Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si](C)(C)CC[O:5][NH:6][C:7]([C@H:9]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[C:11](=[O:28])[NH:10]1)=[O:8].B(F)(F)F.CCOCC>C(Cl)Cl>[OH:5][NH:6][C:7]([C@H:9]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:16][CH:15]=2)[C:11](=[O:28])[NH:10]1)=[O:8]
Reactant: C[Si](C)(C)CCONC(=O)[C@H]1C[C@@H](c2ccc(OCc3ccccc3)cc2)C(=O)N1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: O=C1N[C@@H](C(=O)NO)C[C@H]1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a suspension of (2R, 4S)-4-(4-benzyloxyphenyl)-5-oxo-pyrrolidine-2-carboxylic acid (2-trimethylsilanylethoxy)amide (95 mg, 0.22 mmol) in methylene chloride was added boron trifluoride etherate (0.86 μL, 0.68 mmol). The mixture was stirred at room temperature for 75 minutes. During this period the suspended solid dissolved completely and the product precipitated. The mixture was quenched by addition of saturated aqueous NH4Cl solution. The title compound was collected by filtration, washing well with ethyl acetate and water, and dried. The yield was 56 mg (78%).
Reaction SMILES: CS[C:3]1[N:4]=[C:5]([CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[NH:6][C:7](=[O:11])[C:8]=1[C:9]#[N:10].[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([NH:23][C:3]2[N:4]=[C:5]([CH2:12][C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[NH:6][C:7](=[O:11])[C:8]=2[C:9]#[N:10])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CSc1nc(Cc2ccsc2)[nH]c(=O)c1C#N
Reactant: NC1CCCC1
Product: N#Cc1c(NC2CCCC2)nc(Cc2ccsc2)[nH]c1=O

Procedure:
In analogy to the preparation of Example 1, 150 mg (0.57 mmol) of 4-(methylsulphanyl)-6-oxo-2-(3-thienylmethyl)-1,6-dihydropyrimidine-5-carbonitrile are reacted with 485 mg (5.70 mmol) of cyclopentylamine to give 46 mg (26% of theory) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[F:22][C:23]1[CH:42]=[CH:41][C:26]([CH2:27][NH:28][C:29]([C:31]2[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=2)=[O:30])=[CH:25][CH:24]=1>CN(C=O)C>[F:22][C:23]1[CH:24]=[CH:25][C:26]([CH2:27][NH:28][C:29](=[O:30])[C:31]2[CH:36]=[CH:35][C:34]([S:37]([N:9]3[C:10]4=[N:11][CH:12]=[CH:13][CH:14]=[C:15]4[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8]3)(=[O:38])=[O:39])=[CH:33][CH:32]=2)=[CH:41][CH:42]=1
Reactant: c1ccc(-c2c[nH]c3ncccc23)cc1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)n2cc(-c3ccccc3)c3cccnc32)cc1
Reaction time: 0.08 h
Yield: 18.5 %

