Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([CH3:25])[N:23]=[CH:24][C:10]=13)[CH2:2]2.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C1(N)CC1.[N:42]([C:45]1[CH:50]=[CH:49]C(C2N=C3N(C)N=CC3=C(N3CC4OC(CC4)C3)N=2)=CC=1)=[C:43]=[O:44]>ClCCl>[CH:45]1([NH:42][C:43]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([C:13]3[N:12]=[C:11]4[N:22]([CH3:25])[N:23]=[CH:24][C:10]4=[C:9]([N:3]4[CH2:2][CH:1]5[O:8][CH:5]([CH2:6][CH2:7]5)[CH2:4]4)[N:14]=3)=[CH:16][CH:17]=2)=[O:44])[CH2:50][CH2:49]1
Reactant: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N)cc3)nc21
Reactant: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(N=C=O)cc3)nc21
Agent: NC1CC1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)NC4CC4)cc3)nc21

Procedure:
A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (51 mg, 0.15 mmol) in dichloromethane (4 mL) was treated with triphosgene (23 mg, 0.08 mmol) as a solution in dichloromethane (1 mL). After the passage of 5 minutes, the appropriate nucleophile—in the case, cyclopropylamine (104 μL, 10 equivalents, 1.5 mmol)—was added to the 3-(6-(4-isocyanatophenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (“isocyanate”) mixture. The reaction mixture was concentrated to dryness under reduced pressure. The residue was purified by reverse-phase high performance liquid chromatography using a Phenomenex Prodigy 21 mm×250 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 90% acetonitrile to provide 1-cyclopropyl-3-{4-[1-methyl-4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]phenyl}urea. MS (ES+): 420.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:20]>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:19]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:20])=[CH:23][CH:24]=1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)Oc4ccc(F)cc4)cc3c2C1
Yield: 39.8 %

Procedure:
Beginning with 6.0 mg (0.026 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 4.8 mg (0.0273 mMol) 4-fluorophenyl chloroformate, 3.8 mg (40%) of the title compound were recovered.
Reaction SMILES: C[CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH3:10]C(CC=O)C>>[CH3:10][CH2:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][CH3:9]
Reactant: CC(C)CC=O
Reactant: CC(=O)CCCC(C)C
Product: CCCCCC(=O)CC
Yield: 95.4 %

Procedure:
Quantification shows that 606.3 g 6-methylheptanone (4.73 mole) were obtained, which corresponds to a 95.4% yield of methylheptanone in relation to isovaleral. The isovaleraldehyde conversion is 99.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:29]=[CH:28][C:15]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[N:18]=2)=[CH:14][CH:13]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[N:18]=3)=[CH:28][CH:29]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)Nc1ccc(Oc2ccnc(NCCCO)n2)cc1
Reaction time: 8 h
Yield: 16.1 %

Procedure:
A solution of 159 mg (1.033 mmol) 4-chlorophenyl isocyanate in 3 ml THF was given at 0° C. to a solution of 269 mg (1.033 mmol) 3-[4-(4-Amino-phenoxy)-pyrimidin-2-ylamino]-propan-1-ol in 5 ml THF within 10 min. After stirring overnight the reaction mixture was evaporated and the residue purified by chromatography on silica gel (ethyl acetate). The obtained material was recrystallized from 9 ml methanol to give 69 mg (16%) of the title compound.
Reaction SMILES: [C:1]1(=O)O[C:4](=O)[CH:3]=[CH:2]1.[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[CH2:1]=[CH:2][CH2:3][CH2:4][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C1C=CC(=O)O1
Reactant: C=CCCCC
Product: C=CCCCCCCCC

Procedure:
The same procedure as in Example 1 was performed with the exception that 100 parts of (A-2), 116.8 parts of maleic anhydride and 50.5 parts of 1-hexene (C-2) (SP value: 7.5) were used in place of 100 parts of (A-1), 24 parts of maleic: anhydride and 18.5 parts of 1-decene (C-1) in Example 1, to obtain a modifier for polyolefin resin. (K-5) containing a copolymer (X-5). The (X-5) had an SP value of 9.9, an acid value of 250 and an Mn of 2,500.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([O:19][C:20]([F:23])([F:22])[F:21])[CH:12]=2)[N:9]=[N:8][N:7]=1)(=O)C.[OH-].[Li+]>CO.C1COCC1.O>[OH:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[C:13]([O:19][C:20]([F:23])([F:22])[F:21])[CH:12]=2)[N:9]=[N:8][N:7]=1
Reactant: CC(=O)OCc1nnnn1-c1ccc(C#N)c(OC(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(-n2nnnc2CO)cc1OC(F)(F)F
Temperature: 0 °C
Reaction time: 3 h
Yield: 57.3 %

