Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:5]1[CH2:10][CH2:9][CH:8]([S:11]([CH2:14][S:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19]2)(=[O:17])=[O:16])(=[O:13])=[O:12])[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].C1(C)C=CC(S([N:37]=[N+:38]=[N-])(=O)=O)=CC=1.O.Cl>ClCCl>[CH2:1]([CH:5]1[CH2:6][CH2:7][CH:8]([S:11]([C:14]([S:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[N+:37]=[N-:38])(=[O:13])=[O:12])[CH2:9][CH2:10]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1CCC(S(=O)(=O)CS(=O)(=O)C2CCC(CCCC)CC2)CC1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CCCCC1CCC(S(=O)(=O)C(=[N+]=[N-])S(=O)(=O)C2CCC(CCCC)CC2)CC1
Reaction time: 0.25 h
Yield: 20.6 %

Procedure:
In 91 g of dichloromethane were dissolved 10.5 g (0.025 mol) of the bis(4-n-butylcyclohexylsulfonyl)methane prepared above and 7.5 g (0.038 mol) of p-toluenesulfonylazide. The solution was cooled on an ice bath, to which 3.7 ml (0.0025 mol) of diazabicyclo[5.4.0]-7-undecene (DBU) was added dropwise at a temperature below 5° C. The solution was ripened at the temperature for 15 minutes, after which 38 g of water and 10 g of 12N conc. hydrochloric acid were added. The organic layer was separated and washed with 50 g of water. The solvent was distilled off in vacuum, leaving an oily matter. It was purified by silica gel column chromatography (using dichloromethane as a developing solvent), obtaining 2.3 g of the desired bis(4-n-butylcyclohexylsulfonyl)diazomethane. The yield was 20%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[C:21]([C:23]4[O:24][C:25]([CH3:28])=[N:26][N:27]=4)[CH:20]=[CH:19][C:18]=3[CH3:29])=[CH:13][CH:12]=2)=[O:10])=[CH:5][CH:4]=1.I[CH2:33][CH3:34]>>[CH2:33]([N:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=1)[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[C:21]([C:23]3[O:24][C:25]([CH3:28])=[N:26][N:27]=3)[CH:20]=[CH:19][C:18]=2[CH3:29])=[CH:15][CH:16]=1)=[O:10])[CH3:34]
Reactant: CCI
Reactant: COc1ccc(CNC(=O)c2ccc(-c3cc(-c4nnc(C)o4)ccc3C)cc2)cc1
Product: CCN(Cc1ccc(OC)cc1)C(=O)c1ccc(-c2cc(-c3nnc(C)o3)ccc2C)cc1

Procedure:
N-Ethyl-N-(4-methoxybenzyl)-2′-methyl-5′-(5-methyl- 1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide was prepared from N-(4-methoxybenzyl)-2′-methyl-5′-(5-methyl-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-4-carboxamide and iodoethane using method L. NMR; δH [2H6]—DMSO 7.89,(1H, d), 7.75,(1H, s), 7.55-7.47,(5H, m), 7.30,(1H, m), 6.92,(2H, d), 4.64-4.45,(2H, m), 3.74,(3H, s), 3.34-3.16,(2H, m), 2.55,(3H, s), 2.31,(3H, s), 1.05,(3H, b). LCMS; retention time 3.54 min, MH+ 442.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:25])=[C:16]([N:19]4[CH2:23][CH2:22][CH:21]([NH2:24])[CH2:20]4)[CH:17]=3)[C:12](=[O:26])[N:11]([OH:27])[C:10]2=[O:28])[CH:5]=[CH:6][C:7]=1[F:8].F[C:30](F)(F)C([O-])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:18]3[C:13](=[CH:14][C:15]([F:25])=[C:16]([N:19]4[CH2:20][CH2:21][N:24]([CH3:30])[CH2:22][CH2:23]4)[CH:17]=3)[C:12](=[O:26])[N:11]([OH:27])[C:10]2=[O:28])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: NC1CCN(c2cc3c(cc2F)c(=O)n(O)c(=O)n3-c2ccc(F)c(Cl)c2)C1
Reactant: O=C([O-])C(F)(F)F
Product: CN1CCN(c2cc3c(cc2F)c(=O)n(O)c(=O)n3-c2ccc(F)c(Cl)c2)CC1

