Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[NH:17][C:16](=[O:18])[C@@H:15]([CH2:19][CH:20]=[CH2:21])[CH2:14]2)=[CH:9][C:8]=1[CH3:22]>C(Cl)Cl>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[NH:17][C:16](=[O:18])[C@@H:15]([CH2:19][CH:20]=[CH2:21])[CH2:14]2)=[CH:9][C:8]=1[CH3:22]
Reactant: C=CC[C@H]1C[C@H](c2ccc(OC)c(C)c2)NC1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=CC[C@H]1C[C@H](c2ccc(O)c(C)c2)NC1=O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
Boron tribromide (10.1 mL, 1.0 M in CH2Cl2, 10.1 mmol) was added dropwise to a solution of trans-5-(4-methoxy-3-methyl-phenyl)-3-(2-propenyl)-2-pyrrolidinone (1.13 g, 4.61 mmol) in 10.0 mL of CH2Cl2 at −78° C. The mixture was stirred at −78° C. for 30 min and then at 0° C. for 1 hr. The reaction was quenched by 20 mL of H2O. The mixture was poured into a mixture of ethyl ether and EtOAc (1:1, 50.0 mL) and extracted with 2.0 N of NaOH (3×30 mL). Aqueous layers were combined and acidified using 5.0 N HCl and extracted with EtOAc (3×50 mL). Organic layers were combined, dried over MgSO4, and concentrated to give 940 mg (88%) of the crude title compound as a light brown solid, which was used for next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[C:9](/[P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])\[C:10]([O:12][CH3:13])=[O:11].[CH:22]#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[C:22]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1/[CH:8]=[C:9](/[P:14]([O:19][CH2:20][CH3:21])([O:16][CH2:17][CH3:18])=[O:15])\[C:10]([O:12][CH3:13])=[O:11])#[C:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: C#CCCCCCCCCCCC
Reactant: CCOP(=O)(OCC)/C(=C/c1ccccc1Br)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC#Cc1ccccc1/C=C(\C(=O)OC)P(=O)(OCC)OCC
Temperature: 25 °C
Yield: 29.2 %

Procedure:
Methyl 3-(2-bromophenyl)-2-E-(diethoxyphosphinyl)-2-propenoate (11.31 g, 29.99 mmol) prepared according to Example 16 was mixed with 1-tridecyne (9.50 g, 52.68 mmol) and triphenylphosphine (0.214 g, 0.82 mmol) in a 500 ml four-neck round bottom flask equipped with a magnetic stir bar, condenser topped with an argon inlet, and an internal thermometer. Dry triethylamine (156 ml) was added, and the flask was closed. The system was inerted and a bubbler was connected to the argon line. Palladium acetate (0.0733 g, 0.33 mmol) was added, and the reaction mixture was heated in an oil bath (T=100° to 105° C.). The reaction was refluxed for 50 hours. At the end of this time, the reaction mixture was cooled to room temperature and was filtered. The white precipitate was washed with triethyl amine (100 ml). The filtrates were stripped down to a dark oil. This oil was extracted three times with acetonitrile (50 ml). The combined acetonitrile extracts were stripped down to an orange oil which was chromatographed on silica eluting with petroleum ether-dichloromethane (68:32) increasing to pure dichloromethane, then with hexanes-ethyl acetate (1:1) increasing to pure ethyl acetate. Fractions containing a spot with Rf =0.20 on silica developed with hexane-dichloromethane (68:32) were combined and stripped. Reverse phase chromatography on C18 silica, eluting with 10% water in methanol, was done. Fractions were combined which showed the above Rf. These fractions were rechromatographed on silica eluting with hexanes-ethyl acetate (66:34) and progressing to hexanes-ethyl acetate (60:40). Additional rechromatography of impure fractions gave 4.18 g (8.77 mmol, 29% yield) of pure product as a pale yellow oil. 1H NMR (CDCl3) ∂0.88 (t, J=6.7 Hz, 3H), 1.17 to 1.50 (several m, 22H), 1.63 quintet, J=7.6 Hz, 2H), 2.43 (t, J=7.2 Hz, 2H), 3.72 (s, 3H), 4.21 (m, 4H), 7.19 to 7.36 (several m, 3H), 7.44 (m, J=7.6 Hz, 1H), 8.05 (d, J=23.8 Hz); EI mass spectrum m/z 476 (M+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:11]3[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:23]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[S:28][C:27]=2[C:26](B(O)O)=[CH:25][CH:24]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)C.C1(C)C=CC=CC=1>[CH:23]1[C:31]2[C:30]3[CH:32]=[CH:33][CH:34]=[CH:35][C:29]=3[S:28][C:27]=2[C:26]([C:6]2[CH:5]=[C:4]([C:8]3[N:12]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:11]4[CH:19]=[CH:20][CH:21]=[CH:22][C:10]=4[N:9]=3)[CH:3]=[CH:2][CH:7]=2)=[CH:25][CH:24]=1
