Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C([Li])(C)(C)C.C1([O:30][C:31]([C:33]2[N:34]([CH3:45])[C:35]([CH2:38][N:39]([CH2:41][CH2:42][O:43][CH3:44])[CH3:40])=[N:36][CH:37]=2)=O)C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1.CCCCC.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:31]([C:33]3[N:34]([CH3:45])[C:35]([CH2:38][N:39]([CH2:41][CH2:42][O:43][CH3:44])[CH3:40])=[N:36][CH:37]=3)=[O:30])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: COCCN(C)Cc1ncc(C(=O)Oc2ccccc2)n1C
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCC
Product: COCCN(C)Cc1ncc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)n1C
Temperature: -30 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution of 4-methoxy-7-morpholin-4-yl-benzothiazol-2-ylamine (220 mg, 0.83 mmol) in dry tetrahydrofurane (10 ml) at −70° C. is slowly added a solution of tert.butyllithium (1.1 ml of a 1.5 M solution in pentane corresponding to 1.65 mmol) and the remaining suspension slowly warmed to about −30° C. At this time, a solution of 2-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-3-methyl-3H-imidazole-4-carboxylic acid phenyl ester (252 mg, 0.83 mmol) in tetrahydrofurane (4 ml) was added and the mixture stirred for 1 h at room temperature. The reaction mixture was treated with saturated aqueous ammonium chloride solution (10 ml) followed by ethyl acetate (20 ml) and the formed precipitate collected. The phases were separated and the aqueous phase extracted three times with ethyl acetate. The combined organic layers were extracted twice with water, dried with magnesium sulfate and evaporated to dryness to yield another batch of raw product. Flash-chromatography on silica (eluent trichloromethane containing 30% of ethyl acetate) yielded the title compound as white solid (31% yield). MS: m/e=475(M+H+), mp 176-178° C.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][CH2:14][C:15](=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][C:11]=1[Cl:12].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>C(O)C>[CH2:22]([NH:29][CH:15]([CH2:14][CH2:13][C:8]1[CH:9]=[CH:10][C:11]([Cl:12])=[C:6]([Cl:5])[CH:7]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C(=O)CCc1ccc(Cl)c(Cl)c1
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(CCc1ccc(Cl)c(Cl)c1)NCc1ccccc1
Yield: 33.9 %

Procedure:
A mixture of acetic acid (0.29 ml, 5 mmol), the product of step (a) (700 mg, 2.5 mmol), benzylamine (0.56 ml, 5 mmol) and sodium cyanoborohydride (320 mg, 5 mmol) in ethanol (10 ml) was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and aqueous sodium carbonate (saturated). The organic layer was dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with ethyl acetate/hexane (10:90) to give the title compound as an oil (310 mg). m/e (CI+) 366 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[F:17][C:18]([F:29])([F:28])[C:19]1[CH:23]=[CH:22][N:21]([CH2:24][C:25](O)=[O:26])[N:20]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:25](=[O:26])[CH2:24][N:21]4[CH:22]=[CH:23][C:19]([C:18]([F:28])([F:17])[F:29])=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1ccc(C(F)(F)F)n1
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Cn1ccc(C(F)(F)F)n1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (0.026 g, 0.12 mmol), 2-(3-(trifluoromethyl)-pyrazol-1-yl)acetic acid (0.024 g, 0.12 mmol) and NEt3 (0.060 mL, 0.43 mmol) in DMF (0.5 mL) was added HATU (0.060 g, 0.15 mmol). The mixture was stirred at rt for 30 min. It was then quenched with water. The mixture was partitioned between EtOAc (50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.035 g, 74%). 1H NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.64 (m, 1H), 7.43 (m, 2H), 7.15 (dd, J=8.8, 8.4 Hz, 2H), 6.62 (d, J=2.4 Hz, 1H), 5.23 (s, 2H), 3.82 (m, 2H), 2.84 (t, J=6.4 Hz, 2H), 2.08 (m, 2H); MS: (ES) m/z calculated for C18H15F4N5O [M+H]+ 394.1, found 394.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH:18]=[C:19]([CH3:21])[O:20][C:16]=3[C:15]([C:22](O)=[O:23])=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.[N:31]1(OC(N(C)C)=[N+](C)C)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2N=N1.C1COCC1.C1(N)CCCCC1>CN(C=O)C>[CH:35]1([NH:31][C:22]([C:15]2[C:16]3[O:20][C:19]([CH3:21])=[CH:18][C:17]=3[C:11]3[NH:10][C:9]([NH:8][C:7]4[C:6]([Cl:25])=[CH:5][N:4]=[CH:3][C:2]=4[Cl:1])=[N:13][C:12]=3[CH:14]=2)=[O:23])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:34]1
Reactant: Cc1cc2c(o1)c(C(=O)O)cc1nc(Nc3c(Cl)cncc3Cl)[nH]c12
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1cc2c(o1)c(C(=O)NC1CCCCC1)cc1nc(Nc3c(Cl)cncc3Cl)[nH]c12
Yield: 33.1 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7-methyl-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-8, 0.050 g, 0.132 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.085 g, 0.265 mmol), THF (5.0 mL), DMF (1.0 mL) and cyclohexyl amine (0.026 g, 0.265 mmol) to afford 0.020 g of the desired product. 1HNMR (DMSO-d6): δ 1.23 (s, 3H), 1.36 (t, J=9.6 Hz, 3H), 1.71 (m, 2H), 1.88 (m, 2H), 2.50 (s, 3H), 3.84 (m, 1H), 6.62 (s, 1H), 7.31 (m, 1H), 7.75 (d, J=7.8 Hz, 1H), 8.44 (s, 2H), 11.23 (s, 1H), 11.74 (s, 1H); MS [M+H]+: 458.38.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([S:16](=[O:21])(=[O:20])[N:17]([CH3:19])[CH3:18])=[CH:12][C:11]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[Cl:30]>Cl.CO.C(O)C>[Cl:30][C:24]1[CH:25]=[C:26]([I:29])[CH:27]=[CH:28][C:23]=1[NH:22][C:11]1[CH:12]=[C:13]([S:16](=[O:21])(=[O:20])[N:17]([CH3:19])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:9]([NH:8][OH:7])=[O:31]
Reactant: CN(C)S(=O)(=O)c1ccc(C(=O)NOC2CCCCO2)c(Nc2ccc(I)cc2Cl)c1
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CN(C)S(=O)(=O)c1ccc(C(=O)NO)c(Nc2ccc(I)cc2Cl)c1

