Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1C=C(O)C=CC=1.C12(O)CC3CC(CC(C3)C1)C2.S(=O)(=O)(O)O.[CH:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][CH:27]([CH2:28]3)[CH:26]1[C:35]1[CH:40]=[CH:39][C:38]([I:41])=[CH:37][C:36]=1[OH:42])[CH2:32]2.COS(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CC(C)=O>[CH:27]12[CH2:28][CH:29]3[CH2:30][CH:31]([CH2:32][CH:25]([CH2:34]3)[CH:26]1[C:35]1[CH:40]=[CH:39][C:38]([I:41])=[CH:37][C:36]=1[O:42][CH3:2])[CH2:33]2
Reactant: Oc1cc(I)ccc1C1C2CC3CC(C2)CC1C3
Reactant: Oc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: OC12CC3CC(CC(C3)C1)C2
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: COS(=O)(=O)OC
Product: COc1cc(I)ccc1C1C2CC3CC(C2)CC1C3
Yield: 81 %

Procedure:
For 4-(1-Adamantyl)-3-methoxybenzaldehyde (3c): scale=3.51 mmol, yield=43%: The precursor aryl halide, 2-adamantyl-5-iodoanisole, was obtained in two steps from 3-iodophenol via the following procedure. 3-Iodophenol was treated with 1-adamantanol and sulfuric acid in methylene chloride following the general procedure of Shreet et al. U.S. Pat. No. 4,717,720, January 1988. This gave, without recrystallization, pure 2-adamantyl-5-iodophenol: scale=114 mmol, yield=91%; mp 142°-44° C.; 1H NMR (300 MHz, DMSO-d6) δ7.08 (d, J=2 Hz, 1H, ArH), 7.04 (dd, J=2, 8 Hz, 1H, ArH), 6.80 (d, J=8 Hz, 1H, ArH), 3.36 (s, 1H, OH), 1.99 (s, 9 H, adamantyl), and 1.68 (s, 6H, adamantyl); 13C NMR (75 MHz, CDCl3) δ157.26, 135.66, 128.32, 127.54, 124.50, 91.23, 39.61, 36.56, 36.12, and 28.32; IR (KBr) 3480 (OH), 2900, 2845, 1490, 1395, 1210, and 875 cm-1 ; MS (DCI) m/e 355 (MH+), 354 (M+), 353 (M--H)+, 135 (C10H15+). Anal. Calcd for C16H19OI: C, 54.25; H, 5.41. Found: C, 54.32; H, 5.37. A solution of 2-adamantyl-5-iodophenol (7.70 g, 21.7 mmol) in acetone (100 mL) was treated with dimethylsulfate (4.11 g, 32.6 mmol) and potassium carbonate (4.50 g, 32.6 mmol). The reaction mixture was stirred at reflux for 24 h, cooled, and concentrated in vacuo. The crude product was partitioned between methylene chloride and water. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to provide 6.5 g (81%) of 2-adamantyl-5-iodoanisole; 1H NMR (300 MHz, CDCl3) δ7.22 (dd, J=2, 8 Hz, 1H, ArH), 7.10 (d, J=2 Hz, 1H, ArH), 6.89 (d, J=8 Hz, 1H, ArH), 3.79 (s, 3H, OCH3), 2.02 (s, 9H, adamantyl), and 1.73 (s, 6H, adamantyl); 13C NMR (75 MHz, CDCl3) δ159.35, 138.43, 129.63, 128.25, 120.75, 91.20, 55.22 (OCH3), 40.35, 37.02, 36.92, and 28.97; MS (DCI) m/e 369 (MH+), 368 (M+), 367 (M--H)+, 135 (C10H15+). Anal. Calcd for C17H21OI: C, 55.45; H, 5.75. Found: C, 55.51; H, 5.81. Reaction of 2-adamantyl-5-iodoanisole according to general procedure A gave 3c: 1H NMR (300 MHz, CDCl3) δ9.92 (s, 1H, CHO), 7.35-7.41 (m, 3H, ArH), 3.88 (s, 3H, OCH3), 2.08 (s, 9H, adamantyl), and 1.76 (s, 6H, adamantyl); 13C NMR (75 MHz, CDCl3) δ192.04 (C=O), 159.38, 146.00, 135.36, 127.06, 124.45, 109.54, 55.09 (OCH3), 40.15, 37.79, 36.95, and 28.90; IR (KBr) 2965, 2900, 2850, 1690 (C=O), 1250, 1160, 1135, 1035, and 1025 cm-1 ; MS (DCI) m/e 271(MH+), 135 (C10H15 +). Anal. Calcd for C18H22O2.0.02H2O: C, 79.86; H, 8.21. Found: C, 79.48; H, 8.34.
Reaction SMILES: N[C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[BrH:10].N([O-])=O.[Na+]>O.C(OCC)C>[Br:10][C@@H:2]([CH2:3][C:4]([OH:6])=[O:5])[C:7]([OH:9])=[O:8]
Reactant: N[C@@H](CC(=O)O)C(=O)O
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: O=C(O)C[C@H](Br)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 51 %

