Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:9])[CH:8]=1)[NH2:5].C([Sn](CCCC)(CCCC)[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)CCC>C1(C)C=CC=CC=1.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>[N:16]1[CH:17]=[CH:18][CH:19]=[N:20][C:15]=1[C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:15]2[N:16]=[CH:17][CH:18]=[CH:19][N:20]=2)[CH:8]=1)[NH2:5].[Br:9][C:7]1[CH:6]=[C:4]([CH:3]=[C:2]([C:15]2[N:20]=[CH:19][CH:18]=[CH:17][N:16]=2)[CH:8]=1)[NH2:5]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccn1
Reactant: Nc1cc(Br)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Nc1cc(-c2ncccn2)cc(-c2ncccn2)c1
Product: Nc1cc(Br)cc(-c2ncccn2)c1
Temperature: 110 °C
Reaction time: 72 h

Procedure:
The mixture of 3,5-dibromoaniline (1.05 g, 4.2 mmol), 2-tributylstannylpyrimidine (5.00 g, 13.6 mmol), Pd(Ph3P)4 (0.97 g, 0.84 mmol) in 60 mL toluene was degassed with argon stream and stirred at 110° C. in argon atmosphere for three days. It was cooled to RT, diluted with EtOAc, filtered through celite, concentrated in vacuo, and subjected to silica flash column to isolate 3,5-di(pyrimidin-2-yl)aniline and 3-bromo-5-(pyrimidin-2-yl)aniline.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)P(N(C)C)(N(C)C)=O>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([NH:1][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])=[CH:3][C:4]=1[F:12]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: COC(=O)c1ccc(N)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OC)c(F)c1

Procedure:
A mixture of 8.3 g. of methyl 4-amino-2-fluorobenzoate, 15.0 g of hexadecylbromide, 6.8 g of anhydrous potassium carbonate and 50 ml of hexamethylphosphoramide is heated to 135° for 20 hours. Upon cooling, dilution with water and extraction with ether, the orange colored ethereal extract is washed with water, dried and evaporated to yield an off-white solid. Recrystallization of this material from hexane affords methyl-2-fluoro-4-(hexadecylamino)benzoate.
Reaction SMILES: C1(S([O-])(=O)=O)C=CC=CC=1.C(C[N+:14]1([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22]N=2)[CH2:18][CH2:17][CH2:16][CH2:15]1)#N.Br[CH2:27][CH2:28][C:29]#[N:30].[C:31](NC#N)#[N:32].[BH4-].[Na+]>C(O)C>[CH3:22][C:23]1[C:24]([CH2:25][CH2:20][CH:19]([N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C:31]#[N:32])=[CH:27][CH:28]=[CH:29][N:30]=1
Reactant: N#CNC#N
Reactant: N#CCCBr
Reactant: N#CC[N+]1(Cc2ccccn2)CCCC1
Agent: O=S(=O)([O-])c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ncccc1CCC(C#N)N1CCCC1

Procedure:
1-cyanomethyl-1-(2-picolyl)pyrrolidinium benzenesulfonate (see Preparation II) is rearranged and alkylated with 3-bromopropionitrile as in Example 2. The resulting dicyanoamine is decyanated with sodium borohydride in ethanol to give the product. Purification is effected via the picrate.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[C:14]1([CH3:27])[CH:19]=[CH:18][C:17]([O:20][CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1>>[C:14]1([CH3:27])[CH:15]=[CH:16][C:17]([O:20][CH:21]2[CH2:26][CH2:25][N:24]([CH2:2][CH2:3][S:4]([C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=3)(=[O:6])=[O:5])[CH2:23][CH2:22]2)=[CH:18][CH:19]=1
Reactant: Cc1ccc(OC2CCNCC2)cc1
Reactant: O=S(=O)(CCCl)c1ccc(O)cc1
Product: Cc1ccc(OC2CCN(CCS(=O)(=O)c3ccc(O)cc3)CC2)cc1
Yield: 59 %

