Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11]N=C1)([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1CCN>C(#N)C>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:11][CH2:12][NH:8][C:1]([N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1)=[S:2]
Reactant: NCCc1ccccn1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: S=C(NCCc1ccccn1)n1ccnc1
Yield: 92.1 %

Procedure:
A solution of 1,1'-thiocarbonyldiimidazole (9.9 g, 50 mmol) and 2-(2-pyridyl)ethylamine (6.43 g, 50 mmol) in acetonitrile (120 mL) was stirred at room temperature for 24 h. The solution was concentrated under reduced pressure and the resulting brown oil was triturated with ethyl ether. The remaining oil was placed under vacuum to provide 10.7 g of crude titled product as a black solid:
Reaction SMILES: COC1C=CC([O:9][CH2:10][CH2:11][O:12][CH2:13][N:14]2[C:22]3[C:17](=[N:18][CH:19]=[N:20][C:21]=3[NH2:23])[N:16]=[CH:15]2)=CC=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].CCO>CC#N.O>[OH:9][CH2:10][CH2:11][O:12][CH2:13][N:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]=[CH:15]1
Reactant: COc1ccc(OCCOCn2cnc3ncnc(N)c32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Solvent: CC#N
Product: Nc1ncnc2ncn(COCCO)c12
Yield: 79.9 %

Procedure:
Compound 14 (0.74 g, 3.54 mmol) was prepared in 80% yield from 13 (1.39 g, 4.43 mmol) and CAN (2.43 g, 4.43 mmol) in CH3CN (30 mL) and water (10 mL) by the method used for the synthesis of 9: mp 122-123° C.; Rf(hexanes/EtOAc=1:2) 0.12; UV (EtOH) λmax 265 (ε 14,800); 1H NMR (CD3OD) δ 3.69-3.79 (m, 4 H, O(CH2)2O), 5.79 (s, 2 H, H2C1′), 8.32 (s, 1 H, HC2), 8.60 (s, 1 H, HC8); 13C NMR (CD3OD) δ 61.80 (CH2OH), 72.27 (OCH2) 82.01 (C1′), 119.62 (C5), 144.29 (C2), 147.68 (C8), 150.32 (C4), 152.12 (C6); MS m/z 209 (M+). Anal (C8H11N5O2) C, H, N; calcd (%): 45.93, 5.30, 33.48; found (%): 45.80, 5.45, 33.51.
Reaction SMILES: CON(C)[C:4](=[O:30])[CH2:5][CH:6]1[S:10][C:9]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][C:14]=3[N:20]([CH3:29])[S:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)(=[O:23])=[O:22])=[N:8][CH2:7]1.O1CC[CH2:34][CH2:33]1.C([Mg]Br)=C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[CH3:29][N:20]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11]([C:9]1[S:10][CH:6]([CH2:5][C:4](=[O:30])[CH:33]=[CH2:34])[CH2:7][N:8]=1)=[CH:19]2)[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:22])=[O:23]
Reactant: CON(C)C(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Reactant: C1CCOC1
Agent: C=C[Mg]Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: C=CC(=O)CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Reaction time: 5 h
Yield: 38 %

Procedure:
N-Methoxy-N-methyl-2-(2-{7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetamide (589 mg) was dissolved in absolute tetrahydrofuran (20 mL), and 1M vinylmagnesium bromide tetrahydrofuran solution (3.7 mL) was added under ice-cooling. The mixture was stirred for 5 hr under ice-cooling, 1M vinylmagnesium bromide tetrahydrofuran solution (2.0 mL) was added again, and the mixture was further stirred under ice-cooling for 2 hr. The reaction solution was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate), and the obtained pale-yellow crystals were washed with ethyl acetate-hexane to give the title compound (210 mg, yield: 38%) as pale-yellow crystals. MS: 446 (MH+). melting point 157-158° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl-].[NH4+]>C1COCC1.O.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1)[NH2:8]
Reactant: COc1cc(Br)cc([N+](=O)[O-])c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N)cc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
To a solution of 1-bromo-3-methoxy-5-nitrobenzene (1 g, 4.33 mmol) in THF (10 ml) were added a solution of ammonium chloride (1.83 g, 34.6 mmol, 8 eq.) in water (5 ml) and zinc (1.93 g, 34.6 mmol, 8 eq.). The mixture was stirred at RT for 30 min and filtered. The filtrate was diluted with water and extracted as in Example 1(d). The solvent was distilled off to afford the product in 92% yield (0.8 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:13]([CH3:14])[C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)=[C:4]([F:17])[CH:3]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>N1C=CC=CC=1.C(OCC)(=O)C>[C:15]([C:12]1[N:13]([CH3:14])[C:9]([C:5]2[C:4]([F:17])=[CH:3][C:2]([NH:1][S:19]([CH3:18])(=[O:21])=[O:20])=[C:7]([F:8])[CH:6]=2)=[CH:10][CH:11]=1)#[N:16]
Reactant: Cn1c(C#N)ccc1-c1cc(F)c(N)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: Cn1c(C#N)ccc1-c1cc(F)c(NS(C)(=O)=O)cc1F
Reaction time: 16 h
Yield: 76 %

