Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([CH3:11])[S:8][C:7]=2[CH:12]=1.B(Br)(Br)Br>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([CH3:11])[S:8][C:7]=2[CH:12]=1
Reactant: COc1ccc2cc(C)sc2c1
Agent: BrB(Br)Br
Product: Cc1cc2ccc(O)cc2s1
Yield: 93.2 %

Procedure:
This material was prepared from 6-methoxy-2-methylbenzo[b]thiophene 1b (2.92 g, 16.4 mmole) by treatment with BBr3 in a manner as previously described for example 1d to give 2.51 g (93%) of a white solid. 1H NMR (DMSO-d6) δ 9.43 (1H, s), 7.47 (1H, d, J=8.5 Hz), 7.14 (1H, d, J=2.2 Hz), 6.92 (1H, s), 6.78 (1H, dd, J=2.2, 8.5 Hz), 2.46 (3H, s). Anal. Calcd. for C9H8OS: C, 65.82; H, 4.91; S, 19.53. Found: C, 65.96; H, 5.11; S, 19.69.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[I:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>ClCCl.N1C=CC=CC=1>[I:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:26][C:25]2[CH:27]=[CH:28][C:22]([I:21])=[CH:23][CH:24]=2)=[O:13])=[CH:24][CH:23]=1
Reactant: Nc1ccc(I)cc1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(I)cc1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(I)cc1
Yield: 36 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 4-iodoaniline (2.54 g, 11.6 mmol) in 20 mL of pyridine. The crude product was recrystallized from water-DMF to yield 1.48 g of the title compound, mp 268-271° C. (dec.).
Reaction SMILES: [C:1]1([C@H:7]([NH2:10])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.C[CH2:13][O:14]CC>CCOCC>[C:1]1([C@H:7]([N:10]=[C:13]=[O:14])[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOCC
Reactant: CC[C@@H](N)c1ccccc1
Agent: Cl
Product: CC[C@@H](N=C=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1(R)-phenylpropylamine (14.33 g, 106 mmol) in Et2O (102 mL) was added a 1.0 M solution of HCl/Et2O (212 mL, 212 mmol). The mixture was stirred for 30 min, then the crude solution was evaporated to dryness on a rotary evaporator. The resulting white hydrochloride salt was suspended in toluene (200 mL), triphosgene was added (11.67 g, 39.3 mmol) and the resulting suspension was stirred at reflux for 3 h at room temperature overnight. The reaction mixture was concentrated and the final volume adjusted to 200 mL with toluene giving a final concentration of 0.53M. The resulting isocyanate solution was used as such. An aliquot (170 mL) was concentrated to give a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)=[N:5][N:6]=1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:55]1([C:61]2[N:66]=[C:65]3[N:67]=[C:68]([N:70]4[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]4)[S:69][C:64]3=[C:63]([C:76](O)=[O:77])[CH:62]=2)[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>CN(C=O)C.O>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:4]1[O:3][C:2]([NH:1][C:76]([C:63]2[CH:62]=[C:61]([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[N:66]=[C:65]3[N:67]=[C:68]([N:70]4[CH2:75][CH2:74][CH2:73][CH2:72][CH2:71]4)[S:69][C:64]=23)=[O:77])=[N:6][N:5]=1
Reactant: Nc1nnc(-c2ccco2)o1
Reactant: O=C(O)c1cc(-c2ccccc2)nc2nc(N3CCCCC3)sc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nnc(-c2ccco2)o1)c1cc(-c2ccccc2)nc2nc(N3CCCCC3)sc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 24 %

Procedure:
2-Amino-5-(2-furyl)-1,3,4-oxadiazole (76 mg, 0.50 mmol), HOAt (68 mg, 0.50 mmol), HATU (190 mg, 0.50 mmol), and N,N-diisopropylethylamine (97 μL, 0.56 mmol) were added to a solution of commercially available 5-phenyl-2-piperidino-7-thiazolo[4,5-b]pyridinecarboxylic acid (85 mg, 0.25 mmol) in DMF (1 mL), followed by stirring overnight at room temperature in an argon atmosphere. To the reaction solution were added 2-amino-5-(2-furyl)-1,3,4-oxadiazole (76 mg, 0.50 mmol), HOAt (68 mg, 0.50 mmol), HATU (190 mg, 0.50 mmol), and N,N-diisopropylethylamine (97 μL, 0.56 mmol), and the mixture was stirred at room temperature for further 4 days. Water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and recrystallized from methanol to obtain the title compound (27 mg, 0.06 mmol) (yield: 240).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:36]([O:38][CH:39]1[CH:44]([CH:45]([CH3:47])[CH3:46])[CH2:43][CH2:42][CH:41]([CH3:48])[CH2:40]1)=[O:37]>CN(C=O)C>[CH:45]([CH:44]1[CH2:43][CH2:42][CH:41]([CH3:48])[CH2:40][CH:39]1[O:38][C:36]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[C:17]([N+:18]([O-:20])=[O:19])=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[N:13]=[CH:14][N:15]=2)[CH2:23][CH2:24]1)=[O:37])([CH3:46])[CH3:47]
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CCC(C(C)C)C(OC(=O)N2CCC(Oc3ncnc(Nc4ccc(S(C)(=O)=O)cc4)c3[N+](=O)[O-])CC2)C1