Procedure:
The title compound was prepared from 4-(2-chloro-ethanesulfonyl)-phenol and 4-p-tolyloxy-piperidine (prepared according to J. Med. Chem., 1978, 21, 309) in 59% yield as a white solid.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].N([C:15]1[NH:16][CH2:17][CH2:18][N:19]=1)[N+]([O-])=O.C1(C)C(C)=CC=CC=1>CC(C)=O>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH:4][C:15]1[NH:19][CH2:18][CH2:17][N:16]=1
Reactant: NCC(O)c1ccccc1
Reactant: O=[N+]([O-])NC1=NCCN1
Solvent: Cc1ccccc1C
Solvent: CC(C)=O
Product: OC(CNC1=NCCN1)c1ccccc1
Temperature: 160 °C

Procedure:
A mixture of 15.8 parts β-hydroxy-phenethyl-amine, 13 parts 2-nitramino-2-imidazoline and 8 parts xylene is stirred and heated for 30 minutes at 160°C. (oil-bath). After cooling the reaction mixture to a temperature of about 70°C., there are added 40 parts acetone. The whole is filtered warm and after cooling the filtrate to room temperature, the precipicated product is filtered off and dried, yielding 2-(β-hydroxy-phenethyl-amino)-2-imidazoline; m.p. 147°-149°C.
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8](OCC)OCC)(=[O:5])[CH2:2][CH2:3][CH3:4].[SH:15][CH2:16][C:17]([OH:19])=[O:18].CC1C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:7][CH:8]1[S:15][CH2:16][C:17](=[O:19])[O:18]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)CS
Reactant: CCCC(=O)OCC(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC(=O)OCC1OC(=O)CS1
Temperature: 25 °C
Yield: 85 %

Procedure:
A well-stirred solution of 28 (6.13 g, 30 mmol), mercaptoacetic acid (4.14 g, 3.13 ml, 45 mmol) and p-TsOH. H2O (60 mg, 0.31 mmol) in dry toluene was refluxed for 2 hours. Solvent was occasionally removed with a Dean-Stark trap, and fresh dry toluene was added. After cooling to room temperature, the reaction mixture was diluted with AcOEt (50 ml) and successively washed with: concentrated NaHCO3 (2×100 ml) and brine (2×100 ml), dried, filtered and evaporated to afford 25 (5.2 g, 25.5 mmol, 85%) as a yellow liquid that was used in the next step without any further purification.
Reaction SMILES: Cl.[CH2:2]([N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C@@H:12]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][Si](C(C)(C)C)(C)C)[CH:26]=2)[C:13]2[CH:18]=[CH:17][C:16]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[C@H:7]([CH3:39])[CH2:6]1)[CH:3]=[CH2:4].O>O1CCCC1>[CH2:2]([N:5]1[C@@H:10]([CH3:11])[CH2:9][N:8]([C@@H:12]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)[C:13]2[CH:14]=[CH:15][C:16]([S:19]([N:22]([CH3:24])[CH3:23])(=[O:20])=[O:21])=[CH:17][CH:18]=2)[C@H:7]([CH3:39])[CH2:6]1)[CH:3]=[CH2:4]
Reactant: C=CCN1C[C@@H](C)N([C@H](c2ccc(S(=O)(=O)N(C)C)cc2)c2cccc(O[Si](C)(C)C(C)(C)C)c2)C[C@@H]1C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C=CCN1C[C@@H](C)N([C@H](c2ccc(S(=O)(=O)N(C)C)cc2)c2cccc(O)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
3 N HCl (7 mL) was added to the solution of 4-{(R)-((2R,5S)-4-allyl-2,5-dimethylpiperazin-1-yl)[3-(tert-butyl-dimethylsilanyloxy)-phenyl]methyl}-N,N-dimethylbenzenesulfonamide (1.3 g) in tetrahydrofuran (15 mL). The mixture was stirred at room temperature overnight. Water (15 mL) was added to the reaction. The reaction mixture was extracted with diethyl ether (25 mL×3). The remaining water layer was neutralized by 10% aqueous NaOH to pH=8-9 and then extracted with ethyl acetate (30 mL×3). The combined ethyl acetate layers were washed with water (20 mL×3) and brine (20 mL), dried over sodium sulfate and concentrated to give 0.83 g of crude product. The crude product was purified by silica gel chromatography conducted on CombiFlash™ Sq 16× (gradient: 100% CH2Cl2 to 7% MeOH in CH2Cl2) to give 4-[(R)-((2R,5S)-4-allyl-2,5-dimethylpiperazin-1-yl)(3-hydroxyphenyl)methyl]-N,N-dimethylbenzenesulfonamide (720 mg; 70%). 1H NMR (300 MHz, CDCl3) δ 7.71 (d, 2H, J=8.5 Hz), 7.35 (d, 2H, J=8.5 Hz), 7.14 (dd, 1H, J=8.0, 8.0 Hz), 6.89 (bs, 1H), 6.85 (d, 1H, J=8.0 Hz), 6.68 (d, 1H, J=8.0, 2.5 Hz), 5.83 (1H, m), 5.24-5.12 (m, 3H), 3.32 (dd, 1H, J=13.5, 5.0 Hz), 2.86 (dd, 1H, J=13.5, 8.0 Hz), 2.78 (dd, 1H, J=11.5, 3.0 Hz), 2.72 (s, 6H), 2.65 (dd, 1H, J=11.0, 2.5 Hz), 2.51 (m, 2H), 2.14 (dd, 1H, J=11.5, 9.0 Hz), 1.81 (dd, 1H, J=11.0, 9.5 Hz), 1.16 (d, 3H, J=6.0 Hz), 0.98 (d, 3H, J=6.0 Hz); MS (FAB, glycerol) m/z: 444 (M++H), 290, 153. Found: C, 58.32; H, 6.66; N, 8.18. Calc. (C24H33N3O3S 0.8 CH2Cl2): C, 58.23; H, 6.82; N, 8.21.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C:8]1[CH:13]=[CH:12][C:11]([Mg]Br)=[CH:10][CH:9]=1.[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19](Cl)=[O:20]>C1COCC1.[Zn+2].[Br-].[Br-]>[F:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:18]=1[C:19]([C:11]1[CH:12]=[CH:13][C:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)=[CH:9][CH:10]=1)=[O:20]
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Reactant: O=C(Cl)c1c(F)cccc1F
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1c(F)cccc1F
Reaction time: 0.17 h