Procedure:
Slowly add 3-phenyl-1H-pyrrolo[2,3-b]pyridine (178 mg, 0.915 mmol, 1.0 eq) as a 2 ml DMF solution to a flask under N2 containing potassium tertbutoxide (108 mg, 0.961 mmol, 1.05 eq) in 1 ml DMF solution. Stir solution for 5 minutes. Slowly add 4-(4-Fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (300 mg, 0.915 mmol, 1.0 eq) as a 3 ml DMF solution. Stir reaction for 18 hours at room temperature. Strip reaction of solvent and purify on silica gel chromatography to give N-(4-Fluoro-benzyl)-4-(3-phenyl-pyrrolo[2,3-b]pyridine-1-sulfonyl)-benzamide (82 mg, 18% yield). Mass Spectrum (m/e): 485.94 (MH+).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[CH2:12][C:13]1([C:22]#[N:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1>CCOCC>[O:7]1[CH2:11][CH2:10][O:9][CH:8]1[CH2:12][C:13]1([CH2:22][NH2:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1
Reactant: N#CC1(CC2OCCO2)CCc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: NCC1(CC2OCCO2)CCc2ccccc21
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A 1M solution of lithium aluminum hydride in Et2O was added dropwise to a solution of 1-(1,3-dioxolan-2-ylmethyl)-1-indanecarbonitrile (9.9376 g, 43.343 mmole) in Et2O at 0° C. After warming to room temperature overnight the reaction was quenched by the dropwise addition of water resulting in a fine white precipitate. The solid was filtered of and washed 4 times with 100 ml of Et2O. The combined ether layers were evaporated to afford 8.1770 g of [1-(1,3-dioxolan-2-ylmethyl)-2,3-dihydro-1H-inden-1-yl]methanamine (81% yield) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:40]([Cl:41])=[CH:39][C:5]2[NH:6][C:7]([O:9][CH:10]([C:19]3([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=5)=[CH:27][CH:26]=4)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[N:8][C:4]=2[CH:3]=1.[CH2:42]([N:44]=[C:45]=[O:46])[CH3:43].C(N(C(C)C)CC)(C)C>ClCCl>[CH2:42]([NH:44][C:45]([N:22]1[CH2:23][CH2:24][C:19]([C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=3)=[CH:27][CH:26]=2)([CH:10]([O:9][C:7]2[NH:8][C:4]3[CH:3]=[C:2]([Cl:1])[C:40]([Cl:41])=[CH:39][C:5]=3[N:6]=2)[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:20][CH2:21]1)=[O:46])[CH3:43]
Reactant: C[Si](C)(C)CCOCC(Oc1nc2cc(Cl)c(Cl)cc2[nH]1)C1(c2ccc(-c3cccc(C#N)c3)cc2)CCNCC1
Reactant: CCN=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)N1CCC(c2ccc(-c3cccc(C#N)c3)cc2)(C(COCC[Si](C)(C)C)Oc2nc3cc(Cl)c(Cl)cc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.5 %

Procedure:
To a solution of 0.045 g of 4′-{4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-piperidin-4-yl}-biphenyl-3-carbonitrile (0.073 mmol, 1 eq) in 0.7 mL of dichloromethane was added ethyl isocyanate (6.5 μL, 0.088 mmol, 1.2 eq) and 15.4 μL of diisopropylethyl amine (0.088 mmol, 1.2 eq) and the resulting mixture was stirred at room temperature for 16 h. The solvent was removed by rotary evaporation to yield the crude product which was purified by preparative TLC eluting with 10% methanol in dichloromwthane to give 0.030 g of 4-(3′-cyano-biphenyl-4-yl)-4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-piperidine-1-carboxylic acid ethylamide. This intermediate was dissolved in 2 mL of tetrahydrofuran and 0.080 g of tetrabutylammonium fluoride on silica gel (1.0-1.5 mmol/g, 2 eq) was added. The mixture was heated at 60° C. for 16 h then filtered and the resin washed with 10 mL of tetrahydrofuran. The filtrate was concentrated by rotary evaporation and the crude product was purified by flash silica gel chromatography eluting with 1% methanol in dichloromethane with 3% triethylamine to give 0.0054 g of the desired product 4-(3′-cyano-biphenyl-4-yl)-4-(5,6-dichloro-1H-benzoimidazol-2-yloxymethyl)-piperidine-1-carboxylic acid ethylamide 58. MS (ESI): Calcd m/z for C29H27Cl2N5O2.H+=548.2; found m/z=547.8/549.8 [(M+1)+/(M+3)+].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:16]=[CH:17][CH:18]=1)[CH:7]=[C:8]([C:13]([CH3:15])=O)[C:9]([O:11][CH3:12])=[O:10])([O-:3])=[O:2].[NH2:19]/[C:20](/[CH2:29][N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)=[CH:21]\[C:22]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[O:23]>C(O)C>[CH3:12][O:11][C:9]([C:8]1[CH:7]([C:6]2[CH:16]=[CH:17][CH:18]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:21]([C:22]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[O:23])=[C:20]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)[NH:19][C:13]=1[CH3:15])=[O:10]
Reactant: COCCOC(=O)/C=C(\N)Cn1ccnc1
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: CCO
Product: COCCOC(=O)C1=C(Cn2ccnc2)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1

