Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[CH:21]=4)[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2].[F:29][C:30]([F:36])([F:35])[CH2:31][CH2:32]C=O>>[CH2:1]([C@:3]1([OH:28])[C:25]2[CH:24]=[C:23]3[N:10]([CH2:11][C:12]4[C:13]3=[N:14][C:15]3[CH:16]=[C:17]([F:22])[CH:18]=[CH:19][C:20]=3[C:21]=4[CH2:32][CH2:31][C:30]([F:36])([F:35])[F:29])[C:9](=[O:26])[C:8]=2[CH2:7][O:6][C:5](=[O:27])[CH2:4]1)[CH3:2]
Reactant: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2cc3ccc(F)cc3nc2-1
Reactant: O=CCCC(F)(F)F
Product: CC[C@@]1(O)CC(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1cc(F)ccc1c2CCC(F)(F)F

Procedure:
The product of Example 84 is treated with 4,4,4-trifluorobutyraldehyde according to a procedure similar to Stage 95e in order to produce the expected solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:66])[C@H:10]([CH2:62][CH:63]([CH3:65])[CH3:64])[NH:11][C:12](=[O:61])[C@H:13]([C:57]([CH3:60])([CH3:59])[CH3:58])[NH:14][C:15](=[O:56])[C@H:16]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH3:55])[NH:17][C:18](=[O:47])[C@H:19]([CH2:38][CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[NH:20]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N1CCCCC1.ClCCl>[CH2:1]([O:8][C:9](=[O:66])[C@H:10]([CH2:62][CH:63]([CH3:64])[CH3:65])[NH:11][C:12](=[O:61])[C@H:13]([C:57]([CH3:59])([CH3:58])[CH3:60])[NH:14][C:15](=[O:56])[C@H:16]([CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[CH3:55])[NH:17][C:18](=[O:47])[C@H:19]([CH2:38][CH2:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])[NH2:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cc1ccccc1C[C@H](NC(=O)[C@@H](N)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1)C(C)(C)C

Procedure:
A solution of 10.89 g (12.07 mmol) of N-[N-[N-[N-[(9-fluorenyl)methoxycarbonyl]-O-tert-butyl-L-a-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in 30 ml of piperidine and 120 ml of dichloromethane was stirred for 30 minutes at room temperature. The solvent was removed by evaporation and the residue was chromatographed on silica gel using firstly 20% ethyl acetate in hexane and then 10% methanol in dichloromethane for the elution. Evaporation gave N-[N-[N-[O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine benzyl ester in the form of an oil which was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C:6]3[NH:13][CH:14]=[CH:15][C:5]=3[C:4]=2[CH:3]=1.Cl.[CH2:17]([C:19]([OH:21])=[O:20])[CH3:18].[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:1][C:2]2[CH:11]=[CH:10][C:9]3[NH:8][C:7](=[O:12])[C:6]4[NH:13][CH:14]=[CH:15][C:5]=4[C:4]=3[CH:3]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1.[CH2:17]([C:19]([O-:21])=[O:20])[CH3:18]
Reactant: Nc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: CCC(=O)O
Agent: Cl
Product: CCC(=O)[O-]
Product: O=c1[nH]c2ccc(NS(=O)(=O)c3ccc(Br)cc3)cc2c2cc[nH]c12
Yield: 40.7 %

Procedure:
This compound is prepared according to synthesis 43, from 60 mg (0.20 mmol) of 8-amino-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate hydrochloride (synthesis 64) and 52 mg (0.21 mmol) of 4-bromo-benzenesulfonyl chloride. After recrystallization from methanol, 40 mg (42%) of 8-(4-bromo-benzenesulfonylamino)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a light brown solid.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[NH:13][N:12]=[C:11](I)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]#[CH:22].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:1]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[NH:13][N:12]=[C:11]([C:22]#[C:21][CH2:20][CH2:19][CH2:18][CH2:17][Cl:16])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C#CCCCCCl
Reactant: CCCCc1nc2c(I)n[nH]c2c(=O)[nH]1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1nc2c(C#CCCCCCl)n[nH]c2c(=O)[nH]1
Temperature: 60 °C
Yield: 166.9 %