Procedure:
Compound A23 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (50 μl), menthyl chloroformate (10 mg, 0.046 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 0.81 (d, 3H), 0.92 (d, 6H), 1.06 (m,1H), 1.10 (m, 1H), 1.41 (m, 1H), 1.51 (m, 1H), 1.67 (m,2H), 1.94 (m, 4H), 2.08 (m, 2H), 3.08 (s, 3H), 3.65 (m, 4H), 4.58 (m, 1H), 5.60 (m, 1H), 7.86 (d, 2H), 7.97 (d, 2H), 8.41 (s, 1H), 10.18 (s, 1H). Exact mass calculated for C27H37N5O7S 575.24, found 576.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[CH:12]([NH2:14])=O>>[CH3:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4]([OH:5])=[N:14][CH:12]=[N:1][C:2]=2[N:10]=1
Reactant: Cc1ccc(C(=O)O)c(N)n1
Reactant: NC=O
Product: Cc1ccc2c(O)ncnc2n1
Temperature: 170 °C
Reaction time: 2 h
Yield: 51.8 %

Procedure:
A mixture of 2-Amino-6-methyl-nicotinic acid (1.44 g, 9.46 mmol) and formamide (8.0 g, 178 mmol) was stirred at 170° C. for 2 hours. After cooling, the mixture was quenched with water (4 mL). The precipitate was filtered, washed with water and dried to afford 7-Methyl-pyrido[2,3-d]pyrimidin-4-ol (0.79 g, 51%). 1H NMR (CDCl3, 400 MHz) δ 8.49 (d, J=8.4 Hz, 1H), 8.22 (s, 1H), 7.35 (d, J=8.0 Hz, 1H), 2.75 (s, 3H). MS (APCI+) [M+H]+162.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([NH:26][C:27](=[O:36])[CH2:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[N:16]=2)=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18](=[O:25])[N:17]([NH:26][C:27](=[O:36])[CH2:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)[N:16]=2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Sc2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(Sc2nn(NC(=O)Cc3ccc(Cl)cc3)c(=O)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 49.5 %

Procedure:
The product from Example 103C (23 mg, 0.043 mmol) in CH2Cl2 (4 mL) was treated with TFA (1 mL). The reaction mixture was stirred at room temperature for 20 minutes, concentrated, and the resulting residue was purified by HPLC (conditions from Example 10C) to afford 9.3 mg (50%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 11.56 (s, 1H), 8.31 (dd, J=7.9, 0.9, 1H), 8.12 (d, J=7.8, 1H), 8.06-7.98 (m, 1H), 7.97-7.89 (m, 1H), 7.46-7.36 (m, 2H), 7.34-7.28 (m, 2H), 7.24-7.15 (m, 2H), 6.64-6.56 (m, 2H), 3.63 (s, 2H); MS (APCI+) M/Z 437 (M+H)+.
Reaction SMILES: [C:1]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(=[O:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[BrH:24].[NH+]1C=CC=CC=1.CCOC(C)=O>C(O)C>[Br:24][CH:11]([C:1]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)=[O:10])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: Br
Reactant: CCOC(=O)CC(=O)c1ccc(OC)cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(Br)C(=O)c1ccc(OC)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
To a solution of ethyl p-anisoylacetate (1.00 g, 4.5 mmol) in ethanol (14 mL) at 50° C. was added triethylamine (0.63 mL, 4.5 mmol) followed by pyridinium hydrobromide perbromide (1.44 g, 4.5 mmol) and the resulting mixture was then stirred at 50° C. for 2 hours. The reaction was cooled to room temperature and poured into EtOAc. The organic phase was then washed with saturated sodium bicarbonate solution and 0.5M aqueous HCl, dried over MgSO4 and the solvent removed in vacuo to afford ethyl 2-bromo-3-(4-methoxyphenyl)-3-oxopropanoate (1.209 g, 4.0 mmol, 89%) which was used without further purification. 1H NMR (CDCl3) δ 1.26 (3H, t), 3.89 (3H, s), 4.28 (2H, q), 5.62 (1H, s), 6.96 (2H, d), 7.98 (2H, d). LCMS (2) Rt: 3.06 min; m/z (ES+) 301/303.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[C:9]1[C:15]1[S:31][C:18]2[C:19]3[CH:27]=[CH:26][C:25]([C:28]([OH:30])=O)=[CH:24][C:20]=3[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1.O=S(Cl)[Cl:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](=[O:13])[N:11]([CH3:14])[N:10]=[C:9]1[C:15]1[S:31][C:18]2[C:19]3[CH:27]=[CH:26][C:25]([C:28]([Cl:34])=[O:30])=[CH:24][C:20]=3[O:21][CH2:22][CH2:23][C:17]=2[CH:16]=1
Reactant: Cn1nc(-c2cc3c(s2)-c2ccc(C(=O)O)cc2OCC3)n(-c2ccccc2Cl)c1=O
Reactant: O=S(Cl)Cl
Product: Cn1nc(-c2cc3c(s2)-c2ccc(C(=O)Cl)cc2OCC3)n(-c2ccccc2Cl)c1=O

