Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7](Cl)=[N:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19].[CH3:21][O-:22].[Na+].CO>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:22][CH3:21])=[N:6][C:5]=1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[F:19]
Reactant: C[O-]
Reactant: COC(=O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(OC)nc1Nc1ccc(Br)cc1F
Temperature: 62.5 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
To a mixture of 2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid methyl ester (2.00 g, 5.56 mmol) and sodium methoxide (0.791 g, 13.9 mmol) was added MeOH (50 mL) to give a slurry that was stirred at 60-65° C. for 16 hours under N2. Additional sodium methoxide (0.791 g, 13.9 mmol) was added and the reaction mixture was allowed to stir another 3 days at 60-65° C. The reaction mixture was cooled to room temperature and glacial acetic acid was added dropwise until the pH was 7. The resulting suspension was filtered and washed with H2O to yield a pink solid that was collected and dried under vacuum to yield 1.74 g (88%) pure desired product.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][N:36]2[C:44](=[O:45])[C:43]3C(=CC=CC=3)C2=O)=[CH:4][N:3]=1.NN.[CH2:49]([OH:51])[CH3:50]>>[C:44]([OH:45])(=[O:51])[CH3:43].[C:49]([OH:19])(=[O:51])[CH3:50].[C:44]([OH:45])(=[O:51])[CH3:43].[C:44]([OH:45])(=[O:51])[CH3:43].[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5](/[CH:32]=[CH:33]/[CH2:34][CH2:35][NH2:36])=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(/C=C/CCN4C(=O)c5ccccc5C4=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: CCO
Agent: NN
Product: CC(=O)O
Product: COc1cc(-c2csc3c(/C=C/CCN)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 1 %

Procedure:
A suspension of N-(4-{4-amino-7-[(1E)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)but-1-enyl]thieno[3,2-c]pyridin-3-yl}-2-methoxyphenyl)-1-methyl-1H-indole-2-carboxamide (0.024 g, 0.038 mmol) in ethanol (5 mL) was treated with anhydrous hydrazine (0.01 g, 0.30 mmol). The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed and the crude material was purified by preparative HPLC chromatography to give 0.001 g (1%) of the title compound as a tetraacetate salt. 1H NMR (DMSO-d6, 400 MHz) δ 9.55 (s, 1H), 8.05 (d, 1H), 8.03 (s, 1H), 7.70 (d, 1H), 7.60 (m, 2H), 7.35 (m, 2H), 7.20 (m, 1H), 7.15 (m, 1H), 7.10 (m, 1H), 6.60 (d, 1H), 6.30–6.20 (m, 1H), 5.60 (s, 3H), 4.05 (s, 3H), 3.95 (s, 3H), 2.75 (t, 2H), 2.40 (q, 2H); LCMS (conditions a) Rt 2.38 min (95%), M+ 498.3.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12](O)=[O:13].Cl.[CH3:22][NH:23][O:24][CH3:25].CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:25][O:24][N:23]([CH3:22])[C:12](=[O:13])[C:11]1[CH:15]=[CH:16][C:17]([N+:18]([O-:20])=[O:19])=[C:9]([CH3:8])[CH:10]=1
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc([N+](=O)[O-])c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (7.6 mL, 54.65 mmol) was added slowly to a mixture of 3-methyl-4-nitrobenzoic acid (5 g, 27.33 mmol), N,O-dimethylhydroxylamine hydrochloride (2.99 g, 30.06 mmol), and EDCI (6.28 g, 32.79 mmol) in DCM (30 mL). The mixture was stirred at room temperature overnight, quenched with saturated aqueous NaHCO3 and stirred at room temperature for 30 minutes. Water (50 mL) was added followed by additional DCM. The mixture was stirred for 10 minutes and layers were separated. The aqueous layer was again extracted with DCM. The combined organic layer was dried over Na2SO4, then filtered. The solvent was removed and the residual oil chromatographed (DCM/EtOAc) to provide the title compound as a white solid.