Procedure:
A solution of ZnBr2 in THF (1.5 M, 2 mL, 3.0 mmol) was added to a solution of (4-(tetrahydro-2H-pyran-2-yloxy)phenyl)magnesium bromide in THF (0.2 M, 15 mL, 3 mmol) under an atomsphere of argon atr.t. The reaction mixture was stirred for 10 minutes, cooled with a dry-ice acetone bath. Palladium tetrakistriphenylphosphine (50 mg) and a solution of 2,6-difluorobenzoyl chloride (0.37 mL, 3 mmol) in THF (2 mL) were added. The mixture was stirred over night at r.t. The organic phase was washed with brine (2×20 mL), dried (Na2SO4) and concentrated yielding a solid. Purified by flash chromatography (eluent: heptane→20% ethyl acetate in heptane). Yield: 318 mg, 33% (approx. 85% pure according to 1H-NMR). 1H-NMR (400 MHz, CDCl3): δ 7.83-7.78 (m, 2H), 7.49-7.38 (m, 1H), 7.14-7.07 (m, 2H), 7.03-6.95 (m, 2H), 5.52 (t, J=3.1 Hz, 1H), 3.83-3.80 (m, 1H), 3.63-3.58 (m, 1H), 2.10-1.90 (m, 1H), 1.89-1.85 (m, 2H), 1.72-1.58 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][C@@H:14]3[CH2:18][CH2:17][N:16]([C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[CH2:15]3)=[N:11][NH:10][C:9]2=[O:24])=[CH:4][CH:3]=1.[NH:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31](B(O)O)[CH:32]=2)[CH:27]=[CH:26]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)C.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>[CH:21]1([C:19]([N:16]2[CH2:17][CH2:18][C@@H:14]([CH2:13][C:12]3[N:8]([C:5]4[CH:6]=[CH:7][C:2]([C:31]5[CH:32]=[C:33]6[C:28]([CH:27]=[CH:26][NH:25]6)=[CH:29][CH:30]=5)=[CH:3][CH:4]=4)[C:9](=[O:24])[NH:10][N:11]=3)[CH2:15]2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Reactant: OB(O)c1ccc2cc[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4cc[nH]c4c3)cc2)C1
Yield: 105.1 %