Procedure:
A solution of 2-(4-(2-chlorophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylic acid (300 mg, 0.66 mmol) in 10 mL of SOCl2 was heated at 80° C. for 3 h. Concentration gave the crude acid chloride, 2-(4-(2-chlorophenyl)-1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonyl chloride which was slowly added (ca. 312 mg, ca. 0.66 mmol in 10 mL of THF), to a solution of NH3 (saturated solution in THF) and pyridine (0.5 mL) in 5 mL of THF at 0° C. The mixture was stirred at room temperature overnight, Diluted with water, the solids were washed with water and dried in vacuum. The crude product was purified by HPLC separation, gave 160.1 mg of 363, isolated yield: 54%. ESI-MS: 453. 1H NMR (DMSO-d6, 400 MHz): δ 7.98-7.41 (m, 9H, ArH, NH2), 6.49 (s, 1H, ═CH), 4.20 (s, 2H, CH2), 3.49 (s, 3H, CH3), 2.99 (s, 2H, CH2).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N+:12]=2[O-])[CH:6]=[CH:7][CH:8]=1.COS(OC)(=O)=O.[C-:27]#[N:28].[Na+]>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]2[N:12]=[C:13]([C:27]#[N:28])[CH:14]=[CH:15][CH:16]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: [O-][n+]1ccccc1C=Cc1cccc(C(F)(F)F)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Product: N#Cc1cccc(C=Cc2cccc(C(F)(F)F)c2)n1

Procedure:
Following the general method described in example 2b, 2-[2-(3-trifluoromethyl-phenyl)-vinyl]-pyridine 1-oxide was reacted first with dimethylsulfate and then with NaCN. After extraction and chromatography (SiO2 with CH2Cl2/MeOH=97/3) the title compound was obtained as a yellow oil and directly used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[C:12]1[O:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1.BrC1(OC=CC1)C=O.[S:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:9])([F:10])[F:11])=[CH:4][C:3]=1[C:12]1[O:16][C:15](/[CH:17]=[C:31]2/[C:30](=[O:32])[NH:29][C:28](=[O:33])[S:27]/2)=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(-c2cc(C(F)(F)F)ccc2Cl)o1
Reactant: O=C1CSC(=O)N1
Agent: O=CC1(Br)CC=CO1
Product: O=C1NC(=O)/C(=C/c2ccc(-c3cc(C(F)(F)F)ccc3Cl)o2)S1

Procedure:
The titled compound was prepared by the condensation of 5-(2-chloro-5-trifluoromethylphenyl)furan-2-aldehyde (1g) [prepared by the condensation of (2-chloro-5-trifluoromethyl)phenyl boronic acid with 2-bromo-furfural] with 2,4-thiazolidinedione (0.52 g) under the reaction condition described in Step B of EXAMPLE 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[O:17]=[C:18]1[N:26]2[CH:21]([CH2:22][C:23](=O)[CH2:24][CH2:25]2)[CH2:20][CH2:19]1.C([Sn](Cl)(Cl)CCCC)CCC.C1([SiH3])C=CC=CC=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:23]1[CH2:22][CH:21]2[N:26]([C:18](=[O:17])[CH2:19][CH2:20]2)[CH2:25][CH2:24]1)=[O:4]
Reactant: O=C1CCN2C(=O)CCC2C1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1sc(C2=CCCCC2)cc1NC1CCN2C(=O)CCC2C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.6 %