Procedure:
1-(3-Chloro-4-fluorophenyl)-6-fluoro-3-hydroxy-7-(3-aminopyrrolidin-1-yl)-1H-quinazoline-2,4-dione, trifluoroacetate;
Reaction SMILES: COC([C:5]1[CH:10]=[CH:9][C:8]([S:11][C:12]2([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=[O:18])=[CH:7][CH:6]=1)=O.[CH3:26][OH:27]>C(OCC)(=O)C>[CH3:26][O:27][C:13](=[O:18])[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]([S:11][C:8]1[CH:7]=[CH:6][CH:5]=[CH:10][C:9]=1[C:19]([O:21][CH3:22])=[O:20])[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20]
Reactant: COC(=O)c1ccc(SC2(C(=O)OC(C)(C)C)CCCCC2=O)cc1
Reactant: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCCCC(Sc1ccccc1C(=O)OC)C(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
1 g (30.2 mmol) of 2-(4-methoxycarbonylphenylthio)2-tert.butoxycarbonylcyclohexanone is dissolved, together with 0.37 g (3.3 mmol) of potassium tert. butylate, in 100 ml of methanol of reagent purity and the solutions is left to stand for 2 hours at room temperature. It is then diluted with 500 ml of ethyl acetate and the organic phase is washed with water and a saturated sodium chloride solution, dried with sodium sulphate and concentrated by evaporation. After drying in a high vacuum 11.3 g of an oily product are obtained, which is sufficiently pure to be used for further reactions.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][OH:24])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27].C(N(CC)CC)C.[S:35](Cl)([CH3:38])(=[O:37])=[O:36]>C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:25])[CH2:23][O:24][S:35]([CH3:38])(=[O:37])=[O:36])[CH3:21])[C:14]=3[Cl:26])[C:5]2=[N:4][C:3]=1[CH3:27]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CO)c3Cl)cccn2c1Br
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)COS(C)(=O)=O)c3Cl)cccn2c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-(N-glycoloyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (700 mg) and triethylamine (269 mg) in methylene chloride (14 ml) was added mesyl chloride (224 mg) under ice-cooling, and the mixture was stirred for 1 hour at ambient temperature. The reaction mixture was washed with water twice and brine, dried over magnesium sulfate and concentrated in vacuo to give the residue of 3-bromo-8-[2,6-dichloro-3-(N-mesyloxyacetyl-N-methylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine. The residue was dissolved in N,N-dimethylformamide (7 ml) and potassium phthalimide (362 mg) was added thereto at ambient temperature under N2 atmosphere. The mixture was stirred for 1 day, and water was added thereto. The precipitate was collected by filtration and dried to give 3-bromo-8-[2,6-dichloro-3-(N-methyl-N-phthalimidoacetylamino)benzyloxy]-2-methylimidazo[1,2-a]pyridine (629 mg).
Reaction SMILES: Cl.Cl[C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:4]=1.Cl.Cl.[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[CH:34][CH:33]=[C:32]([NH:38][CH2:39][CH2:40][NH2:41])[N:31]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[NH2:29][C:30]1[C:35]([C:36]#[N:37])=[CH:34][CH:33]=[C:32]([NH:38][CH2:39][CH2:40][NH:41][C:3]2[N:8]3[N:9]=[C:10]([CH:12]4[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]4)[N:11]=[C:7]3[CH:6]=[C:5]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[N:4]=2)[N:31]=1
Reactant: N#Cc1ccc(NCCN)nc1N
Reactant: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(Cl)n3n2)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CN1CCC(c2nc3cc(-c4ccc(Cl)cc4Cl)nc(NCCNc4ccc(C#N)c(N)n4)n3n2)CC1
Temperature: 130 °C

Procedure:
50 mg (0.12 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(1-methylpiperidin-4-yl)[1,2,4]triazolo-[1,5-c]-pyrimidine hydrochloride (Example 49A), 32 mg (0.15 mmol) of 2-amino-6-[(2-aminoethyl)-amino]pyridine-3-carbonitrile dihydrochloride (Example 9A) and 0.13 ml (0.75 mmol) of N,N-diisopropylethylamine were initially charged in 1.5 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 43 mg (64% of theory) of the product as a solid.
Reaction SMILES: [Br:1]Br.[C:3]([O:6][CH2:7][CH2:8][N:9]1[CH:13]=[N:12][N:11]=[N:10]1)(=[O:5])[CH3:4]>C(Cl)(Cl)Cl.C(O)(=O)C>[C:3]([O:6][CH2:7][CH2:8][N:9]1[C:13]([Br:1])=[N:12][N:11]=[N:10]1)(=[O:5])[CH3:4]
Reactant: CC(=O)OCCn1cnnn1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCCn1nnnc1Br
Yield: 94.7 %

