Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].O1[C:7]23[C@:23]([CH3:28])([CH2:24][CH2:25][C:26](=[O:27])[CH:6]12)[C@@H:22]1[C@H:10]([C@H:11]2[C@:19]([CH3:29])([CH2:20][CH2:21]1)[C@@H:14]([C@H:15]([CH3:18])[CH2:16][OH:17])[CH2:13][CH2:12]2)[CH2:9][CH2:8]3.[N-:30]=[N+:31]=[N-:32].[Na+].S(=O)(=O)(O)O.O>CS(C)=O>[C:1]([OH:4])(=[O:3])[CH3:2].[N:30]([C:6]1[C:26](=[O:27])[CH2:25][CH2:24][C@@:23]2([CH3:28])[C:7]=1[CH2:8][CH2:9][C@@H:10]1[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:29])[C@H:11]1[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:18])[CH2:16][OH:17])=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC45OC4C(=O)CC[C@]5(C)[C@H]3CC[C@]12C
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3CCC4=C(N=[N+]=[N-])C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
To a vigorously stirred solution of the (20S)-4,5-epoxy21-hydroxy-20-methylpregnan-3-one acetate (3.0 g, 7.72 mmole) obtained in the preceding example, in dimethyl sulfoxide (100 mL), there was added sodium azide (8.2 g) and then concentrated sulfuric acid (0.55 mL). The mixture was heated at 60° C. for 1.5 hours and the cooled mixture was poured into cold water (700 mL). After stirring for 30 minutes, the solids were collected by filtration, washed with water and dried by suction. The resulting solid was purified by flash chromatography on silica gel to give (20S)-4-azido-21-hydroxy-20-methylpregn-4-en-3-one acetate as a white solid (1.6 g, 50.1%), melting at 137°-138° C., with decomposition, after recrystallization from aqueous acetone. IR 2110, 1736, 1670, 1588 (m), 1254 cm-1 ; MS (CI) 386 (3%, M +1 -N2), 326 (100%, M+1 -N2 -AcOH); 1H NMR (CDCl3) δ 0.72 (3H, s, C18 -Me), 1.01 (d, C22 -Me), 1.14 (s, C19 -Me), 2.06 (s, Ac-Me), 3.02 (1H, dq, C6 -H), 3.77 (1H, dd, 1/2 C21 -CH2), 4.08 (1H, dd, 1/2 C21 -CH2).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13]O)=[CH:9][CH:8]=2)=[N:3]1.S(Cl)([Cl:17])=O>C1COCC1.O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:17][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[CH:5]=[CH:6][N:2]([CH3:1])[N:3]=2)=[CH:8][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1ccc(-c2ccc(CO)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1ccc(-c2ccc(CCl)cc2)n1
Temperature: 17 °C
Reaction time: 16 h

Procedure:
To a solution of [4-(1-methyl-1H-pyrazol-3-yl)phenyl]methanol (1.00 g) in THF (15.0 mL) was added dropwise thionyl chloride (0.58 mL) under ice-cooling, and the mixture was stirred at 17° C. for 16 hr. The reaction mixture was diluted with water and ethyl acetate, and saturated aqueous sodium bicarbonate was added thereto. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.65 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:8](Cl)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH:22][CH2:23][C:24]1[CH:35]=[CH:34][C:27]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[CH:26][CH:25]=1>>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[C:8]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[CH:34][CH:35]=1)=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=O)Cl)ccc1O[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)c1ccc(CO)cc1
Product: C=CCOC(=O)c1ccc(COC(=O)c2ccc(O[Si](C)(C)C(C)(C)C)c(C(C)(C)C)c2)cc1

