Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[NH:31]1[CH2:36][CH2:35][CH:34]([OH:37])[CH2:33][CH2:32]1>>[OH:37][CH:34]1[CH2:35][CH2:36][N:31]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)[CH2:32][CH2:33]1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: OC1CCNCC1
Product: CC1(C)c2cc(N3CCC(O)CC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound B2-1, the title compound was prepared from Compound B1 and piperidin-4-ol.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[C:3]=1I.[C:11]([C:13]1[CH:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.[Cu]I.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>[NH2:19][C:16]1[N:17]=[CH:18][C:13]([C:11]#[C:12][C:3]2[C:4]([NH2:9])=[N:5][C:6]([NH2:8])=[N:7][C:2]=2[Cl:1])=[CH:14][CH:15]=1
Reactant: Nc1nc(N)c(I)c(Cl)n1
Reactant: C#Cc1ccc(N)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1ccc(C#Cc2c(N)nc(N)nc2Cl)cn1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 850 mg (3.1 mmol) 6-chloro-5-iodo-pyrimidine-2,4-diamine, 2.2 g (19 mmol) 5-ethynyl-2-amino-pyridine, 59 mg (0.31 mmol) CuI, 218 mg (0.31 mmol) PdCl2(PPh3)2 and 21 mL triethylamine in 25 mL dry DMF. Yield after purification by RP-HPLC: 720 mg (88%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1I.CN(C)C=O.[CH2:27]([OH:30])[C:28]#[CH:29]>C(N(CC)CC)C.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>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:29]#[C:28][CH2:27][OH:30]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1I
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1C#CCO
Temperature: 70 °C

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-iodopyrazole (200 mg, the compound of Example A1) in triethylamine (2 ml) and dimethylformamide (1 ml) at room temperature was added propargyl alcohol (0.2 ml), cuprous iodide (10 mg) and bis(triphenylphosphine)palladium(II) chloride (20 mg). The reaction mixture was heated at 70° C. for two hours. The reaction mixture was partitioned between ether (10 ml) and water (10 ml). The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography on silica gel eluted with ether:dichloromethane (10:1) to provide the title compound as a pale yellow solid m.p. 237-9° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=4[CH3:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Reactant: Cc1cccc(C(=O)Cl)c1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)Nc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)c1C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
To a stirred solution of 0.320 g of 2,3-dimethylbenzoyl chloride in 10 ml of methylene chloride is added 0.33 ml of triethylamine. After stirring for 15 minutes, 0.485 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 5 hours. The reaction mixture is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.39 g of solid, m.p. 168°-170° C.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].[Br:17][CH2:18][C:19](Br)=[O:20]>C1C=CC=CC=1>[Br:17][CH2:18][C:19]([NH:1][C:2]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5])=[O:20]
Reactant: Nc1ccc(I)cc1C(=O)c1ccccn1
Reactant: O=C(Br)CBr
Solvent: c1ccccc1
Product: O=C(CBr)Nc1ccc(I)cc1C(=O)c1ccccn1
Reaction time: 0.5 h

Procedure:
To a suspension of 18.7 g of 2-(2-amino-5-iodobenzoyl)pyridine (R. I. Fryer, P. Zhang & R. Rios, Synth.Commun. 1993, 23, 985-992) in 760 ml of benzene were added 10.2 ml of bromoacetyl bromide and the mixture was heated to reflux temperature for 20 h. After cooling the crystals are filtered off and these are then stirred for 30 min. in a mixture of 3 l of saturated aqueous sodium hydrogen (sic) carbonate solution and 1 l of dichloromethane. The aqueous phase was separated and extracted again with dichloromethane. The dichloromethane solutions were dried over sodium sulphate and evaporated. The dark brown crystalline residue (25 g) was chromatographed over 400 g of silica gel. With toluene/ethyl acetate 8:1 there were eluted 19.1 g of the desired product which was recrystallized from ethanol/diethyl ether. There were obtained 17.6 g of 2-[2-(bromoacetylamino)-5-iodobenzoyl]-pyridine, which was used without further purification for the next step.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[S:6].Cl.I[CH3:18].[OH-].[Na+]>O.C(O)C>[NH2:1][CH2:2][CH2:3][NH:4][C:5](=[N:7][C:8]1[C:9]([Cl:15])=[CH:10][CH:11]=[CH:12][C:13]=1[Cl:14])[S:6][CH3:18]
Reactant: NCCNC(=S)Nc1c(Cl)cccc1Cl
Reactant: CI
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CSC(=Nc1c(Cl)cccc1Cl)NCCN