Reaction SMILES: Br[C:2]1[C:22]([F:23])=[CH:21][C:5]2[O:6][CH2:7][C:8]([F:20])([F:19])[C:9]3[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:10]=3[C:4]=2[CH:3]=1.[C:24]([C@:26]1([OH:33])[CH2:30][CH2:29][N:28]([CH3:31])[C:27]1=[O:32])#[CH:25]>>[F:19][C:8]1([F:20])[C:9]2[S:13][C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:11][C:10]=2[C:4]2[CH:3]=[C:2]([C:25]#[C:24][C@:26]3([OH:33])[CH2:30][CH2:29][N:28]([CH3:31])[C:27]3=[O:32])[C:22]([F:23])=[CH:21][C:5]=2[O:6][CH2:7]1
Reactant: C#C[C@]1(O)CCN(C)C1=O
Reactant: CCOC(=O)c1nc2c(s1)C(F)(F)COc1cc(F)c(Br)cc1-2
Product: CCOC(=O)c1nc2c(s1)C(F)(F)COc1cc(F)c(C#C[C@]3(O)CCN(C)C3=O)cc1-2

Procedure:
Ethyl 9-bromo-8-fluoro-4-oxo-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate was subjected to General Procedure P to afford 400 mg (95%) of ethyl 9-bromo-4,4,8-trifluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate. Ethyl 9-bromo-4,4,8-trifluoro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford (R)-ethyl 4,4,8-trifluoro-9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[2,3]oxepin o[4,5-d]thiazole-2-carboxylate. Crude (R)-ethyl 4,4,8-trifluoro-9-((3-hydroxy-1-methyl-2-oxopyrrolidin-3-yl)ethynyl)-4,5-dihydrobenzo[2,3]oxepin o[4,5-d]thiazole-2-carboxylate was subjected to General Procedure P to afford 190 mg (44.4%) of 4,4,8-trifluoro-9-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-5H-[1]benzoxepino[5,4-d]thiazole-2-carboxamide. M+1=438.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH2:14][CH2:15][N:16]=[C:17]([CH3:18])[C:12]3=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+].[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25]>CO.O.C(O)C>[C:21]([OH:28])(=[O:27])/[CH:22]=[CH:23]/[C:24]([OH:26])=[O:25].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH2:14][CH2:15][NH:16][CH:17]([CH3:18])[C:12]3=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC1=NCCn2c1ccc2-c1ccc(Cl)c(Cl)c1
Agent: O=C(O)/C=C/C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CO
Product: CC1NCCn2c(-c3ccc(Cl)c(Cl)c3)ccc21
Yield: 92 %

Procedure:
6-(3,4-Dichlorophenyl)-3,4-dihydro-1-methylpyrrolo[1,2-a]pyrazine (1.8 g) was dissolved in a mixture of 100 ml of methanol and 10 ml of water under argon. The solution was treated portionwise with 0.7 g of sodium borohydride while stirring and stirred at room temperature overnight. Thereafter, the methanol was removed in a vacuum, the residue was taken up in 150 ml of methylene chloride and washed with 65 ml of 10% ammonia solution. The phases were separated and the aqueous phase was extracted twice with 70 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The crude product, 1.8 g of brown oil, was dissolved in a 20-fold amount of ethanol and treated with 1.1 equivalents of a saturated solution of fumaric acid in ethanol. There were obtained 2.0 g (92%) of 6-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-methylpyrrolo[1,2-a]pyrazine fumarate (2:1); m.pt.: 224°-226° C. (dec.).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9](F)[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].[NH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[N:31]1[CH:32]=[CH:33][CH:34]=[C:29]([CH2:28][NH:27][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][N:8]=2)[N:5]=[CH:4][C:3]([C:13]#[N:14])=[C:2]3[NH:21][C:20]2[CH:22]=[CH:23][CH:24]=[C:18]([O:17][C:16]([F:25])([F:26])[F:15])[CH:19]=2)[CH:30]=1
Reactant: NCc1cccnc1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Product: N#Cc1cnc2cnc(NCc3cccnc3)cc2c1Nc1cccc(OC(F)(F)F)c1