Procedure:
To a 500 mL round bottom flask was added L-aspartic acid ((S)-aspartic acid, 25 g, 188 mmol) and 245 mL of 5 N HBr. The reaction was cooled in an ice bath to 0-50° C., followed by the dropwise addition of sodium nitrite (20.7 g, 301 mmol) in 75 mL of water over five hours. The temperature was maintained below 50° C. during the addition. After the addition was complete, the reaction was allowed to stir for 12 hours at 23-25° C. The reaction was diluted with diethyl ether (120 mL). The aqueous layer was removed and the organic phase was washed with 1 N HCl (100 mL). The combined aqueous phases were washed with EtOAc (100 ml). The combined organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure to leave the product as a slightly yellow solid. The solid was recrystallized from EtOAc (˜100 mL) and hexanes (˜10 mL) to obtain the product (19.03 g, 97 mmol, 51%) as a white crystalline solid.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.CC1(C)COB([C:22]2[CH:23]=[CH:24][C:25]([F:37])=[C:26]([C:28]3[C:29]([C:35]#[N:36])=[CH:30][CH:31]=[C:32]([F:34])[CH:33]=3)[CH:27]=2)OC1>>[F:34][C:32]1[CH:33]=[C:28]([C:26]2[CH:27]=[C:22]([C:2]3[N:6]4[N:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]4=[N:4][CH:3]=3)[CH:23]=[CH:24][C:25]=2[F:37])[C:29]([C:35]#[N:36])=[CH:30][CH:31]=1
Reactant: CC1(C)COB(c2ccc(F)c(-c3cc(F)ccc3C#N)c2)OC1
Reactant: FC(F)(F)c1cnn2c(Br)cnc2n1
Product: N#Cc1ccc(F)cc1-c1cc(-c2cnc3nc(C(F)(F)F)cnn23)ccc1F
Yield: 46 %

