Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([NH:10][C:11]2[C:16](I)=[CH:15][C:14]([S:18][CH3:19])=[CH:13][N:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([O:22][C:23]([C:25]1[CH:26]=[CH:27][C:28]([C:31]#[C:32][Si](C)(C)C)=[N:29][CH:30]=1)=[O:24])[CH3:21].C([O-])(=O)C.[K+].O>O1CCOCC1>[CH2:20]([O:22][C:23](=[O:24])[C:25]1[CH:26]=[CH:27][C:28]([C:31]2[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[C:11]3=[N:12][CH:13]=[C:14]([S:18][CH3:19])[CH:15]=[C:16]3[CH:32]=2)=[N:29][CH:30]=1)[CH3:21]
Reactant: CSc1cnc(NS(=O)(=O)c2ccccc2)c(I)c1
Reactant: CCOC(=O)c1ccc(C#C[Si](C)(C)C)nc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(-c2cc3cc(SC)cnc3n2S(=O)(=O)c2ccccc2)nc1
Temperature: 100 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
To a solution of 2-benzenesulfonylamino-5-methylthio-3-iodo-pyridine (100 mg) in 1,4-dioxane (2.5 ml), 5-ethoxycarbonyl-2-trimethylsilylethynylpyridine (185 mg), bistriphenylphosphine palladium dichloride (9 mg), cuprous iodide (5 mg) and potassium acetate (37 mg) were added successively and the mixture was stirred in a sealed tube at 100° C. for 15 hours. After cooling, the reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=2:1) to obtain 110 mg of the desired product as an orange oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1.[CH3:19][NH:20][CH3:21]>CO>[Cl:1][C:2]1[N:3]=[C:4]([N:20]([CH3:21])[CH3:19])[C:5]2[CH2:11][O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)COC2
Reactant: CNC
Solvent: CO
Product: CN(C)c1nc(Cl)nc2c1COCC2c1ccccc1
Yield: 100 %

Procedure:
A solution of 2,4-dichloro-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidine (135 mg, 0.480 mmol) and excess dimethylamine (216 mg, 4.80 mmol) in MeOH (2 mL) was stirred at rt for 1.5 h. The solvent was removed in vacuum to afford 2-chloro-N,N-dimethyl-8-phenyl-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-4-amine (139 mg, 0.480 mmol, 100% yield). LC-MS (M+H)+=290.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][NH:7][C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[CH2:13]([N:31]=[C:32]=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH2:13]([NH:31][C:32]([N:7]1[C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:8]1)=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: CC1(C)CNC(=O)CC(C)(C)N1
Product: CCCCCCCCCCCCCCCCCCNC(=O)N1CC(C)(C)NC(C)(C)CC1=O

Procedure:
Using the same procedure as described in Example 4, 17 parts of 2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one and 32 parts of n-octadecyl isocyanate were reacted together and afforded 4-n-octadecylcarbamoyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one as a colourless solid which was recrystallised from petroleum ether (of boiling range 60° to 80°C) and had a melting point of 56.5°-58°C. This material gave the following elemental analysis by weight:
Reaction SMILES: [N:1]1([C:7]2[C:8]([O:13][CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)[CH2:16][CH2:15]3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:37](Cl)(=[O:39])[CH3:38]>C(Cl)Cl>[N:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[N:17]1[CH2:18][CH2:19][CH:14]([O:13][C:8]2[C:7]([N:1]3[CH2:2][CH2:3][N:4]([C:37](=[O:39])[CH3:38])[CH2:5][CH2:6]3)=[N:12][CH:11]=[CH:10][N:9]=2)[CH2:15][CH2:16]1
Reactant: CC(=O)Cl
Reactant: c1ccc2nc(N3CCC(Oc4nccnc4N4CCNCC4)CC3)ccc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(c2nccnc2OC2CCN(c3ccc4ccccc4n3)CC2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75.8 %