Procedure:
(1-{4-Cyano-3-[(trifluoromethyl)oxy]phenyl}-1H-tetrazol-5-yl)methyl acetate (Intermediate 53, 7.0 g, 21.4 mmol) was dissolved in MeOH:THF:H2O (1:2:1) and the solution was cooled to 0° C. Lithium hydroxide (770 mg, 32.2 mmol) was added at 0° C. The reaction was slowly allowed to reach room temperature and stirred for 3 hr. The solvent was removed under reduced pressure. The residue was diluted with DCM, and washed with ice-cooled water, saturated aq. NaHCO3 and brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product. This was purified by column chromatography (100-200 mesh silica gel), eluting with 30% EtOAc/pet ether to give the title compound (3.50 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.Cl.[CH3:11][NH:12][O:13][CH3:14].CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH3:14][O:13][N:12]([CH3:11])[C:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:9]
Reactant: CNOC
Reactant: O=C(O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CON(C)C(=O)c1ccccn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
Picolinic acid (1.00 g, 8.12 mmol) was dissolved in DMF (40 mL), and N,O-dimethylhydroxylamine hydrochloride (1.58 g, 16.2 mmol), EDC hydrochloride (3.12 g, 16.2 mmol), 1-hydroxybenzotriazole monohydrate (2.48 mg, 16.2 mmol) and triethylamine (2.25 ml, 16.2 mmol) were added thereto, followed by stirring at 50° C. for 3 hours. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:4) to afford N-methoxy-N-methylpyridine-2-carboxamide (988 mg, 73%).
Reaction SMILES: [CH3:1][C:2]([CH3:26])([O:13][C:14]([NH:16][C@H:17]([C@H:21]([OH:25])[CH:22]([CH3:24])[CH3:23])[C:18](O)=[O:19])=[O:15])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)(OC(N[C@H]([C@@H](O)C(C)C)C(O)=O)=O)CCCCC1C=CC=CC=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH3:1][C:2]([O:13][C:14](=[O:15])[NH:16][C@H:17]1[C:18](=[O:19])[O:25][C@@H:21]1[CH:22]([CH3:24])[CH3:23])([CH3:26])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)[C@@H](O)[C@@H](NC(=O)OC(C)(C)CCCCc1ccccc1)C(=O)O
Agent: CC(C)[C@H](O)[C@@H](NC(=O)OC(C)(C)CCCCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[C@H]1OC(=O)[C@@H]1NC(=O)OC(C)(C)CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 18 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-2-[(1,1-dimethyl-5-phenyl-pentoxy)-carbonylamino]-3-hydroxy-4-methyl-pentanoic acid and (2R*,3S*)-2-[(1,1-dimethyl-5-phenyl-pentoxy)-carbonylamino]-3-hydroxy-4-methyl-pentanoic acid (0.11 g, 0.30 mmol) in dry CH2Cl2 (15 mL), at 0° C., Et3N (0.126 mL, 0.9 mmol) and subsequently TBTU (0.116 g, 0.36 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy:AcOEt (from 100:0 to 80:20) to afford the pure title compound (0.019 g, 18%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 365 [M−NH4]+; (ESI) m/z: 346 [M−H]−. 1H NMR (DMSO-d6) δ 0.86 (d, J=6.66 Hz, 3H), 0.95 (d, J=6.54 Hz, 3H), 1.27-1.35 (m, 2H), 1.36 (s, 6H), 1.55 (p, J=7.56 Hz, 2H), 1.66-1.85 (m, 2H), 1.96 (dt, J=6.52, 8.91 Hz, 1H), 2.57 (t, J=7.71 Hz, 2H), 4.17 (dd, J=4.40, 9.09 Hz, 1H), 4.69 (dd, J=4.40, 8.33 Hz, 1H), 7.11-7.33 (m, 5H), 7.81 (d, J=8.32 Hz, 1H).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][CH:19]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[I:1])[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccccc1I
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2I)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.6 %