Procedure:
The compound 2-(2-chloro4-iodo-phenylamino)-4-dimethylsulfamoyl-benzoic acid O-(tetrahydro-2H-pyran-2-yl)-oxyamide is dissolved in an appropriate hydrogen chloride-saturated solvent like methanol or ethanol. Once homogeneous, the solution is concentrated in vacuo to give the desired product. The product may be triturated with an appropriate solvent like chloroform or dichloromethane if further purification is necessary.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[C:5]([NH:7][C:8]1[CH:13]=[C:12]([C:14]2[N:15]=[C:16]3[N:21]([CH:22]=2)[N:20]=[C:19]([C:23]2[C:24]([C:29]([F:32])([F:31])[F:30])=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:18]=[CH:17]3)[CH:11]=[CH:10][C:9]=1[CH3:33])=[O:6].[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH:38]=[CH2:39].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCN(C(C)C)C(C)C>CN(C=O)C.CN(P(N(C)C)(N(C)C)=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:42]([O:41][C:37](=[O:40])[CH:38]=[CH:39][C:2]1[CH:36]=[CH:35][CH:34]=[C:4]([C:5](=[O:6])[NH:7][C:8]2[CH:13]=[C:12]([C:14]3[N:15]=[C:16]4[N:21]([CH:22]=3)[N:20]=[C:19]([C:23]3[C:24]([C:29]([F:32])([F:31])[F:30])=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:18]=[CH:17]4)[CH:11]=[CH:10][C:9]=2[CH3:33])[CH:3]=1)[CH3:43]
Reactant: Cc1ccc(-c2cn3nc(-c4cccnc4C(F)(F)F)ccc3n2)cc1NC(=O)c1cccc(Br)c1
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)C=Cc1cccc(C(=O)Nc2cc(-c3cn4nc(-c5cccnc5C(F)(F)F)ccc4n3)ccc2C)c1
Temperature: 100 °C
Reaction time: 24 h
Yield: 106.1 %