Procedure:
4-(4-Bromophenyl)-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (0.100 g, 0.256 mmol), 1H-indol-6-ylboronic acid (0.082 g, 0.511 mmol), tetrakis(triphenylphosphine)palladium(0) (0.030 g, 0.026 mmol), and K3PO4 (0.217 g, 1.022 mmol) were combined in ethanol (4 mL) and water (4 mL), purged with N2, and irradiated in a microwave reactor for 1 h at 110° C. after which time LCMS indicated complete conversion. The reaction mixture was filtered through Celite, diluted with 100 mL EtOH and concentrated to dryness. The residue was partitioned between dichloromethane and water (a minimal amount of CH3OH was added to achieve complete solubility), and the organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was purified on 40 g silica gel eluted with 100% EtOAc to 10% CH3OH/CH2Cl2 to give 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[4-(1H-indol-6-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.115 g, 0.269 mmol, quantitative yield) as a white foam. LC-MS (ES−) m/z 426.51 [M−1]. LC-MS (ES+) m/z 428.30 [M+H]. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.72 (d, J=4.08 Hz, 1H), 11.23 (s, 1H), 7.82 (dd, J=8.49, 2.79 Hz, 2H), 7.69 (s, 1H), 7.64 (d, J=8.27 Hz, 1H), 7.48 (dd, J=8.43, 6.50 Hz, 2H), 7.41 (t, J=2.69 Hz, 1H), 7.36 (dd, J=8.27, 1.50 Hz, 1H), 6.47 (t, J=2.04 Hz, 1H), 3.61-3.86 (m, 1H), 3.47-3.60 (m, 1H), 2.87-3.43 (m, 2H), 2.34-2.66 (m, 3H), 1.91-2.13 (m, 1H), 1.44-1.74 (m, 2H), 0.61-0.73 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:11]([C:17]([OH:19])=O)[N:10]=[C:9]2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:48]2[CH:49]=[CH:50][CH:51]=C[C:47]=2[N:46]=[N:45]1.NN1CCCCC1>CC#N>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([S:13]([CH3:16])(=[O:15])=[O:14])=[C:11]([C:17]([NH:45][N:46]3[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]3)=[O:19])[N:10]=[C:9]2[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[Cl:27])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1c(C(=O)O)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NN1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1c(C(=O)NN2CCCCC2)nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Reaction time: 16 h
Yield: 84 %

Procedure:
To a magnetically stirred suspension of 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfonyl-1H-imidazole-4-carboxylic acid (2.23 g, 5.01 mmol) in anhydrous CH3CN (50 ml) was successively added N,N-diisopropylethylamine (Hunig's base) (1.90 ml, 11.0 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (2.27 g, 5.99 mmol) and 1-aminopiperidine (0.65 ml, 6.03 mmol). After stirring for 16 h, the resulting mixture was concentrated in vacuo. The residue was dissolved in EtOAc, successively washed with aqueous NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated to give a crude solid. This solid was further purified by flash chromatography (silicagel, EtOAc) and triturated with methyl-tert-butyl ether to give 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methylsulfonyl-N-(piperidin-1-yl)-1H-imidazole-4-carboxamide in 84% yield, mp 181–185° C. (dec); 1H-NMR (600 MHz, DMSO-d6) δ 1.35–1.41 (m, 2H), 1.61–1.66 (m, 4H), 2.80–2.84 (m, 4H), 3.52 (s, 3H), 7.38 (d, J=8 Hz, 2H), 7.42 (dd, J=8 and 2 Hz, 1H), 7.46 (d, J=8 Hz, 2H), 7.57 (d, J=2 Hz, 1H), 7.62 (d, J=8 Hz, 1H), 9.40 (s, 1H); HRMS (C22H22Cl3N4O3S) [M+H]+: found m/z 527.0469, calcd 527.0478.
Reaction SMILES: [O-][CH2:2]C.[Na+].[Br:5][C:6]1[C:7]([CH2:14][C:15]#[N:16])=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].IC>C(O)C.O1CCCC1>[Br:5][C:6]1[C:7]([CH:14]([C:15]#[N:16])[CH3:2])=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10]
Reactant: CC[O-]
Reactant: N#CCc1c(Br)cccc1C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCO
Product: CC(C#N)c1c(Br)cccc1C#N
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 67.5 %