Procedure:
7-Bromo-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine was coupled with 5′-(5,5-dimethyl-[1,3,2]dioxaborinan-2-yl)-5,2′-difluorobiphenyl-2-carbonitrile as described in Example 3 to give 68.7 mg (46%) of 5,2′-difluoro-5′-(3-trifluoromethylimidazo[1,2-b][1,2,4]triazin-7-yl)biphenyl-2-carbonitrile as a yellow solid: mp 200-201° C.; 1H NMR (360 MHz, CDCl3) δ 7.25-7.34 (2H, m), 7.44 (1H, t, J 8.9 Hz), 7.87 (1H, dd, J 5.4, 8.6 Hz), 8.18-8.26 (2H, m), 8.63 (1H, s), 8.82 (1H, s); MS (ES+) m/z 401. Anal. Found: C, 55.98; H, 2.13; N, 17.49%. Required for C19H8F5N5.0.3H2O: C, 56.11; H, 2.13; N, 17.22%.
Reaction SMILES: ClC(OCC)=O.O1CCCC1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:20]=[C:21]([N:30]3[CH:34]=[CH:33][N:32]=[C:31]3[CH3:35])[O:22][C:23]=2[CH2:24][CH2:25][CH2:26][C:27]([OH:29])=O)=[CH:15][CH:14]=1.[Cl:36][CH2:37][CH2:38][NH2:39]>O.CN(C)C=O.C(N(CC)CC)C>[Cl:36][CH2:37][CH2:38][NH:39][C:27](=[O:29])[CH2:26][CH2:25][CH2:24][C:23]1[O:22][C:21]([N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])=[N:20][C:19]=1[C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1
Reactant: NCCCl
Reactant: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCC(=O)O)o1
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCC(=O)NCCCl)o1
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
Ethyl chloroformate (375mg) was added dropwise to a tetrahydrofuran (20ml)-N,N-dimethylformamide (10 ml) solution of 4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanoic acid (1.00 g) and triethylamine at −30° C. After stirring for 30 minutes, the reaction mixture was added to the solution of 2-chloroethylamine (1.45g) and N,N-dimethylformamide (20ml) at QOC. The resulting mixture was stirred for 1 hour at room temperature. Water was poured into the reaction mixture to give N-(2-chloroethyl)-4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutyramide (1.00 g, 85%). This was recrystallized from ethyl acetate-hexane to give colorless needles. mp 131-132° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH:14]=[C:13](Br)[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:22](/B(O)O)=[CH:23]\[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[C:1]1([S:7]([N:10]2[CH:14]=[C:13]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c(-c2cccnc2)n1
Reactant: CCCCCC/C=C/B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCCCCC=Cc1cn(S(=O)(=O)c2ccccc2)nc1-c1cccnc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
To toluene (20 ml) containing 36A (0.91 g, 2.5 mmol) (see Scheme 7), was added 1.5 eq (E)-octene-1-ylboronic acid (0.59 g). The resulting mixture was stirred for 2 hours under N2. Successively were added 2 eq of K3PO4 (1.06 g), 4 mol % of Pd(OAc)2 (22.4 mg) and 8 mol % of S-Phos (82 mg). After the addition, the resulting solution was warmed at 90° C. for 18 hours under N2. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed three times with a saturated NaHCO3 solution, dried (Na2SO4), filtered and concentrated. The resulting residue was purified by flash chromatography (diethyl ether/PE 1/1) to afford 3-(1-phenylsulfonyl-4-oct-1-enyl-1H-pyrazol-3-yl)-pyridine (46C) as an oil (0.31 g, 32%). 1H-NMR (400 MHz, CDCl3): δ 8.85 (d, J=2 Hz, 1H), 8.65 (dd, J=5 Hz, 2 Hz, 1H), 8.15 (s, 1H), 8.08-8.05 (m, 2H), 7.93 (dt, J=8 Hz, 2 Hz, 1H), 7.69-7.64 (m, 1H), 7.59-7.52 (m, 2H), 7.37-7.33 (m, 1H), 6.19 (d, J=16 Hz, 1H), 6.10-6.03 (m, 1H), 2.19-2.12 (m, 2H), 1.45-1.37 (m, 2H), 1.36-1.23 (m, 6H), 0.90 (t, J=7 Hz, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8](=[O:16])[CH2:7]2)[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([O:25][C:26]2[CH:35]=[C:34]([CH3:36])[C:29]3[NH:30][C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][C:34]1[C:29]2[NH:30][C:31](=[O:33])[O:32][C:28]=2[CH:27]=[C:26]([O:25][C:20]2[CH:19]=[C:18]([N:1]3[CH2:2][CH2:3][C:4]4([C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8](=[O:16])[CH2:7]4)[CH2:5][CH2:6]3)[N:23]=[C:22]([CH3:24])[N:21]=2)[CH:35]=1
Reactant: O=C1CC2(CCNCC2)c2cccnc2N1
Reactant: Cc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Oc2cc(C)c3[nH]c(=O)oc3c2)cc(N2CCC3(CC2)CC(=O)Nc2ncccc23)n1

Procedure:
26 mg (0.12 mmol) 1H-spiro[[1,8]naphthyridin-4,4′-piperidin]-2(3H)-one, 35 mg (0.12 mmol) 6-(6-chloro-2-methylpyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 42 μL (0.24 mmol) DIPEA in 2.0 mL DMF were stirred for 4 days at 60° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and lyophilised.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][CH3:10])[CH2:4][C:5]#[C:6][CH2:7][OH:8])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([N:3]([CH2:9][CH3:10])[CH2:4][C:5]#[C:6][CH:7]=[O:8])[CH3:2]
Reactant: CCN(CC)CC#CCO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCN(CC)CC#CC=O
Temperature: 25 °C
Yield: 35.7 %