Procedure:
A solution of 12.68 g. of 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)thiourea in 80 ml. of ethanol, 4.0 ml. of concentrated hydrochloric acid and 12 ml. of iodomethane was refluxed for 2 hours. On cooling, the mixture was poured onto 200 ml. of water and sufficient 4N sodium hydroxide was added to bring the pH to 11. The aqueous solution was extracted 3×150 ml. of methylene chloride, and the combined organic layers were washed 1×100 ml. of water, dried over potassium carbonate and concentrated. The resulting gum gave a solid on standing, i.e., 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-2-methylthiopseudourea, m.p. 74°-79°, whose spectral data were consistent with the assigned structure. The material was too labile for purification and was acidified with hydrochloric acid and crystallized from ethanol-ether to give 14.10 g. (84%) of 1-(2-aminoethyl)-3-(2,6-dichlorophenyl)-2-methylthiopseudourea dihydrochloride, m.p. 179°-184°. Two crystallizations from ethanol-ether gave an analytical sample, m.p. 179°-182°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[N:21]=2)=[O:19])=[CH:4][CH:3]=1.[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:54]3[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[N:21]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(-c3cccc(C=O)c3)c2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(-c3cccc(CN4CCN(C)CC4)c3)c2)n1
Temperature: 25 °C
Yield: 33.6 %

Procedure:
A mixture of N-[(6-chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (50 mg, 0.074 mmol), 1-methylpiperazine (7.36 mg, 0.074 mmol), sodium triacetoxyborohydride (31.2 mg, 0.147 mmol) and acetic acid (5.05 μL, 0.088 mmol) in DCM (1 mL) was stirred at room temperature over the weekend. The reaction mixture was quenched with saturated NaHCO3, and extracted with DCM twice. The combined organic layers were concentrated under vacuum to give a crude residue. It was purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, converted to the free base with saturated NaHCO3 and the basified solution was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N-({6-chloro-3′-[(4-methyl-1-piperazinyl)methyl]-3-biphenylyl}methyl)-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide as a solid (19 mg, 33.8%). LC-MS m/z 765 (M+H)+, 1.44 min (ret time).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:35]1([C:38]2[CH:42]=[C:41]([Sn](CCCC)(CCCC)CCCC)[S:40][N:39]=2)[CH2:37][CH2:36]1.O>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>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:41]3[S:40][N:39]=[C:38]([CH:35]4[CH2:37][CH2:36]4)[CH:42]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C2CC2)ns1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(-c2cc(C3CC3)ns2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (50 mg, 0.100 mmol), 3-cyclopropyl-5-(tributylstannyl)isothiazole (62.0 mg, 0.150 mmol) and tetrakis(triphenylphosphine)palladium(0) (34.6 mg, 0.030 mmol) in toluene (10 mL) was heated to 120° C. for 45 minutes via microwave irradiation. The reaction mixture was poured into water and was extracted with EtOAc. The extracts were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (1:1) to give the title compound as a yellow solid, which was used without further purification (58.9 mg, 100%). ESI-MS m/z [M+H]+ calc'd for C28H36FN5O6S, 590. found, 590.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]=1)[C:2]#[CH:3]>CO>[N:4]1[CH:1]=[CH:2][CH2:3][N:6]2[C:7](=[O:10])[S:8][CH2:9][C:5]=12
Reactant: C#CCNC1=NC(=O)SC1
Solvent: CO
Product: O=C1SCC2=NC=CCN12
Yield: 31.7 %

