Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[N:12]1([C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[NH:24][N:25]=[C:26]([O:27][CH2:28][CH2:29][OH:30])[C:19]=23)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[C:31]([O:35][C:36]([N:38]([CH:51]([CH3:53])[CH3:52])[CH2:39][C@H:40]([C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[C:41](O)=[O:42])=[O:37])([CH3:34])([CH3:33])[CH3:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:50][C:47]1[CH:48]=[CH:49][C:44]([C@H:40]([C:41]([N:15]2[CH2:16][CH2:17][N:12]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]4[NH:24][N:25]=[C:26]([O:27][CH2:28][CH2:29][OH:30])[C:19]=34)[CH2:13][CH2:14]2)=[O:42])[CH2:39][N:38]([CH:51]([CH3:52])[CH3:53])[C:36](=[O:37])[O:35][C:31]([CH3:33])([CH3:32])[CH3:34])=[CH:45][CH:46]=1
Reactant: OCCOc1n[nH]c2nccc(N3CCNCC3)c12
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2ccnc3[nH]nc(OCCO)c23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.0815 mL, 0.468 mmol) was added to 2-(4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-3-yloxy)ethanol dihydrochloride (0.0472 g, 0.140 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.234 mL, 0.117 mmol, see Example B) and TBTU (0.0451 g, 0.140 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1). A LiOH solution (1 mL, 2M) was added and stirred for 10 minutes. Ether (20 mL) was added. The organic layer was separated, washed with brine (5 mL), and dried over sodium sulfate. After removal of the solvent, the resulting residue was purified by chromatography (ethyl acetate) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(3-(2-hydroxyethoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The solvent was removed, and the resulting solid was dissolved in MeOH (2 mL). A LiOH solution (2 mL, 2M) was added and stirred for 10 minutes. DCM (20 mL) and water (10 mL) were added. The organic layer was separated, dried over sodium sulfate and concentrated to give (S)-2-(4-chlorophenyl)-1-(4-(3-(2-hydroxyethoxy)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one (0.018 g, 32%) as a solid. MS APCI (+) m/z 487.3 detected.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1.Cl[CH2:17][C:18]1[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:20][O:21][C:22]=1[CH3:23].Cl>C1COCC1>[CH3:23][C:22]1[O:21][N:20]=[C:19]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]=1[CH2:17][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][N:8]=1
Reactant: Cc1ccc(C(=O)O)cn1
Reactant: Cc1onc(-c2ccccc2)c1CCl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1onc(-c2ccccc2)c1CCc1ccc(C(=O)O)cn1
Temperature: -74 °C
Reaction time: 1 h
Yield: 6.5 %

Procedure:
n-Butyllithium solution was added dropwise to a stirred suspension of 6-methylnicotinic acid (137 mg, 1.0 mmol) in THF (3 mL) over 30 min at −74° C. After 1 h a solution of 4-chloromethyl-5-methyl-3-phenyl-isoxazole (208 mg, 1.0 mmol) in THF (3 mL) was added dropwise such that the temperature did not exceed −68° C. The reaction mixture was stirred at −74° C. for 1 h, then HCl (1 N, 10 mL) added and the reaction mixture warmed to room temperature and extracted with ethyl acetate. The combined organic extracts were dried, filtered and concentrated. Purification by chromatography (silica, heptane:ethyl acetate=100:0 to 9:1) afforded the title compound (20 mg, 6%) as a light yellow oil. MS: m/e=168.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N-]1C=CN=C1.[CH2:16]([C:20]1[C:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:41])(=[O:40])[NH2:39])=[CH:28][C:27]=2[F:42])=[C:23]([C:43]#[N:44])[N:22]([C:45]2[CH:50]=[C:49]([N+:51]([O-:53])=[O:52])[CH:48]=[CH:47][C:46]=2[C:54]([F:57])([F:56])[F:55])[N:21]=1)[CH2:17][CH2:18][CH3:19].C1CCN2C(=NCCC2)CC1>>[CH2:16]([C:20]1[C:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38](=[O:40])(=[O:41])[NH:39][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[Cl:1])=[CH:28][C:27]=2[F:42])=[C:23]([C:43]#[N:44])[N:22]([C:45]2[CH:50]=[C:49]([N+:51]([O-:53])=[O:52])[CH:48]=[CH:47][C:46]=2[C:54]([F:56])([F:55])[F:57])[N:21]=1)[CH2:17][CH2:18][CH3:19]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(C#N)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Reactant: O=C(O)c1ccccc1Cl
Agent: c1c[n-]cn1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(C#N)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1F