Procedure:
A mixture of methyl 2-(3-nitrobenzylidene)-acetoacetate (2.5 g, 0.01 mol), ethanol (20 ml) and 2-methoxyethyl 3-amino-4-(imidazol-1-yl)crotonate (3 g) is heated at reflux for 5 hours to give the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Mg].II.[CH2:15]([N:22]1[CH2:27][CH2:26][C:25](=[C:28]([C:34]#[N:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+]>C(OCC)C.O1CCCC1>[C:34]([CH:28]([C:25]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)[CH2:24][CH2:23][N:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:27][CH2:26]1)[C:29]([O:31][CH2:32][CH3:33])=[O:30])#[N:35]
Reactant: Brc1ccc2ccccc2c1
Reactant: CCOC(=O)C(C#N)=C1CCN(Cc2ccccc2)CC1
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)C(C#N)C1(c2ccc3ccccc3c2)CCN(Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.9 %

Procedure:
2-Bromonaphthalene (26 g) was dissolved in anhydrous diethyl ether (100 ml) and ⅕ of this solution added to a vigourously stirred mixture of magnesium turnings (3.3 g) and 2-3 iodine crystals under a nitrogen atmosphere. Gentle heating was applied to initiate formation of the Grignard reagent since it proved difficult to maintain spontaneous refluxing. The remainder of the 2-bromonaphthalene solution was added in 4 portions, allowing the refluxing to subside after each addition, and the mixture finally heated under reflux for 1 hour after which time two dark organic phases had formed. The mixture was cooled in an ice-bath and anhydrous tetrahydrofiran (50 ml) added followed by dropwise addition of a solution of ethyl 2-(1-benzylpiperidin-4-ylidene)-2-cyanoacetate (12 g) (see Preparation 2) in tetrahydrofuran (100 ml). The single phase mixture was stirred at 0° C. for 30 minutes before being left to stand at room temperature overnight. The mixture was then poured into saturated aqueous ammonium chloride solution (450 ml) and extracted twice with diethyl ether. The organic extracts were combined and the solvent removed under reduced pressure to give a residue which was chromatographed on silica gel eluting with a solvent gradient of 4:0 changing to 4:1, by volume, dichloromethane:diethyl ether to give the title compound (5.9 g) as an oil.
Reaction SMILES: [NH2:1][C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[O:24][CH3:25])(=[O:14])=[O:13])[C:3]1=[O:26].[H][H]>CO.C1COCC1.[Ni]>[NH2:1][C:2]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[O:24][CH3:25])(=[O:14])=[O:13])[C:3]1=[O:26]
Reactant: COc1cc([N+](=O)[O-])ccc1S(=O)(=O)N1C(=O)C(N)(c2ccccc2Cl)c2cc(Cl)ccc21
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(N)ccc1S(=O)(=O)N1C(=O)C(N)(c2ccccc2Cl)c2cc(Cl)ccc21

Procedure:
2.17 g of the compound obtained in EXAMPLE 16 in 30 ml of MeOH and 30 ml of THF are reduced with hydrogen under a pressure of 40 bar for 4 hours at RT, in the presence of 1 g of Raney nickel. The mixture is vacuum. The residue is chromatographed on silica using DCM and then a DCM/AcOEt mixture (90/10; v/v) as the eluent to give the expected product after crystallization from a DCM/iso ether mixture. m=1.3 g. M.p.=198° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].N1C=CC=CC=1.[N:31]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:37]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:38])[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)N3CCOCC3)c1)N2
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.9 %

