxylic acid tert-butyl ester (0.390 g, 1.72 mmol) is added to a stirred suspension of 2-(2,5-dichloro-pyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.250 g, 0.686 mmol) and diisopropylethylamine (0.300 mL, 1.72 mmol) in anhydrous 1,4-dioxane (4 mL) at room temperature under nitrogen. The resultant mixture is heated at 95° C. for 12 hours then cooled to room temperature and purified (silica gel chromatography, eluting with 2 M NH3/CH3OH in dichloromethane: 0 to 7%) to give 4-{2-[5-chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester as a solid.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[C:15]([O:16][CH2:17][CH:18]4[CH2:20][CH2:19]4)=[CH:14][C:13]([CH:21]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:22]([O:24]CC4CC4)=[O:23])=[C:12]([F:33])[CH:11]=3)[CH:7]=[CH:6][C:5]=12>CCO.O.[OH-].[K+]>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[C:15]([O:16][CH2:17][CH:18]4[CH2:20][CH2:19]4)=[CH:14][C:13]([CH:21]([CH2:29][CH:30]([CH3:31])[CH3:32])[C:22]([OH:24])=[O:23])=[C:12]([F:33])[CH:11]=3)[CH:7]=[CH:6][C:5]=12
Reactant: CC(C)CC(C(=O)OCC1CC1)c1cc(OCC2CC2)c(-c2ccc3nonc3c2)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(OCC2CC2)c(-c2ccc3nonc3c2)cc1F

Procedure:
Cyclopropylmethyl 2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoate (0.14 g, 0.29 mmol) was dissolved in a mixture of EtOH/H2O (9 mL/1 mL) and KOH (0.3 g) was added. The reaction mixture was refluxed for 2 h and after cooling the solvent was evaporated. Then, 6 N HCl was added to adjust the pH to 5, and the reaction mixture was extracted with EtOAc (3×10 mL). The combined organic phases were dried over MgSO4 and evaporated under reduced pressure to give a colorless oil. Purification by gradient column chromatography on silica gel Heptane-EtOAc (50:1-9:1) gave 2-(4-(benzo[c][1,2,5]oxadiazol-5-yl)-5-(cyclopropylmethoxy)-2-fluorophenyl)-4-methylpentanoic acid as a white solid (0.12 g, quantitative); pure portion (0.03 g, 25%); white microcrystals, M.P.=110-111° C., 1H NMR (300 MHz, CDCl3/TMS): δ 8.99 (br s, 1H), 7.66 (br s, 4H), 7.05 (d, J=9.9 Hz, 1H), 6.94 (d, J=5.2 Hz, 1H), 4.08 (t, J=7.7 Hz, 1H), 3.76 (d, J=6.6 Hz, 2H), 2.04-1.90 (m, 1H), 1.81-1.65 (m, 1H), 1.60-1.45 (m, 1H), 1.32-1.05 (m, 2H), 0.94 (d, J=6.0 Hz, 6H), 0.54 (d, J=7.4 Hz, 2H), 0.24 (d, J=3.9 Hz, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 179.2, 154.7 (d, 1JCF=239.8 Hz), 152.0, 140.6, 132.0, 129.9, 129.6, 125.7 (d, 2JCF=16.2 Hz), 124.8 (q, 3JCF=3.6 Hz), 124.0 (q, 1JCF=270 Hz), 117.2 (d, 2JCF=25.2 Hz), 113.9, 74.2, 41.3, 29.8, 25.9, 22.8, 22.1, 10.3, 3.2.
Reaction SMILES: Cl[C:2]1[C:3]([C:22]2[C:27]([CH3:28])=[CH:26][C:25]([CH3:29])=[CH:24][N:23]=2)=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:21])[CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[NH4+].[OH-]>[Pd].CO.O>[CH3:28][C:27]1[C:22]([C:3]2[CH:2]=[CH:7][N:6]=[C:5]([N:8]3[CH2:9][CH2:10][N:11]([C:14](=[O:21])[CH2:15][CH2:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH2:12][CH2:13]3)[CH:4]=2)=[N:23][CH:24]=[C:25]([CH3:29])[CH:26]=1
Reactant: Cc1cnc(-c2cc(N3CCN(C(=O)CCS(C)(=O)=O)CC3)ncc2Cl)c(C)c1
Agent: [Pd]
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cnc(-c2ccnc(N3CCN(C(=O)CCS(C)(=O)=O)CC3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.4 %