Procedure:
5-(4-amino-2,5-difluorophenyl)-1-methyl-1H-pyrrole-2-carbonitrile (0.15 g, 0.64 mmol) was dissolved in pyridine (2.0 mL). Methanesulfonyl chloride (46 μL, 0.6 mmol) was added and the mixture was stirred for 16 hours, followed by the addition of water. The mixture was diluted with ethyl acetate, washed with water, saturated CuSO4, 2N HCl, brine, dried over MgSO4, and concentrated. The crude product was purified via Isco chromatography (the Redisep® column, silica, gradient 5-50% ethyl acetate in hexane) to afford 0.142 g of N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluorophenyl]-methane-sulfonamide.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH2:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1[O:21]C1.C1OC1.C(C1C=CC=CC=1O)CCCCCCCC>>[CH2:2]1[O:3][CH2:1]1.[CH2:4]([C:12]1([OH:21])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCc1ccccc1O
Agent: CCCCCCCCCc1ccccc1O
Solvent: C1CO1
Product: CCCCCCCCC1(O)CCCCC1

Procedure:
The reaction, filtration, dehydration and solvent removal were carried out by the same procedures as Example 12 except that n-octylphenol ethylene oxide adduct having an ethylene oxide addition mole number of 5.0 was used in place of nonylphenol ethylene oxide adduct having an ethylene oxide addition mole number of 5.0. n-Octylcyclohexanol ethylene oxide adduct was obtained.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][C:6]([CH3:14])([CH3:13])[C:7]#[C:8][CH:9](O)[CH:10]=[CH2:11]>Br>[Br:2][CH2:11][CH:10]=[CH:9][C:8]#[C:7][C:6]([CH3:14])([CH3:13])[CH3:5]
Reactant: BrP(Br)Br
Reactant: C=CC(O)C#CC(C)(C)C
Agent: Br
Product: CC(C)(C)C#CC=CCBr
Temperature: 25 °C
Reaction time: 2 h

Procedure:
50 ml 48% HBr and 10 g PBr3 are stirred to homogeneity at 40°. An alcoholic solution of 13.5 g of 6,6-dimethyl-hept-1-en-4-yn-3-ol is then added dropwise at 10° and the resulting mixture stirred at room temperature for 11/2 hours. The reaction mixture is poured onto ice-water and repeatedly extracted with hexane. The organic phase is separated, washed repeatedly with aqueous NaCl, dried and concentrated on a rotary evaporator. NMR spectroscopy reveals that the resulting oily reaction product comprises a 3:1 mixture of trans- and cis-1-bromo-6,6-dimethyl-hept-2-en-4-yne which is employed directly in further alkylation.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][C@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][C@H:23]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24]1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CN1CC[C@H](ON)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CN1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol, US2005/20572 A1, 2005) in DCM (20 mL) was added (3S)-3-(aminooxy)-1-methylpyrrolidine 109 (0.32 g, 1.39 mmol, J. Med. Chem., 2008, 51, 4601-4608), 1-hydroxybenzotriazole (0.18 g, 1.33 mmol), and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.26 g, 1.36 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, then concentrated in vacuo to provide a residue, which was subjected to chromatography to give 110 (0.26 g, 77%) as a yellow foam.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH2:9])[CH2:2]2.[CH2:10]([C:12]1[C:20]2[C:19]([C:21](O)=[O:22])=[CH:18][C:17]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[N:16][C:15]=2[NH:14][N:13]=1)[CH3:11].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>CN(C=O)C.CN1CCOCC1>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([NH:9][C:21]([C:19]1[C:20]3[C:12]([CH2:10][CH3:11])=[N:13][NH:14][C:15]=3[N:16]=[C:17]([C:24]3[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=3)[CH:18]=1)=[O:22])[CH2:2]2.[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]
Reactant: CCc1n[nH]c2nc(-c3ccc(O)cc3)cc(C(=O)O)c12
Reactant: NC1CN2CCC1CC2
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCc1n[nH]c2nc(-c3ccc(O)cc3)cc(C(=O)NC3CN4CCC3CC4)c12
Temperature: 25 °C