Procedure:
To a solution of 5-butyl-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (4.97 g, 15.62 mmol) in N,N-dimethylformamide (100 mL) was added bis(triphenylphosphine)palladium(II)dichloride (1.228 g, 1.750 mmol) and copper(I) iodide (0.595 g, 3.12 mmol). The solution was stirred and degassed with nitrogen for 5 minutes then the reaction mixture placed under a nitrogen atmosphere. A solution of 6-chloro-1-hexyne (3.64 g, 31.2 mmol) and triethylamine (4.36 mL, 31.2 mmol) in N,N-dimethylformamide (30 mL) was added dropwise over 10 minutes. The reaction mixture was stirred at ambient temperature for a further 10 minutes then heated to 60° C. for 2.5 hours. The reaction mixture was concentrated in vacuo at 60° C. and the resulting residue partitioned between ethyl acetate (250 mL) and a 1:1 mixture of water:brine (500 mL). The organic layer was separated and the aqueous layer back extracted with ethyl acetate (250 mL). The combined organic phases were dried through a hydrophobic frit and concentrated in vacuo to give a brown solid (8.0 g). The residue was dissolved in a 1:1 mixture of MeOH:DCM and absorbed onto Florisil. The solid was loaded and purified by chromatography on silica (330 g) using a 0-100% ethyl acetate-cyclohexane gradient over 10 column volumes followed by flushing with ethyl acetate for 9 column volumes. The appropriate fractions were combined and evaporated in vacuo to give a yellow solid (3.55 g). The solid was triturated with diisopropyl ether, filtered and dried in vacuo at 50° C. to give the title compound as a pale yellow solid (3.14 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[CH3:35][NH:36][CH3:37]>C(O)C>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:36]([CH3:37])[CH3:35])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: CNC
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Solvent: CCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN(C)C)c(OC)cc23)c2c1OCO2
Yield: 77 %

Procedure:
N-[5-Chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (200 mg, 0.40 mmol) and dimethylamine (5 ml of a 33% solution in ethanol) were stirred and heated under reflux at 90° for 30 min. before evaporating the solution. A further 5 ml of dimethylamine solution were added to the residue and the solution heated for a further 90 min. then evaporated. Again a further 5 ml of dimethylamine solution were added to the residue and the solution heated for 1 hr. before quenching in water and extracting with dichloromethane. The extract was washed with saturated brine, dried over magnesium sulphate and evaporated to an orange oil. It was then purified by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent. There was thus obtained the title compound (156 mg, 77%) as a pale orange solid; NMR Spectrum:(DMSOd6) 1.95 (quintet, 2H), 2.17 (s, 6H), 2.38 (t, 2H), 2.71 (t, 2H), 3.30 (s, 3H), 3.52 (t, 2H), 3.92 (s, 3H), 4.17 (t, 2H), 6.14 (s, 2H), 7.07 (s, 1H), 7.17 (s, 1H), 7.81 (s, 1H), 8.31 (s, 1H), 9.50 (s, 1H); Mass Spectrum: M+H+ 513/515.
Reaction SMILES: [C:1]([C:4]1[C:9](F)=[CH:8][C:7](C2C=CC3C(=CC=C([C@H]4CC[C@H](CCC)CC4)C=3)C=2)=[CH:6][C:5]=1F)(=[O:3])N.FC1C2C(=CC([C@H]3CC[C@H](CCC)CC3)=CC=2)C=CC=1C1C=C(F)C=C(F)C=1.C([Li])CCC.C(=O)=[O:65]>>[C:1]([OH:3])(=[O:65])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C=O
Reactant: CCC[C@H]1CC[C@H](c2ccc3cc(-c4cc(F)c(C(N)=O)c(F)c4)ccc3c2)CC1
Agent: CCC[C@H]1CC[C@H](c2ccc3c(F)c(-c4cc(F)cc(F)c4)ccc3c2)CC1
Agent: [Li]CCCC
Product: O=C(O)c1ccccc1

Procedure:
10 g of 2-(4-carbamoyl-3,5-difluorophenyl)-6-(trans-4-propylcyclohexyl)naphthalene (synthesized by lithioating 1-fluoro-2-(3,5-difluorophenyl)-6-(trans-4-propylcyclohexyl)naphthalene obtained in Example 5 with butyl lithium, blowing carbon dioxide through the material to produce benzoic acid, reacting the product with thionyl chloride to produce acid chloride, and then blowing ammonia gas through the material) was dissolved in 40 ml of DMF. To the solution was then added 2.5 ml of phosphorus oxychloride. The reaction mixture was then allowed to undergo reaction at a temperature of 25° C. for 2 hours. The reaction solution was then poured into ice water. To the reaction solution was then added diluted hydrochloric acid. The resulting aqueous phase was then extracted with toluene. The material thus extracted and the organic phase were together washed with water, saturated aqueous solution of sodium bicarbonate and saturated brine, and then dehydrated and dried over anhydrous sodium sulfate. The residue was purified through silica gel column chromatography (hexane/dichloromethane=6/4), and then recrystallized from ethanol to obtain 7.4 g of 1-fluoro-2-(3,5-difluoro-4-cyanophenyl)-6-(trans-4-propylcyclohexyl)naphthalene.
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[CH3:14][C:15](=[CH:17][CH2:18][CH2:19]/[C:20](=[CH:22]/[CH2:23]O)/[CH3:21])[CH3:16].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>ClCCl>[CH3:21][C:20]([CH2:19][CH2:18][CH:17]=[C:15]([CH3:16])[CH3:14])=[CH:22][CH2:23][O:6][C:5](=[O:7])[CH2:4][CH2:3][C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCC(=O)CCC(=O)O
Reactant: CC(C)=CCC/C(C)=C/CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCCCCC(=O)CCC(=O)OCC=C(C)CCC=C(C)C
Yield: 218.8 %