Procedure:
To a solution of 5-cyclohex-1-enyl-3-aminothiophene-2-carboxylic acid methyl ester (689 mg, 2.90 mmol) and 3-oxo-octahydro-indolizin-7-one (750 mg, 4.90 mmol; prepared as described in Tetrahedron, 1975, 1437) in 3 mL of dry THF was added dibutyltin dichloride (88 mg, 0.29 mmol), and the mixture was stirred for 10 min at room temperature under nitrogen. Then phenylsilane (394 μL, 3.19 mmol) was added, and the mixture was stirred overnight at room temperature. Solvent was evaporated under reduced pressure, and the residue was purified by column chromatography on silica gel using gradient 30-100% EtOAc in hexane to afford 973 mg (90%) of 5-cyclohex-1-enyl-3-[(3-oxo-octahydro-indolizin-7-yl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC>ClCCCl>[C:12]1([NH:11][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccccc1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1ccncc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 4-necked RBF equipped with an overhead stirrer, J-Kem internal temperature probe, a reflux condenser and an addition funnel was placed isonicotinoyl chloride-hydrochloride (50 g, 0.28 mol). To this solid was added 500 ml of 1,2-dichloroethane and the slurry cooled to 0° C. using an ice/water bath. To the addition funnel was added a mixture of the aniline (31.4 g, 0.34 mol) and Et3N (59.5 g, 0.59 mol) in 50 ml of 1,2-dichloroethane. This mixture was slowly added to the slurry over 25 min. A slight exotherm was observed from 2.4° C. to 15° C. after the addition of the first 10 ml. The reaction mixture was observed to cool down slowly. The reaction mixture turned yellow and became heterogeneous. After 30 min., the ice bath was removed and the reaction heated to reflux for 1.5 h. Deionized water, 100 ml, was added and an off-white precipitate formed. The precipitate was collected by filtering through paper on a Buchner funnel and placed in a drying oven (60° C.) overnight to give 45 g (81% th) of an off-white crystalline solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=5[C:31]5[NH:35][C:34](=[O:36])[O:33][N:32]=5)=[CH:21][C:20]=4[F:37])=[C:14]([CH2:38][CH2:39][CH3:40])[N:13]4[N:41]=[C:42]([CH3:44])[N:43]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[F:37][C:20]1[CH:21]=[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[NH:35][C:34](=[O:36])[O:33][N:32]=2)[CH:23]=[CH:24][C:19]=1[CH2:18][C:15]1[C:16](=[O:17])[N:11]([CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[C:12]2[N:13]([N:41]=[C:42]([CH3:44])[N:43]=2)[C:14]=1[CH2:38][CH2:39][CH3:40]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2F)c(=O)n(C2CCC(=O)CC2)c2nc(C)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.7 %

Procedure:
A mixture of 4-(1,4-dioxaspiro[4.5]dec-8-yl)-6-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.25 g), 6N hydrochloric acid (2 mL) and tetrahydrofuran (10 mL) was stirred at room temperature for 2 hr. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was adjusted to pH 4 with 1 N hydrochloric acid and extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate and hexane to give the title compound as colorless crystals (0.18 g, 74%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH2:8][C:7](=[O:14])[CH2:6][CH2:5]2.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:44][N:45](C=O)C.O>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[C-]#N.[Zn+2].[C-]#N>[CH3:13][O:12][C:11]1[C:2]([C:44]#[N:45])=[CH:3][C:4]2[CH2:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]=2[CH:10]=1
Reactant: COc1cc2c(cc1Br)CCC(=O)C2
Reactant: CN(C)C=O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1C#N)CCC(=O)C2
Temperature: 170 °C

