Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([OH:14])=O)[CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:42][C:43]1[CH:49]=[CH:48][C:47]([CH3:50])=[CH:46][C:44]=1[NH2:45].C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=2)[C:12]([NH:45][C:44]2[CH:46]=[C:47]([CH3:50])[CH:48]=[CH:49][C:43]=2[F:42])=[O:14])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccc(F)c(N)c1
Reactant: O=C(O)c1cccc(Oc2ccnc(Br)c2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1ccc(F)c(NC(=O)c2cccc(Oc3ccnc(Br)c3)c2)c1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
A mixture of 3-(2-bromo-pyridin-4-yloxy)-benzoic acid (200 mg, 0.68 mmol), HATU (312 mg, 0.82 mmol), 2-fluoro-5-methylaniline (125 mg, 1.0 mmol) and N,N-diisopropylethylamine (193 mg, 1.5 mmol) in anhydrous DMF (10 ml) was stirred at 60° C. for 90 minutes. The mixture was poured into 100 ml of water. The precipitates were filtered, washed with water and dried in vacuo to give 3-(2-bromo-pyridin-4-yloxy)-N-(2-fluoro-5-methyl-phenyl)-benzamide as off-white solid. Yield: 200 mg, 74%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](O)=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.C(N(CC)CC)C.[F:22][C:23]([F:36])([F:35])[S:24]([O:27]S(C(F)(F)F)(=O)=O)(=[O:26])=[O:25]>CN(C)C1C=CN=CC=1.ClCCl>[F:22][C:23]([F:36])([F:35])[S:24]([OH:27])(=[O:26])=[O:25].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1ccc(Cl)cc1C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1cccc(C2CCCCC2)c1
Product: O=S(=O)(O)C(F)(F)F
Temperature: -5 °C
Reaction time: 8 h

Procedure:
19 g (90.2 mmol) of 4-chloro-2-cyclohexylphenol, 4.64 ml (33.18 mmol) of triethylamine and 223 mg (1.8 mmol) of 4-(dimethylamino)pyridine are dissolved in 264 ml of dichloromethane, the mixture is cooled to −5° C., and 29.6 ml (180 mmol) of trifluoromethanesulfonic anhydride are added dropwise. The batch is stirred overnight at room temperature and filtered through silica gel with dichloromethane, giving the product 7, which is employed in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([B:9]2[O:13][CH2:12][CH2:11]O2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:15]1C=[CH:19][C:18]([F:21])=[CH:17][C:16]=1COCOC>>[F:21][C:18]1[CH:17]=[CH:16][C:15]2[B:9]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])[O:13][CH2:12][C:11]=2[CH:19]=1
Reactant: N#Cc1cccc(B2OCCO2)c1
Reactant: COCOCc1cc(F)ccc1Br
Product: N#Cc1cccc(B2OCc3cc(F)ccc32)c1

Procedure:
This was prepared as per the procedure in Example 11, from 2-(3-cyanophenyl)-[1,3,2]-dioxaborolane and 1-bromo-4-fluoro-2-((methoxymethoxy)methyl)benzene to afford white crystalline product.
Reaction SMILES: [C:1]([P:3](=[O:10])([O:7]CC)[O:4][CH2:5][CH3:6])#[N:2].[Cl-].[CH:12]([NH3+:15])([CH3:14])[CH3:13]>CN(C=O)C>[CH2:5]([O:4][P:3]([C:1]#[N:2])(=[O:7])[O-:10])[CH3:6].[CH:12]([NH3+:15])([CH3:14])[CH3:13]
Reactant: CCOP(=O)(C#N)OCC
Agent: CC(C)[NH3+]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCOP(=O)([O-])C#N
Reaction time: 8 h
Yield: 81.6 %