Procedure:
In a manner similar to Example 1(d), by reaction of 4.9 g (15 mmol) of 3-tert-butyl-4-(tert-butyldimethylsilyloxy)benzoyl chloride with 2.9 g (15 mmol) of allyl 4-hydroxymethylbenzoate, 4.1 g (60%) of the allyl ester are obtained in the form of a slightly yellow oil.
Reaction SMILES: ClC1C=C(CCC[N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][CH2:42][C:43](O)=O)=[CH:36][CH:35]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C:34]1[CH:35]=[CH:36][C:37]([CH2:40][CH2:41][CH2:42][CH2:43][N:11]([CH:25]2[CH2:26][CH2:27][CH:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)=[CH:38][CH:39]=1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: COc1ccc(CCCC(=O)O)cc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(CCCCN(C(=O)Nc2ncc(SCC(=O)O)s2)C2CCC(C)CC2)cc1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(4-methoxy-phenyl)-butyric-acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: O.[NH2:2][NH2:3].[N:4]1([C:9]2[CH:10]=[C:11]([C:19]([O:21]C)=O)[C:12](=[CH:17][CH:18]=2)[C:13](OC)=[O:14])[CH:8]=[CH:7][CH:6]=[N:5]1>C(O)C>[N:4]1([C:9]2[CH:10]=[C:11]3[C:12](=[CH:17][CH:18]=2)[C:13](=[O:14])[N:3]=[N:2][C:19]3=[O:21])[CH:8]=[CH:7][CH:6]=[N:5]1
Reactant: COC(=O)c1ccc(-n2cccn2)cc1C(=O)OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=C1N=NC(=O)c2cc(-n3cccn3)ccc21

Procedure:
22 ml hydrazine monohydrate was added to a mixture of 77 g dimethyl 4-(1H-1-pyrazolyl)phthalate and 500 ml ethanol, and heated under reflux for 6 hr. After cooling, the resulting precipitates were collected by filtration to give 36 g of 6-(1H-1-pyrazolyl)-1,4-phthalazine dione.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[C:17](=[O:20])([O-])[O-].[K+].[K+]>C(O)CCC>[ClH:1].[F:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:7][CH2:9][CH2:10][C:17](=[O:20])[C:6]3[CH:15]=[CH:16][C:3]([F:2])=[CH:4][CH:5]=3)[CH2:11][CH2:10]2)=[O:8])=[CH:15][CH:16]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Agent: [K+]
Solvent: CCCCO
Product: O=C(CCCN1CCC(C(=O)c2ccc(F)cc2)CC1)c1ccc(F)cc1
Reaction time: 1 h

Procedure:
A mixture of 13.9 g. (0.057 mole) of 4-(p-fluorobenzoyl)piperidine hydrochloride, 15.5 g. (0.063 mole) of 2-(p-fluorophenyl)-2-(ω-chloropropyl)-1,3-dioxolane, and 27.6 g. (0.2 mole) of potassium carbonate in 150 ml. of 1-butanol was refluxed 20 hours. The mixture was filtered, the filtrate concentrated, the oily residue dissolved in 50 ml. of an ether-methanol mixture and this solution stirred with 100 ml. of 3N HCl for one hour. The mixture was cooled, the layers separated, the aqueous layer basified and the basic mixture extracted with ether. The ethereal extracts were dried over anhydrous sodium sulfate, the mixture filtered and the filtrate treated with ethereal hydrogen chloride. The salt, which weighed 17.2 g. (74%), was recrystallized from an isopropanol-methanol mixture. The dried hydrochloride salt melted at 255°-257° C. The free base which was prepared by neutralization of a portion of the hydrochloride salt melted at 133°-135° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([OH:14])=O)[S:11][C:7]=2[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:5][CH:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][CH2:35][C:36]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)=[O:37].C(N(CC)CC)C>CN(C=O)C.O>[O:37]=[C:36]([C:38]1[S:39][CH:40]=[CH:41][CH:42]=1)[CH2:35][NH:34][C:12]([C:10]1[S:11][C:7]2[C:6]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:14]
Reactant: NCC(=O)c1cccs1
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)O)nc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCOCC2)c2sc(C(=O)NCC(=O)c3cccs3)nc12
Yield: 44.1 %

Procedure:
0.40 g 4-Methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid and 0.25 g 1,1′-carbonyl-diimidazole in 40 ml DMF were stirred at room temperature for 1.5 hours. 0.27 g 2-amino-1-(2-thienyl)ethanone hydrochloride and 0.15 g triethylamine were added and stirring was continued over night at room temperature. 350 ml water was added and the mixture was extracted with ethylacetate. Chromatography on silicagel with ethylacetate/hexane 4:6 yielded 0.25 g (43%) 4-methoxy-7-morpholin-4-yl-benzothiazole-2-carboxylic acid (2-oxo-2-thiophen-2-yl-ethyl)-amide as a yellow solid; MS (ISP): m/e=418 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[C:5]([C:11]#[N:12])[CH:4]=1)#[N:2].CO.[H][H]>[OH-].[Na+].C1(C)C=CC=C(C)C=1>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[C:7]([CH2:9][NH2:10])[CH:8]=1
Reactant: [H][H]
Reactant: N#Cc1cc(C#N)cc(C#N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1cccc(C)c1
Product: NCc1cc(CN)cc(CN)c1
Yield: 79.1 %