Procedure:
To a solution of 1-aza-bicyclo[2.2.2]oct-3-ylamine (17 mg, 0.135 mmol) in 1 mL of DMF, N-methyl morpholine was added (42 mg, 0.42 mmol) followed by 3-ethyl-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (34 mg, 0.12 mmol) dissolved in 0.5 mL of DMF. Then a solution of TOTU (43 mg, 0.13 mmol) in 0.5 mL DMF was added and the mixture stirred at r.t. over the weekend. The mixture was treated with 0.1 mL TFA, filtered off and purified by prep. HPLC to obtain the desired product 3-ethyl-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (1-aza-bicyclo[2.2.2]oct-3-yl)-amide as TFA salt. In order to change from TFA salt to HCl salt and deprotection (for compounds bearing BOC-protecting groups) the compound was dissolved in 2 mL of 5-6M HCl iPrOH and the reaction was stirred at r.t. overnight. Then 10 mL of water were added and the mixture was freezed dried to give the desired product 3-ethyl-6-(4-hydroxy-phenyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (1-aza-bicyclo[2.2.2]oct-3-yl)-amide as hydrochloride salt (12.7 mg, 23%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@@:8]2([CH3:17])[NH:13][C:12](=S)[CH2:11][S:10](=[O:16])(=[O:15])[CH2:9]2)[CH:7]=1.[NH3:19]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[CH2:9][S:10](=[O:16])(=[O:15])[CH2:11][C:12]([NH2:19])=[N:13]2)[CH:7]=1
Reactant: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)CC(=S)N1
Reactant: N
Product: C[C@@]1(c2cc(Br)ccc2F)CS(=O)(=O)CC(N)=N1
Temperature: 60 °C
Reaction time: 5 h
Yield: 69.2 %

Procedure:
A mixture of (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1λ6-thiomorpholin-3-thione (2.7 g, 7.67 mmol, Eq: 1.00) in ammonia (7 M in MeOH) (47.2 g, 60 ml, 420 mmol, Eq: 54.8) was stirred at 60° C. in a sealed tube for 5 hours. The yellow solution was evaporated, then chromatographed on 20 g silica gel with 0-80% ethyl acetate in heptane to give the (R)-5-(5-bromo-2-fluoro-phenyl)-5-methyl-1,1-dioxo-1,2,5,6-tetrahydro-1λ6-[1,4]thiazin-3-ylamine (1.78 g, 5.31 mmol, 69.3% yield) as a white foam. MS (ISP): m/z=335.0 [M+H]+ and 337.0 [M+2+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][O:11][C:5]=2[CH:4]=1)#[CH:2].I[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=1>>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([C:2]#[C:1][C:3]2[CH:15]=[CH:14][C:6]3[O:7][CH2:8][C:9]([CH3:12])([CH3:13])[CH2:10][O:11][C:5]=3[CH:4]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: C#Cc1ccc2c(c1)OCC(C)(C)CO2
Reactant: COc1cccc(I)c1
Product: COc1cccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)c1

Procedure:
The title compound is prepared in analogy to example 1 from 7-ethynyl-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (6) (example 1d) and 1-iodo-3-methoxy-benzene. MS (ESI) 308.2 (M•)+.
Reaction SMILES: C(N(CC)CC)C.C(O[C:12](=[O:14])[CH3:13])(=O)C.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[N:17]=1>ClCCl.C(OCC)(=O)C>[C:12]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][C:18]1[N:17]=[C:16]([NH2:15])[CH:21]=[C:20]([CH3:22])[CH:19]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(N)nc(CCCCN)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)NCCCCc1cc(C)cc(N)n1
Reaction time: 48 h
Yield: 44 %

Procedure:
Triethylamine (0.059 mL, 43 mg, 0.42 mmol) and acetic anhydride (0.029 mL, 31 mg, 0.031 mmol) were added to a solution of 50 mg (0.028 mmol) of 2-amino-6-(4-aminobutyl)-4-methylpyridine (from Example 56) in 1.0 mL of dichloromethane. The solution was allowed to stand for 48 h at room temperature, then diluted with 25 mL of ethyl acetate and washed with 12 mL of saturated aqueous sodium bicarbonate and 12 mL of saturated aqueous sodium chloride. The aqueous layers were extracted in succession with 15 mL of ethyl acetate. The combined organic layers were dried (sodium sulfate), decanted, and evaporated. The residue was purified by flash column chromatography on 3.5 g of silica gel, eluting with 100 mL of 5% methanol in dichloromethane to give 27 mg (44% yield of 6-(4-acetamidobutyl)-2-amino-4-methylpyridine as an oil which spontaneously crystallized.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][C:17]#[N:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[SH2:26]>C(OCC)C>[C:17](=[S:26])([S:16][C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=1)[NH2:18]
Reactant: CC(C)(C)c1cc(SC#N)cc(C(C)(C)C)c1O
Reactant: S
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SC(N)=S)cc(C(C)(C)C)c1O