Procedure:
By the method of Example 1, Step H, 2-chlorobenzoic acid is converted to its imidazolide and reacted with 3-n-butyl-4-[(3-fluoro-2'-sulfamoylbiphenyl-4-yl)methyl]-1-[5-nitro-2-(trifluoromethyl)phenyl]-1H-pyrazole-5-carbonitrile (from Step B) in the presence of DBU to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].[Cl:14][CH2:15][C:16](Cl)=[O:17]>C1(C)C=CC=CC=1>[Cl:14][CH2:15][C:16]([NH:6][C:5]1[CH:7]=[C:8]([O:12][CH3:13])[C:9]([O:10][CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: O=C(Cl)CCl
Reactant: COc1cc(N)cc(OC)c1OC
Solvent: Cc1ccccc1
Product: COc1cc(NC(=O)CCl)cc(OC)c1OC
Temperature: 25 °C
Yield: 91.2 %

Procedure:
3,4,5-Trimethoxyaniline (Aldrich, 4.06 g, 22.2 mmol) and chloroacetyl chloride (2.60 mL, 32.7 mmol) in toluene (50 mL) were heated at 100° C. for 24 hours. The mixture was allowed to cool to room temperature and the volatiles were removed under reduced pressure. The residue was taken up in toluene and concentrated (3×) to remove traces of starting acid chloride and placed under high vacuum to provide 5.26 g (91%) of the title compound as a light brown solid. 1H NMR (500 MHz, DMSO-d6) δ 3.62 (s, 3H), 3.74 (s, 6H), 4.21 (s, 2H), 6.96 (s, 2H), 10.19 (br s, 1H); MS (DCI/NH3) m/e 260 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[NH:11][N:10]=2)[CH:5]=[CH:4][N:3]=1.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1B(O)O.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:14]1([C:12]2[NH:11][N:10]=[C:9]([NH:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:18]4[S:17][CH:21]=[CH:20][CH:19]=4)[N:7]=3)[CH:13]=2)[CH2:16][CH2:15]1
Reactant: Brc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: OB(O)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: c1csc(-c2nccc(Nc3cc(C4CC4)[nH]n3)n2)c1
Temperature: 100 °C
Reaction time: 15 h
Yield: 50.8 %

Procedure:
A mixture of 2-bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidin-4-amine (170 mg, 0.64 mmol, 1.0 equiv.), thiophen-2-ylboronic acid (107 mg, 0.83 mmol, 1.3 equiv.), Pd(PPh3)4 (148 mg, 0.128 mmol, 0.2 equiv.), Na2CO3 (238 mg, 2 mmol, 3.5 equiv.), 1,4-dioxane (5 ml) and water (1 ml) was stirred at 100° C. under a nitrogen atmosphere for 15 h. The reaction mixture was allowed to cool down to room temperature and concentrated to give a residue. The residue was purified by silica gel chromatography (CH2Cl2/methanol 500:1 to 100:1 as eluent) to afford title compound N-(5-cyclopropyl-1H-pyrazol-3-yl)-2-(thiophen-2-yl)pyrimidin-4-amine (Compound 27)(92.2 mg, 50.9%) as solid. LC-MS (m/z)=284.0 [M+H]+; 1H NMR (400 MHz, DMSO-d6): δ 0.71 (m, 2H), 0.95 (m, 2H), 1.94 (m, 1H), 6.35 (s, 1H), 6.87 (s, 1H), 7.17 (m, 1H), 7.70 (m, 1H), 7.83 (d, J=2.8 Hz, 1H), 8.23 (d, J=5.6 Hz, 1H), 9.91 (s, 1H), 12.08 (s, 1H).
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.[CH2:11]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]3[CH:36]=[CH:35][C:31]([C:32]([NH2:34])=O)=[CH:30][CH:29]=3)=[N:26][CH:27]=2)[CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15].N1C=CC=CC=1>C(Cl)Cl>[CH2:11]([C@H:16]1[CH2:17][CH2:18][C@H:19]([C:22]2[CH:27]=[N:26][C:25]([C:28]3[CH:36]=[CH:35][C:31]([C:32]#[N:34])=[CH:30][CH:29]=3)=[N:24][CH:23]=2)[CH2:20][CH2:21]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCC[C@H]1CC[C@H](c2cnc(-c3ccc(C(N)=O)cc3)nc2)CC1
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](c2cnc(-c3ccc(C#N)cc3)nc2)CC1
Temperature: 55 °C