Procedure:
Bromine (69.1 g) in chloroform (80 ml) was added to a stirred refluxing solution of 1H-tetrazole-1-ethanol acetate (ester) (33.8 g) in acetic acid (200 ml) and chloroform (400 ml). After 72 h the mixture was cooled and evaporated, excess, saturated potassium carbonate solution was added and the mixture was extracted with ethyl acetate to give the title compound (48.2 g) as a cream solid, m.p. 55°-6° (from diethyl ether).
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1.[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1B1OC(C)(C)C(C)(C)O1)[CH3:20].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.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>[CH2:19]([C:21]1[C:26](/[CH:27]=[CH:28]/[O:29][CH3:30])=[CH:25][CH:24]=[CH:23][C:22]=1[C:2]1[N:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:15][CH:16]([CH3:18])[CH3:17])=[C:11]([CH:14]=2)[C:12]#[N:13])[S:4][N:3]=1)[CH3:20]
Reactant: CC(C)Oc1ccc(-c2nc(Br)ns2)cc1C#N
Reactant: CCc1c(/C=C/OC)cccc1B1OC(C)(C)C(C)(C)O1
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: O
Solvent: CN(C)C=O
Product: CCc1c(/C=C/OC)cccc1-c1nsc(-c2ccc(OC(C)C)c(C#N)c2)n1
Temperature: 120 °C
Yield: 85 %

Procedure:
To a solution of 5-(3-bromo-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile (D44) (630 mg), 2-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (560 mg) and tripotassium phosphate (1237 mg) in N,N-dimethylformamide (DMF) (5 mL) and water (1.25 mL) stirred under nitrogen was added Pd(Ph3P)4 (225 mg). The mixture was sealed and heated under microwave at 120° C. for 15 min. After cooling the reaction, the mixture was concentrated and purified by column chromatography to give 5-(3-{2-ethyl-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,2,4-thiadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile (D54) (670 mg) as a colorless oil. MS (ES): C23H23N3O2S requires 405. found 406.2 (M+H+).
Reaction SMILES: [C:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7](=O)[CH:6]=1)([O:3][CH3:4])=[O:2].O=P(Cl)(Cl)[Cl:18]>C1(C)C=CC=CC=1>[Cl:18][C:7]1[CH:6]=[C:5]([C:1]([O:3][CH3:4])=[O:2])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(=O)[nH]c2ccccc12
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)nc2ccccc12
Temperature: 25 °C

Procedure:
A stirred solution of 4-carbomethoxy quinolin-2-one (prepared as shown in Method D (1.76 g, 9 mmol), POCl3 (4.6 g, 30 mmol) in toluene (40 mL) was heated at reflux for 2 h then allowed to cool to room temperature and poured into ice water (50 mL). The mixture was extracted with ethyl acetate (3×50 mL). The organics were combined, washed with water, brine, dried (MgSO4) and concentrated in vacuo to afford the desired 2-chloro-4-carbomethoxyquinoline lv (1.50 mg). 1H NMR (DMSO-d6) δ 8.54 (d, J=8 Hz, 1H), 8.03-8.06 (m, 1H), 7.89-7.94 (m, 2H), 7.75-7.77 (m, 1H), 3.98 (s, 3H); ESI-MS m/z 222.1 (100, M+H+).
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([NH2:12])[N:11]=2)[N:8]=1.[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1.O>CC(N(C)C)=O>[I:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[C:10]([NH:12][C:16]([CH:13]3[CH2:15][CH2:14]3)=[O:17])[N:11]=2)[N:8]=1
Reactant: Nc1cn2nc(I)ccc2n1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
Compound 3C was synthesized according to a procedure analogous to that described in International Patent Publication No. WO 2008/06192 (Takeda Pharmaceutical Company Limited), which is incorporated by reference herein in its entirety. 6-Iodoimidazo[1,2-b]pyridazin-2-amine hydrochloride (4.45 g, 17.11 mmol) and cyclopropanecarbonyl chloride (1.35 mL, 18.82 mmol) were dissolved in DMA (85 mL) and stirred for 3 hours at ambient temperature. The reaction mixture was then poured into water (400 mL) resulting in the formation of a brown precipitate. The solid was filtered and dried under vacuum to give N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (4.2 g, 77%). 1H NMR (400 MHz, DMSO-d6) δ=11.21 (s, 1 H), 8.26-8.17 (m, 1 H), 7.74 (d, J=9.3 Hz, 1 H), 7.49 (d, J=9.1 Hz, 1 H), 2.07-1.87 (m, 1 H), 0.97-0.77 (m, 4 H) ESI-MS:m/z 329.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.[N+:7]([C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)([O-:9])=[O:8].F[P-](F)(F)(F)(F)F.ClC1N(C)C=C[N+]=1C.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][CH2:3][C:4]([NH:14][C:13]1[CH:15]=[CH:16][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=1)=[O:6]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COCC(=O)O
Agent: Cn1cc[n+](C)c1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCC(=O)Nc1ccc([N+](=O)[O-])cc1
Yield: 71.4 %