Procedure:
A mixture of 2-iodoaniline (1.100 g, 5.00 mmol), 1-Boc-4-piperidone (1.500 g, 7.50 mmol)), acetic acid (1.0 mL, 17.5 mmol) and sodium triacetoxy borohydride (2.420 g, 11 mmol) in 1,2-dichloroethane (30 mL) was stirred at ambient temperature for 2 days. The reaction was quenched with water, and the organic phase was separated. The aqueous phase was extracted with dichloromethane. The combined organic phase was washed with water, brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by flash chromatography to afford 4-(2-Iodophenylamino)piperidine-1-carboxylic acid tert-butyl ester (1.560 g, 50%). 1H NMR (300 MHz, CDCl3) δ 7.63 (dd, J=1.5 and 7.8 Hz, 1H), 7.20-7.14 (m, 1H), 6.56 (d, J=8.4 Hz, 1H), 6.41 (dt, J=1.5 and 7.8 Hz, 1H), 3.99-3.95 (m, 2H), 3.48-3.43 (m, 1H), 3.03-2.94 (m, 2H), 2.02-1.97 (m, 2H), 1.52-1.36 (m, 11H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([OH:40])[CH:34]=[C:35]([O:37][CH2:38][CH3:39])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:40][C:33]2[CH:34]=[C:35]([O:37][CH2:38][CH3:39])[CH:36]=[C:31]([Br:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CCOc1cc(O)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC)c2)c1CCC(=O)OCC
Yield: 82.1 %

Procedure:
A similar procedure as described in Example 43, step 3 was used, starting from 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (8.07 g, 17.13 mmol), 3-bromo-5-ethoxy-phenol (3.38 g, 15.57 mmol), and potassium carbonate (4.3 g, 31.14 mmol) to obtain 4-[3-[6-(3-bromo-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (7.77 g, 82%) as a colorless oil: ES(+)-HRMS m/e calcd for C31H43BrO7 (M+H)+ 607.2265. found 607.2270.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]2[NH:20][CH:19]=[N:18][CH:17]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:29]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([C:16]2[N:20]=[CH:19][N:18]([C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:17]=2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1-c1cnc[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Oc1ccc(OCc2ccccc2)cc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.17 h
Yield: 92.7 %

Procedure:
To a solution of 4-(benzyloxy)-2-(1H-imidazol-5-yl)phenol (0.488 mmol) in DMF (5 mL) was added triethylamine (0.585 mmol). After stirring for 10 min, chlorotriphenylmethane (0.512 mmol) was added and continued stirring for 16 h. The reaction mixture was diluted with water (25 mL) and the precipitated product was filtered and washed with water (3×10 mL). The solid cake was dissolved in CH2Cl2, washed with water, brine and dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. The crude was purified by column chromatography to afford the final product (0.230 g, 47%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]2[N:15]=[CH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[C:19]([Br:24])[CH:18]=3)(=O)=O)=CC=1.[CH3:25][C@@H:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:24][C:19]1[CH:18]=[C:17]2[C:22]([CH:23]=[C:14]([CH2:13][CH2:12][N:27]3[CH2:28][CH2:29][CH2:30][C@H:26]3[CH3:25])[N:15]=[CH:16]2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cc3ccc(Br)cc3cn2)cc1
Reactant: C[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1cc2ccc(Br)cc2cn1
Temperature: 25 °C

Procedure:
The product from Example 52F was dissolved in a solution of (2R)-2-methylpyrrolidine (0.26 g, 3.0 mmol) in acetonitrile (20 mL). The solution was treated with potassium carbonate (0.5 g, 3.6 mmol) and heated at 50–55° C. for 20 hours in a sealed flask. The mixture was allowed to cool to room temperature, filtered, and the filtrate was concentrated in vacuo. The residue was diluted with MTBE (20 mL) and water (20 mL) and the pH was adjusted to 3–3.5 with concentrated HCl. The aqueous layer was separated, extracted with MTBE (10 mL), adjusted to a pH of 8–8.5 with potassium carbonate, and extracted with isopropyl acetate (20 mL). The organic layer was separated and concentrated in vacuo. The residue was dissolved in heptane (20 mL), filtered, and the filtrate concentrated under vacuum to provide the title compound. 1H NMR (CDCl3) δ 1.10 (d, J=6.1 Hz, 3H); 1.35–1.49 (m, 1H); 1.62–1.85 (m, 2H); 1.85–1.98 (m, 1H); 2.23 (q, J=8.8. Hz, 1H); 2.28–2.42 (m, 1H); 2.46–2.57 (m, 1H), 3.04–3.19 (m, 2H); 3.19–3.30 (m, 2H); 7.47 (s, 1H); 7.60 (d, J=8.8 Hz, 1H), 7.647.70 (m, 1H), 8.05 (m, 1H); 9.09 (s, 1H); HRMS Calcd. for [C16H19BrN2+H+]: 319.0810. Found: 319.0795.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1Cl)[C:5]#[N:6].[K+].C(O[C:15]([S-:17])=[S:16])C.Cl>CN(C=O)C>[SH:17][C:15]1[S:16][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=1
Reactant: N#Cc1ccc(Cl)c(N)c1
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2sc(S)nc2c1
Temperature: 115 °C
Yield: 49.4 %