Procedure:
In a 300 ml capacity, magnetic-stirring autoclave was sealed 15 g of 1,3,5-tricyanobenzene (MTN), together with 15 g of Raney nickel chromium catalyst (atomic ratio of Ni:Cr=49:1), 27 ml of methanol, 63 ml of m-xylene and 0.18 g of caustic soda. Hydrogen was charged under pressure into it at initial pressure of 100 kg/cm2G, and the reaction was carried out at 100° C., whereby 0.59 mole of hydrogen was absorbed for 35 minutes. The catalyst was filtered out, and the solvent was distilled off, followed by distilling under reduced pressure, thereby yielding 12.8 g of colorless crystals of 1,3,5-tris(aminomethyl)-benzene (MTA). The substance exhibited melting point of 49° to 51° C. and boiling point of 136° to 139° C./0.4 mmHg.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([NH2:14])[CH:6]=[C:7]([F:13])[C:8]=2[CH3:12])[C:3]1=[O:15].C(O)C.C([O:21][C:22](=O)[C:23]([F:26])([F:25])[F:24])C.Cl>C(N(CC)CC)C.C1COCC1>[NH2:14][C:5]1[CH:6]=[C:7]([F:13])[C:8]([CH3:12])=[C:9]2[C:4]=1[C:3](=[O:15])[CH:2]([NH:1][C:22](=[O:21])[C:23]([F:26])([F:25])[F:24])[CH2:11][CH2:10]2
Reactant: Cc1c(F)cc(N)c2c1CCC(N)C2=O
Reactant: CCOC(=O)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1c(F)cc(N)c2c1CCC(NC(=O)C(F)(F)F)C2=O
Temperature: 20 °C
Reaction time: 20 h

Procedure:
The compound obtained in (8) above (1.66 gm) was dissolved into a mixed solvent of 70 ml of ethanol and 10 ml of THF. To the solution were added 2 ml of triethylamine and 1.5 ml of ethyltrifluoroacetate, followed by stirring for 20 hours at 20° C. The reaction product was added to dilute aqueous solution of hydrochloric acid and extracted with chloroform. The extract was washed with water, saturated sodium bicarbonate and saturated brine in this order, and dried over anhydrous sodium sulfate. After removal of the solvent by evaporation, the residue was subjected to silica gel column chromatography using chloroform as an eluant to obtain fractions containing the target compound. The fractions were concentrated to obtain 1.79 gm of the title compound.
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]1[S:27][CH2:28][C@H:29]([C:31](OC)=[O:32])[N:30]=1)=[CH:9]2.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[BH4-].[Na+].CO>O1CCCC1.O>[OH:32][CH2:31][C@H:29]1[CH2:28][S:27][C:26]([C:10]2[NH:11][C:12]3[C:8]([CH:9]=2)=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:14][C:13]=3[N:15]([CH3:25])[S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)(=[O:17])=[O:18])=[N:30]1
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@@H](C(=O)OC)CS3)cc2c1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@@H](CO)CS3)cc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of triphenylphosphine oxide (1.3 g) in dichloromethane (3 mL) was added dropwise trifluoromethanesulfonic anhydride (0.59 mL) at 0° C., and the mixture was stirred at 0° C. for 15 min. The obtained suspension was diluted with dichloromethane (5 mL), and a solution of N-({5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}carbonyl)-S-trityl-D-cysteine methyl ester (0.60 g) and thioanisole (0.74 mL) in dichloromethane (8 mL) was added. The reaction mixture was stirred at 0° C. for 2 hr, and saturated aqueous sodium hydrogencarbonate solution was added. The mixture was concentrated, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:1, volume ratio) to give a mixture (0.39 g) of methyl (4S)-2-{5-(2-methoxyethoxy)-7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazole-4-carboxylate and triphenylphosphine oxide. The obtained mixture of the ester and triphenylphosphine oxide was dissolved in tetrahydrofuran (3 mL), sodium borohydride (0.010 mg) was added at 0° C., and methanol (1.5 mL) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 30 min, and then at room temperature for 2 hr. Water was added, the mixture was concentrated, and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate-methanol (4:1:0-0:10:1, volume ratio) to give the title compound (0.076 g, yield 20%) as colorless crystals. melting point 146.6-146.7° C.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[O:3].Cl[Sn](Cl)(Cl)Cl.C(#N)C.C(O[C@@H:26]1[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:58])[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[C@@H:37]([O:38][C:39](=[O:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@:27]1([CH3:59])[O:28][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=O)C1C=CC=CC=1>>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]([CH:26]2[C:27]([O:28][C:29](=[O:36])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([CH3:59])[CH:37]([O:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:47]([CH2:49][O:50][C:51](=[O:58])[C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48]2)[C:2](=[O:3])[N:4]=1
Reactant: Nc1cc[nH]c(=O)n1
Reactant: C[C@]1(OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(OC(=O)c2ccccc2)C(OC(=O)c2ccccc2)C(COC(=O)c2ccccc2)OC1n1ccc(N)nc1=O