Reactant: OB(O)c1cccc2c1sc1ccccc12
Reactant: Brc1cccc(-c2nc3ccccc3n2-c2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: CCO
Product: c1ccc(-n2c(-c3cccc(-c4cccc5c4sc4ccccc45)c3)nc3ccccc32)cc1
Yield: 53.6 %

Procedure:
Into a 50-mL three-neck flask were put 1.2 g (3.3 mmol) of 2-(3-bromophenyl)-1-phenyl-1H-benzimidazole, 0.8 g (3.3 mmol) of dibenzothiophen-4-boronic acid, and 50 mg (0.2 mmol) of tri(ortho-tolyl)phosphine. The air in the flask was replaced with nitrogen. To this mixture were added 3.3 mL of a 2.0 mmol/L aqueous solution of potassium carbonate, 12 mL of toluene, and 4 mL of ethanol. Under reduced pressure, this mixture was stirred to be degassed. Then, 7.4 mg (33 μmol) of palladium(II) acetate was added to this mixture, and the mixture was stirred at 80° C. for 6 hours under a nitrogen stream. After a predetermined time, the aqueous layer of the obtained mixture was subjected to extraction with toluene. The solution of the obtained extract combined with the organic layer was washed with saturated brine, and then the organic layer was dried over magnesium sulfate. This mixture was separated by gravity filtration, and the filtrate was concentrated to give an oily substance. This oily substance was purified by silica gel column chromatography. The silica gel column chromatography was carried out using toluene as a developing solvent. The obtained fraction was concentrated to give an oily substance. This oily substance was purified by high performance liquid chromatography. The high performance liquid chromatography was performed using chloroform as a developing solvent. The obtained fraction was concentrated to give an oily substance. This oily substance was recrystallized from a mixed solvent of toluene and hexane, so that the substance which was the object of the synthesis was obtained as 0.8 g of a pale yellow powder in 51% yield. The synthesis scheme is illustrated in the following formula.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]([O-])=[O:20])[S:18][C:11]=12.[Li+]>>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:19]([C:17]2[S:18][C:11]3[C:12](=[N:13][CH:14]=[CH:15][C:10]=3[Cl:9])[CH:16]=2)=[O:20])[CH:4]=1
Reactant: NCc1cccnc1
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Agent: [Li+]
Product: O=C(NCc1cccnc1)c1cc2nccc(Cl)c2s1

Procedure:
The title compound was prepared from 3-aminomethylpyridine and lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate by a procedure analogous to Example 1B. MS: n.d.; HPLC Rf: n.d.; HPLC purity: n.d.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12](SC)=[N:13][C:14]([S:18][CH3:19])=[N:15]3)=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:22])[CH2:3]1.[CH3:23][NH2:24]>CO>[CH3:1][CH:2]1[C:7]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([NH:24][CH3:23])=[N:13][C:14]([S:18][CH3:19])=[N:15]3)=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:22])[CH2:3]1
Reactant: CSc1nc(SC)c2ccc(C3=NNC(=O)CC3C)cc2n1
Reactant: CN
Solvent: CO
Product: CNc1nc(SC)nc2cc(C3=NNC(=O)CC3C)ccc12
Temperature: 60 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
In 50 ml of 40% methylamine solution in methanol was suspended 0.40 g of Compound 59 obtained in Example 61. The suspension was stirred at 60° C. for 3 hours and then concentrated. Thereafter, water was added to the residue, and the crystals precipitated were collected by filtration and dried to give 0.34 g (89%) of 4,5-dihydro-5-methyl-6-(4-methylamino-2-methylthioquinazolin-7-yl)-3(2H)-pyridazinone (Compound 60).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[N:9]1.C(N(CC)CC)C.[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.O>O1CCCC1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:39]([CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:40])[CH2:22][CH2:21]2)=[O:19])=[N:9]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1noc2ccccc12)N1CCN(C(=O)C2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) and triethylamine (0.309 ml, 2.22 mmol) in tetrahydrofuran (4 ml) was added cyclohexanecarbonyl chloride (0.111 ml, 0.833 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 160 mg (80.8%) of the desired product as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: NCCCCO