Procedure:
To a solution of 4-diethylamino-2-butyn-1-ol (1.00 g, 7.08 mmol) in anhydrous DCM (60 mL) was added MnO2 (20 g, 230 mmol) portion wise on one hour. The resulting mixture was stirred at rt for two additional hours, then filtered on a bed of Celite. The filtrates were evaporated under reduced pressure to give 352 mg (36%) the title compound as an orange oil (352 mg, 36% yield). 1H NMR (CDCl3) δ: 9.22 (s, 1H), 3.65 (s, 2H), 2.58 (q, J=7.2 Hz, 4H), 1.08 (t, J=7.2 Hz, 6H).
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[N:17]1([CH2:23][C:24]2[CH:25]=[N:26][C:27]3[C:32]([CH:33]=2)=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CS(C)=O>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([NH:9][C:8]([N:20]2[CH2:21][CH2:22][N:17]([CH2:23][C:24]3[CH:25]=[N:26][C:27]4[C:32]([CH:33]=3)=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:18][CH2:19]2)=[O:16])[CH:11]=1
Reactant: c1ccc2ncc(CN3CCNCC3)cc2c1
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCN(Cc2cnc3ccccc3c2)CC1
Yield: 80 %

Procedure:
A solution of pyridin-3-yl-carbamic acid phenyl ester (0.3 g) and 3-piperazin-1-ylmethyl-quinoline (0.32 g) in DMSO (0.5 mL) was heated in a microwave reactor at 100° C. for 0.5 h. The reaction mixture was partitioned between DCM and water. The combined organic layers were washed with brine (3×), dried (Na2SO4), and concentrated. The residue was purified by column chromatography to yield the title compound as a beige solid (80%). 1H NMR (400 MHz, CDCl3): 8.92 (d, J=2.3 Hz, 1H), 8.72 (d, J=2.3 Hz, 1H), 8.28 (d, J=8.1 Hz, 1H), 8.23-8.21 (m, 1H), 8.13-8.10 (m, 2H), 7.84-7.82 (m, 1H), 7.74-7.70 (m, 1H), 7.59-7.55 (m, 1H), 7.37-7.34 (m, 2H), 3.77 (s, 2H), 3.64-3.62 (m, 4H), 2.62-2.59 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[SH2:12].C(NCC)C>CN(C=O)C>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[S:12])[NH2:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: S
Reactant: COc1cc(C#N)ccc1O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: COc1cc(C(N)=S)ccc1O
Temperature: 70 °C

Procedure:
A solution of 4-hydroxy-3-methoxybenzonitrile (15.0 g, 0.1 mol) in DMF (150 mL) was treated with a slow flow of gaseous hydrogen sulfide for 30 minutes at rt. Diethyl amine (15.6 mL, 11.0 g, 0.15 mol) was added and the solution was heated at 70° C. for 4 h. The solution was cooled to rt and the residual H2S was removed by passing argon through the solution for 30 minutes. The solvent was evaporated under reduced pressure and the residue was filtered through a plug of silica, followed by washing with EtOAc. Removal of the solvent resulted in a crude brown oil, which was used in the next step without further purification.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][C:28]([CH3:34])([CH3:33])[C:29]([O:31]C)=[O:30])=[O:26])=[CH:20][C:19]=3[Cl:35])=[CH:14][CH:13]=2)[C:9]([CH3:36])=[N:8][C:7]=1[CH3:37])(=[O:5])[NH2:4]>CC(O)(C)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH:27][C:28]([CH3:33])([CH3:34])[C:29]([OH:31])=[O:30])=[O:26])=[CH:20][C:19]=3[Cl:35])=[CH:14][CH:13]=2)[C:9]([CH3:36])=[N:8][C:7]=1[CH3:37])(=[O:5])[NH2:4]
Reactant: COC(=O)C(C)(C)NC(=O)Cc1ccc(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3ccc(CC(=O)NC(C)(C)C(=O)O)cc3Cl)cc2)nc1C(N)=O
Temperature: 45 °C
Reaction time: 5 h
Yield: 5.8 %