Procedure:
A solution of 5.2 g 4-oxo-decanoic acid, 13.5 g geraniol, 17.5 g N,N′-dicyclohexyl-carbodiimide and 1.0 g 4-pyrrolidinopyridine in 250 ml of dichloromethane was stirred for 24 hours at room temperature. The precipitate was filtered off, the filtrate was diluted with ether, washed with aqueous hydrochloric acid, saturated NaHCO3 and brine. The organic phase was dried, filtered and evaporated to dryness. The resulting oil-cristall mixture was purified by chromatography to yield 19.7 g of a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=O)=[C:4]([CH3:26])[CH:3]=1.Cl.[NH2:28][OH:29].C(=O)([O-])O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[N:28][OH:29])=[C:4]([CH3:26])[CH:3]=1
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(O)cc2)c2ccc(Cl)cc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(C(C[C@@H](c2ccc(O)cc2)c2ccc(Cl)cc2C)=NO)ccn1

Procedure:
In analogy to example 132, step 6, from (S)-3-(4-chloro-2-methyl-phenyl)-3-(4-hydroxy-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow foam, MS (ESI+): m/z=381.2 ([M+H]+).
Reaction SMILES: [CH:1]([N:3]=[C:4]=[O:5])=[CH2:2].[CH:6]1([OH:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.[N-]=C=O>C(OCC)(=O)C>[CH:1]([NH:3][C:4](=[O:5])[O:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[CH2:2]
Reactant: OC1CCCCC1
Reactant: C=CN=C=O
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Agent: [N-]=C=O
Solvent: CCOC(C)=O
Product: C=CNC(=O)OC1CCCCC1
Temperature: 40 °C

Procedure:
69 parts of vinyl isocyanate and 89.5 parts of ethyl acetate are introduced into a reaction vessel and heated to 40° C. A mixture of 110 parts of cyclohexanol and 89.5 parts of ethyl acetate (containing 0.02% of dibutyl-tin dilaurate as the catalyst) is added in the course of 1 hour. The mixture is then allowed to react for a further 2 hours at 40° C. A light yellow solution is obtained, from which the reaction product separates out, as crystals, on cooling. Blocked isocyanate content: 11.7%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11](OCC)(=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[C:11](=[O:17])[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:10])[CH3:16]
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)C(=O)OCC
Product: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1
Yield: 60 %

Procedure:
The general procedure of Referential Example 3-1) was repeated through use of 4′-fluoroacetophenone (3.0 g) and diethyl oxalate (5.9 mL), to thereby give the title compound as a solid (3.12 g, 60%).
Reaction SMILES: [ClH:1].[C:2]1([S:8]([N:11]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]4[CH2:20][CH2:21][NH:22][CH2:23][C:13]([C:14]=34)=[CH:12]2)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C=O.Cl>C1COCC1>[ClH:1].[CH3:24][N:22]1[CH2:21][CH2:20][C:15]2[C:14]3[C:13](=[CH:12][N:11]([S:8]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)(=[O:10])=[O:9])[C:19]=3[CH:18]=[CH:17][CH:16]=2)[CH2:23]1
Reactant: O=S(=O)(c1ccccc1)n1cc2c3c(cccc31)CCNC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN1CCc2cccc3c2c(cn3S(=O)(=O)c2ccccc2)C1
Temperature: 70 °C
Yield: 12 %