Procedure:
9.5 Ml. of benzenesulfonyl chloride are added dropwise while stirring to a suspension of 17.2 g. of crude trans-p-[5-(4-n-pentylcyclohexyl)-2-pyrimidinyl]benzamide in 150 ml. of pyridine. The mixture is then warmed to 55° C. for 6 hours in an oil-bath. The mixture is poured into 500 ml. of ice-cold 0.5-N hydrochloric acid and the product is taken up in methylene chloride. The extract is washed three times with 200 ml. of 3-N hydrochloric acid each time, then with 100 ml. of saturated sodium bicarbonate solution and with water, dried over sodium sulfate and evaporated. The crude product is chromatographed on a column of 600 g. of silica gel with toluene/5% acetone (v/v). The fractions which are pure according to thin-layer chromatography are dissolved in hexane, filtered hot with active carbon and recrystallized. There is obtained trans-p-[5-(4-n-pentylcyclohexyl)-2-pyrimidinyl]benzonitrile; melting point 100.5° C., clearing point 231° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)OCC1.[H-].[Na+].[CH3:15]I.O>O1CCCC1>[CH3:15][O:12][CH2:11][CH:8]1[CH2:7][CH2:6][C:5](=[O:1])[CH2:10][CH2:9]1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCC1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol (10 g) in tetrahydrofuran (300 mL) in an ice bath was added sodium hydride (3.6 g of 60% in mineral oil) and the mixture stirred for 30 min. Methyl iodide 7.8 mL in THF (20 mL) was added dropwise and the reaction was allowed to warm slowly to room temperature overnight. Water (20 mL) was added and the reaction mixture partially concentrated, then partitioned between water (100 mL) and diethyl ether (300 mL). The organic phase was isolated, dried and concentrated in vacuo. The crude was then taken up in tetrahydrofuran (250 mL) and 40 mL of 3N aqueous HCl was added. The reaction was stirred for 2 h at room temperature, partially concentrated and then the crude product was extracted with diethyl ether, dried, concentrated and purified by flash chromatography (4 hexane: 1 ethyl acetate) to give 4-methoxymethyl-cyclohexanone 4.9 g.
Reaction SMILES: [H-].[Na+].[C:3](=[N:7][OH:8])([NH2:6])[CH2:4][CH3:5].[C:9]1([C:15]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:16]2[CH2:21][CH:20]([C:22](OC)=O)[CH2:19][N:18]=[CH:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1COCC1>[C:32]1([C:15]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:16]2[CH2:21][CH:20]([C:22]3[O:8][N:7]=[C:3]([CH2:4][CH3:5])[N:6]=3)[CH2:19][N:18]=[CH:17]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COC(=O)C1CN=CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: CCC(N)=NO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1noc(C2CN=CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)n1
Temperature: 0 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
Prepared by a procedure similar to Example 9, where sodium hydride (60% dispersion in mineral oil 56 mg, 1.4 mmol) and propionamidoxime (123 mg, 1.4 mmol) were suspended in dry THF in an oven dried round bottom flask with stirring under nitrogen at 0° C. After 15 minutes stirring the ice bath was removed and the grey suspension refluxed 45 minutes to give a white suspension. 1-Triphenylmethyl-1,4,5,6-tetrahydro-5-methoxycarbonylpyrimidine (540 mg, 1.4 mmol) was added, dissolved in dry THF and reflux continued 18 hours. The solvents were evaporated in vacno and the residue was chromatographed (silica, chloroform/methanol 9:1) to yield 1-triphenylmethyl-1,4,5,6-tetrahydro-5-(3-ethyl-1,2,4-oxadiazol-5-yl)pyrimidine 420 mg (70%). This product was dissolved in triflouroacetic acid (2 mL), with stirring at room temperature for 24 hours. The yellow solution was then evaporated in vacuo, and the residue recrystallized from methanol/ether to yield 144 mg (49%) white crystals, mp 116°-118° C. identified by 300 MHz nmr.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:16])OC(C)(C)C.[F:17][C:18]([F:27])([F:26])[C:19](=O)C(OCC)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[F:8][C:5]1[CH:4]=[C:3]2[C:2]([N:1]=[C:19]([C:18]([F:27])([F:26])[F:17])[C:10]([OH:16])=[N:9]2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)ccc1N
Reactant: CCOC(=O)C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Oc1nc2cc(F)ccc2nc1C(F)(F)F
Temperature: 63 °C
Yield: 83 %