Procedure:
To a mixture of 3-bromo-N-[2-methyl-5-[6-[2-(trifluoromethyl)-3-pyridyl]imidazo[2,1-f]pyridazin-2-yl]phenyl]benzamide (0.442 g, 0.8 mmol), ethyl acrylate (0.872 mL, 8 mmol), palladium(II) acetate (9 mg, 0.04 mmol), tri(o-tolyl)phosphine (0.049 g, 0.16 mmol) in DMF (4.6 mL) and HMPA (0.4 mL) is added DIPEA (0.557 mL, 3.2 mmol). The mixture is degassed with N2 then sealed and heated at 100° C. for 15 hours. The reaction is not complete, and is stirred at 100° C. for another 24 hours. The mixture is poured into saturated aqueous NaHCO3 and extracted with EtOAc (2×). Organic layers are combined, dried and concentrated to give the title compound as a solid (485 mg), which is used without further purification. LCMS (m/z)=572.5 [M+H]+, tR=3.14 min.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH:30]([CH2:34][OH:35])[C:31](O)=[O:32])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:29][CH:30]([CH2:34][O:35][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[C:31]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])=[O:32])(=[O:27])=[O:28])=[CH:24][CH:25]=1
Reactant: COC(=O)CCCCCCN
Reactant: O=C(O)C(CO)NS(=O)(=O)c1ccc(Cl)cc1
Reactant: C1=COCCC1
Agent: Cl
Product: COC(=O)CCCCCCNC(=O)C(COC1CCCCO1)NS(=O)(=O)c1ccc(Cl)cc1

Procedure:
The procedure described in Example 1 was repeated, except that dihydropyran (1.93 ml) and methyl 7-aminoheptanate hydrochloride (1.679 g) were successively reacted with (RS)-2-(4-chlorobenzenesulfonylamino)-3-hydroxypropanoic acid (2 g) to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-N-(6-methoxycarbonylhexyl)-3-(tetrahydropyran-2-yloxy)propanamide (1. 497 g).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:51])[N:20]([CH2:39][C:40]2[N:44]=[C:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[O:42][N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:51])[N:20]([CH2:39][C:40]2[N:44]=[C:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[O:42][N:41]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(Cc2noc(-c3ccccc3)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2noc(-c3ccccc3)n2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogen carbonate (0.76 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C. for 30 min, 4′-({4-butyl-2-methyl-6-oxo-1-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.79 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.37 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.61 g, 69%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][CH:5]2[OH:14].[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])([CH3:13])[CH2:7][CH2:6][CH:5]2[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: CC1(C)CCC(O)c2cc(Br)ccc21
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC1(C)CCC(O[Si](C)(C)C(C)(C)C)c2cc(Br)ccc21

Procedure:
Continuing on with the description of Reaction Scheme 6, 6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-hydroxynaphthalene is reacted in the presence of base with t-butyldimethylsilyl chloride to provide 6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl-4-(t-butyldimethylsilyloxy)naphthalene (Compound B15). The starting 6-bromo-1,2,3,4-tetrahydro-1,1-dimethyl4-hydroxynaphthalene can be obtained by reduction of 7-bromo-3,4-dihydro-4,4-dimethylnaphthalen-1(2H)-one (Compound G). Under conditions similar to the ones described above Compound B15 is converted to the boronic acid derivative (5,5-dimethyl-8-(t-butyldimethylsilyloxy)-5,6,7,8-tetrahydro-naphth-2-yl)boronic acid (Compound B14). Compound B14 is then coupled with ethyl 6-bromo-naphthalene-2-carboxylate to yield ethyl 6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(t-butyldimethylsilyloxy)-naphth-2-yl]naphth-2-oate (Compound B3). Compound B3 is then reacted with tetrabutylammonium fluoride to remove the t-butyldimethylsilyl blocking group and to give ethyl 6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-hydroxynaphth-2-yl]naphth-2-oate (Compound B4). Compound B4 can be acylated to give ethyl 6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(O-acetyl)-naphth-2-yl]naphth-2-oate (Compound B10), or methoxymethylated with methoxymethyl chloride in the presence of base (preferably ethyl N,N-diisopropylamine, Hunig's base) to give ethyl 6-[5,6,7,8-tetrahydro-5,5-dimethyl-8-(methoxymethyloxy)-naphth-2-yl]naphth-2-oate (Compound B8), and oxidized with N-methyl morpholine N-oxide to provide ethyl-6-[5,5-dimethyl-5,6-dihydro-naphthlen-8(7H)-one-2-yl]-naplithalen-2-oate (Compound B6). Compounds B8 and B10 of the invention are within the scope of Formula 1, whereas Compound B6 is within the scope of Formula 2. Compound B6 can be converted into the O-methyloxine (ethyl 6-[5,5-dimethyl-5,6-dihydro-naphthlen-8(7H)-anti-(O-methyl-oxime)-2-yl]-naphthalen-2-oate (Compound B11) not shown in the scheme) and into other derivatives such as oximes, imnines, hydrazones and the like, as is described above in connection with Reaction Scheme 2. Further derivatives of Compound B6 (and of analogous compounds) wherein the 8oxo function of the molecule is modified can be obtained in accordance with the general synthetic methodology described in this specification. For example the trifluoromethylsulfonyl (triflate) derivative can be obtained in analogy to the reaction leading to Compound A9 as described in Reaction Scheme 2, and the trifluoromethylsulfonyl (triflate) derivative is reacted with the reagents R14Me to provide compounds of Formula 6.
Reaction SMILES: [O:1]1[C@H:7]2[C@@H:2]1[CH2:3][C@@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:5][CH2:6]2.[Cl-].[NH4+].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O>[N:15]([C@H:2]1[C@H:7]([OH:1])[CH2:6][CH2:5][C@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)[C@H]1CC[C@H]2O[C@H]2C1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H]1CC[C@@H](O)[C@H](N=[N+]=[N-])C1
Temperature: 75 °C
Reaction time: 13 h
Yield: 100.3 %