Procedure:
To 1-[4-(5′-chloro-3,5-dimethyl-2,4′-bipyridin-2′-yl)piperazin-1-yl]-3-(methylsulfonyl)propan-1-one (44 mg, 0.10 mmol) was added MeOH/Water 6:1 (5 mL, 0.02M), then 10% Pd/C (25 μL=20 w/w % relative to substrate) followed by NH4OH (1.0 mL, 5 eq, 0.5M solution in MeOH). The reaction of mixture was stirred at ambient temperature at 25° C. under balloon H2 for 12 hrs. After filtering off catalyst through celite, the concentrated crude product was diluted with EtOAc (25 mL), washed with water (10 mL), then brine (10 mL), dried over MgSO4, filtered. The solution was concentrated in vacuo. The residue was purified by chromatography on silica gel (EtOAc/heptane=1:3) to give the title compound (36 mg, 90%) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.36 (s, 1 H) 8.24-8.29 (m, 1 H) 7.42 (s, 1 H) 6.79-6.84 (m, 2 H) 3.75-3.81 (m, 4 H) 3.58-3.66 (m, 4 H) 3.47 (t, J=7.33 Hz, 2 H) 3.00 (s, 3H) 2.93-2.99 (m, 2 H) 2.37 (s, 3 H) 2.33 (s, 3 H); m/z for C20H26N4O3S 403.1 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH2:23]([NH2:25])[CH3:24]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:25][CH2:23][CH3:24])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CCN
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CCNCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and Ethylamine were converted to yield {4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-ethyl-amine as white solid, MS: 405 (MH+,1Br).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([CH2:14][CH3:15])[CH3:13])[CH:2]1[O:4][CH2:3]1.[NH3:16]>O>[OH:4][CH:2]([CH2:1][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([CH2:14][CH3:15])[CH3:13])[CH2:3][NH2:16]
Reactant: CCC(C)c1ccccc1OCC1CO1
Reactant: N
Solvent: O
Product: CCC(C)c1ccccc1OCC(O)CN
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A 2.5 liter autoclave is charged, at room temperature and under nitrogen blanketing, with 429 g (2.1 mol) of o-sec-butylphenyl glycidyl ether and 30.2 g of water. Then 698.5 g (41.08 mol) of ammonia gas is blown in under pressure over 5 minutes and the reaction mixture is thereafter heated to 80° C. over 2 hours. After 1 hour at 80° C., the reaction mixture is cooled to room temperature, the pressure in the system is removed and the reaction product is concentrated on a rotary evaporator at 80° C./13 mbar. Gas chromatographic analysis shows the resultant amine to be 92.5% pure. It has a viscosity of 1240 mPa·s.
Reaction SMILES: [C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([OH:15])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1.[Na].[CH3:20]N(C)P(N(C)C)(N(C)C)=O.CI>O>[C:1]1([C:6]([C:8]2[CH:18]=[CH:17][C:11]([CH:12]([CH3:16])[C:13]([O:15][CH3:20])=[O:14])=[CH:10][CH:9]=2)=[O:7])[S:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C(=O)O)c1ccc(C(=O)c2cccs2)cc1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: [Na]
Solvent: O
Solvent: CI
Product: COC(=O)C(C)c1ccc(C(=O)c2cccs2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 28.2 parts of p-(2-thenoyl)hydratropic acid, sodium salt and 250 parts of hexamethylphosphoramide are added 56.8 parts of methyl iodide at room temperature (slightly exothermic reaction). The whole is stirred at room temperature for 1 hour. The reaction mixture is poured onto 1000 parts of water and the product is extracted three times with 140 parts of diisopropylether. The combined extracts are washed with 200 parts of water, dried, filtered and evaporated. The residue is crystallized from 35 parts of diisopropylether at 0° C, washed with cooled ether and dried, yielding methyl p-(2-thenoyl)hydratropate; mp. 62° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]2[N:14]=[C:15]([S:27][CH3:28])[C:16]([S:17]([C:20]3[CH:25]=[CH:24][C:23](C)=[CH:22][CH:21]=3)(=[O:19])=[O:18])=[C:12]2[N:11]=[C:10]([CH3:29])[CH:9]=1>CN(C=O)C>[C:20]1([S:17]([C:16]2[C:15]([S:27][CH3:28])=[N:14][N:13]3[C:8]([N:1]4[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]4)=[CH:9][C:10]([CH3:29])=[N:11][C:12]=23)(=[O:19])=[O:18])[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: C1CNCCN1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccc(C)cc1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3CCNCC3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
0.3 g (3.4 mmol) of piperazine in 10 ml of DMF was added to a solution of 0.62 g (1.7 mmol) of 7-chloro-5-methyl-2-methylsulphanyl-3-(toluene-4-sulphonyl)-pyrazolo[1,5-a]pyrimidine in 10 ml of DMF and stirred at 60° for 2 hrs. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2, and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 6:1) and crystallization from EtOH yielded 0.30 g (42%) of 3-benzenesulphonyl-5-methyl-2-methylsulphanyl-7-piperazin-1-yl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 137-139°.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30]([CH2:33][C:34]([O:36]C)=[O:35])(=[O:32])=[O:31])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO>[C:1]1([C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][S:30]([CH2:33][C:34]([OH:36])=[O:35])(=[O:32])=[O:31])[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)CS(=O)(=O)CCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CS(=O)(=O)CCCCCCn1nc(-c2ccccc2)c(-c2ccccc2)c1-c1ccccc1
Reaction time: 0.33 h
Yield: 79.6 %