Procedure:
tert-Butyl 2-amino-5-fluorophenylcarbamate (30.5 g), toluene (300 mL), triethylamine (34.1 g) and ethyl 3,3,3-trifluoro-2-oxopropanoate (69.5 g) were charged into a reactor and warmed to 63° C. for 14 h, then cooled to ambient temperature. A 5% aq. NaOH solution (390 mL) was added, stirred, settled, and then the lower layer was separated. The organic layer extracted with another charge of 5% aq. NaOH solution (130 mL). To the combined aq. NaOH layers was charged 2-methyl-THF (390 mL) and concentrated HCl (77.9 g), keeping the temperature below 25° C. The layers were mixed, settled and separated. The acidic aq. layer was separated, and the organic layer was extracted with water (260 mL). The layers were separated and the organic layer was filtered to remove insoluble material. The product was isolated by switching the solvent to toluene by distillation (a total of 1.1 L toluene used). The final slurry was briefly warmed to 80° C. and then cooled −10° C. and filtered. The cake was washed with toluene (128 mL), then dried under vacuum at 60° C. To the crude solid was added ethanol (350 mL) and warmed to reflux to dissolve the solids. The solution was cooled to room temperature and concentrated to approximately 270 mL total volume by distillation. Water (250 g) was then added over 30 min. The slurry was filtered and washed with cold (1:1) ethanol: water (2×60 mL). The solid was dried under vacuum at 60° C. (26.1 g, 83% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[CH3:18][C:19]1[O:20][C:21]([CH3:27])=[CH:22][C:23]=1[C:24](O)=[O:25]>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:24]([C:23]3[CH:22]=[C:21]([CH3:27])[O:20][C:19]=3[CH3:18])=[O:25])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: Cc1cc(C(=O)O)c(C)o1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: Cc1cc(C(=O)Nc2ccc(F)c([C@@]3(C)N=C(N)OC[C@@H]3F)c2)c(C)o1

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 2,5-dimethyl-furan-3-carboxylic acid (CAS 636-44-2) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=364.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH2:14][C:13]2[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(CNc2ccc(Br)cn2)cc1
Reaction time: 8 h

Procedure:
5-Bromo-pyridin-2-ylamine (9, 4.0 g, 23 mmol) was dissolved in 100 mL of acetonitrile and 4-chloro-benzaldehyde (10, 3.2 g, 23 mmol) was added. Triethylsilane (11.0 mL, 69 mmol) was added followed by trifluoroacetic acid (5.0 mL, 65 mmol). The reaction was heated to reflux and stirred overnight. The solvent was removed under vacuum and the residue was poured into a solution of 1M potassium carbonate. This was extracted with ethyl acetate and the organic portion was isolated and washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting solid was washed with ether to give the desired compound. The remaining material was purified with silica gel chromatography eluting with a gradient of 0-25% ethyl acetate in hexane. Appropriate fractions were combined and the solvents removed under vacuum to provide additional compound (11, 6.36 g, 92%).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)=[CH:27][CH:26]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2].[C:39]([O-])([O-])=O.[K+].[K+]>CC(C)=O.CI>[C:1]([C:3]1[C:4]([C:25]2[CH:30]=[CH:29][C:28]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[CH:27][CH:26]=2)=[N:5][N:6]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]([CH3:39])[C:19](=[O:24])[C:20]([F:21])([F:23])[F:22])[CH2:10][CH2:9][NH:8][C:7]=12)#[N:2]
Reactant: N#Cc1c(-c2ccc(Oc3ccc(F)cc3)cc2)nn2c1NCCC2c1ccccc1NC(=O)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: CN(C(=O)C(F)(F)F)c1ccccc1C1CCNc2c(C#N)c(-c3ccc(Oc4ccc(F)cc4)cc3)nn21
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of N-(2-(3-cyano-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydro pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoroacetamide (187 mg, 0.36 mmol) in acetone (10 mL) was added K2CO3 (100 mg, 0.72 mmol) and CH3I (15 drops). After stirring at RT for 2 hr, the mixture was filtered. The filtrate was concentrated to afford 192 mg (100%) of N-(2-(3-cyano-2-(4-(4-fluorophenoxyl)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-7-yl)phenyl)-2,2,2-trifluoro-N-methylacetamide as yellow solid. MS (ESI) m/e [M+1]+ 535.8.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:10][O:11][C:12](=[O:16])[C@@H:13]([CH3:15])[NH2:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:10][O:11][C:12](=[O:16])[C@@H:13]([CH3:15])[NH:14][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: COC(=O)[C@@H](C)N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](C)NCc1ccccc1
Temperature: 22 °C
Reaction time: 19 h