Yield: 0.36 %

Procedure:
Following the procedure described above in Example 29, 4-chloro-6-fluoro-1,7-naphthyridine-3-carbonitrile (0.200 g, 0.963 mmol) was reacted with 3-(trifluoromethoxy)aniline (0.14 mL, 0.19 g, 1.1 mmol), then with 3-(aminomethyl)pyridine. The crude product was purified by preparative HPLC and lyophilized to give a fluffy, bright yellow solid (1.5 mg, 0.36% yield): 1H NMR (400 MHz, DMSO-D6) δ 4.56 (d, J=6.8 Hz, 2 H) 7.03-7.29 (m, 4 H) 7.33 (dd, J=8.0, 4.9 Hz, 1 H) 7.48 (br s, 2 H) 7.74 (d, J=7.3 Hz, 1 H) 8.31 (br s, 1 H) 8.43 (d, J=4.8 Hz, 1 H) 8.58 (s, 1 H) 8.87 (br s, 1 H) 9.73 (br s, 1 H).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH:22][CH2:23][CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44]1([CH3:53])[CH:49]=[CH:48][C:47]([C:50](Cl)=[O:51])=[CH:46][CH:45]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([Br:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([N:22]([CH2:23][CH2:24][CH2:25][N:26]1[C:27](=[O:36])[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]1=[O:35])[C:50](=[O:51])[C:47]1[CH:48]=[CH:49][C:44]([CH3:53])=[CH:45][CH:46]=1)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C(NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Br)ccc2n1Cc1ccccc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N(CCCN2C(=O)c3ccccc3C2=O)C(c2nc3cc(Br)ccc3n2Cc2ccccc2)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
To a solution of 2-{3-[1-(1-Benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methyl-propylamino]-propyl}-isoindole-1,3-dione (310 mg, 0.56 mmol) and triethylamine (0.47 ml, 3.36 mmol, 6 eq) in DCM (3 ml) at 0° C., was added p-toluoyl chloride (0.38 ml, 2.8 mmol, 5 eq). The reaction mixture was stirred at 0° C. for 30 minutes. Ethyl acetate and saturated sodium bicarbonate were added. The mixture was extracted with ethyl acetate. The organic layers was combined, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The crude material was purified by flash chromatography to give N-[1-(1-Benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methyl-propyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-4-methyl-benzamide (242 mg, yield 65%)
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH2:16])[C:5]2[N:6]([N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:7]=1.[CH2:17]([OH:20])[C:18]#[CH:19].[C:21]1(O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[O:12]1[CH:13]=[CH:14][CH:15]=[C:11]1[C:9]1[N:10]=[C:5]2[C:4]([NH2:16])=[N:3][C:2]([C:19]#[C:18][CH2:17][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:7][N:6]2[N:8]=1
Reactant: C#CCO
Reactant: Nc1nc(Br)cn2nc(-c3ccco3)nc12
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Nc1nc(C#CCOc2ccccc2)cn2nc(-c3ccco3)nc12

Procedure:
Alternatively, a compound of formula (I) can react with an alkynyl (e.g., a compound of the formula L′-X1a where L′ is a precursor of L and X1a has been defined above) to form an intermediate, which can further react with a compound of the formula R1—X3—Y—X2-L″ to form a compound of formula (I). As an example, 6-bromo-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine can react with prop-2-yn-1-ol to form 3-(8-amino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-prop-2-1-ol, which can then react with phenol in the presence of triphenyl phosphine and diisopropyl azodicarboxylate to form 2-furan-2-yl-6-(3-phenoxy-prop-1-ynyl)-[1,2,4]triazolo[1,5-a]pyrazin-8-ylamine, a compound of formula (I). See, e.g., Example 22 below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C=O.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[CH:28][NH:29]2.[C:34](=O)(O)[O-].[Na+]>O1CCOCC1.C(O)(=O)C>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[C:27]([CH2:34][N:12]1[CH2:11][CH2:10][N:9]([CH:8]([C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:14][CH2:13]1)=[CH:28][NH:29]2