Procedure:
Potassium hydroxide (109 mg, 1.94 mmol) was added in one portion to methyl 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)-2-methylpropanoate (Intermediate 14-1; 319.5 mg, 0.65 mmol) in t-BuOH (4164 μL) at room temperature. The resulting solution was stirred at 45° C. for 5 hours and a precipitate formed. The reaction mixture was quenched with 2M HCl (5 mL), The reaction mixture was evaporated to dryness and redissolved in water (10 mL), and filtered through nylon, washed with water and dried under vacuum. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 50 mm diameter, 150 mm length), using decreasingly polar mixtures of water (containing 0.1% formic acid) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2-chlorobiphenyl-4-yl)acetamido)-2-methylpropanoic acid (18.20 mg, 5.86%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:18])[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]=3[C:10](=[O:17])[O:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:19]([N:26]=[C:27]=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[CH2:19]([NH:26][C:27]([N:14]1[CH2:15][CH2:16][C:11]2[C:10](=[O:17])[O:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=3)([CH3:18])[C:12]=2[CH2:13]1)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC1(c2cccc(O)c2)OC(=O)C2=C1CNCC2
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: CC1(c2cccc(O)c2)OC(=O)C2=C1CN(C(=O)NCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
A mixture of 3-(3-hydroxyphenyl)-3-methyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (75 mg, 0.31 mmol) and benzyl isocyanate (48 μL, 0.40 mmol) in dichloromethane (5 mL) was stirred at room temperature for 1 h. The solvent was removed and the resulting residue was purified on silica to give the desired product (68 mg, 58.8%). 1H NMR (300 Hz, CDCl3) δ 1.82 (s, 3H), 2.39 (br s, 2H), 3.30-3.40 (m, 1H), 3.42-3.55 (m, 1H), 3.94 (d, J=18.0, 1H), 4.25-4.40 (m, 3H), 4.97 (t, J=6.0, 1H), 6.77-6.84 (m, 2H), 7.15-7.38 (m, 7H).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:26][C:27]1[CH:28]=[C:29]([S:34]([NH2:37])(=[O:36])=[O:35])[C:30]([CH3:33])=[CH:31][CH:32]=1>>[CH3:33][C:30]1[CH:31]=[CH:32][C:27]([NH:26][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=4)=[N:6][C:7]=23)=[O:14])=[CH:28][C:29]=1[S:34](=[O:36])(=[O:35])[NH2:37]
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: Cc1ccc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(N)(=O)=O

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-amino-6-methyl-benzenesulfonamide [CAS-No. 6973-09-7] according to general procedure II. Yellow solid. MS (ISP) 526.2 [(M+H+]; mp 249° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22]([NH2:24])=O)[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1.S(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([C:22]#[N:24])[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1
Reactant: NC(=O)c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: N#Cc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 50 °C
Reaction time: 0.67 h
Yield: 98.1 %

Procedure:
To a suspension of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxamide (280 mg, 0.775 mmol) in N,N-dimethylformamide (3.0 mL) was added thionyl chloride (0.17 mL, 2.33 mmol), and the mixture was stirred at 50° C. for 40 min. The mixture was poured into saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/diisopropyl ether to give the title compound as a colorless crystal (261 mg, 0.760 mmol, 98%).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12]>C(Cl)(Cl)Cl.C(Cl)Cl>[CH3:12][C:11]1([CH3:14])[CH2:10][CH2:9][CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:13]1
Reactant: CC(C)(O)CCCc1ccccc1O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1(C)CCCc2ccccc2O1
Temperature: 80 °C

Procedure:
To a solution of 100 mg (0.52 mmol) 5-(o-hydroxyphenyl)-2-methyl-2-pentanol in 2 ml chloroform is added 25 mg (25 wt %) of p-tosic acid in one portion. The resulting solution is then heated at 80° C. for 2 hours. The reaction mixture is then diluted with methylene chloride and washed with a sat. solution of sodium bicarbonate. The organic layer is dried (MgSO4), filtered and concentrated to obtain 2,2-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin which is used directly in the next step.
Reaction SMILES: [NH:1]1[CH:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3][C:2]1=[O:9].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S(=O)(=O)(O)O.C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH2:10]([O:7][C:6]([CH:5]1[NH:1][C:2](=[O:9])[CH2:3][CH2:4]1)=[O:8])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCO
Reactant: O=C1CCC(C(=O)O)N1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCCCCCCOC(=O)C1CCC(=O)N1
Temperature: 25 °C
Yield: 65.1 %