Procedure:
To a solution of 3-amino-4-chloro-benzonitrile (Example 251, 9.0 g, 59 mmol) in 90 mL of DMF was added O-ethylxanthic acid potassium salt (Aldrich, 21.23 g, 133 mmol). The mixture was heated to 115° C. for 4 h. After cooled to room temperature, the mixture was diluted with ice/water and was acidified to pH 2 with 2N HCl. Filtration followed by washing with water gave a crude product, which was recrystalized from EtOH/water to give 5.6 g (49%) of product. 1H NMR (400 MHz, DMSO-d6) δ 14.10 (br s, 1H), 7.90 (d, J=8.3 Hz, 1H), 7.69 (dd, J=8.3, 1.1 Hz, 1H), 7.60 (s, 1H). MS (EI): m/z 191 (M−H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.Cl.[C:26]1([S:32]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([N:38]3[CH2:37][CH2:36][CH:35]([S:32]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)(=[O:33])=[O:34])[CH2:40][CH2:39]3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: O=S(=O)(c1ccccc1)C1CCNCC1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCC(S(=O)(=O)c4ccccc4)CC3)n2n1
Temperature: 25 °C
Yield: 72.9 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 86 mg, 0.25 mmol), 4-(phenylsulfonyl)piperidine hydrochloride (145 mg, 0.50 mmol), and N,N-diisopropylethylamine (116 mg, 0.90 mmol) in DMF (1.0 mL) was stirred at 100° C. for 2 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (40-55% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (97.2 mg, 73%). 1H NMR (DMSO-d6) δ: 10.90 (s, 1H), 7.99 (d, J=8.8 Hz, 2H), 7.89-7.95 (m, 2H), 7.78-7.85 (m, 1H), 7.68-7.76 (m, 2H), 7.60 (d, 2H), 7.28 (s, 1H), 6.18 (s, 1H), 4.53 (d, J=12.6 Hz, 2H), 3.69 (tt, J=11.8, 3.7 Hz, 1H), 3.00-3.11 (m, 2H), 2.37 (s, 3H), 2.04 (d, J=10.9 Hz, 2H), 1.75 (qd, J=12.3, 3.8 Hz, 2H), 1.45 (s, 6H); ESI-MS: m/z 534.2 (M+H)+.
Reaction SMILES: Cl.C(=N)([O:4]CC)C.[O-]CC.[Na+].[Na].[Cl-].[Na+].[NH:15]([C:19]1[S:20][CH:21]=[C:22]([C:24](NN)=[O:25])[N:23]=1)[C:16]([NH2:18])=[NH:17]>C(O)C>[NH:15]([C:19]1[S:20][CH:21]=[C:22]([C:24]([OH:25])=[O:4])[N:23]=1)[C:16]([NH2:18])=[NH:17]
Reactant: CCOC(C)=N
Reactant: N=C(N)Nc1nc(C(=O)NN)cs1
Agent: CC[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: N=C(N)Nc1nc(C(=O)O)cs1
Reaction time: 60 h
Yield: 128.9 %