Procedure:
Diethyl cyanophosphonate (0.50 g, 3.06 mmol) and isopropylammonium chloride (0.29 g, 3.03 mmol) were added to DMF (3 mL) and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure to give 0.48 g (88% yield) of an oil which was analyzed by NMR and mass spectrometry without additional purification. 31P NMR (CD2Cl2) δ (ppm) -21.2 (t, 3JPH =8.4 Hz); 13C NMR (CD2Cl2) δ (ppm) 121.0 (d, 1JCP =177.8 Hz), 63.2 (d, 2JCP 6.3 Hz), 42.1 (s), 20.9 (s), 16.0 (d, 3JCP =7.5 Hz). Mass spectral analysis (FAB+TGL) detected the peak at m/z 195, corresponding to the protonated form of the salt [+NH3CH(CH3)2 --O(OC2H5)POCN+H+ ], the presence of the cation at m/z 60 ([NH3CH(CH3)2 ]+) and an anionic species (FAB-, TGL) at m/z 134 [NCP(O)(OC2H5)O- ].
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]2[N:13]3[N:14]=[C:15](N)[CH:16]=[CH:17][C:12]3=[N:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O[CH:22](OCC)[N:23]([CH3:25])[CH3:24])C.C[N:30](C)C=O>>[N+:1]([C:4]1[S:8][C:7]([C:9]2[N:13]3[NH:14][C:15](=[CH:22][N:23]([CH3:25])[CH3:24])[C:16]([NH2:30])=[CH:17][C:12]3=[N:11][N:10]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(OCC)N(C)C
Reactant: Nc1ccc2nnc(-c3ccc([N+](=O)[O-])s3)n2n1
Reactant: CN(C)C=O
Product: CN(C)C=C1Nn2c(nnc2-c2ccc([N+](=O)[O-])s2)C=C1N
Reaction time: 2 h

Procedure:
0.8 g. 3-(5-nitro-2-thienyl)-6-amino-s-triazolo[4,3-b]pyridazine was suspended in a mixture of 3 ml. N,N-dimethylformamide and 1. ml. N,N-dimethyl formamide-diethyl acetal and heated, while stirring, on a waterbath for two hours. Thereafter, the reaction mixture was cooled, solid material was filtered off with suction and the residue is washed with N,N-dimethyl formamide. There was thus obtained 0.4 g. (41% of theory) 3-(5-nitro-2-thienyl)-6-(diethylaminomethylene)-amino-s-triazolo[4,3-b]pyridazine (m.p. 247°-249°C). After recrystallization from N,N-dimethyl-formamide, with the addition of charcoal the product was obtained in the form of yellow crystals which melt at 249°-252°C. The elementary analyses and spectra confirm the structure.
Reaction SMILES: [Li]CCCC.CCCCCC.[CH3:12][O:13][C@@:14]1([C:22]#[CH:23])[CH:19]2[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]2)[CH2:15]1.[CH:24]1([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[CH:24]1([C:31]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([OH:32])[C:23]#[C:22][C@:14]2([O:13][CH3:12])[CH:19]3[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]3)[CH2:15]2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: C#C[C@@]1(OC)CN2CCC1CC2
Reactant: O=C(c1ccccc1)C1CCCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CO[C@]1(C#CC(O)(c2ccccc2)C2CCCCCC2)CN2CCC1CC2
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
A 1.6 N solution of BuLi in hexane (41.7 ml, 66.7 mmol) was added dropwise to a solution of (3R)-3-ethynyl-1-azabicyclo[2.2.2]oct-3-yl methyl ether 53 (11 g, 66.7 mmol) in THF (100 ml) cooled at −5° C. After stirring for 10 minutes, the medium was cooled at −15° C., and a solution of cycloheptyl(phenyl)methanone 44 (14.2 g, 70.2 mmol) in THF (50 ml) was slowly added. The cooling bath was removed and the reaction was allowed to gradually warm to room temperature during 2 hours. The reaction was quenched by the addition of saturated aqueous NH4Cl solution. The reaction mixture was washed with brine, dried over Na2SO4 and evaporated. The yellowish oil was purified by chromatography over silica gel (CH2Cl2/EtOH/NH4OH 94/6/1). 1-cycloheptyl-3-[(3R)-3-methoxy-1-azabicyclo[2.2.2]oct-3-yl]-1-phenyl-2-propyn-1-ol 116 was obtained as a white solid (20.35 g, 83%, mixture of diastereomers).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C=O)C>[CH2:9]([N:6]1[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: BrCc1ccccc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(Cc2ccccc2)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 48 h
Yield: 68.5 %