Procedure:
To a solution of 2-(4-((3-(piperazin-1-yl)pyrazin-2-yl)oxy)piperidin-1-yl)quinoline (130 mg, 0.33 mmol) in dry DCM (10 mL) was added Et3N (1 mL). The reaction mixture was cooled to 0° C. with an ice bath, and acetyl chloride (80 mg, 0.66 mmol) was added dropped to the reaction mixture. 1 hour later, the reaction mixture was warmed to RT, and stirred overnight. Then the reaction mixture was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified via flash chromatography on silica gel (20% to 45% EtOAc in petroleum ether) to give 1-(4-(3-((1-(quinolin-2-yl)piperidin-4-yl)oxy)pyrazin-2-yl)piperazin-1-yl)ethanone (108 mg, 0.25 mmol, 78% yield) as a white solid. ESI-MS (M+1): 433 calc. for C24H28N6O2 432.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][N:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]2=[N:4][CH:3]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:36])([F:35])[F:34])=[CH:30][CH:31]=2)[C:26]([Sn](CCCC)(CCCC)CCCC)=[N:25]1>CN(C=O)C.[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29]([C:33]([F:34])([F:35])[F:36])=[CH:30][CH:31]=2)[C:26]([C:2]2[N:7]=[C:6]3[C:8]([C:19]([O:21][CH3:22])=[O:20])=[CH:9][N:10]([CH2:11][O:12][C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]3=[N:4][CH:3]=2)=[N:25]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2ccc(C(F)(F)F)cc12
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4ccc(C(F)(F)F)cc34)nc12
Temperature: 80 °C
Yield: 70.6 %

Procedure:
To a solution of methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (300 mg, 0.81 mmol) and 1-methyl-3-(tributylstannyl)-5-(trifluoromethyl)-1H-indazole (396 mg, 0.89 mmol) in DMF (10 mL) were added CuI (30 mg, 0.16 mmol) and Pd(PPh3)4 (47 mg, 0.041 mmol), the reaction mixture was degassed by bubbling nitrogen for 3 minutes and refilled with nitrogen. The mixture was heated to 80° C. for 5 hours under nitrogen, after cooling, water (50 mL) was added to the mixture and product extracted with EtOAc (3×40 mL), the combined organic layers were dried over Na2SO4, concentrated under reduced pressure and the residue was triturated with petroleum ether (2 mL) then decanted and dried to give methyl 2-(1-methyl-5-(trifluoromethyl)-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylate (280 mg, 70.7%) as an orange solid. LCMS: (M+H)+=490.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[N:11]=[C:12]([SH:14])[N:13]=[C:6]2[C:5]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:2][CH3:3].[CH3:25]I>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[N:11]=[C:12]([S:14][CH3:25])[N:13]=[C:6]2[C:5]=1[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc(C)n2nc(S)nc2c1Cc1ccc([N+](=O)[O-])cc1
Reactant: CI
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCc1nc(C)n2nc(SC)nc2c1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g of 7-n-propyl-5-methyl-2-mercapto-8-(4-nitrobenzyl)-1,2,4-triazolo[1,5-c]pyrimidine, prepared in Example 37, are dissolved in 50 ml of chloroform and 2.2 ml of triethylamine. 1.5 ml of methyl iodide are added and the mixture is stirred at room temperature for 2 hours and then left overnight. The mixture is then washed with dilute sodium hydroxide solution and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated under vacuum to give a residue which crystallise in an ether/pentane mixture to yield 4 g of 7-n-propyl-5-methyl-2-methylmercapto-8-(4-nitrobenzyl)-1,2,4triazolo[1,5-c]pyrimidine in the form of crystals of melting point 130° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N+:22]([O-])=O)=[C:8]([NH:11][C:12](=O)[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:9]=2)[N:4]([CH2:25]/[CH:26]=[CH:27]/[CH2:28][CH3:29])[C:3]1=[O:30]>C(O)(=O)C.[Fe]>[CH3:1][C:2]1([CH3:31])[C:10]2[CH:9]=[C:8]3[NH:11][C:12]([CH2:13][CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:22][C:7]3=[CH:6][C:5]=2[N:4]([CH2:25]/[CH:26]=[CH:27]/[CH2:28][CH3:29])[C:3]1=[O:30]
Reactant: CC/C=C/CN1C(=O)C(C)(C)c2cc(NC(=O)CCc3ccccc3)c([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: CC(=O)O
Product: CC/C=C/CN1C(=O)C(C)(C)c2cc3[nH]c(CCc4ccccc4)nc3cc21
Temperature: 25 °C
Yield: 82.6 %