Procedure:
A solution of sodium ethoxide (8.76 mL, 23.5 mmol, 21 wt % ethanol solution) in ethanol (10 mL) was cooled to 0° C. under argon atmosphere, and thereto was added dropwise a solution of 3-bromo-2-(cyanomethyl)benzonitrile (4.33 g, 19.6 mmol) and iodomethane (1.46 mL, 23.5 mmol) in tetrahydrofuran (10 mL) over 30 minutes, and then the mixture was stirred at room temperature for 6.5 hours. The mixture was concentrated under reduced pressure, and then the residue was neutralized by 2 mol/L hydrochloric acid, and extracted with ethyl acetate three times. The organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=10%→40%) to give 3-bromo-2-(1-cyanoethyl)benzonitrile (3.11 g, 67%) as a yellow viscous material.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:29]=[CH:28][C:11]([O:12][CH:13]([CH3:27])[C:14]([O:16][CH2:17][CH2:18][S:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[CH:10][CH:9]=1.Cl[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][N:32]=1>CS(C)=O>[F:38][C:37]([F:40])([F:39])[C:34]1[CH:35]=[CH:36][C:31]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:27])[C:14]([O:16][CH2:17][CH2:18][S:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:15])=[CH:28][CH:29]=2)=[N:32][CH:33]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(Oc1ccc(O)cc1)C(=O)OCCSCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)C(=O)OCCSCc1ccccc1
Temperature: 90 °C
Yield: 76.1 %

Procedure:
15.2 g of potassium carbonate were added to a solution of 33.2 g of 2-benzylthioethyl 2-(4-hydroxyphenoxy)-propionate in 100 ml of dimethyl sulfoxide at room temperature whilst stirring. The mixture was heated to 90° C. for 1 hour with stirring. Then, 20.0 g of 2-chloro-5-trifluoromethyl-pyridine were added thereto while maintaining the temperature between 80° and 90° C. After the addition was completed, the reaction mixture was further stirred at this temperature for 2 hours, and then cooled to room temperature. Then the reaction mixture was poured into ice water and extracted with chloroform. After drying the organic phase, the chloroform was removed under reduced pressure. There were obtained 36.3 g of 2-benzylthioethyl 2-[4-(5-trifluoromethyl-2-pyridyloxy)-phenoxy]-propionate in the form of a pale yellow viscous oil.
Reaction SMILES: [O:1]1[C:5]2[C:6](=O)[NH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O.[OH-].[Na+]>>[Cl:13][C:6]1[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2][O:1][C:5]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2ccoc12
Agent: [Na+]
Agent: [OH-]
Product: Clc1nccc2ccoc12
Temperature: 25 °C
Yield: 74.3 %