Reactant: Clc1ccc(C(c2ccccc2Cl)N2CCNCC2)cc1
Reactant: Clc1cccc2[nH]ccc12
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Clc1ccc(C(c2ccccc2Cl)N2CCN(Cc3c[nH]c4cccc(Cl)c34)CC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A stirred solution of 0.4 gram (0.001 mole) of N′-[(2-chlorophenyl)(4-chlorophenyl)methyl]piperazine in 1 mL of dioxane was cooled to 0° C. To this was added 2 mL of glacial acetic acid followed by 0.14 mL of 37% aqueous formaldehyde. A solution of 0.2 gram (0.001 mole) of 4-chloroindole in 1 mL of dioxane was then slowly added. Upon completion of the addition the reaction mixture was warmed to ambient temperature where it stirred for five hours. The reaction mixture was then cooled to 0° C., neutralized with aqueous saturated sodium bicarbonate solution, and extracted with two portions of diethyl ether. The combined extracts were washed with an aqueous saturated sodium chloride solution and dried with sodium sulfate, yielding 0.6 gram of crude material. The crude material was purified by preparative TLC. Elution was accomplished with 3:2 ethyl acetate: methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.4 gram of N-(4-chloroindol-3-ylmethyl)-N′-[(4-chlorophenyl)(2-chlorophenyl)methyl]piperazine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH2:1][CH2:2][C@:3]1([OH:21])[CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][N:10]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:4]1.C1C[O:25][CH2:24]C1>>[O:25]=[C:24]1[NH:1][CH2:2][C@@:3]2([CH2:8][CH2:7][CH2:6][C@H:5]([CH2:9][N:10]3[C:14]4[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=4[N:12]=[CH:11]3)[CH2:4]2)[O:21]1
Reactant: N#Cc1ccc2ncn(C[C@H]3CCC[C@@](O)(CN)C3)c2c1
Reactant: C1CCOC1
Product: N#Cc1ccc2ncn(C[C@H]3CCC[C@@]4(CNC(=O)O4)C3)c2c1
Temperature: 160 °C
Yield: 97 %

Procedure:
A suspension of 1-[(3S,5S)-1-oxaspiro[2.5]oct-5-ylmethyl]-1H-benzimidazole-6-carbonitrile (760 mg, 2.84 mmol) in MeOH (8 mL) was treated with 7M ammonia in MeOH (1.429 mL, 10.00 mmol) in a 20 mL microwave vial. The vial was sealed and heated in a microwave at 100° C. for 3 h. The reaction mixture was cooled to RT and blown down to dryness with nitrogen for 24 h to give crude 1-{[(1S,3S)-3-(aminomethyl)-3-hydroxycyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile which was used without further purification. A solution of 1-{[(1S,3S)-3-(aminomethyl)-3-hydroxycyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile (808 mg, 2.84 mmol) in THF (24 mL) was sealed under nitrogen in three 20 mL microwave vials and heated with microwave at 160° C. for 3 h. The combined reaction mixture was then concentrated to dryness and 50 mL of water was added. The solid was then filtered and washed with 2×10 mL of water. The solid was air-dried under house vacuum overnight. The compound was purified under normal phase flash column chromatography (ISCO CombiFlash Rf, 120 g silica column, MeOH/DCM 0-10%) to give 1-{[(5S,7S)-2-oxo-1-oxa-3-azaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile as an off-white solid (856 mg, 97% yield). The aromatic region of the NMR spectra showed that the product contained less than 8% of the cis-diastereomer. MS (m/z) 311.1 (M+H+).