Procedure:
N-[3,3-Dimethyl-6-nitro-2-oxo-1-((E)-pent-2-enyl)-2,3-dihydro-1H-indol-5-yl]-3-phenyl-propionamide (470 mg) is dissolved in acetic acid (7 ml) and iron powder (470 mg; 8.42 mmol) is added. The mixture is heated and irradiated in a microwave apparatus (150° C., 15 min) and afterwards cooled to RT. Aqueous work-up as described in Example 3b gives the desired compound (344 mg).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[C:8]([S:13][C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[C:7]([CH3:21])[C:6]=2[C:5]([OH:22])=[CH:4][CH:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36](=[O:39])[CH2:37]Br>ClCCl>[CH3:34][O:35][C:36](=[O:39])[CH2:37][O:22][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:21])=[C:8]([S:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:9]([CH3:12])=[N:10]2
Reactant: Cc1nc2c(Cl)ccc(O)c2c(C)c1Sc1ccc(Cl)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)COc1ccc(Cl)c2nc(C)c(Sc3ccc(Cl)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 8-chloro-3-(4-chlorophenylsulfanyl)-2,4-dimethylquinolin-5-ol (0.050 μg), N,N-dimethylformamide (2.0 mL), potassium carbonate (0.059 g) and bromoacetic acid methyl ester (0.031 g) was stirred at room temperature for 15 hours. The mixture was diluted with dichloromethane and this solution was washed with water and then dried over magnesium sulfate. The solvent was removed under reduced pressure to afford title compound as brown solid, 0.11 g.
Reaction SMILES: OCC1C(CO)CC1N1C=NC2C(=O)NC(N)=NC1=2.[OH:20][CH2:21][CH:22]1[CH:25]([CH2:26]O)[CH2:24][CH:23]1[N:28]1[CH:36]=[N:35][C:34]2[C:29]1=[N:30][CH:31]=[N:32][C:33]=2[NH2:37]>>[OH:20][CH2:21][CH:22]1[CH:25]([CH3:26])[CH2:24][CH:23]1[N:28]1[CH:36]=[N:35][C:34]2[C:29]1=[N:30][CH:31]=[N:32][C:33]=2[NH2:37]
Reactant: Nc1ncnc2c1ncn2C1CC(CO)C1CO
Agent: Nc1nc2c(ncn2C2CC(CO)C2CO)c(=O)[nH]1
Product: CC1CC(n2cnc3c(N)ncnc32)C1CO

Procedure:
Following the procedures described in Example 40, replacing 9-(2',3'-bis(hydroxymethyl)-cyclobutyl)guanine, the product of Example 1, with 9-(2',3'-bis(hydroxymethyl)cyclobutyl)adenine, Example 4, the title compound is prepared.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:35])[N:5]([C:12]1([CH2:20][CH2:21][CH2:22][CH2:23][NH:24]C(=O)OCC3C=CC=CC=3)[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[H][H].[ClH:38]>C(O)C.[Pd]>[ClH:38].[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:35])[N:5]([C:12]1([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11]
Reactant: [H][H]
Reactant: Nc1cccc2c1C(=O)N(C1(CCCCNC(=O)OCc3ccccc3)CCC(=O)NC1=O)C2=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: NCCCCC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Reaction time: 4 h
Yield: 69 %