Procedure:
A solution of 4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one (120 mg) in methanol (2 mL) was stirred at 140° C. for 1 hr under microwave irradiation, and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (38 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]=[N+:12]=[N-:13])[CH:5]=1.[C:15]([O:19][Si](C)(C)C)(=[O:18])[C:16]#[CH:17].CO>O>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[CH:17]=[C:16]([C:15]([OH:19])=[O:18])[N:13]=[N:12]2)[CH:5]=1)=[O:14]
Reactant: COC(=O)c1ccc(C)c(N=[N+]=[N-])c1
Reactant: C#CC(=O)O[Si](C)(C)C
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C)c(-n2cc(C(=O)O)nn2)c1
Reaction time: 2 h
Yield: 68.5 %

Procedure:
3-Azido-4-methyl-benzoic acid methyl ester (878 mg, 4.60 mmol) and trimethylsilyl propiolate (777 mg, 5.05 mmol) were heated to 80° C. in a sealed tube overnight. The tube was cooled and the contents were mixed with 20 mL of MeOH. After 2 h, the mixture was poured into rapidly stirring cold water, and the resulting precipitate was filtered and dried under air to provide 823 mg of 1-(5-Methoxycarbonyl-2-methyl-phenyl)-1H-[1,2,3]triazole-4-carboxylic acid.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:15]1[C:24]2[CH:23]([NH2:25])[CH2:22][CH2:21][CH2:20][C:19]=2[CH:18]=[CH:17][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C1COCC1>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:25][CH:23]2[C:24]3[N:15]=[CH:16][CH:17]=[CH:18][C:19]=3[CH2:20][CH2:21][CH2:22]2)[CH2:10][CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NC1CCCc2cccnc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(NC2CCCc3cccnc32)CC1
Yield: 98 %

Procedure:
Using general procedure B: Reaction of Boc-4-piperidone (641 mg, 3.22 mmol 5,6,7,8-Tetrahydro-quinolin-8-ylamine (476 mg, 3.22 mmol), sodium triacetoxyborohydride (1.36 g, 6.44 mmol) and acetic acid (0.25 mL) in THF (25 mL) at room temperature under N2 for 20 min afforded the title compound (1.05 g, 98%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([CH3:15])=[CH:7][C:6]=1[Si:16](Cl)([CH3:18])[CH3:17])[CH:2]=[CH2:3].[CH3:20][CH:21]1[S:25][C:24]2=[C:26]([Li])[C:27]3[S:28][C:29]([CH3:32])=[CH:30][C:31]=3[C:23]2=[CH:22]1>C1(C)C=CC=CC=1.O1CCCC1>[CH2:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]([CH3:15])=[CH:7][C:6]=1[Si:16]([C:26]1[C:27]2[S:28][C:29]([CH3:32])=[CH:30][C:31]=2[C:23]2[C:24]=1[S:25][CH:21]([CH3:20])[CH:22]=2)([CH3:17])[CH3:18])[CH:2]=[CH2:3]
Reactant: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)Cl
Reactant: [Li]C1=C2SC(C)C=C2c2cc(C)sc21
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](C)(C)C1=C2SC(C)C=C2c2cc(C)sc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of (2-allyloxy-3-tert-buyl-5-methylphenyl)chlorodimethylsilane (0.71 g, 2.40 mmol) in toluene (4 mL) was added dropwise to a solution of (2,5-dimethylcyclopenta[1,2-b:4,3-b′]dithiophen-7-yl)lithium (0.51 g, 2.40 mmol) in tetrahydrofuran (10 mL) at −78° C. The resulting reaction mixture was warmed to room temperature and stirred for 5 hours. After the solvent was distilled off under reduced pressure, hexane was added and the mixture was filtered to remove insoluble substances. The filtrate was concentrated under reduced pressure to quantitatively obtain (2-allyloxy-3-tert-butyl-5-methylphenyl)(2,5-dimethylcyclopenta[1,2-b:4,3-b′]dithiophen-7-yl)dimethylsilane.
Reaction SMILES: C([O:8][C:9](=O)[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:33])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)=[O:22])C1C=CC=CC=1.[CH3:35][S@@:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=1)=[O:37]>>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([CH2:24][NH:23][C:21]([N:17]2[CH2:18][CH2:19][CH2:20][C@H:16]2[C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9](=[O:8])[CH2:35][S@@:36]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[O:37])=[O:33])=[O:22])=[CH:30][CH:29]=1
Reactant: COc1ccc([S@](C)=O)cc1
Reactant: COc1ccc(CNC(=O)N2CCC[C@H]2C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Product: COc1ccc(CNC(=O)N2CCC[C@H]2C(=O)N2CCC[C@H]2C(=O)C[S@](=O)c2ccc(OC)cc2)cc1
Yield: 31.2 %