Procedure:
To a mixture solution of 384 μL (5.0 mmol) of methoxyacetic acid and 691 mg (5.0 mmol) of p-nitroaniline in 10 mL of dichloromethane were added 1.53 mg (5.5 mmol) of 2-chloro-1,3-dimethyl imidazolium hexafluorophosphate and 1.53 mL (11.0 mmol) of triethylamine, and the mixture was refluxed for 7 hours. Then, the reaction mixture was extracted with ethyl acetate, the extract was washed with water and saturated saline solution, then, dried over with anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to give 750 mg (71%) of the title compound.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[CH2:10]([O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)[CH2:11][CH2:12][CH3:13]>>[CH2:10]([O:14][C:15]1[CH:20]=[C:19]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=2)[CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cc1F
Product: CCCCOc1cccc(-c2ccc(N)c(F)c2)c1
Yield: 52 %

Procedure:
The title compound (170 mg) was prepared from 4-bromo-2-fluoroaniline (240 mg, 1.26 mmol) and 3-butoxyphenylboronic acid (310 mg, 1.59 mmol) as a yellow liquid.
Reaction SMILES: [SH-:1].[Na+].Cl[C:4]1[N:9]([CH2:10][CH2:11][CH2:12]Cl)[C:8](=[O:14])[N:7]([CH2:15][CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[C:19]1([C:5]2[C:6](=[O:18])[N:7]([CH2:15][CH2:16][CH3:17])[C:8](=[O:14])[N:9]3[CH2:10][CH2:11][CH2:12][S:1][C:4]=23)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: [SH-]
Reactant: CCCn1c(=O)c(-c2ccccc2)c(Cl)n(CCCCl)c1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)c(-c2ccccc2)c2n(c1=O)CCCS2
Reaction time: 1 h
Yield: 62.1 %

Procedure:
Sodium hydrosulfide (3.3 g) was added to a solution of 6-chloro-1-(3-chloropropyl)-5-phenyl-3-propyluracil (7 g) in DMF (60 ml) little by little under ice cooling and the mixture was stirred for 1 hour. The reaction solution was concentrated to dryness. The residue was dissolved in methylene chloride-H2O, and the organic layer was washed with water and dried. The solvent was evaporated and the resulting crude crystals were recrystallized from methanol to give colorless crystals (3.85 g, 62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](I)=[C:26]([F:31])[CH:25]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:27]3[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][C:26]=3[F:31])=[CH:16][CH:15]=2)[N:13]=1
Reactant: Fc1cc(Cl)ccc1I
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2ccc(Cl)cc2F)cc1
Yield: 31.9 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 4-chloro-2-fluoro-1-iodobenzene (0.123 g, 0.479 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 ml). The obtained crude product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.045 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.38 (d, J=8.4 Hz, 1H), 7.50 (t, J=8.7 Hz, 1H), 7.57-7.70 (m, 6H), 8.02 (d, J=8.7 Hz, 2H), 12.74 (br s, 1H). MS (m/z): 442.38 (M+).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])([O-:5])=[O:4]>O1CCOCC1.O>[C:16]([C:14]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([N+:3]([O-:5])=[O:4])[CH:15]=1)([OH:18])=[O:17]
Reactant: COC(=O)c1ccc(C(=O)OC)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 71684 %

Procedure:
1N NaOH (50 mL) was slowly added dropwise at room temperature over 30 min to a stirred solution of di-methyl nitroterephthalate (12 g, 0.05 mmol) in dioxane (100 mL). After stirring overnight at room temperature the reaction was diluted with water, washed with ether, acidified with 1N HCl (50 mL) and extracted with ethyl acetate. After drying the ethyl acetate phase (MgSO4) and evaporation, the resulting residue was purified by flash chromatography (silica gel, 98:2:0.1 CHCl3 :MeOH:HOAc) to yield the title compound (8.07 g, 72%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=O)[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18].N1CCCCC1>C(O)C>[CH2:17]([O:19][C:20]([C:22]1[C:26]([CH2:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]2)=[C:25]([CH:37]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[NH:11][C:10]2=[O:16])[NH:24][C:23]=1[CH3:39])=[O:21])[CH3:18]
Reactant: O=C1Cc2c(cccc2-c2cccnc2)N1
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4cccnc4)c32)c1CCCN1CCN(C)CC1
Temperature: 70 °C