Procedure:
To a solution of 6 (0.111 g, 0.232 mmol) in 2% HCl in ethanol (60 mL) was added palladium on activated charcoal (0.025 g) under an atmosphere of argon. The mixture was subsequently saturated with hydrogen using a hydrogen balloon. After 4 h, the mixture was flushed with argon, filtered using ethanol and methanol. Preparative HPLC afforded 7 (0.055 g, 69%) as a bright yellow solid. 1H NMR (400 MHz, DMSO) δ 8.31 (s, 1H), 7.52-7.34 (m, 1H), 6.94 (m, 2H), 6.53 (br s, 2H), 2.74 (t, J=7.4 Hz, 2H), 2.65 (m, 1H), 2.63-2.56 (m, 1H), 2.54 (m, 1H), 2.44 (m, 1H), 2.31 (m, 1H), 2.21 (m, 1H), 2.02 (m, 1H), 1.52 (m, 1H), 1.48-1.38 (m, 1H), 1.26 (m, 2H). MS (ESI) m/z calcd for C17H21N4O4 [M+H]+ 345.4, found 345.7.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([OH:29])=O)[CH2:10][CH:11]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:12][NH:13][C:14](=[NH:16])[NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.Cl.[NH2:58][CH2:59][C:60]([O:62]CC)=[O:61].CN1CCOCC1>ClCCl.CC(N(C)C)=O.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:27]([NH:58][CH2:59][C:60]([OH:62])=[O:61])=[O:29])[CH2:10][CH:11]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)(=[O:18])=[O:19])[CH2:12][NH:13][C:14](=[NH:16])[NH2:15])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)C(CNC(=N)N)C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CCOC(=O)CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)C(CNC(=N)N)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O)cc1

Procedure:
N-t-Butoxycarbonyl-g-p-toluenesulfonylarginine (10 mmoles), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP, 10 mmoles), ethyl glycinate hydrochloride (13 mmoles) and N-methylmorpholine (50 mmoles) are stirred in a mixture of dichloromethane and dimethylacetamide (1:1, 50 ml) for 2 hr at room temperature. At the end of the reaction time the mixture is acidified with acetic acid, concentrated in vacuo, and the residue taken up in ethyl acetate. The resulting solution is washed with 10% citric acid (3 times), water (2 times), saturated sodium bicarbonate (3 times), water (2 times) and brine (2 times). The organic solution is dried over magnesium sulfate, filtered, dried and concentrated to afford the crude ethyl ester of the title compound. Crystalline material can be obtained from ethyl acetate-hexane mixtures.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:10]([C:33]([F:36])([F:35])[F:34])=[C:11]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][NH:29][CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[F:15].[CH3:37][CH:38]([CH3:43])[CH2:39][C:40](Cl)=[O:41]>>[F:8][C:9]1[C:10]([C:33]([F:34])([F:35])[F:36])=[C:11]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][N:29]([C:40](=[O:41])[CH2:39][CH:38]([CH3:43])[CH3:37])[CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:20][CH2:21]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: CC(C)CC(=O)Cl
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC(=O)N1CCc2c(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)n[nH]c2C1

Procedure:
Following general procedure GP-E1, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone TFA salt (34) and 3-methylbutanoyl chloride were converted to l-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-1,4,5,7-tetrahydro-6Hpyrazolo[3,4-c]pyridin-6-yl)-3-methylbutan-1-one as a white solid (37 mg, 63%): mp 184-188° C.; 1H NMR (500 MHz, DMSO-d6) δ 13.13-13.11 (m, 0.25H), 12.87-12.84 (m, 0.75H), 7.79-7.70 (m, 1H), 7.51-7.49 (m, 1H), 4.89-4.86 (m, 1H), 4.67-4.57 (m, 3H), 3.67-3.64 (m, 2H), 3.15-3.13 (m, 2H), 2.79-2.77 (m, 1H), 2.68-2.64 (m, 2H), 2.55-2.51 (m, 1H, partially merged with DMSO peak), 2.02 (pent, J=7.0 Hz, 1H), 1.76-1.70 (m, 4H), 1.26 (t, J=7.0 Hz, 1H), 0.92-0.90 (m, 6H); ESI MS m/z 499 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:22](=[O:23])[NH:21][C:10]3=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:12]=[N:13][CH:14]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:31][C:32]1[N:33]([CH3:37])[N:34]=[CH:35][N:36]=1.O>CN(C=O)C>[C:1]1([C:7]2[C:22]([O:23][CH2:31][C:32]3[N:33]([CH3:37])[N:34]=[CH:35][N:36]=3)=[N:21][C:10]3=[C:11]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:12]=[N:13][CH:14]=[C:9]3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1ncnc1CCl
Reactant: O=c1[nH]c2c(-c3ccccc3)nncc2cc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncnc1COc1nc2c(-c3ccccc3)nncc2cc1-c1ccccc1