Procedure:
3,5-Di-tert-butyl-4-hydroxyphenyl thiocyanate (8.7 g) and 0.3 g of triethylamine were dissolved in 80 ml of diethyl ether, and hydrogen sulfide was blown into the solution at room temperature over 4.5 hours. The reaction mixture was concentrated, and the crude product thus obtained was washed with diethyl ether to give 7.5 g of the desired compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:27][C:28]1[N:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1>C1COCC1>[Cl:19][C:6]1[CH:5]=[C:4]([NH:20][S:34]([C:31]2[CH:32]=[N:33][C:28]([Cl:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(Cl)nc1
Yield: 55.8 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90) (150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and 6-chloro-pyridine-3-sulfonyl chloride (Qorpark, 109 mg, 0.52 mmol) in THF. 130 mg (56%) of 96 was obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:12][C:13]([O:15]C2C=CC=CC=2)=O)[CH:3]=1.[NH:22]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=2)=[N:25][N:24]=[N:23]1>>[NH:25]1[C:26]([C:27]2[CH:32]=[CH:31][C:30]([S:33]([NH:36][C:13]([NH:12][C:4]3[CH:3]=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=3[C:6]([O:8][CH3:9])=[O:7])=[O:15])(=[O:34])=[O:35])=[CH:29][CH:28]=2)=[N:22][N:23]=[N:24]1
Reactant: NS(=O)(=O)c1ccc(-c2nnn[nH]2)cc1
Reactant: COC(=O)c1ccc(Cl)cc1NC(=O)Oc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1NC(=O)NS(=O)(=O)c1ccc(-c2nnn[nH]2)cc1

Procedure:
As the starting substances, methyl 4-chloro-2-phenoxycarbonylaminobenzoate and 4-(5-tetrazolyl) benzenesulfonamide were used and the same method was applied as in Example 36 to obtain N-[4-(5-tetrazolyl)benzenesulfonyl]-N'-(2-methoxycarbonyl-5-chlorophenyl)urea and further to obtain from 2.00 g (4.44 mmol) of N-[4-(5-tetrazolyl)benzenesulfonyl]-N'-(2-carboxyl-5-chlorophenyl)urea 602 mg of the above-identified compound (yield 33.5%). Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6):7.14 (1H,s), 7.24 (1H,d), 7.87 (2H,d), 8.34 (4H,q), 11.66 (1H,br).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:18]=1[OH:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O)([CH3:4])([CH3:3])[CH3:2].[CH3:24][N:25]([CH3:27])[NH2:26].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[CH3:24][N:25]([CH3:27])[N:26]=[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:18]([OH:19])=[C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=1
Reactant: CC(C)(C)c1cc(C(=O)c2ccccc2)cc(C(C)(C)C)c1O
Reactant: CN(C)N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CN(C)N=C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
One gram of 3,5-di-t-butyl-4-hydroxybenzophenone was added to 2 ml of 1,1-dimethylhydrazine, and the mixture was heated at 70° to 75° C. for 8 hours in the presence of 20 mg of p-toluenesulfonic acid in autoclave. After cooling, the reaction mixture was poured into water and extracted with diethyl ether. The ethereal layer was washed with water and dried. The ether was distilled, and the residue was chromatographed on a silica gel column, and recrystallized from diethyl ether to give 3,5-di-t-butyl-4-hydroxybenzophenone dimethylhydrazone as pale yellow needles.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:6].[Br:16]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:16][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])=[CH:12][CH:11]=1)([CH3:15])[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(Br)c1ccc(C(=O)CCCCl)cc1