Procedure:
1-(Phenylsulfonyl)-3,4,5,6-tetrahydro-1H-azepino[3,4,5-cd]indole hydrochloride, Example 12 (100 mg, 0.3 mmol) was dissolved in THF (4 mL) before sodium triacetoxyborohydride (203 mg, 1.0 mmol) and acetic acid (191 mg, 3.2 mmol) was added. Aqueous formaline (37%, 1 mL) was added and the reaction mixture was heated in MW at 70° C. for 300 s. The reaction mixture was evaporated and the crude product was purified by preparative HPLC using System B, 100 mM NH4HCO3/MeCN (36-66% MeCN). The product was isolated and transformed to the hydrochloride. 15.2 mg of the pure product was isolated as an yellow oil, yield 12%. MS m/z 327 [M+H]+.
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:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=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>[Cl:17][C:10]1[CH:9]=[C:8]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[C:7]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[F:26])=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: OB(O)c1ccccc1F
Reactant: CON(C)C(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CON(C)C(=O)c1cc(Cl)c2cccnc2c1-c1ccccc1F
Temperature: 100 °C

Procedure:
To a mixture of 5-chloro-7-{[methoxy(methyl)amino]carbonyl}quinolin-8-yl trifluoromethanesulfonate (0.16 g, 0.41 mmol) and (2-fluorophenyl)boronic acid (0.069 g, 0.49 mmol) in 1,4-dioxane (2 mL) was added 1 N solution of sodium carbonate in water (0.62 mL, 34 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.020 mmol). The mixture was heated at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, and then concentrated. The residue was purified on silica gel (eluting with 0-60% EtOAc in Hexane) to give the desired compound as a bis-trifluoroacetate salt (42 mg, 29%). LCMS calculated for C18H15ClFN2O2(M+H)+: m/z=345.1; found: 345.0.
Reaction SMILES: [NH:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[C:4](=[O:10])[C:3]2[CH2:11][CH2:12][CH2:13][C:2]1=2.CN(C=O)C.ClC(OCC)=O.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>C1COCC1.O>[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:7]([C:5]2[C:4](=[O:10])[C:3]3[CH2:11][CH2:12][CH2:13][C:2]=3[NH:1][CH:6]=2)=[O:9])=[CH:29][CH:28]=1
Reactant: O=C(O)c1c[nH]c2c(c1=O)CCC2
Reactant: COc1ccc(CN)cc1
Agent: CCOC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)c2c[nH]c3c(c2=O)CCC3)cc1
Temperature: 90 °C
Yield: 48.9 %

Procedure:
A quantity of 100 mg (0.61 mmole, 1.0 eq) of 4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxylic acid is dissolved in 5 mL THF and 1 mL DMF and treated at 0° C. with 0.18 mL (1.2 mmole, 2.2 eq) TEA followed by 0.12 mL (1.2 mmole, 2.2 eq) of ethyl chloroformate. The resulting solution is stirred for 30 min. at which time 0.17 mL (1.2 mmole, 2.2 eq) of 4-methoxybenzylamine is added. The solution is allowed to warm to room temperature for 1 hr before the addition of 20 mL of H2O, the THF is removed under reduced pressure, and the resulting solid is filtered and washed with H2O and then Et2O. The resulting solid is slurried in 1 mL EtOH and 5 mL 10% NaOH, warmed to 90° C. for 10 min., cooled to 0° C., and pH adjusted to 9.0 with 3N HCl. The resulting solid is filtered, washed with H2O, Et2O, and purified by chromatography (silica gel, 10% CH3OH/CH2Cl2), to yield 89 mg of N-(4-Methoxybenzyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide (compound 1), mp 240-241° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1C(O)=O.C([O:15][CH2:16]C)(=O)C.O.Cl.C([N:22](CC)CC)C>O1CCOCC1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>[CH3:11][C:8]1[CH:9]=[CH:10][C:2]2[NH:1][C:16](=[O:15])[NH:22][C:3]=2[CH:7]=1
Reactant: CCOC(C)=O
Reactant: Cc1ccc(N)c(C(=O)O)c1
Reactant: CCN(CC)CC
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c(=O)[nH]c2c1
Reaction time: 1.5 h

Procedure:
4.00 g of 2-amino-5-methylbenzoic acid was dissolved in 40 mL of 1,4-dioxane, to which 5.5 mL of triethylamine and 6.8 mL of diphenylphosphoryl azide were successively added, and this mixture was stirred for 1.5 hours while heating it under reflux. The reaction mixture, to which a mixture of ethyl acetate and water was added, was adjusted to pH 7 with 1M hydrochloric acid, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous sodium sulfate, and the solvent was distilled out under reduced pressure to yield 2.96 g of 5-methyl-1,3-dihydro-2H-benzimidazol-2-one as light yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([Br:16])[CH:3]=1.[CH3:17][O:18][C:19](=[O:32])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[CH:31])=[CH:24][CH:23]=1>CN(C=O)C.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.[Cu]I>[CH3:17][O:18][C:19](=[O:32])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]#[C:31][C:2]2[CH:7]=[C:6]([C:8]#[C:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=[C:4]([Br:16])[CH:3]=2)=[CH:24][CH:23]=1
Reactant: C#CCOc1ccc(OCC(=O)OC)cc1
Reactant: Brc1cc(Br)cc(C#Cc2ccccc2)c1
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: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#Cc3ccccc3)c2)cc1
Temperature: 70 °C