Procedure:
To a solution of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (324 mg, 1 mmol) in dichloromethane (5 mL) and pyridine (0.5 mL, 6 mmol) was added a solution of morpholine-4-carbonyl chloride (0.12 mL, 1 mmol) in dichloromethane (2 mL) dropwise at 0° C. The reaction mixture was stirred at 25° C. for 5 h. Then the reaction mixture was extracted with dichloromethane (2×50 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3,3-dimethyl-2-{3-[(morpholine-4-carbonyl)-amino]-phenyl}-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (437 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C25H31N3O4 (M+H)+: 438.54, observed: 438.2.
Reaction SMILES: [BH4-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P:15]([CH2:20][P:21](=[O:24])([OH:23])[OH:22])([O:17]CC)=[O:16]>CC(O)C.O.Cl>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][P:15]([CH2:20][P:21](=[O:22])([OH:23])[OH:24])([OH:17])=[O:16]
Reactant: CCOP(=O)(CCCCCCCCCCCN)CP(=O)(O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: NCCCCCCCCCCCP(=O)(O)CP(=O)(O)O
Temperature: 10 °C

Procedure:
((11—N-phthalimidoundecyl)-ethoxyphosphinyl)methylphosphonic acid dimethyl ester (37.15 g, 78 mmol) was dissolved in a mixture of 2-propanol (165 mL) and water (26 mL). The mixture was cooled to about 10° C. in an ice bath and NaBH4 (11.11 g, 293 mmol, 3.8 eq.) was added slowly. The mixture was filtered and then cooled to below 5° C. in an ice bath. Acetic acid (70 mL) was then added slowly to the mixture. When the addition was complete the mixture was heated to 90° C. for 6 days. The mixture was then cooled to room temperature and the solvent removed. Residual water and acetic acid were removed from the residue azeotropically using ethyl acetate (200 mL), and then again using acetone two times (500 mL) and then again using toluene two times (500 mL). The resulting residue was free from acetic acid. This residue was partitioned between water (300 mL) and ethyl acetate (300 mL). The layers were separated and the organic layer was discarded. The aqueous layer was lyophilized to give a mixture of inorganic salts and ((11-aminoundecyl)-ethoxyphosphinyl)methylphosphonic acid. This solid was suspended in HCl (36%, 75 mL) and heated to 90° C. overnight. A clear solution was obtained. The mixture was cooled to room temperature and a solid precipitate formed. This solid was removed by centrifugation and found (by NMR) to contain no product. This solid was discarded. The supernatant was concentrated and again a solid appeared as a suspension in solution. HCl was removed from this suspension azeotropically using water (100 mL). After removal of HCl, an oily suspension was obtained. When additional water was added (100 mL), the product appeared as a white solid. This solid was collected by centrifugation. The solid was washed two times with acetone (70 mL) and dried in vacuum oven at 35° C. (recovery=9.98 g). A second crop was obtained by concentrating the supernatant and heating it with HCl (36%, 40 mL) for 2 hours. The solvent was removed to dryness and the mixture was suspended in water (20 mL), centrifuged to collect solid product, and the solid was washed with water (10 mL) and two times with acetone (20 mL) (recovery=2 g). 1H NMR (D2O) δ=2.3 (t, 2H), 1.6 (t, 2H), 1.4 (m, 2H), 1.2-1.0 (m, 18H). 31P NMR (D2O) δ=13.8, 42.6.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:8]([S:13][C:14]2[CH:15]=[C:16]([O:22][C:23]3[C:24]([CH3:29])=[N:25][CH:26]=[CH:27][CH:28]=3)[C:17]([C:20]#[N:21])=[N:18][CH:19]=2)=[N:9][CH:10]=[CH:11][CH:12]=1.[OH-:30].[Na+]>>[CH3:6][C:7]1[C:8]([S:13][C:14]2[CH:15]=[C:16]([O:22][C:23]3[C:24]([CH3:29])=[N:25][CH:26]=[CH:27][CH:28]=3)[C:17]([C:20]([NH2:21])=[O:30])=[N:18][CH:19]=2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1cccnc1Sc1cnc(C#N)c(Oc2cccnc2C)c1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cccnc1Sc1cnc(C(N)=O)c(Oc2cccnc2C)c1
Yield: 94.9 %