Procedure:
To an ice cold (0° C.) suspension of cis-2,6-dimethylpiperazine (4.0 g, 35 mmol) in DMF (100 mL) was benzyl bromide (6.0 g, 35.0 mmol) added in portions under a period of 45 min and the reaction mixture was stirred at room temperature for 48 h. The solvent was evaporated from the suspension and the residue was dissolved in aqueous HCl and washed twice with CHCl3. The aqueous phase was made alkaline and extracted twice with CHCl3. The combined organic phases were washed with H2O and brine, dried (MgSO4), and concentrated to give 4.9 g (68%) of the title product as a colorless oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:25])[S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:26](O)=[O:27])=[CH:9]2.[CH2:29]([S:36][CH:37]([CH:40]([O:43][CH3:44])[O:41][CH3:42])[CH2:38][NH2:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>O.CN(C)C=O>[CH2:29]([S:36][CH:37]([CH:40]([O:41][CH3:42])[O:43][CH3:44])[CH2:38][NH:39][C:26]([C:10]1[NH:11][C:12]2[C:8]([CH:9]=1)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=2[N:15]([CH3:25])[S:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)(=[O:18])=[O:17])=[O:27])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)O)cc2c1
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C(=O)NCC(SCc3ccccc3)C(OC)OC)cc2c1
Temperature: 25 °C
Reaction time: 60 h
Yield: 80.2 %

Procedure:
5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indole-2-carboxylic acid (2.50 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (1.79 g), diisopropylethylamine (2.00 g) and N,N-dimethylformamide (30 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 3.19 g) at room temperature, and the mixture was stirred at room temperature for 2.5 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with aqueous citric acid solution, saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (1:1-1:4, volume ratio) to give the title compound (3.11 g, yield 80%) as a colorless amorphous solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].[Br:13]N1C(=O)CCC1=O>C(OC)(C)(C)C.C(#N)C>[Br:13][C:11]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([CH:2]2[CH2:3][CH2:4][CH2:5][O:1]2)[CH:12]=1
Reactant: Nc1ccccc1C1CCCO1
Reactant: O=C1CCC(=O)N1Br
Solvent: COC(C)(C)C
Solvent: CC#N
Product: Nc1ccc(Br)cc1C1CCCO1