Procedure:
Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (2.10 g, 9.35 mmol) in carbontetrachloride (30 mL), add N-bromosuccinimide (1.75 g, 9.83 mmol) and benzoylperoxide (3 mg) and stir at reflux for 1 hour. Cool the reaction mixture, filter, wash with water and brine. Dry (MgSO4), filter and evaporate the solvent in vacuo to give the title compound as an amber oil.
Reaction SMILES: O.O.Cl.[NH2:4][C:5]1[N:14]=[C:13]([NH2:15])[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:16][N:17]([CH3:27])[C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)[N:11]=2)[N:6]=1.NC1N=C(N)C2C(=NC=C(C[N:41]([C:43]3[CH:51]=CC(C(O)=O)=C[CH:44]=3)C)N=2)N=1.O.O.C([P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59])#N.CCN(C(C)C)C(C)C.C(OP(CCCN)(=O)OCC)C>CN(C=O)C>[CH2:58]([O:57][P:56]([CH2:51][CH:43]([NH:41][C:22](=[O:24])[C:21]1[CH:20]=[CH:19][C:18]([N:17]([CH2:16][C:10]2[N:11]=[C:12]3[C:7](=[N:8][CH:9]=2)[N:6]=[C:5]([NH2:4])[N:14]=[C:13]3[NH2:15])[CH3:27])=[CH:26][CH:25]=1)[CH3:44])(=[O:63])[O:60][CH2:61][CH3:62])[CH3:59]
Reactant: CCOP(=O)(C#N)OCC
Reactant: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)O)cc1
Agent: CCOP(=O)(CCCN)OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(CC(C)NC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.7 %

Procedure:
To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acid hemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL) were added diethyl cyanophosphonate (31.8 μL, 210 μmol) and DIEA (27.8 μL, 161 μmol). The solution was stirred at ambient temperature for 3 hours, when diethyl(aminopropyl)phosphonate (34.9 mg, 122.6 μmol) was added. The solution was stirred for 2 additional hours, whereupon complete consumption of the starting materials was observed. The reaction was worked up by removal of the solvent in vacuo and purifying the residue by silica gel chromatography using MeOH—CH2Cl2 (10-30%). The product (65.5 mg) collected from this chromatography step was sufficiently pure to be carried on to the next reaction. A small amount (32.8 mg) was re-purified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 23.2 mg (75%) of the pure product. 1H NMR (300 MHz, DMSO-d6) δ 1.20 (t, 6H, J=7.2 Hz), 1.64-1.75 (m, 4H), 3.22 (s, 3H), 3.41 (m, 2H), 3.98 (appt septet, 4H, J=7.2 Hz), 4.85 (s, 2H), 6.79 (d, 2H, J=9 Hz), 7.68 (d, 2H, J=9 Hz), 8.17 (br s, 1H), 8.70 (s, 1H); 31P (121.4 MHz, DMSO-d6) δ 31.9; MS (m/z) 503.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([O:10][CH3:11])=[CH:4][CH:3]=1.[CH2:12](O)[CH2:13][OH:14]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:7]2[O:14][CH2:13][CH2:12][O:8]2)[CH:9]=1
Reactant: COc1ccc(Br)cc1C=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Br)cc1C1OCCO1
Yield: 126.5 %

Procedure:
A solution of 5-bromo-o-anisaldehyde (49.7 g, 231 mmol), ethylene glycol (17.2 g, 277 mmol) and p-toluene sulfonic acid (4.3 g, 23 mmol) in dry toluene (400 ml) was heated at reflux for 21 hr. And then ethylene glycol (4.3 g, 70 mmol) was added to the reaction mixture and heated at reflux for 6 hr. The resulting solution was washed with sat. NaHCO3, water and brine, dried over MgSO4 and concentrated in vacuo to give crude 2-(5-bromo-2-methoxyphenyl)-1,3-dioxolane (75.7 g) as a dark red oil. The residue was added NaHCO3 and then distilled to give 2-(5-bromo-2-methoxyphenyl)-1,3-dioxolane (52.8 g, 88.3%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][OH:23])[CH2:18][CH2:17]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:31][S:32]([O:23][CH2:22][C@H:19]1[CH2:20][CH2:21][C@H:16]([NH:15][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[N:3]=3)[N:8]=[CH:7][C:6]=2[C:12](=[O:14])[CH3:13])[CH2:17][CH2:18]1)(=[O:34])=[O:33]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CO)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 1-{6-chloro-4-[trans-4-(hydroxymethyl)cyclohexylamino]-1,5-naphthyridin-3-yl}ethanone (140 mg, 0.42 mmol) in methylene chloride (10 mL) was added triethylamine (0.12 mL, 0.84 mmol) and methanesulfonyl chloride (65 μL, 0.84 mmol) and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with satd. aq. sodium bicarbonate, the layers were separated and the organic layer was concentrated to afford the crude product (180 mg) as a yellow solid which was used without further purification: 1H NMR (500 MHz, CDCl3) δ 10.90 (br s, 1H), 8.95 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 5.10-4.95 (m, 1H), 4.11 (d, J=6.5 Hz, 2H), 3.03 (s, 3H), 2.68 (s, 3H), 2.39-2.26 (m, 2H), 2.01-1.92 (m, 2H), 1.90-1.78 (m, 1H), 1.47-1.24 (m, 4H); ESI MS m/z 412 [M+H]+