Procedure:
A 200-ml eggplant-shaped flask equipped with a condenser and a mechanical stirrer was charged with 6.5 g (0.05 mole) of 2-pyrrolidone-5-carboxylic acid, 23.2 g (0.20 mole) of n-heptyl alcohol, a catalytic amount of concentrated sulfuric acid and 40 ml of benzene and the mixture was refluxed for 3.5 hours. The reaction mixture was cooled to room temperature and poured into saturated aqueous NaHCO3, followed by extraction with benzene. Washing, drying, solvent removal and distillation under reduced pressure as performed in the conventional manner gave 7.4 g of yellow 2-pyrrolidone-5-carboxylic acid n-heptyl ester. Boiling point: 186°-188° C./3 mm Hg.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[C:9]=1[F:18])(C)(C)C.FC(F)(F)C(O)=O>>[F:18][C:9]1[C:10]([O:16][CH3:17])=[CH:11][C:12]([O:14][CH3:15])=[CH:13][C:8]=1[NH2:7]
Reactant: COc1cc(NC(=O)OC(C)(C)C)c(F)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N)c(F)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
To 56.6 g (0.21 mol) of (2-fluoro-3,5-dimethoxy-phenyl)-carbamic acid tert-butyl ester, 184 mL of trifluoroacetic acid was added to give a homogeneous solution which was stirred at room temperature for 30 minutes. After 30 minutes, the reaction mixture was concentrated in vacuo. To the residue, a saturated solution of sodium bicarbonate was carefully added to pH 8. The resulting suspension was extracted two times with diethylether. The combined diethylether layers were washed one time with brine, dried over sodium sulfate, filtered and evaporated to give 34.1 g (95.5%) of title compound. MS (APCI) (m+1)/z 172.0.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7](=[N:9][OH:10])[CH3:8].C[O:12][C:13]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.Cl>C1COCC1>[CH2:20]([N:16]1[CH2:17][CH2:18][CH2:19][C@H:15]1[C:13](=[O:12])[CH2:6][C:7](=[N:9][OH:10])[CH3:8])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)[C@@H]1CCCN1Cc1ccccc1
Reactant: CC(C)=NO
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(CC(=O)[C@@H]1CCCN1Cc1ccccc1)=NO
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 12.5 ml BuLi (1.6 M in hexane) was added a solution of 0.73 g acetone oxime in 8 ml THF at 0° C. After 30 minutes a solution of 1.0 g (S)-1-Benzyl-pyrrolidine-2-carboxylic acid methyl ester in 5 ml THF was added dropwise over a period of 20 minutes at this temperature. The resulting suspension was stirred for another 3 h at 0° C. before being cannulated into 21 ml 3 M HCl. The phases were separated; the aqueous phase was brought to pH8 using solid NaHCO3 and extracted with dichloromethane (3×) to give the crude product. Yield: 1.3 g mixture of E/Z isomers.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=2[O:15][CH3:16])[N:5]=[C:4]([NH2:17])[CH:3]=1.[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1.CO.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH:23][C:2]2[CH:3]=[C:4]([NH2:17])[N:5]=[C:6]([C:8]3[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=3[O:15][CH3:16])[N:7]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(Cl)cc1-c1nc(N)cc(Cl)n1
Reactant: Nc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: O
Product: COc1ccc(Cl)cc1-c1nc(N)cc(Nc2ccc(Br)cc2)n1
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
To a stirred suspension of the hydrochloride salt of 6-chloro-2-(5-chloro-2-methoxy-phenyl)-pyrimidin-4-yl-amine (0.020 g, 0.065 mmol) in ethanol (5.0 ml) was added 4-bromoaniline (0.022 g, 0.13 mmol). After heating under reflux for 20 hours, the solvent was evaporated under reduced pressure. The residue was treated with 1.0 M hydrochloric acid (10 ml) and stirred for 30 minutes. Filtration provided a solid which was treated with methanol (10 ml) and stirred while a solution of sodium carbonate in water (1.0 M, 1 ml) was added. After stirring for 1 hour, the solvents were evaporated under reduced pressure. The residue was treated with water (10 ml) and stirred for 15 minutes. Filtration provided the title compound (0.011 g, 42% yield) as a beige powder. 1H NMR (DMSO-d6) δ 3.83 (s, 3H, CH3), 5.74 (s, 1H, Ar), 6.50 (s, 2H, NH2), 7.14 (d, 1H, J=8.9 Hz, Ar), 7.40-7.45 (m, 3H, Ar), 7.55 (d, 1H, J=2.7 Hz), 7.65-7.67 (m, 2H, Ar), 9.16 (s, 1H, NH).