Procedure:
By the same procedure as in Example 15-D) using N-(4-methoxybenzylaminocarbonyl)-L-prolyl-L-proline benzyl ester (1.30 g) and (S)-(-)-4-methoxyphenyl methyl sulfoxide (480 mg) as obtained in Example 15-C), there was obtained 460 mg of the title compound as colorless needles (See Table 7).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[C:18]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH:28]2[CH2:32][O:31]C(C)(C)[O:29]2)[CH:23]=[CH:22][C:21]=1[F:35])=[O:19]>C(O)(C(F)(F)F)=O.O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH:5]=[CH:4][C:3]=1[C:18]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][CH:28]([OH:29])[CH2:32][OH:31])[CH:23]=[CH:22][C:21]=1[F:35])=[O:19]
Reactant: CC1(C)OCC(COc2ccc(F)c(C(=O)c3ccc(Nc4ccccc4[N+](=O)[O-])cc3Cl)c2)O1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cc(OCC(O)CO)ccc1F)c1ccc(Nc2ccccc2[N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 519 (46 mg, 0.092 mmol) was dissolved in TFA:H2O (3:1, 10 mL) and stirred at RT for 1 h. The reaction mixture was concentrated in vacuo and purified by flash chromatography using DCM/MeOH (v:v=4:1 to 1:4) as the eluent, affording the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])=[O:16])[N:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:35][C:36]([F:41])([F:40])[CH:37]1[O:39][CH2:38]1>CS(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:38][CH:37]([OH:39])[C:36]([F:41])([F:40])[F:35])[C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:26])([F:27])[F:28])=[O:16])[N:9]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)C1CO1
Reactant: O=C(Cn1nc(-c2ccc(Cl)cc2)[nH]c1=O)NCc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O)NCc1ccccc1C(F)(F)F
Temperature: 120 °C
Reaction time: 3 h

Procedure:
100 mg (0.24 mmol) of 2-[3-(4-chlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-[2-(trifluoromethyl)benzyl]-acetamide from Example 243A are placed with 119 mg (0.37 mmol) of caesium carbonate in 0.6 ml of DMSO and treated with 137 mg (1.22 mmol) of 1,1,1-trifluoro-2,3-epoxypropane. This is stirred for 3 hrs at 120° C. Next, 137 mg (1.22 mmol) of 1,1,1-trifluoro-2,3-epoxypropane are again added and the mixture stirred for a further hour at 120° C. The suspension is then cooled to RT, diluted with ethyl acetate and washed three times with saturated ammonium chloride solution. The organic phase is dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 10]. 30.6 mg (24% of theory) of the target compound are thus obtained.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[Cl:17])=[C:6]([CH3:18])[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[K].[CH:26]([C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[N:33][CH:34]=1)([CH3:28])[CH3:27]>CS(C)=O>[Cl:17][C:10]1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=1[O:8][C:7]1[C:2]([NH:38][S:35]([C:32]2[CH:31]=[CH:30][C:29]([CH:26]([CH3:28])[CH3:27])=[CH:34][N:33]=2)(=[O:37])=[O:36])=[N:3][C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[N:5][C:6]=1[CH3:18]
Reactant: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2Cl)c1
Reactant: CC(C)c1ccc(S(N)(=O)=O)nc1
Agent: [K]
Solvent: CS(C)=O
Product: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)C)cn2)c1
Yield: 77.6 %