Procedure:
37.1 g (0.3 mol) of ethyl acetimidate hydrochloride was dissolved in 200 ml absolute ethanol. A solution of sodium ethoxide (6.9 g (0.3 mol) sodium in 300 ml absolute ethanol) was added The resulting precipitate of sodium chloride was removed by filtration and to the clear filtrate was added 20.0 g (0.1 mol) of 2-guanidino-4-thiazole carboxylic acid hydrazide. The slurry was stirred at 25° for 60 hours, during which time complete dissolution occurred. The clear, pale orange solution was concentrated in vacuo to a soft solid which was triturated in 10:1 ethyl acetate-ethanol to give 24.0 g (88%) of crude 2-guanidino-4-thiazole carboxylic acid 2-acetiminohydrazide, with a broad melting point, 150° to 178° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[C:9]1[S:13][C:12]([CH3:14])=[N:11][CH:10]=1.C([N:24]=[C:25]=[S:26])(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:25]([NH2:24])=[S:26])[CH:6]=[CH:7][C:8]=1[C:9]1[S:13][C:12]([CH3:14])=[N:11][CH:10]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1cc(N)ccc1-c1cnc(C)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(NC(N)=S)ccc1-c1cnc(C)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
To a solution of 3-methoxy-4-(2-methyl-thiazol-5-yl)-phenylamine (100 mg, 0.45 mmol) in tetrahydrofurane (4 mL) was added drop wise under stirring and under an atmosphere benzoyl isothiocyanate (67.7 ul, 0.48 mmol). The reaction was stirred at room temperature for 3 hours and the solvent was removed under reduced pressure. The residue was dissolved in methanol (6 mL) and a solution of potassium carbonate (188 mg, 1.36 mmol) in water (3 mL) was added. The resulting suspension was stirred at room temperature over night. The precipitate was filtered off, washed with water and diethyl ether to yield the title compound as a pale yellow solid (113 mg, 89%). MS ISP (m/e): 280.1 (100%) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.82 (s, 1H, NH), 8.02 (s, 1H), 7.62 (d, 1H), 7.40 (s, 1H), 7.01 (s, 1H), 3.87 (s, 3H), 2.64 (s, 3H).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:4]=[C:5]([N+:10]#N)[CH:6]=[CH:7][C:8]=1[Cl:9].ClC1C=C(C=CC=1Cl)N.N([O-])=O.[Na+].[OH-].[K+].ClC1C=C(NN=[C:37]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=2[Cl:51])[C:38]([O:40][CH2:41][CH3:42])=[O:39])C=CC=1Cl>Cl.O.C(O)C.S(=O)(=O)(O)O>[Cl:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[Cl:2])[NH:10][C:37]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[C:43]2[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][C:45]=1[Cl:51]
Reactant: CCOC(=O)C(Cc1ccc(Cl)cc1Cl)=NNc1ccc(Cl)c(Cl)c1
Reactant: N#[N+]c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: Nc1ccc(Cl)c(Cl)c1
Agent: O=N[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1[nH]c2cc(Cl)c(Cl)cc2c1-c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Prepare a solution of 3,4-dichlorophenyl-diazonium chloride by treating 8.2 g. of 3,4-dichloroaniline in 25 ml of concentrated hydrochloric acid with a solution of 3.5 g. of sodium nitrite in 35 ml of water at -5°. Dissolve ethyl 2-(2,4-dichlorobenzyl) acetoacetate (14.3 g.) in 100 ml of ethanol with 8.3 g. of potassium hydroxide in 8.3 ml of water and cool to -5°. Add the solution of the diazonium salt to the latter solution, keeping the temperature at 0°, and stir for 15 minutes. Extract with ether and wash the ether solution with two 75 ml portions of 5% sodium hydroxide and then with water and dry (MgSO4). Evaporate to yield the intermediate: ethyl 2,4-dichlorophenylpyruvate 3,4-dichlorophenyl hydrazone. The analytical sample is obtained from ethanol; m.p. 160°-161°. Dissolve the hydrazone (125 g.) in 700 ml of 20% ethanolic sulfuric acid and boil under reflux for 2 hours. Cool to room temperature and collect the crystalline product. Wash with 50% aqueous alcohol. Recrystallize from ethanol; m.p. 230°-231°.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[S:11][C:10]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[S:11][C:10]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:37])([F:36])[F:38])[CH:29]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ncc(N)n3)s2)OCCO1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(OC(F)(F)F)c2)o1
Product: CC(=O)c1ccc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(OC(F)(F)F)c3)n2)s1

Procedure:
Following general procedure A followed by B, starting from 2-[5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 2-methyl-5-(3-trifluoromethoxy-phenyl)-oxazole-4-carboxylic acid.