Procedure:
Concentrated sulfuric acid (8 mL) was added to 5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)picolinonitrile (1.40 g, 4.19 mmol). The reaction was stirred over the weekend, then poured onto ice (100 g), cooled in an ice bath and made basic to pH 10 with 50% NaOH. The reaction mixture was extracted with ethyl acetate, washed with brine, dried (MgSO4), and concentrated to afford 5-(3-methylpyridin-2-ylthio)-3-(2-methylpyridin-3-yloxy)picolinamide (1.40 g, 3.97 mmol, 94.9% yield) as a colorless oil which became a white crystalline solid overnight under vacuo.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[CH3:7].[C:8](OC(=O)C)(=[O:10])[CH3:9].P(=O)(O)(O)O>O>[Cl:1][C:2]1[S:3][C:4]([C:8]([CH3:9])=[O:10])=[CH:5][C:6]=1[CH3:7]
Reactant: Cc1ccsc1Cl
Reactant: CC(=O)OC(C)=O
Agent: O=P(O)(O)O
Solvent: O
Product: CC(=O)c1cc(C)c(Cl)s1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
A mixture of 20 g (0,15 mol) of 2-chloro-3-methylthiophene and 18,6 g (0,18 mol) of acetic acid anhydride were heated to 70° C. and 1,8 ml of orthophosphoric acid were dropped thereto such that the reaction temperature remained below 75° C. Then it was stirred 3 hours at 100° C., 50 ml of H2O were added, the organic phase was extracted twice with 10 ml of saturated NaHCO3 -solution, dried over Na2SO4 and fractionated distilled in vacuo. Yield 15,8 g (60%), b.p. 85°-88° C./4 mbar.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:40][CH2:41][C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:40][CH2:41][C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[C:19]([F:25])[CH:18]=2)[N:3]=1
Reactant: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)O)C3)nc(N)n2)cc1F
Reactant: NCc1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2cc(N3CCC[C@H](C(=O)NCc4ccncc4)C3)nc(N)n2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.3 %

Procedure:
To a solution of (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-3-piperidinecarboxylic acid (150 mg, 0.439 mmol), EDC (118 mg, 0.615 mmol), and HOBT (83 mg, 0.615 mmol) in DMF (3 mL) was added 4-(aminomethyl)pyridine (47.5 mg, 0.439 mmol), and the mixture was stirred at room temperature for 4 hours. LCMS showed reaction was completed. The reaction was poured onto water, and EtOAc was added to extract the product. The product stayed in the EtOAc layer. The organic solution was concentrated to dryness to give the title compound (190 mg) as a yellow solid. LC-MS (ES) m/z=432 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[C:15]([O:19][C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O.C(O)C.C1(C)C=CC=CC=1.CCOC(C)=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>[NH2:14][C:11]1[N:10]=[CH:9][C:8]([C:26]2[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=2)[C:20]([O:19][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:21])=[CH:13][N:12]=1
Reactant: Nc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)c1cccc(B(O)O)c1
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: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(-c2cnc(N)nc2)c1
Temperature: 120 °C
Yield: 73.5 %