Procedure:
To a stirring solution of 2-tetrahydrofuran-2-yl-aniline (4) (53.45 g, 327.5 mmol) in methyl tert-butyl ether (MTBE, 641.4 mL) and acetonitrile (213.8 mL) cooled to 2° C. was added N-bromosuccinimide (NBS, 58.88 g, 99%, 327.5 mmol, Aldrich B81255) in 4 portions maintaining internal temperature below about 8° C. The reaction mixture was stirred while cooling with an ice-water bath for 30 minutes (NMR of a worked-up aliquot showed complete consumption of starting material). Aqueous 1 N Na2S2O3 (330 mL) was added to the reaction mixture, removed the cold bath and stirred for 20 minutes. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with saturated aqueous NaHCO3 (2×), water, brine, dried over MgSO4, filtered through a short plug of silica, eluted with EtOAc, and concentrated under reduced pressure to give (5) as a very dark amber oil (82.25 g, 77-94% HPLC purity). Carried forward without further purification. LCMS (C18 column eluting with 10-90% CH3CN/water gradient over 5 minutes with formic acid modifier) M+1: 242.10 (2.89 min). 1H NMR (300 MHz, CDCl3) δ 7.22 (d, J=2.3 Hz, 1H), 7.16 (dd, J=8.4, 2.3 Hz, 1H), 6.54 (d, J=8.4 Hz, 1H), 4.79-4.73 (m, 1H), 4.15 (s, 2H), 4.10-4.01 (m, 1H), 3.93-3.85 (m, 1H), 2.26-2.13 (m, 1H), 2.12-1.97 (m, 3H) ppm.
Reaction SMILES: Cl[CH2:2][C:3]([O:5]C)=[O:4].[Br:7][C:8]1[C:9]([OH:17])=[C:10]([CH:13]=[C:14]([F:16])[CH:15]=1)[CH:11]=O.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+]>O1CCCC1.O>[Br:7][C:8]1[C:9]2[O:17][C:2]([C:3]([OH:5])=[O:4])=[CH:11][C:10]=2[CH:13]=[C:14]([F:16])[CH:15]=1
Reactant: COC(=O)CCl
Reactant: O=Cc1cc(F)cc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2cc(F)cc(Br)c2o1
Temperature: 130 °C
Reaction time: 18 h
Yield: 62.3 %

Procedure:
Methyl chloroacetate (7.6 mL, 86.8 mmol) was added to a mixture of 3-bromo-5-fluoro-2-hydroxy-benzaldehyde (9.5 g, 43.4 mmol), tetra-N-butyl-ammonium iodide (1.6 g, 4.34 mmol) and anhydrous potassium carbonate (24 g, 174 mmol). The reaction mixture was heated at 130° C. for 4 h, cooled to 0° C., diluted with tetrahydrofuran (100 mL) and then potassium hydroxide (17 g, 303 mmol) in water (100 mL). The mixture was stirred at rt for 18 h and then, concentrated under reduced pressure. The residue was acidified with HCl and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude compound was purified by flash chromatography (SiO2; toluene/EtOAc, 40/1) to give 7.0 g (63%) of the product.
Reaction SMILES: N[C@H](C=O)CCSC.[CH2:9]([C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)[CH2:10][CH3:11].[CH2:19]1[O:29][C:22]2([CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]2)[O:21][CH2:20]1.[Cl-].[NH4+]>C1COCC1>[CH2:19]1[CH2:20][O:21][C:22]2([CH2:23][CH2:24][C:25]([OH:28])([C:15]3[CH:16]=[CH:17][C:12]([CH2:9][CH2:10][CH3:11])=[CH:13][CH:14]=3)[CH2:26][CH2:27]2)[O:29]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CCCc1ccc(Br)cc1
Agent: CSCC[C@H](N)C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCCc1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Metal magnesium in an amount of 12 g was suspended in 50 ml of THF under nitrogen gas stream, and a solution prepared by dissolving 100 g of 4-n-propylbromobenzene in 300 ml of THF was added dropwise and stirred at room temperature for 1 hour. A solution prepared by dissolving 78 g of 1,4-cyclohexanedione-monoethylene ketal in 300 ml of THF was added dropwise thereto and stirred at room temperature for 1 hour. After finishing of the reaction, 500 ml of a saturated aqueous solution of ammonium chloride was added and extracted with 500 ml of ethyl acetate. Organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under a reduced pressure to obtain 98 g of 1,1-ethylenedioxy-4-hydroxy-4-(4-n-propylphenyl)cyclohexane.
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH3:4].[C:6]1([S:12]([C:15]#[N:16])(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C1(C)C=CC=CC=1.B(OCCCC)(OCCCC)OCCCC>C(O)CCC>[C:6]1([S:12]([C:15]2[CH:4]=[CH:3][CH:2]=[CH:1][N:16]=2)(=[O:13])=[O:14])[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C/C=C/C=O
Reactant: N#CS(=O)(=O)c1ccccc1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: CCCCO
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccccn1
Temperature: 110 °C
Yield: 90.1 %