Procedure:
Benzaldehyde (19 mL, 19 g, 0.18 mol) was added to a solution of D-alanine methyl ester hydrochloride (25 g, 0.18 mol) in dry CH2Cl2 (300 mL). The solution was stirred at 22° C. for 19 h. The reaction mixture was cooled with an ice-water bath and solid sodium triacetoxyborohydride (46 g, 0.22 mol) was added in portions over ˜15 min. The cooling bath was removed and the milky white solution was stirred at 22° C. for 7 h. The solvent was removed by rotary evaporation under reduced pressure and the resulting slush was partitioned between EtOAc (˜100 mL) and 1 N HCl (˜400 mL). The aqueous layer was extracted with EtOAc (˜50 mL). The aqueous layer was adjusted to pH ˜10 with 1 N NaOH (˜50 mL) and the milky aqueous layer was extracted immediately with EtOAc (3×250 mL). The combined organic layers were washed with brine (˜250 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to afford N-benzyl-D-alanine methyl ester A51(28 g, 80%) as a colorless semi-solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH3:13])[S:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2].C1[C:21](=O)[N:20](Br)[C:18](=O)C1.CNC>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[CH:15]=[CH:14][C:9]2[N:10]=[C:11]([CH2:13][N:20]([CH3:21])[CH3:18])[S:12][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2nc(C)sc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CNC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ccc2nc(CN(C)C)sc2c1
Yield: 32 %

Procedure:
6-ethoxycarbonyl-2-methylbenzothiazole (2.09 g) prepared according to the method described in J. Gen. Chem. vol. 5, pp. 260-266 (1945) was subjected to bromination with NBS (1.78 g) in carbon tetrachloride (30 mg). Then, the product was caused to react with dimethylamine to yield a new compound of 6-ethoxycarbonyl-2-dimethylaminomethylbenzothiazole (0.8 g). Then, the compound was provided with the same treatment as that described in Examples 49-51 to yield 6-[(2-aminoethyl)thiomethyl]-2-(dimethylaminomethyl)benzothiazole.2hydrobromide (1.2 g).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[CH:5]=1.Cl[C:33]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:34]>O.C1COCC1>[Cl:3][C:4]1[CH:31]=[CH:30][C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:33]([O:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:34])=[CH:23][C:22]=3[O:28][CH3:29])(=[O:20])=[O:19])[C:9](=[O:17])[N:10]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)[C:6]=2[CH:5]=1
Reactant: COc1cc(N)ccc1S(=O)(=O)n1c(=O)n(C2CCCCC2)c2cc(Cl)ccc21
Reactant: O=C(Cl)Oc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(NC(=O)Oc2ccccc2)ccc1S(=O)(=O)n1c(=O)n(C2CCCCC2)c2cc(Cl)ccc21
Reaction time: 5 h

Procedure:
0.24 g of NaOH pellets in 2 ml of water was added at 5° C., with stirring, to a solution of 1.05 g of the compound obtained in Example 7 in 25 ml of THF. 1 ml of phenyl chloroformate was then added with continued stirring. The reaction mixture was then stirred for 5 hours, the temperature being allowed to rise to 20° C. The mixture was then concentrated under vacuum, the residue was taken up with water, extracted with ether and washed with water and the organic phase was dried over sodium sulfate and concentrated under vacuum. 1.35 g of the expected product were obtained by crystallization from iso ether. M.p.=236° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH:29]2[C:24]([CH2:25][NH:26][CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:23])([OH:22])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1.[CH:31]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>CN(C)C=O>[CH3:30][C:2]1([CH3:1])[CH:29]2[C:24]([CH2:25][N:26]([C:35]([CH:31]3[CH2:34][CH2:33][CH2:32]3)=[O:36])[CH2:27][CH2:28]2)=[C:5]2[C:6]([OH:22])([OH:23])[CH:7]=[C:8]([CH:10]([CH3:21])[CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[CH:9]=[C:4]2[O:3]1
Reactant: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CNCCC3C(C)(C)OC2=C1
Reactant: O=C(Cl)C1CCC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CCCc1ccc(F)cc1)C1=CC(O)(O)C2=C3CN(C(=O)C4CCC4)CCC3C(C)(C)OC2=C1

Procedure:
5,5-Dimethyl-8-(4-p-fluorophenyl-1-methylbutyl)-10-hydroxy-1,2,3,4-tetrahydro-5H[1]benzopyrano[4,3-c]pyridin-10-ol (1 mole) and cyclobutanecarbonyl chloride (1 mole) with triethylamine (1 mole) in dimethylformamide, stirring 16 hours at 25°C gave the desired product.