Procedure:
Sodium carbonate (0.636 g, 6.0 mmol) in water (2.0 mL) was added to a mixture of 5-bromopyrimidin-2-amine (0.348 g, 2.0 mmol), [3-(tert-butoxycarbonyl)phenyl]boronic acid (0.533 g, 2.4 mmol) and tetrakis(triphenylphosphine)palladium (69 mg, 0.06 mmol) in ethanol (3.0 mL) and toluene (3.0 mL). The resulting mixture was heated at 120° C. for 3 h. The mixture was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was treated with methanol. The precipitate was filtered and dried to give the product (399 mg, 73.5%). 272.1.
Reaction SMILES: Br[C:2]1[C:3]([C@@H:13]([NH:23][C:24](=[O:41])[CH2:25][N:26]2[C:30]3[C:31]([F:36])([F:35])[C@@H:32]4[CH2:34][C@@H:33]4[C:29]=3[C:28]([C:37]([F:40])([F:39])[F:38])=[N:27]2)[CH2:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=2)=[N:4][CH:5]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:7]=1.[CH3:42][C:43]1[N:48]2[C:49](=[O:52])[NH:50][N:51]=[C:47]2[CH:46]=[CH:45][C:44]=1B1OC(C)(C)C(C)(C)O1.C(=O)(O)[O-].[Na+]>C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.Cl[Pd]Cl.O1CCOCC1>[F:36][C:31]1([F:35])[C:30]2[N:26]([CH2:25][C:24]([NH:23][C@H:13]([C:3]3[C:2]([C:44]4[CH:45]=[CH:46][C:47]5[N:48]([C:49](=[O:52])[NH:50][N:51]=5)[C:43]=4[CH3:42])=[CH:7][C:6]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])=[CH:5][N:4]=3)[CH2:14][C:15]3[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([F:22])[CH:16]=3)=[O:41])[N:27]=[C:28]([C:37]([F:40])([F:38])[F:39])[C:29]=2[C@H:33]2[CH2:34][C@@H:32]12
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)ccc2n[nH]c(=O)n12
Reactant: CS(=O)(=O)Nc1cnc([C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)c(Br)c1
Agent: Cl[Pd]Cl
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: Cc1c(-c2cc(NS(C)(=O)=O)cnc2[C@H](Cc2cc(F)cc(F)c2)NC(=O)Cn2nc(C(F)(F)F)c3c2C(F)(F)[C@@H]2C[C@H]32)ccc2n[nH]c(=O)n12
Temperature: 170 °C

Procedure:
A microwave tube was charged with N—((S)-1-(3-bromo-5-(methylsulfonamido)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide (41D, 20 mg, 0.03 mmol), 5-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (12.3 mg, 0.045 mmol) and PdCl2[P(Cy)3]2 (2.2 mg, 0.003 mmol). To the mixture was added 0.6 mL of 1,4-dioxane and 0.09 mL of sodium bicarbonate aqueous solution (1M). The system was purged with argon and then the microwave tube was sealed and the reaction mixture was heated in a microwave synthesizer at 170° C. for 15 min. After cooling, the reaction was partitioned between EtOAc and water. The organic layer was separated and washed with brine, then dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC eluting with acetonitrile and water (with 0.1% TFA) to afford the title compound. 1H NMR (400 MHz, methanol-d4) δ 8.91-8.48 (m, 1H), 7.40 (dd, J=13.1, 2.6 Hz, 1H), 7.07-5.77 (m, 5H), 5.38-5.02 (m, 1H), 4.85 (s, 2H), 3.29-2.92 (m, 5H), 2.66-1.95 (m, 5H), 1.41 (dd, J=8.1, 6.0 Hz, 1H), 1.10 (m, 1H). MS (m/z) 738.92 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:14][CH:13]=3)=[O:11])=[C:8]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[S:7][C:6]=2[CH:33]=1.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1>[C:34]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([C:10]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:16][CH:17]=3)=[O:11])=[C:8]([CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[S:7][C:6]=2[CH:33]=1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(C2CCCCC2)sc2cc(O)ccc12
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: O=C(Oc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(C3CCCCC3)sc2c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
27 mg of (6-hydroxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone was dissolved in 1 ml of pyridine, 0.1 ml of benzoyl chloride was added, and the mixture was stirred at room temperature for 1 hour. After addition of ice, the reaction mixture was stirred for 1 hour and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off, and the resultant crude product was purified by TLC (developing solvent, chloroform:methanol=9:1) to obtain 37 mg of (6-benzoyloxy-2-cyclohexylbenzo[b]thien-3-yl)[4-[2-(1-piperidinyl)ethoxy]phenyl]methanone.