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCCO
Yield: 89.1 %

Procedure:
A modification of the method described in Part E of Example 1 was used to treat 7-bromo-4-chloro-3-nitroquinoline (20.0 g, 69.6 mmol) with 4-amino-1-butanol (6.9 mL, 76.5 mmol). The addition of 4-amino-1-butanol was carried out at ambient temperature. The product, 4-(7-bromo-3-nitroquinolin-4-ylamino)butan-1-ol (21.1 g) was isolated as a yellow solid and used without purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O:22][CH3:23])[CH:16]=3)[CH2:11][C@H:10]2[CH3:24])[CH:5]=[CH:4][C:3]=1[N:25]1[C@@H:29]([CH2:30][C:31]([O:33]C)=[O:32])[C@H:28]([CH3:35])[C:27]([C:36]([F:39])([F:38])[F:37])=[N:26]1.[OH-].[Li+]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[C:6]([O:8][C@@H:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O:22][CH3:23])[CH:16]=3)[CH2:11][C@H:10]2[CH3:24])[CH:5]=[CH:4][C:3]=1[N:25]1[C@@H:29]([CH2:30][C:31]([OH:33])=[O:32])[C@H:28]([CH3:35])[C:27]([C:36]([F:37])([F:39])[F:38])=[N:26]1
Reactant: COC(=O)C[C@H]1[C@H](C)C(C(F)(F)F)=NN1c1ccc(O[C@@H]2CCN(c3cc(OC)ncc3Cl)C[C@H]2C)cc1Br
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N2CC[C@@H](Oc3ccc(N4N=C(C(F)(F)F)[C@@H](C)[C@@H]4CC(=O)O)c(Br)c3)[C@H](C)C2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 13.5 h
Yield: 94.4 %

Procedure:
To a stirred solution of methyl 2-((4S,5S)-1-(2-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (6.5 mg, 10.25 μmol) in THF (0.5 mL) and water (0.04 mL) at rt was added 1.0M aqueous lithium hydroxide (0.04 mL, 0.040 mmol). The mixture was stirred at rt for 13.5 h and then partially evaporated to remove most of the THF. The remaining solution was partitioned between water (40 mL) and Hex (15 mL). The aqueous layer was acidified to pH 2 by dropwise addition of 1M HCl, and then extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was dried under vacuum to afford 2-((4S,5S)-1-(2-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (6 mg, 89% yield) as a white solid: LC-MS [M+H] 619, 621. 1H NMR (400 MHz, CD2Cl2) δ 7.96 (s, 1H), 7.21 (d, J=8.8 Hz, 1H), 7.19 (d, J=8.8 Hz, 1H), 6.91 (dd, J=8.8, 2.8 Hz, 1H), 6.29 (s, 1H), 4.63 (m, 1H), 3.99 (dt, J=4.1, 8.8 Hz, 1H), 3.86 (s, 3H), 3.52 (m, 2H), 3.27 (m, 1H), 2.89 (m, 1H), 2.66 (dd, J=12.2, 9.3 Hz, 1H), 2.41 (m, 2H), 2.18 (m, 2H), 1.79 (m, 1H), 1.41 (d, J=7.1 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H). Analytical HPLC (Zorbax method, 0% Solvent B start): RT=8.69 min, HI: 97%. hGPR40 EC50=844 nM.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[N:7]([CH3:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:12][N:7]1[C:6](=[O:13])[C:5]2[C:10](=[CH:11][C:2](/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:3][CH:4]=2)[N:9]=[CH:8]1
Reactant: Cn1cnc2cc(Br)ccc2c1=O
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cnc2cc(/C=C/c3ccccc3)ccc2c1=O
Temperature: 25 °C
Yield: 33.6 %

Procedure:
A solution of 7-bromo-3-methylquinazolin-4(3H)-one (100 mg, 0.42 mmol), styrene (109 mg, 1.05 mmol), Cs2CO3 (163.8 mg, 0.5 mmol), Bu4NBr (135 mg, 0.42 mmol), tri(o-tolyl)phosphine (128 mg, 0.42 mmol), and Pd(OAc)2 in DMF (5 mL) was stirred at 100° C. for 3 hours. After it was cooled to room temperature, the mixture was diluted with H2O (30 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the crude product was purified by column chromatography to give the desired product (37 mg). MS (ESI): 263 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 8.37 (s, 1H), 8.15-8.12 (d, J=8.70 Hz, 1H), 7.85-7.82 (m, 2H), 7.69-7.67 (d, J=7.26 Hz, 2H), 7.57-7.30 (m, 5H), 3.49 (s, 3H).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19]3[NH:23][N:22]=[N:21][N:20]=3)=[CH:13][CH:12]=2)[C:8]([S:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=2)=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[OH:41]O>C(O)(=O)C>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([O:17][CH:18]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:19]3[NH:20][N:21]=[N:22][N:23]=3)=[CH:15][CH:16]=2)[C:8]([S:30]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=2)=[O:41])=[N:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nnc(SCc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(c2ccccc2)c2nnn[nH]2)cc1