Procedure:
Another preferred embodiment of the present invention is exemplified in FIG. 4, and comprises reacting cytosine, BSA and SnCl4/acetonitrile with 1,2,3,5-tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose (4) from the first embodiment of the invention to provide 4-amino-1-(3,4-dibenzoyloxy-5-benzoyloxymethyl-3-methyl-tetrahydrofuran-2-yl)-1H-pyrimidin-2-one (5); and reacting (5) with NaOMe/MeOH to provide (4-amino-1-(3,4-dihydroxy-5-hydroxymethyl-3-C-methyl-tetrahydrofuran-2-yl)-1H-pyrimidin-2-one) (6), also known as β-D-2′-C-methyl-cytidine. The use of cytosine as a starting material rather than benzoyl-cytosine improves the “atom economy” of the process and simplifies purification at later steps.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=2)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C>O1CCOCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[C:7]([C:8]#[C:9][C:10]3[CH:11]=[N:12][C:13]([NH2:16])=[CH:14][CH:15]=3)=[C:6]([CH3:17])[N:5]=[CH:4][N:3]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Cc1ncnc(Cl)c1C#Cc1ccc(N)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)c1C#Cc1ccc(N)nc1
Temperature: 80 °C
Yield: 93.2 %

Procedure:
The title compound is synthesized according to general procedure GP7 (method 2) starting from 5.0 g (20.4 mmol) 4-chloro-6-methyl-5-(6-amino-pyridin-3-ylethynyl)-pyrimidine and 4.57 g (24.5 mmol) piperazine 1-carboxylic acid tert-butyl ester using 10.4 mL (61.3 mmoL) DIPEA in 50 mL dioxane. The reaction mixture is stirred at 80° C. over night. The solvent is removed under reduced pressure. The residue is taken up in water extracted three times with ethylacetate. The combined organic layers are dried over MgSO4 filtered off and the solvent is removed under reduced pressure yielding 7.5 g (94%) of the desired product, which is used without further purification for the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1.[S:21]1[C:25]([C:26]([C:28]2[N:29]([CH3:33])[CH:30]=[N:31][CH:32]=2)=[O:27])=[CH:24][C:23]2[CH:34]=[CH:35][CH:36]=[CH:37][C:22]1=2>>[S:21]1[C:25]([C:26]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)([C:28]2[N:29]([CH3:33])[CH:30]=[N:31][CH:32]=2)[OH:27])=[CH:24][C:23]2[CH:34]=[CH:35][CH:36]=[CH:37][C:22]1=2
Reactant: Cn1cncc1C(=O)c1cc2ccccc2s1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(Br)ccc2n1
Product: COc1cc(-c2cccc(Cl)c2)c2cc(C(O)(c3cc4ccccc4s3)c3cncn3C)ccc2n1
Yield: 61.8 %