Procedure:
Ethyl (1S,3S,4R)-3,4-epoxycyclohexane-1-carboxylate (41 g) was dissolved in N,N-dimethyl-formamide (300 ml), ammonium chloride (19.3 g) and sodium azide (23.5 g) were successively added at room temperature, and the mixture was then stirred at 75° C. for 13 hours. The reaction mixture was filtered, the filtrate was concentrated to distill off 400 ml of the solvent, the product captured by the filter was put in the residue, and water was added to dissolve the collected product. The solution was extracted with ethyl acetate. The resultant organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (51.5 g) as an oil.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[NH2:8][CH:9]([C:11]1[N:22]([C@@H:23]2[CH2:28][O:27][C@@H:26]([CH2:29][C:30]#[N:31])[CH2:25][CH2:24]2)[C:14]2=[C:15]3[S:21][CH:20]=[CH:19][C:16]3=[N:17][CH:18]=[C:13]2[N:12]=1)[CH3:10].C(N(CC)CC)C.C(Cl)(=O)C>C(Cl)Cl>[C:30]([CH2:29][C@@H:26]1[O:27][CH2:28][C@@H:23]([N:22]2[C:14]3=[C:15]4[S:21][CH:20]=[CH:19][C:16]4=[N:17][CH:18]=[C:13]3[N:12]=[C:11]2[CH:9]([NH:8][C:3](=[O:5])[CH3:2])[CH3:10])[CH2:24][CH2:25]1)#[N:31]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(N)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: CC(=O)NC(C)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)OC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.7 %

Procedure:
To a mixture of {(2R,5S)-5-[2-(1-aminoethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl]tetrahydro-2H-pyran-2-yl}acetonitrile trifluoroacetate (8.0 mg, 0.018 mmol) (Example 68) and triethylamine (12 μL, 0.088 mmol) in methylene chloride (0.15 mL) was added acetyl chloride (2.0 μL, 0.028 mmol). The resulting mixture was stirred at room temperature for 3 h and then concentrated. The residue was purified using RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give 3.5 mg (52%) of the desired product. LCMS calculated for C19H22N5O2S (M+H)+: m/z=384.1. Found: 384.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[S:7][CH2:8][CH:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)[CH2:11][NH:10]1.[CH2:31]([N:33](CC)CC)C.N#CBr>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:31]([N:10]1[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][CH:15]=2)=[CH:13][CH:9]1[CH2:8][S:7][C:2]1[N:3]=[CH:4][CH:5]=[CH:6][N:1]=1)#[N:33]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(CSc4ncccn4)NC3)cc2)C(=O)O1
Reactant: CCN(CC)CC
Agent: CN(C)c1ccncc1
Agent: N#CBr
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CC(CSc4ncccn4)N(C#N)C3)cc2)C(=O)O1
Reaction time: 1 h
Yield: 65.1 %