Reactant: OO
Solvent: CC(=O)O
Product: CCCCc1nnc(S(=O)Cc2ccc([N+](=O)[O-])cc2)n1Cc1ccc(OC(c2ccccc2)c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
To a stirred solution of 3-Butyl-4-[[4-[1-phenyl-1-(tetrazol-5-yl)methoxy]phenyl]methyl]-5-(4-nitrobenzylthio)-4H-1,2,4-triazole (from Example 3, Step C) in glacial acetic acid is added gradually an equal volume of 30% hydrogen peroxide (aqueous). The resulting solution is stirred at room temperature in a stoppered flask for about 15-20 hours, until TLC and/or NMR (from work-up of an aliquot) indicates complete reaction. The reaction mixture is then partitioned between ethyl acetate and dilute HCl. The ethyl acetate phase is dried (MgSO4), filtered, and concentrated in vacuo. The residue is triturated with ether to give the title compound as a solid, which is collected on a filter and washed further with ether.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C[N:18](C)C=O>>[NH2:18][C:2]1[C:3]2[N:4]([C:12]([CH2:15][CH3:16])=[N:13][N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCc1nnc2c(Cl)nc3ccccc3n12
Reactant: CN(C)C=O
Product: CCc1nnc2c(N)nc3ccccc3n12
Temperature: 0 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
Ammonia gas was bubbled through a solution of 1.2 g. (0.005 mole) of 4-chloro-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline (the product of Example 4) in N,N-dimethylformamide (20 ml.) at 0° C. for about 2 minutes. The solution was stirred at 0° C. for 30 minutes and at room temperature for one hour. The reaction mixture was then poured over ice and stirred for 20 minutes. The precipitate which formed was removed by filtration, washed with water and air dried. Recrystallization from ethanol afforded 220 mg. (22% yield) of pure 4-amino-1-ethyl-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. 284°-8° C. Mass spectrum: m/e, 213 (P).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)=O.[CH:15]([NH2:17])=[S:16].C(N(CC)CC)C>O1CCOCC1>[S:16]1[CH:2]=[C:3]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)[N:17]=[CH:15]1
Reactant: O=C1Cc2cc(C(=O)CCl)ccc2N1
Reactant: NC=S
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(-c3cscn3)ccc2N1
Temperature: 110 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
A suspension of 5-(chloroacetyl)-1,3-dihydro-2H-indol-2-one (630 mg, 3 mmol), thioformamide (30 mL, 30 mmol; described in: J. Med. Chem. 1995, 858-868) and triethylamine (0.42 mL, 3 mmol) in dioxane was heated at 110° C. for 3 h. Additional thioformamide (10 mL, 10 mmol) was added and the reaction was stirred at 110° C. for 2 h. This batch was combined with an new batch starting from 230 mg of 5-(chloroacetyl)-1,3-dihydro-2H-indol-2-one and the combined reaction mixtures was concentrated to approximately 10 mL and an aqueous saturated sodium hydrogencarbonate solution (50 mL) was added and the solution was extracted with ethyl acetate. The combined organic layers were dried (Na2SO4) and evaporated in vacuo. The crude product was purified on a silica gel column using heptane/ethyl acetate, (1:2), as the eluent to give 400 mg (35% yield) of the title compound: 1H NMR (DMSO-d6, 300 MHz) δ 10.47 (s, 1 H), 9.15 (s, 1 H), 7.97 (s, 1 H), 7.83 (br s, 2 H), 6.87 (d, J=8 Hz, 1 H), 3.54 (s, 2 H); MS (ES) m/z 217 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:14][NH:13][CH2:12]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[N:20][CH:19]=[C:18](Cl)[N:17]=1.CCN(C(C)C)C(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]2([CH2:12][N:13]([C:18]3[CH:19]=[N:20][CH:21]=[C:16]([Cl:15])[N:17]=3)[CH2:14]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC2(CNC2)C1
Reactant: Clc1cncc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2(C1)CN(c1cncc(Cl)n1)C2

Procedure:
In analogy to the procedure described for the preparation of intermediate A-20, 2,6-diaza-spiro[3.3]heptane-2-carboxylic acid tert-butyl ester was reacted with 2,6-dichloropyrazine in presence of Hunig's base to give the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3]P(=O)(OC)OC.[H-].[Na+].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH:31]=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C1COCC1.CCOCC>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH:31]=[CH:3][C:2](=[O:1])[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: COP(=O)(CC(=O)c1cccnc1)OC
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C=CC(=O)c2cccnc2)CC1
Temperature: 45 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
A solution of dimethyl (2-oxo-2-(3-pyridyl)ethyl)phosphonate (150 mg, 0.65 mmol, from Procedure 38, Step A) in THF (1.8 mL) was added to a stirred suspension of sodium hydride (60% oil dispersion, 15 mg of sodium hydride, 0.63 mmol) in THF (3.0 mL). The resulting suspension was warmed in a 45° C. oil bath for 30 min. After the mixture had cooled to rt, 1-(t-butoxycarbonyl)-4-piperidinecarboxaldehyde (112 mg, 0.53 mmol) was added in THF (1.5 mL). After stirring overnight at rt, the mixture was diluted with ether (20 mL) and washed with 2.5 N NaOH (20 mL) followed by saturated aq. brine (20 ML). The aq. layers were extracted in succession with ether (20 mL), and the combined organic layers were dried (sodium sulfate), decanted, and evaporated. Purification by flash column chromatography on silica gel, eluting with 80:20 v/v to 60:40 v/v hexanes/ethyl acetate, gave 135 mg of the title compound (trans isomer) as a yellow syrup. For the title compound:
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@@:7]([C:16]([F:19])([F:18])[F:17])([OH:15])[C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32].O>CN(C)C=O>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@:7]([OH:15])([C:16]([F:18])([F:19])[F:17])[C:6]=2[CH:5]=[C:4]([O:20][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:3]=1
Reactant: CCOC(=O)CCCBr
Reactant: Oc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 25 °C
Reaction time: 7 h

Procedure:
(9R)-4-Chloro-9-(trifluoromethyl)-9H-fluorene-2,9-diol (200 mg) obtained in step 10 of example 1 was dissolved in N,N-dimethylformamide (2 ml), potassium carbonate (185 mg) and ethyl 4-bromobutyrate (105 μl) were added, and the mixture was stirred at room temperature for 7 hr. To the reaction mixture was added water, and the mixture was extracted twice with ethyl acetate. The obtained organic layer was washed successively with water (twice) and saturated brine. The obtained organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated. The obtained residue was purified by silica gel column chromatography (a mixture of hexane and ethyl acetate was used as an elution solvent, first eluted with a mixture at a mixing ratio 5:1 (hexane:ethyl acetate), then successively with a mixture at a mixing ratio 3:1, and further with a mixture at a mixing ratio 2:1) to give the title compound (197 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=3)=[O:24])[CH2:19][CH2:18]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=1.[H-].[Na+].[CH3:35]I>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([N:25]([CH3:35])[C:26]3[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=3)=[O:24])[CH2:19][CH2:18]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)[S:8][C:6]=2[N:7]=1
Reactant: CI
Reactant: Cc1ccc(NC(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(N(C)C(=O)N2CCN(c3nc(N)nc4sc(-c5cccnc5)nc34)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
To a suspension of 4-(5-amino-2-(pyridin-3-yl)thiazolo[5,4-d]pyrimidin-7-yl)-N-p-tolylpiperazine-1-carboxamide (90 mg, 0.2 mmol) in DMF (5 ml) was added NaH (60%, 12 mg, 0.31 mmol). The resulting mixture was stirred at room temperature for 10 minutes. Then, methyl iodide (0.3 mmol) was added to the mixture. After stirring at room temperature for 30 minutes, the solvents were evaporated in vacuo and the crude residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1/30), yielding the pure title compound as yellowish solid (40 mg, 43%).