Procedure:
A mixture of methyl [[6-(3,4,5-triphenyl-1H-pyrazol-1-yl)hexyl]sulfonyl]acetate (0.94 g, 2 mmol), 3N sodium hydroxide solution (2.43 mL, 7 mmol) and methanol (100 mL) was heated at reflux. After 20 minutes, the methanol was removed in vacuo, the residue acidified with 1N HCl and extracted with dichloromethane. The organic phase was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated to give a foam. Recrystallization from a mixture of dichloromethane and hexane (1:3) afford [[6-(3,4,5-triphenyl-1H-pyrazol-1-yl) hexyl]sulfonyl]acetic acid (0.80 g, 88%); m.p.=153.5-155° C. MS(CI): m/e=459 (MH+).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][NH:17][CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[F:27][C:28]([F:40])([F:39])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35](Cl)(=[O:37])=[O:36]>ClCCl>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([O:10][C@H:11]3[CH2:19][N:14]4[CH2:15][CH2:16][N:17]([S:35]([C:30]5[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=5[C:28]([F:27])([F:39])[F:40])(=[O:37])=[O:36])[CH2:18][C@@H:13]4[CH2:12]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: c1nc(C2CC2)cnc1O[C@@H]1C[C@H]2CNCCN2C1
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1C(F)(F)F)N1CCN2C[C@H](Oc3cnc(C4CC4)cn3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of Example 27B (50 mg, 0.192 mmol) and triethylamine (29.2 mg, 0.288 mmol) in dichloromethane (1 mL) was added 2-(trifluoromethyl)benzene-1-sulfonyl chloride (47 mg, 1.92 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was purified by chromatography on silica gel (ethyl acetate/hexane=4:1) to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80 (m, 2H), 0.92 (m, 2H), 1.84 (m, 2H), 2.09 (m, 1H), 2.22 (m, 2H), 2.33 (m, 1H), 2.52 (m, 1H), 2.78 (m, 1H), 2.99 (m, 1H), 3.64 (m, 2H), 3.82 (m, 1H), 5.25 (m, 1H), 7.92 (m, 2H), 8.15 (m, 4H); MS (ESI) m/z 469 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[C:15]([C:18]#[N:19])[CH:16]=[CH:17][C:4]=2[O:3]1.C([O:23]CC)C>>[C:18]([C:15]1[CH:16]=[CH:17][C:4]2[O:3][C:2]([CH3:20])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=3[O-:23])[C:5]=2[CH:14]=1)#[N:19]
Reactant: CC1(C)CC(c2ccccn2)c2cc(C#N)ccc2O1
Reactant: CCOCC
Product: CC1(C)CC(c2cccc[n+]2[O-])c2cc(C#N)ccc2O1