Procedure:
The amine (Reference Example 7, 0.103 g, 0.24 mM) in CH2Cl2 (4 ml) was treated with triethylamine (0.073 g, 0.100 ml, 0.72 mM) and 4-dimethylaminopyridine (4-DMAP) (0.003 g, 0.024 mM), followed by a suspension of cyanogen bromide (0.129 g, 1.21 mM) in CH2Cl2 (3 ml). The solution was stirred for 1 hour. The mixture was then diluted with CH2Cl2 (7 ml), washed with sat. aq. NaHCO3 (3 ml), water (3 ml), dried and evaporated to an oil which was purified by Isolute chromatography (using as eluant 6% MeOH/CH2Cl2). The resultant oil was triturated with diethyl ether to give the title product (0.071 g, 66%).
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18](F)=[CH:17][CH:16]=1>>[Br:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[O:13][C:2]([CH3:1])=[CH:3][C:4]2=3)=[CH:17][CH:16]=1
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Reactant: Fc1ccc(Br)c2ccccc12
Product: Cc1cc2c(o1)CN(C)CCC2Oc1ccc(Br)c2ccccc12

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 1-bromo-4-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]2[N:12]=[CH:13][CH:14]=[C:10]2[N:9]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:7]=1)=O)C.[BH4-].[Na+]>CO.O1CCCC1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C:8]2[CH:7]=[C:6]([CH2:4][OH:3])[N:11]3[N:12]=[CH:13][CH:14]=[C:10]3[N:9]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(-c2ccc(Cl)cc2)nc2ccnn12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cc(-c2ccc(Cl)cc2)nc2ccnn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
To a suspension of 5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidine-7-carboxylic acid ethyl ester (60 mg, 0.2 mmol) in MeOH/tetrahydrofuran (1:1 v/v, 1 mL) was added at 0° C. over 5 min sodium borohydride (75 mg, 2.0 mmol). The mixture was stirred at 0° C. for 1 h and then poured into ice-cold 3 N HCl (3 mL). The mixture was extracted with AcOEt and the organic layer was washed with H2O, dried (Na2SO4), and evaporated in vacuo. The residue was chromatographed on silica gel using AcOEt/cyclohexane (1:2 v/v) as eluent to give [5-(4-chloro-phenyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-methanol (45 mg, 87%). Pale yellow solid. MS (ISN) 258.1 [(M−H)−]; mp 185–186° C.
Reaction SMILES: [Se-2:1].[Na+].[Na+].Cl[C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].Cl[CH2:14][C:15]#[N:16].C[O-].[Na+]>CN(C=O)C.CO.O>[NH2:8][C:7]1[C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[Se:1][C:14]=1[C:15]#[N:16]
Reactant: N#CCCl
Reactant: [Se-2]
Reactant: N#Cc1ccccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: N#Cc1[se]c2ccccc2c1N
Temperature: 105 °C
Reaction time: 24 h
Yield: 43.6 %

Procedure:
To a suspension of sodium selenide (9.14 g, 72.6 mmol, prepared from 5.8 g of selenium as described above) in DMF (72 mL) was added a solution of 2-chlorobenzonitrile (10 g, 72.6 mmol) in DMF (25 mL) at rt for 5 min and stirred the mixture at 100-110° C. for 24 h. Then chloroacetonitrile (5.48 mL, 72.6 mmol) was added dropwise to the reaction mixture and again stirred at 60-70° C. for 2 h. Then, a solution of sodium methoxide (3.9 g, 72.6 mmol) in dry methanol (24 mL) was added dropwise and stirring was continued for 2 h at the same temperature. The mixture was allowed to room temperature (rt) and poured into cold water and stirred for 30 min. The precipitated solid was filtered, washed with water and dried to give the product as an off-white color solid (7 g, 44%), mp 158-160° C. 1H NMR (400 MHz, CDCl3): δ 7.76-7.79 (1H, m, H-7), 7.60-7.63 (1H, m, H-4), 7.41-7.52 (2H, m, H-5,6), 4.90 (2H, br s, —NH2).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([NH2:9])[C:3]=1[NH2:10].O.O.[C:13](O)(=[O:17])[C:14](O)=[O:15]>Cl>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:10][C:13](=[O:17])[C:14](=[O:15])[NH:9]2
Reactant: O=C(O)C(=O)O
Reactant: Cc1ccc(N)c(N)c1C
Agent: Cl
Solvent: O
Product: Cc1ccc2[nH]c(=O)c(=O)[nH]c2c1C
Temperature: 100 °C

Procedure:
To a solution of 3,4-dimethyl-benzene-1,2-diamine (67.5 g, 496 mmol) in 5N HCl (250 mL) was added oxalic acid dihydrate (69.3 g, 550 mmol). The reaction mixture was heated to 100° C. under stirring. The reaction mixture was stirred for 8 hours and cooled to room temperature. The dark precipitate was filtered, washed, and dried.