Procedure:
Following the same procedure as described in example 1E, 6-bromo-4-(3-chloro-phenyl)-2-methoxy-quinoline (273 mg, 0.784 mmol) and benzo[b]thiophen-2-yl-(3-methyl-3H-imidazol-4-yl)-methanone (247 mg, 1.01 mmol) generated the title compound of 41A (248 mg, 62% yield).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:31][C:32](O)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:23][C:24]1[C:29]([F:30])=[CH:28][CH:27]=[CH:26][C:25]=1[CH2:31][C:32]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:15](=[N:16][CH:17]=[N:18][C:19]=4[NH2:21])[N:14]([CH3:22])[N:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)=[O:33]
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: O=C(O)Cc1cccc(F)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(-c2ccc3c(c2)CCN3C(=O)Cc2cccc(F)c2F)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial with cap, to the solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine 2HCl (68 mg, 0.20 mmol), (2,3-difluorophenyl)acetic acid (34.5 mg, 0.20 mmol), HATU (76 mg, 0.20 mmol) in DMF (2 mL) was added Hunig's base (0.14 mL, 0.802 mmol). The mixture was stirred at room temperature overnight. LCMS showed reaction was completed. The reaction was poured into water, a white solid formed. The solid was filtered to give a white solid as the title compound. The final product has about 0.7 equivalent of DMF.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>CN(C)C=O.CCCCC>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 15.2 g of methyl-4-hydroxybenzoate (100 mmol) in 125 mL of N,N-dimethylformamide was added under stirring 33.13 g of potassium carbonate (240 mmol). Then 17.45 g of benzyl bromide (102 mmol) was added within 5 min. The mixture was stirred at 25° C. using a water bath. The reaction was complete after 3 h. The reaction mixture was poured into a mixture of 180 g of ice and 200 mL of ethyl acetate. After extraction, the aqueous phase was separated and extracted with three portions of 80 mL of ethyl acetate. The organic phase was washed with two portions of 150 mL of water, combined, dried (MgSO4) and partially concentrated to give a thick suspension. 60 mL of pentane was added and the suspension was stirred during 2 h at room temperature. The crystalline methyl 4-benzyloxybenzoate was collected on a filter, washed with pentane and dried.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:28])=[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[CH:21]=1>>[F:28][C:19]1[CH:18]=[CH:17][C:16]([C:12]2[N:4]3[CH:5]=[CH:6][C:7]([C:8]([F:9])([F:10])[F:11])=[C:2]([F:1])[C:3]3=[N:14][CH:13]=2)=[CH:21][C:20]=1[N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]
Reactant: Fc1c(C(F)(F)F)ccn2ccnc12
Reactant: O=C1CCCN1c1cc(Br)ccc1F
Product: O=C1CCCN1c1cc(-c2cnc3c(F)c(C(F)(F)F)ccn23)ccc1F
Yield: 24 %

Procedure:
8-Fluoro-7-trifluoromethylimidazo[1,2-α]pyridine was coupled to 1-(5-bromo-2-fluorophenyl)pyrrolidin-2-one as described in Example 6 to give 1-[2-fluoro-5-(8-fluoro-7-trifluoromethylimidazo[1,2-α]pyridin-3-yl)-phenyl]pyrrolidin-2-one as a white solid (90 mg, 24%): m/z (ES+) 382 [MH+].
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([O-:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Na+].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>CN(C=O)C>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:8][C:7]2[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc([N+](=O)[O-])cc2)cc1

Procedure:
To a solution of 24.2 g of sodium p-nitrophenoxide in 60 ml of DMF was added 23.5 g of 4-methoxybenzyl chloride. The precipitate was collected after 24 hours, washed with water, and recrystallized from chloroformcyclohexane, providing 1-methoxy-4-[(4-nitrophenoxy)methyl]benzene, mp 122°-124° C.
Reaction SMILES: [Li+].[OH-:2].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@@H:20](OC)[C:21](=C=O)[C:22]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=3)=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:40]=[CH:41][CH:42]=[CH:43][C:6]=2[NH:5]1.C1[CH2:48][O:47]CC1>O>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][C@@H:20]([C:48]([OH:47])=[O:2])[CH2:21][C:22]3[CH:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:33])[F:34])[CH:23]=3)=[O:18])[CH2:15][CH2:16]2)[CH2:9][CH2:8][C:7]2[CH:40]=[CH:41][CH:42]=[CH:43][C:6]=2[NH:5]1
Reactant: C1CCOC1
Reactant: CO[C@H](OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1)C(=C=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Product: O=C(O)[C@@H](Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 307 mg (12.8 mmol) LiOH in 5 mL water was added to a solution of 5.0 g (8.5 mmol) of (R)-2-(3,5-bis-trifluoromethyl-phenyl)-1-methoxy-carbonyl-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 50 mL THF and the reaction mixture was stirred overnight at RT. The mixture was evaporated down in vacuo, the residue was taken up in water, acidified with 1 M HCl, the precipitate was filtered off and dried in the vacuum drying cupboard at 40° C.