Reaction SMILES: S(Cl)(Cl)=O.[C:5]1([C:11]2[CH:15]=[CH:14][O:13][C:12]=2C(O)=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N-:19]=[N+]=[N-].[Na+].C([O:25][CH2:26]C)C>C1C=CC=CC=1.O>[CH:15]1[C:11]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[C:26](=[O:25])[NH:19][C:12]=2[O:13][CH:14]=1
Reactant: O=C(O)c1occc1-c1ccccc1
Reactant: [N-]=[N+]=[N-]
Reactant: CCOCC
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: O
Product: O=c1[nH]c2occc2c2ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
Thionyl chloride (1 ml) was added to a suspension of 3-phenyl-2-furancarboxylic acid (300 mg, 1.46 mmol) in 10 ml of dry benzene and the mixture was refluxed for 2 hours. The solvent and the excess of thionyl chloride were removed under reduced pressure, the residue was taken up using 10 ml of dry THF and cooled to 0° C. Sodium azide (1.5 mmol) dissolved in the minimal amount of water was quickly added and the resulting solution was stirred for 1 hour at room temperature. After pouring into 100 ml of cracked ice/H2O and extraction with diethyl ether (4×100 ml), and the collected organic layers were dried over Na2SO4. The filtrate was gently evaporated under reduced pressure, the residue was dissolved in 10 ml of o-dichlorobenzene, and the resulting mixture was refluxed for 5-10 hours. The mixture was then cooled, and directly submitted to the flash chromatography, elution with dichloromethane/methanol (99/1) afforded to the title compound. Yield: 68%.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[F:26][C:27]1[CH:28]=[C:29]([Zn]I)[CH:30]=[CH:31][CH:32]=1>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:10]1[CH:9]=[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[C:7]([C:31]2[CH:30]=[CH:29][CH:28]=[C:27]([F:26])[CH:32]=2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: Fc1cccc([Zn]I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CON(C)C(=O)c1cc(Cl)c2cccnc2c1-c1cccc(F)c1
Temperature: 60 °C
Yield: 89 %

Procedure:
To a mixture of 5-chloro-7-{[methoxy(methyl)amino]carbonyl}quinolin-8-yl trifluoromethanesulfonate (0.200 g, 0.502 mmol) in tetrahydrofuran (5 mL) was added 0.50 M (3-fluorophenyl)(iodo)zinc in tetrahydrofuran (1.20 mL, 0.602 mmol) with stirring, followed by addition of tetrakis(triphenylphosphine)palladium(0) (29.0 mg, 0.0251 mmol). The reaction mixture was heated at 60° C. overnight. After cooling to room temperature, the mixture was filtered and concentrated under reduced pressure. The crude mixture was purified on silica gel, eluting with 0 to 60% EtOAc in hexane, to give the desired product (154 mg, 89%). LCMS calculated for C18H15ClFN2O2(M+H)+: m/z=345.1; found: 345.0.
Reaction SMILES: [C:1]([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH2:12][CH2:13][CH3:14])[C:9]([OH:11])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].ON1C2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.CN(C)CCCN=C=NCC.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.Cl.[CH3:72][O:73][C:74]1[CH:85]=[C:84]2[C:77]([NH:78][CH:79]=[C:80]2[CH2:81][CH2:82][NH2:83])=[CH:76][CH:75]=1>CN(C=O)C>[CH3:72][O:73][C:74]1[CH:85]=[C:84]2[C:77](=[CH:76][CH:75]=1)[NH:78][CH:79]=[C:80]2[CH2:81][CH2:82][NH:83][C:9](=[O:11])[CH:8]([O:7][C:6]1[CH:15]=[CH:16][C:3]([C:1]#[N:2])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:5]=1)[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(Oc1ccc(C#N)c(C(F)(F)F)c1)C(=O)O