Procedure:
In an analogous manner to that described in the first paragraph of Example 7, from (+)-3,4-dihydro-2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran-6-carbonitrile there was obtained (+)-2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 143°-44° C. (from diethyl ether); [α]58920 =+78.8° (c=1.001 in ethanol).
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:10]=[C:11]3[C:16](=[N:17][CH:18]=2)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]3)=[CH:7][N:6]=[CH:5][C:4]=1[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)#[N:2].[C:28](O)(=[O:30])[CH3:29].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C>[C:28]([N:25]1[CH2:26][CH2:27][CH:22]([C:4]2[CH:5]=[N:6][CH:7]=[C:8]([C:9]3[CH:10]=[C:11]4[C:16](=[N:17][CH:18]=3)[N:15]([C:19]([NH2:21])=[O:20])[CH2:14][CH2:13][CH2:12]4)[C:3]=2[C:1]#[N:2])[CH2:23][CH2:24]1)(=[O:30])[CH3:29]
Reactant: N#Cc1c(-c2cnc3c(c2)CCCN3C(N)=O)cncc1C1CCNCC1
Reactant: CC(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)N1CCC(c2cncc(-c3cnc4c(c3)CCCN4C(N)=O)c2C#N)CC1
Reaction time: 16 h
Yield: 42.7 %

Procedure:
The crude 6-(4-cyano-1′,2′,3′,4′,5′,6′-hexahydro-[3,4]bipyridinyl-5-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (0.22 mmol), acetic acid (0.025 mL, 0.43 mmol) and triethyl amine (0.091 mL, 0.65 mmol) are mixed in acetonitrile (2.5 mL). Then TBTU (104 mg, 0.33 mmol) is added and the mixture is stirred for 16 hrs. All the solvent is removed and the residue is purified by flash column chromatography to give 38 mg of the titled product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C)C=O>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([NH:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])cn2)CC1
Temperature: 90 °C
Reaction time: 14 h
Yield: 90.2 %

Procedure:
A mixture of 2-bromo-5-nitro-pyridine (5 g, 24.6 mmol), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (5 g, 25 mmol), and triethylamine (5 mL) in N,N-dimethylformamide (30 mL) was stirred at 90° C. for 14 h. The reaction mixture was then partitioned between water and ethyl acetate, and the two layers were separated. The aqueous layer was extracted with ethyl acetate three times. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography to give 7.15 g (90%) 4-(5-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester as a yellow solid. LCMS calcd for C15H22N4O4 (m/e) 322, obsd 323 (M+H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]([CH2:10][NH:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])([OH:9])=[O:8].[C:21](OC(=O)C)(=[O:23])[CH3:22].Cl>O>[C:21]([N:11]([CH2:10][C:7]([OH:9])=[O:8])[C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)CNc1ccccc1C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N(CC(=O)O)c1ccccc1C(=O)O

Procedure:
To a solution of sodium carbonate (89 g, 0.84 mol) in water (830 mL), 2-(carboxymethylamino)benzoic acid of Example 1a (100 g, 0.84 mol) was added in small portions at room temperature under stirring while a clear solution was formed. Acetic anhydride (85.68 g, 0.84 mol) was added dropwise at room temperature under stirring. The reaction mixture was stirred for 30 min, and 37% aqueous hydrochloric acid (140 mL) was added dropwise. The product precipitated slowly. The solid product was filtered off in 12 h, washed with water (3×150 mL) and air-dried to afford 110 g (91%), m.p. 206° C.