Procedure:
A mixture of 4-pyridin-3-yl-1,3-dihydroindol-2-one (42 mg, 0.2 mmol), 5-formyl-2-methyl-4-[3-(4-methylpiperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (64 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol was heated in a sealed tube at 70° C. for 5 hours. The reaction was concentrated and the residue was purified by column chromatography to give the title compound.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].N1CCCCC1.N#N.[C:15]([O:19][CH3:20])(=[O:18])[CH:16]=[CH2:17].C([O-])(=O)C=C.Cl>C(OC)(C)(C)C>[CH3:6][O:5][C:1](=[O:4])[CH2:2][S:3][CH2:17][CH2:16][C:15]([O:19][CH3:20])=[O:18]
Reactant: C=CC(=O)OC
Reactant: COC(=O)CS
Agent: C=CC(=O)[O-]
Agent: Cl
Agent: N#N
Solvent: COC(C)(C)C
Solvent: C1CCNCC1
Product: COC(=O)CCSCC(=O)OC
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
Methyl thioglycolate (292 g, 2.61 mol) and piperidine (4.43 g, 0.052 mol) were charged to an inerted jacketed reactor equipped with an addition funnel, mechanical stirrer, N2 line and thermocouple thermometer. Methyl acrylate (250 g, 2.87 mol) was then added slowly over a period of 30 min keeping the temperature at approximately 45° C. Upon complete addition, the mixture was stirred at 45° C. for 30 min Piperidine (17.9 g, 210 mmol) was added and stirring at 45° C. continued for 30 min (in order to scavenge of excess acrylate). Tert-butylmethylether (MTBE) (251 ml) was charged, the mixture was cooled to 15° C. and 1 M HCl (251 ml) was added. The mixture was stirred for 5 min and the organic layer was collected and washed with water (251 ml). The mixture was concentrated to a minimum volume by distillation under reduced pressure at 50° C. Dichloromethane (251 ml) was charged and the mixture was again concentrated under reduced pressure by distillation at 40-45° C. Crude product III (480 g) was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][NH:14][C@H:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:30]=[C:31](Cl)OC(Cl)(Cl)Cl>C(#N)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:31](=[O:30])[N:14]2[CH2:15][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69 %

Procedure:
To a solution of (2S,5R)-tert-butyl 5-(benzyloxyamino)piperidine-2-carboxylate (4.14 g, 13.51 mmol) in dehydrated acetonitrile (615 mL) was added triethylamine (4.9 mL) under an argon atmosphere at 0° C., followed by adding dropwise diphosgene (1.18 mL) for 5 minutes, and stirring at the same temperature for 10 minutes. To this solution was added 4-dimethylaminopyridine (182 mg), followed by raising the temperature to room temperature and allowing to react for 3 hours. The reaction mixture was concentrated under reduced pressure to the volume of one tenth thereof, the resulting concentrated solution was diluted with ethyl acetate, followed by washing with water, 5% citric acid aqueous solution, 6.5% sodium bicarbonate aqueous solution, and saturated brine sequentially, then drying over anhydrous magnesium sulfate, and distilling off the solvent under reduced pressure. The resulting residue was subjected to silica gel column chromatography (hexane/ethyl acetate=2/1) to afford 3.09 g of the title compound (yield 69%). The resulting solid was recrystallized from ethyl acetate-hexane, the generated precipitate was filtered off. The wet crystal was washed with hexane, followed by drying at room temperature under reduced pressure, and the title compound was afforded as a colorless crystalline powder. Enantiomeric excess 99.4% ee (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 mL/min., retention time 8.0 min.).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH:7]12[CH2:14]C[CH:10]([CH2:11][CH2:12]1)[CH:9]=[C:8]2C(O)=O>C(Cl)Cl.CN(C=O)C>[CH:10]12[CH2:11][CH2:12][CH:7]([CH2:8][CH2:9]1)[CH:14]=[C:1]2[C:2]([Cl:4])=[O:3]
Reactant: O=C(O)C1=CC2CCC1CC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1=CC2CCC1CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.9 %

Procedure:
Oxalyl chloride (2.0 M in CH2Cl2, 2.4 mL, 4.8 mmol, 1.2 eq) was added to a solution of compound 11B (600 mg, 3.95 mmol, 1 eq) in CH2Cl2 (8 mL) containing one drop of DMF. The reaction mixture was stirred at rt for 3 h and then concentrated under reduced pressure to give 680 mg of compound 11C which was used in the next step without purification.