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCCC(Oc1ccc(C#N)c(C(F)(F)F)c1)C(=O)NCCc1c[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The compound was prepared in the following manner. To 0.25 gm (0.87 mmol) of 2-(4-cyano-3-trifluoromethyl-phenoxy)-pentanoic acid in dimethylformamdie “DMF” (15 mL) were added 0.14 gm (1.09 mmol) of 1-Hydroxy-benzotriazole HOBT, 0.2 gm (1.09 mmol) of (3-(dimethylamino)propyl)ethylcarbodiimide EDCl, 0.23 gm (2.39 mmol) N-methyl morpholine, and approximately 246 mg of 5-methoxytryptamine hydrochloride (1.09 mmol). The resultant mixtures were stirred at room temperature for approximately 18 hours. The reactions were quenched with sodium bicarbonate (20 mL) and extracted with ethyl acetate (3 times 20 mL). The solvent was removed in vacuo to obtain oils that were then purified by HPLC.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([Cl:21])[CH:23]=3)[CH2:33][CH2:32]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(OC)ccc2nc1OC
Product: COc1ccc2nc(OC)c(NC(=O)N3CCN(c4cccc(Cl)c4)CC3)nc2c1
Yield: 85 %

Procedure:
Ethyl N-(2,6-dimethoxyquinoxalin-3-yl)carbamate and 1-(3-chlorophenyl)piperazine were reacted by the same way with the example 64 to obtain the titled compound (yield, 85%). 1H NMR (300 MHz, CDCl3): δ 3.21-3.32 (m, 4H), 3.75-3.88 (m, 6H), 4.10-4.13 (m, 4H), 6.80-6.90 (m, 4H), 7.14-7.29 (m, 3H), 7.63-7.66 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:21].[CH3:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Br>>[Br-:1].[Br:1][C:2]1[CH:3]=[N+:4]([CH2:22][C:23]2[CH:24]=[C:25]([CH3:26])[CH:28]=[CH:29][CH:30]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:21]
Reactant: Cc1cccc(CBr)c1
Reactant: COc1ccc2c(c1)CCC(Cc1ccncc1Br)C2=O
Product: COc1ccc2c(c1)CCC(Cc1cc[n+](Cc3cccc(C)c3)cc1Br)C2=O
Product: [Br-]

Procedure:
The title compound 118 is prepared according to the procedure reported in Example 38.1 with compound 99 (67 mg, 0.2 mmol) and 3-methylbenzyl bromide as reactants. White solid. (Yield 82.5 mg, 56%).
Reaction SMILES: O.Cl.[NH2:3][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[OH-].[Na+].[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]([CH3:15])=O>O>[CH3:19][CH2:18][O:17][C:12]([C:13]1([CH3:15])[NH:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][S:6]1)=[O:16]
Reactant: N[C@H](CS)C(=O)O
Reactant: CCOC(=O)C(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C1(C)NC(C(=O)O)CS1
Temperature: 40 °C
Reaction time: 4.5 h

Procedure:
D-Cysteine hydrochloride monohydrate (10 g, 57 mmol) was dissolved in water (20 ml), and the pH of the solution was adjusted to 5.13 with 6N aqueous sodium hydroxide solution. The reaction mixture was heated to 40° C., ethyl pyruvate (7.6 ml, 68 mmol) was gradually added thereto, and the mixture was stirred at 40° C. for 4.5 hours to give 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of trans form:cis form of the resultant product in the reaction mixture was confirmed by NMR to find about 55:45). After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. To the obtained ethyl acetate solution was added triethylamine (16 ml, 115 mmol) under argon, acetyl chloride (6.1 ml, 86 mmol) was slowly added dropwise thereto, and the reaction mixture was heated under reflux for 3 hr to give N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of trans form:cis form of the resultant product in the reaction mixture was confirmed by NMR to be about 97:3). After completion of the reaction, water (30 ml) was added thereto, and the pH of the mixture was adjusted to 0.9 with 5.7M HCl. The aqueous layer was separated, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The obtained ethyl acetate solution was concentrated to a weight of 157 g, and to the residue was heptane to be recrystallize the residue. The solid was washed with heptane/ethyl acetate=1.5/1, and dried at 50° C. under reduced pressure to give a crystal of a trans form of N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of the trans form was confirmed by the area ratio of an HPLC chart to find about 99%) (10.7 g, yield 71%).