Procedure:
First, 8.20 g (115 mmol) of crotonaldehyde and 9.55 g (57.2 mmol) of benzenesulfonyl cyanide were introduced to the same reaction vessel as in Example 1. Toluene (15 ml) as the solvent and butanol (1.5 ml) were added, and 1.33 g (5.78 mmol) of tributyl borate was added. Then the mixture was heated under reflux for 3 hours while agitating at an internal temperature of 110° C. in a nitrogen atmosphere, separating and removing water that was produced. After this solution was cooled to room temperature, the low-boiling components, such as solvent, etc., were removed under reduced pressure and the resulting concentrate was cooled in an ice bath to precipitate crystals. The crystals were filtered with a glass filter and washed with 10 ml of toluene that had been cooled to 5° C. or lower. Then the crystals were dried for 2 hours in vacuo to give 11.3 g of 2-benzenesulfonylpyridine as colorless crystals (purity of 99%, yield of 89% based on benzenesulfonyl cyanide).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:13]([O:17][C:18]([NH:20][C:21](=[N:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])SC)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.C([O-])(=O)C.[Ag+]>[C:28]([O:27][C:25]([NH:24][C:21]([NH:20][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])=[N:12][CH2:11][CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: NCCCc1ccc(O)cc1
Reactant: CSC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: [Ag+]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(=NCCCc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reaction time: 3 h

Procedure:
Silver acetate (1.3 g) was added to a solution of 3-(4-hydroxyphenyl)propylamine hydrochloride (1.2 g) and N,N'-Bis(tert-butoxycarbonyl)-S-methylisothiourea (1.86 g) in DMF (10 mL) containing triethylamine (3.0 g). The mixture was stirred for 3 hr, and an additional 1.0 g silver acetate was added. After one hour, the mixture was diluted with ethyl acetate, filtered through Celite, washed with water, dried over magnesium sulfate, and the solution evaporated. Chromatography on silica gel with 20% ethyl acetate in hexane provided the title compound as a white solid, mp 142°-144° C. (dec) after recrystallization from hexane-ethyl acetate (2.1 g, 77%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:30]([C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([F:26])[CH:28]=4)=[O:31])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Reactant: O=C(Cl)c1cccc(F)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc(F)c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 3-fluorobenzoyl chloride as starting compounds. The crude product is purified by crystallization from EA to yield the title compound.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1.C(N(CC)CC)C.[CH3:17][N:18]([CH3:23])[S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:17][N:18]([CH3:23])[S:19]([N:1]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:4]=2[N:3]=[CH:2]1)(=[O:21])=[O:20]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: c1nc2c([nH]1)CCCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)n1cnc2c1CCCC2
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 76.9 %