Procedure:
The mixture of furo[2,3-c]pyridin-7(6H)-one (12.0 g, 87.6 mmol) and phosphorous oxychloride (21.3 g, 139 mmol) was placed in an oven-dried two-necked flask, then was heated to reflux for 3-4 h under a nitrogen atmosphere. The reaction mixture was cooled to RT, then poured into ice-cold water (250 mL). After it was basified with 10% aq. NaOH solution, the mixture was extracted with diethyl ether (3×100 mL), dried over anhydrous potassium carbonate, filtered and concentrated to give 10.0 g (75%) of the title compound as brown crystals. 1H NMR (300 MHz, CDCl3): δ 6.87 (d, J=1.8 Hz, 1H), 7.50 (d, J=6.0 Hz, 1H), 7.82 (d, J=1.8 Hz, 1H), 8.20 (d, J=6.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]4=[O:30])=[CH:20][C:19]=3[F:31])[CH2:12][C@@H:11]2[C:33]([O-:35])=O)=[O:8])=[CH:4][CH:3]=1.[Li+].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:49][NH:50][CH2:51][CH2:52][OH:53]>C1COCC1.CN(C=O)C>[OH:53][CH2:52][CH2:51][N:50]([CH3:49])[C:33]([C@@H:11]1[C@@H:10]([NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])[CH2:14][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]3=[O:30])=[CH:20][C:19]=2[F:31])[CH2:12]1)=[O:35]
Reactant: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](C(=O)[O-])C1)Nc1ccc(-n2ccccc2=O)cc1F
Reactant: CNCCO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CN(CCO)C(=O)[C@H]1CN(CC(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
Lithium (3S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-3-carboxylate (example 41; 0.09 g) is dissolved in THF/DMF (1:1; 3 ml) and CDI (0.083 g) is added. The mixture is stirred for 1 h at 25° C., after that 2-(methylamino)-ethanol (0.03 ml) is added. The reaction mixture is stirred for 18 h at 25° C. and evaporated to dryness followed by flash chromatography over silica gel using DCM/MeOH/NH3 as eluent to yield 0.033 g (33.4%) (3S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidine-3-carboxylic acid (2-hydroxy-ethyl)-methyl-amide. White solid. MS 576.5 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:3]([Sn](CCCC)(CCCC)CCCC)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[C:22]1[N:26]([S:27]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)(=[O:29])=[O:28])[CH:25]=[C:24]([CH2:36][N:37]([CH3:45])[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:23]=1>C1(C)C=CC=CC=1.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>[CH3:45][N:37]([CH2:36][C:24]1[CH:23]=[C:22]([C:3]2[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=2)[N:26]([S:27]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)(=[O:29])=[O:28])[CH:25]=1)[C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:41])[CH3:42]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncccc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccnc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Temperature: 25 °C
Yield: 22.3 %

Procedure:
A solution of 3-methyl-2-(tributylstannyl)pyridine (1.0 g), tert-butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (563 mg) and tetrakis(triphenylphosphine)palladium (454 mg) in toluene was stirred under a nitrogen atmosphere at 120° C. for 30 hr. The mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=4:1) to give the title compound as a colorless oil (yield 129 mg, 22%).
Reaction SMILES: S(Cl)(Cl)=O.CC1OC(C)=CC=1C(O)=O.CC1OC(C)=CC=1C(Cl)=O.[CH3:25][C:26]1[O:27][C:28]([CH3:36])=[CH:29][C:30]=1[C:31]([N:33]=[C:34]=[S:35])=[O:32].[CH3:37][O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][C:48]=1[O:49][CH3:50])[N:45]=[CH:44][CH:43]=[C:42]2[O:51][C:52]1[CH:58]=[CH:57][C:55]([NH2:56])=[C:54]([F:59])[CH:53]=1>C(O)C.C1(C)C=CC=CC=1>[CH3:37][O:38][C:39]1[CH:40]=[C:41]2[C:46](=[CH:47][C:48]=1[O:49][CH3:50])[N:45]=[CH:44][CH:43]=[C:42]2[O:51][C:52]1[CH:58]=[CH:57][C:55]([NH:56][C:34]([NH:33][C:31]([C:30]2[CH:29]=[C:28]([CH3:36])[O:27][C:26]=2[CH3:25])=[O:32])=[S:35])=[C:54]([F:59])[CH:53]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: Cc1cc(C(=O)N=C=S)c(C)o1
Agent: Cc1cc(C(=O)Cl)c(C)o1
Agent: Cc1cc(C(=O)O)c(C)o1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cc(C)oc4C)c(F)c3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 2,5-dimethyl-3-furoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 2,5-dimethyl-3-furancarbonyl isothiocyanate was prepared using the resultant 2,5-dimethyl-3-furancarbonyl chloride as a starting compound according to the description of the literature. 2,5-Dimethyl-3-furancarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (38 mg, yield 48%).