Procedure:
9.2 g of 4-[4-chloro-5-(2-chloro-5-methoxy-phenoxy )-6-methyl-pyrimidin-2-yl]-morpholine and 17.8 g of 5-isopropyl-pyridine-2-sulphonamide potassium in 130 ml of dry dimethyl sulphoxide were heated to 120° C. under argon for 16 hours. Thereafter, the dimethyl sulphoxide was distilled off, the residue was partitioned between ethyl acetate and 1 N hydrochloric acid and the organic phase was washed neutral. The organic phase was dried, the solvent was evaporated and the residue was recrystallized from ethanol. 10.3 g of 5-isopropyl-pyridine-2-sulphonic acid 5-(2-chloro-5-methoxy-phenoxy )-6-methyl-2-morpholin-4-yl-pyrimidin-4-ylamide, MS: M =534, were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[NH:8][C:7](=[O:14])[C:6]2=[O:15].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1Br>>[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[C:6]1([OH:15])[C:5]2[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=2)[NH:8][C:7]1=[O:14]
Reactant: COc1ccc(Br)c(OC)c1
Reactant: COc1cc2c(cc1OC)C(=O)C(=O)N2
Product: COc1ccc(C2(O)C(=O)Nc3cc(OC)c(OC)cc32)c(OC)c1
Yield: 59.6 %

Procedure:
With 1.38 g of 5,6-dimethoxyisatin and 3.61 g of 2,4-dimethoxy bromobenzene as starting material, 1.37 g of the title compound (brown solid) was obtained by a similar method to Step 21-1.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][CH2:8][CH2:9][CH3:10])=[O:6])[CH2:2][CH3:3].[C:11]([OH:17])(=O)[CH2:12][C:13]([OH:15])=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH2:1]([N:4]1[C:11](=[O:17])[CH2:12][C:13](=[O:15])[N:7]([CH2:8][CH2:9][CH3:10])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: O=C(O)CC(=O)O
Reactant: CCCNC(=O)NCCC
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CCCN1C(=O)CC(=O)N(CCC)C1=O

Procedure:
Synthesis was carried out according to the procedure of Goldner, Ann. Chem., 691, 142 (1966) using 1,3-di-n-propylurea (777 g., 5.38 mole), malonic acid (660 g., 6.34 mole), glacial acetic acid (1050 ml.) and acetic anhydride (2160 ml.) to obtain 790 g. (69.2%) of product, melting point 77° - 80° C. NMR and IR spectra were consistent with the assigned structure.
Reaction SMILES: S(Cl)(Cl)=O.[C:5]([C:8]1[O:9][C:10]2[C:16]([N:17]3[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]3=[O:29])=[CH:15][CH:14]=[C:13]([Cl:30])[C:11]=2[CH:12]=1)([OH:7])=O.[CH2:31]([NH2:33])[CH3:32]>O>[Cl:30][C:13]1[C:11]2[CH:12]=[C:8]([C:5](=[O:7])[NH:33][CH2:31][CH3:32])[O:9][C:10]=2[C:16]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:15][CH:14]=1
Reactant: CCN
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3cc(C(=O)O)oc23)c1=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: CCNC(=O)c1cc2c(Cl)ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Reaction time: 3 h
Yield: 77.7 %

Procedure:
10 ml of thionyl chloride was added to 0.37 g (0.96 mmol) of 3-(2-carboxy-4-chlorobenzofuran-7-yl)-1-methyl-6-trifluoromethyluracil, followed by stirring for 3 hours under heating and refluxing. After completion of the reaction, thionyl chloride was distilled off under reduced pressure. The obtained residue was dissolved in 20 ml of tetrahydrofuran. To this solution, 0.24 g (3.84 mmol) of ethylamine (70% aqueous solution) was added, followed by stirring for 10 minutes at room temperature. After completion of the reaction, the reaction solution was poured into water, and precipitated crystals were collected by filtration to obtain 0.31 g (yield: 78.3%) of the desired product as white crystals. Melting point: 225-226° C.