Procedure:
To solution of 4,5,6,7-tetrahydro-1H-benzoimidazole (1.9992 g, 16.4 mmol) and triethylamine (4.60 mL, 32.8 mmol) in CH2Cl2 (20 mL) at 0° C. was added dropwise a solution of dimethyl sulfamoyl chloride (1.76 mL, 16.4 mmol) in CH2Cl2 (10 mL). The reaction was warmed to room temperature and stirred for 3.5 hours. CH2Cl2 (80 mL) was added and the organic phase was washed with distilled water (1×80 mL). The aqueous washing was extracted with CH2Cl2 (2×40 mL), and the combined organic extracts were washed with brine (1×80 mL), dried (Na2SO4), and concentrated. Purification of the crude material by column chromatography on silica gel (2:1 hexanes-EtOAc) provided 2.89 g (77%) of 4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid dimethylamide as a white solid. 1H NMR (CDCl3) δ 1.77-1.86 (m, 4H), 2.58-2.61 (m, 2H), 2.72 (t, 2H, J=6 Hz), 2.87 (s, 6H), 7.77 (s, 11H).
Reaction SMILES: [C:1]([C@@H:3]1[C@@H:7]([CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C@@H:5]([N:29]2[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:4]1)#N.[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H]([OH:40])C1.C1COCC1.CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[C:10]([O:9][CH2:8][C@H:7]1[O:6][C@@H:5]([N:29]2[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:4][C@@H:3]1[CH:1]=[O:40])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#C[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a stirred solution of 3'-cyano-2',3'-dideoxy-5'-O-trityluridine (0.96 g, 2 mmol), (prepared in a manner equivalent to that of the thymidine analog above in dry THF (20 ml) under argon, was added a solution of DIBAL-H in toluene (Aldrich) (1M, 4 ml) at -10° C. over a period of 10 min. After 30 mins the reaction was quenched with MeOH (5 ml) at -10° C. The mixture was further stirred at ambient temperature for 30 mins and diluted with CH2Cl2 (25 ml) before concentrating under vacuum. This process was repeated with CH2Cl2 (3×25 ml) in order to remove the residual THF. The residue was purified by flash chromatography on silica gel (25 g). Elution with CH2Cl2 (9:1, v/v) and crystallization from CH2Cl2,MeOH gave 5'-O-trityl-3'-C-formyl-2',3'-dideoxyuridine (0.53 g, 53%); mp 100° C.; 1H NMR (CDCl3) δ 2.25-2.8 (m, 2, CH2), 3.4 (m, 1, C3,H), 3.45-3.6 (m, 2, C5,CH2), 4.37 (m, 1, C4,H), 5.4 (d, 1, C5H), 6.1 (m, 1, C1,H), 7.2-7.4 (m, 15, C6H5), 7.81 (d, 1, C6H0, 7.95 (br s, 1, NH), 9.61 (s, 1, Hc=O).
Reaction SMILES: C(OC(N=NC(OCC)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36]O.[NH:44]=[N+:45]=[N-:46]>C1(C)C=CC=CC=1>[F:32][C:33]([F:43])([F:42])[C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][N:44]=[N+:45]=[N-:46]
Reactant: OCc1ccccc1C(F)(F)F
Reactant: [N-]=[N+]=N
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
First a solution of 17.4 g (0.1 mol) of azodicarboxylic acid diethyl ester in 50 ml of toluene is added dropwise at 10°-20° to a solution of 26.2 g (0.1 mol) of triphenylphosphine in 260 ml of toluene and then, at 5°-10°, a solution of 17.6 g (0.1 mol) of o-trifluoromethylbenzyl alcohol in 120 ml of a 1N solution of hydrazoic acid in toluene is added dropwise thereto and the whole is stirred at room temperature for 2 hours. The precipitated hydrazinodicarboxylic acid ester is filtered off with suction, the toluene solution is concentrated by evaporation and the residue is treated with cyclohexane. The cyclohexane solution is decanted off from the insoluble portions, filtered through a small amount of silica gel and concentrated by evaporation at 50° in vacuo. In this manner o-trifluoromethylbenzyl azide is obtained in the form of a colourless liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][N:15]([CH3:31])[CH:16]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([NH2:30])[CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17]1>>[CH3:14][N:15]([CH3:31])[CH:16]1[CH2:20][CH2:19][N:18]([C:21]2[S:22][C:23]3[CH:29]=[C:28]([NH:30][C:11]([C:6]4[NH:7][C:8]5[C:4]([CH:5]=4)=[CH:3][C:2]([F:1])=[CH:10][CH:9]=5)=[O:13])[CH:27]=[CH:26][C:24]=3[N:25]=2)[CH2:17]1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)c4cc5cc(F)ccc5[nH]4)cc3s2)C1
Yield: 17.3 %

Procedure:
Prepare according to Method B, using 5-fluoroindole-2-carboxylic acid (110 mg, 0.614 mmol) and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (162 mg, 0.618 mmol) to yield the title compound (45 mg, 28%). mass spectrum (m/e): 424 [M+H], 422 [M−H].