Procedure:
To a microwave tube with a stir bar and charged with 6-Bromo-7-methoxy-3,4-dihydronaphthalen-2(1H)-one (25 mg, 0.098 mmol) was added Pd2(dba)3 (2.69 mg, 2.94 μmol), S-Phos (2.82 mg, 6.86 μmol), zinc cyanide (17 mg, 0.15 mmol), DMF (1.5 ml) and water (0.015 ml). The tube was sealed and heated to 170° C. for 5 minutes. The reaction was then diluted with EtOAc, washed with NH4Cl and brine, and the resulting product was purified by MPLC.
Reaction SMILES: NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1.C(OC(=O)[NH:36][C:37]1([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[C:60](=[O:61])[C:59]4[CH:58]=[C:57]5[C:52]([O:53][CH2:54][CH2:55][O:56]5)=[CH:51][C:50]=4[O:49][C:48]=3[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:43][CH:42]=2)[CH2:40][CH2:39][CH2:38]1)(C)(C)C>>[NH2:36][C:37]1([C:41]2[CH:42]=[CH:43][C:44]([C:47]3[C:60](=[O:61])[C:59]4[CH:58]=[C:57]5[C:52]([O:53][CH2:54][CH2:55][O:56]5)=[CH:51][C:50]=4[O:49][C:48]=3[C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)=[CH:45][CH:46]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc5c(cc4c3=O)OCCO5)cc2)CCC1
Agent: NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4cc5c(cc4c3=O)OCCO5)cc2)CCC1
Yield: 51.2 %

Procedure:
Following the procedure used to prepare 3-[4-(1-amino-cyclobutyl)-phenyl]-6-fluoro-2-phenyl-chromen-4-one, {1-[4-(8-oxo-6-phenyl-2,3-dihydro-8H-1,4,5-trioxa-anthracen-7-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (65 mg, 0.124 mmol) was reacted to give the title compound (27 mg, 51%). LCMS (Method E): RT=3.62 min, [M+H]+=426. 1H NMR (400 MHz, DMSO-d6): δ 7.38 (s, 1H), 7.36-7.23 (m, 7H), 7.19 (s, 1H), 7.04 (d, J=8.6 Hz, 2H), 4.39-4.34 (m, 2H), 4.33-4.28 (m, 2H), 2.36-2.13 (m, 4H), 2.06-1.87 (m, 3H), 1.64-1.53 (m, 1H).
Reaction SMILES: [NH2:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[C:10]([F:14])[C:11](Cl)=[N:12][C:5]=2[N:4]([CH:15]2[CH2:17][CH2:16]2)[C:3]1=[O:18].[C:19]([O:23][C:24](=[O:31])[NH:25][C@H:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)([CH3:22])([CH3:21])[CH3:20].C(N(CC)C(C)C)(C)C.C(#N)C>O>[C:19]([O:23][C:24](=[O:31])[NH:25][CH:26]1[CH2:30][CH2:29][N:28]([C:11]2[C:10]([F:14])=[CH:9][C:6]3[C:7](=[O:8])[N:2]([NH2:1])[C:3](=[O:18])[N:4]([CH:15]4[CH2:17][CH2:16]4)[C:5]=3[N:12]=2)[CH2:27]1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: Nn1c(=O)c2cc(F)c(Cl)nc2n(C2CC2)c1=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN(c2nc3c(cc2F)c(=O)n(N)c(=O)n3C2CC2)C1
Temperature: 0 °C
Yield: 83.2 %

Procedure:
A solution of 0.11 g (0.4 mmol) of 3-amino-7-chloro-1-cyclopropyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example 24b), 0.105 g (0.56 mmol) of (S)-3-pyrrolidinylcarbamic acid tert-butyl ester (J. Med. Chem., 1992; 35:1764), 1.2 mL of N,N-diisopropylethylamine and 3 mL of acetonitrile is heated at 50° C. for 18 hours. The reaction mixture is diluted with 9 mL of water, cooled to 0° C. and the solid is removed by filtration, washed with 50% aqueous acetonitrile and dried in vacuo to give 0.14 g of the title compound, mp 108–110° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[CH3:18]>CC(C)=O>[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:6]2[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:23][CH:22]=1)[CH3:18]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(Oc2nc(Cl)ncc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of Compound 1a (2.0 g; 10.31 mmol) and 0.5N NaHCO3 (20 mL; 10 mmol) in acetone (60 mL) was added a solution of 4-hydroxy-benzoic acid ethyl ester (1.71 g; 10.29 mmol) in acetone (20 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The resultant residue was extracted with EtOAc (2×20 mL). The organic layer was washed with brine and dried over MgSO4 and concentrated. The crude product was purified by normal phase chromatography (SiO2) to give Compound 16a. 1H NMR (300 MHz, CDCl3): δ 9.20 (s, 1H), 8.20 (d, 2H), 7.25 (d, 2H), 4.45 (q, 2H), 1.4 (t, 3H); MS: m/z 324.1 (M+H)+.