Procedure:
A mixture of 1,3-dibromo-5-phenylethynyl-benzene (0.1 g, 0.3 mmol, intermediate 3), (4-prop-2-ynyloxy-phenoxy)-acetic acid methyl ester (66 mg, 0.3 mmol), Pd(PPh3)2Cl2 (10 mg, 0.015 mmol), CuI (16 mg, 0.008 mmol) in dry DMF (1.5 ml) and triethylamine (1.5 ml) was heated in a microwave own for 10 min at 70° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography to give {4-[3-(3-bromo-5-phenylethynyl-phenyl)-prop-2-ynyloxy]-phenoxy}-acetic acid methyl ester in 27 mg (20%) yield.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.[CH2:26]([N:28](CC)[CH2:29][CH3:30])[CH3:27].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:28]4[CH2:29][CH2:30][CH2:27][CH2:26]4)=[CH:4][CH:5]=3)[C:12](=[O:25])[CH:13]=2)[CH:20]=1
Reactant: O=c1cc(OCc2cccnc2)ccn1CCc1ccc(CO)cc1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: ClCCl
Product: O=c1cc(OCc2cccnc2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 50 mg (0.15 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(pyridin-3-ylmethoxy)-1H-pyridin-2-one (example 11.1a) in 3.0 mL DCM is added 62 μL triethylamine (0.45 mmol) and subsequently 23 μL (0.30 mmol) methanesulfonyl chloride at RT. The reaction mixture is stirred 1 h at RT, and then 25 μL (0.30 mmol) pyrrolidine is added. The mixture is stirred additional 2 h at RT and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [SH:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([NH:9]C(NCCN3CCOCC3)=O)[S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:30]1[N:34]2[N:35]=[C:36]([C:39]3[CH:40]=[N:41][N:42]([CH3:44])[CH:43]=3)[CH:37]=[CH:38][C:33]2=[N:32][N:31]=1.C(=O)([O-])O>O.CS(C)=O>[CH3:44][N:42]1[CH:43]=[C:39]([C:36]2[CH:37]=[CH:38][C:33]3[N:34]([C:30]([S:1][C:2]4[CH:22]=[CH:21][C:5]5[N:6]=[C:7]([NH2:9])[S:8][C:4]=5[CH:3]=4)=[N:31][N:32]=3)[N:35]=2)[CH:40]=[N:41]1
Reactant: O=C(NCCN1CCOCC1)Nc1nc2ccc(S)cc2s1
Reactant: Cn1cc(-c2ccc3nnc(Cl)n3n2)cn1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5nc(N)sc5c4)n3n2)cn1
Temperature: 190 °C
Reaction time: 0.5 h
Yield: 38.1 %

Procedure:
280 mg of 1-(6-sulphanyl-benzothiazol-2-yl)-3-(2-morpholin-4-yl-ethyl)urea, 2 cm3 of dimethyl sulphoxide and 240 mg of potassium carbonate are introduced, at 20° C., in a microwave tube equipped with a magnetic stirrer. The suspension thus obtained is stirred for 5 minutes before the addition of 200 mg of 3-chloro-6-(1-methyl-1H-pyrazol-4-yl)-1,2,4-triazolo[4,3-b]pyridazine. The reaction mixture is then heated in a microwave oven for 10 minutes at 190° C., and then poured into 100 cm3 of water. The resulting mixture is stirred for 30 minutes under cold conditions. The solid is filtered off, washed with 3×100 cm3 of water and then spin-filter-dried. The brown powder thus obtained is purified by chromatography on silica gel (eluent: 95/5/0.5 dichloromethane/methanol/aqueous ammonia). A small amount of methanol and of hydrochloric acid in solution in dioxane is added to the fractions containing the expected product (to improve solubility). The fractions are combined and concentrated under reduced pressure. The oil thus obtained is taken up with 20 cm3 of a saturated aqueous solution of hydrogen carbonate (pH 8-9). The precipitate formed is filtered off and then washed with 3×20 cm3 of water and dried under vacuum. 120 mg of 6-{[6-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-1,3-benzothiazol-2-amine are thus obtained in the form of a light brown solid.