Procedure:
3,8-Diphenyl-1H-pyrido[2,3-d]pyridazin-2-one (40 mg), cesium carbonate (174 mg) and 3-(chloromethyl)-2-methyl-2H-[1,2,4]triazole (prepared using the conditions described in EP-A-0170073) (27 mg) were stirred together at room temperature in DMF (4 ml) under nitrogen overnight. Water (25 ml) was added and the resultant solution was washed with dichloromethane (3×25 ml). The combined organic washings were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel, eluting with 5% methanol in dichloromethane. The product was recrystallised froim diethyl ether/ethanol/ethyl acetate, yielding 3,8-diphenyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrido[2,3-d]pyridazine as a white solid (8 mg). Data for the title compound: m.p. 222-223° C. 1H NMR (400 MHz, CDCl3) δ3.62 (3H, s), 5.67 (2H, s), 7.48 (3H, m), 7.56 (3H, m), 7.63 (2H, m), 7.85 (1H, s), 8.13 (2H, m), 8.20 (1H, s), 9.49 (1H, s); MS (ES+) m/e 395 [MH]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]=[C:11]=[O:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.[CH3:13][O:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]1>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([NH:19][C:18]3[CH:20]=[CH:21][C:15]([O:14][CH3:13])=[C:16]([N:22]4[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]4)[CH:17]=3)=[O:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C=Nc1ccc2c(c1)CCO2
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc3c(c2)CCO3)cc1N1CCN(C)CC1
Yield: 47.3 %

Procedure:
To a stirred solution of 2,3-dihydrobenzofuran-5-yl isocyanate (D3, 0.248 g, 1.5 mmol) in CH2Cl2 (20 ml) was added to a solution of 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP 0533268A1, 0.309 g, 1.4 mmol) in CH2Cl2 (10 ml). After 18 hours a precipitate had formed which was filtered off, washed with CH2Cl2 and dried under vacuum to afford the title compound as a cream coloured solid (0.253 g, 47%).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4N4C=NN=N4)=[CH:20][CH:19]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:35]1[CH:39]=[N:38][N:37]=[N:36]1>>[CH:1]1([CH2:7][C:8]2[N:12]=[C:11]([CH2:13][CH2:14][CH2:15][CH3:16])[N:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:39]4[NH:38][N:37]=[N:36][N:35]=4)=[CH:20][CH:19]=3)[N:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCCc1nc(CC2CCCCC2)nn1Cc1ccc(-c2ccccc2-n2cnnn2)cc1
Reactant: c1nnn[nH]1
Product: CCCCc1nc(CC2CCCCC2)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
The slower moving isomer from Example 73 was deprotected to provide 51 mg of 5-[4′-[(3-cyclohexylmethyl-5-butyl-1H-1,2,4-triazol-1-yl)methyl]([1,1-biphenyl]-2-yl]-1H-tetrazole as a colorless solid: NMR (CDCl3) δ 0.84 (t, J=8 Hz, 3H), 0.92 (q, J=8 Hz, 2H), 1.05–1.22 (m, 3H), 1.22–1.36 (m, 2H), 1.52–1.69 (m, 8H), 2.5–0 (d, J=7 Hz, 2H), 2.63 (t, J=8 Hz, 2H), 5.18 (s, 2H), 7.05 (q, J=8 Hz, 4H), 7.35–7.55 (m, 3H), 7.68 (dd, J=8 and 2 Hz, 1H); MS (FAB) m/e (rel intensity) 456 (90), 413 (10), 281 (10), 243 (10), 222 (35), 207 (100), 192 (35); HRMS. Calc'd for M+H: 456.2876. Found: 456.2849.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:11][C:10](=[O:12])[C:8]=2[CH:9]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[CH2:11][C:10](=[O:12])[C:8]=2[CH:9]=1
Reactant: O=C1Cc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-nitrocyclobutabenzen-1(2H)-one (900 mg, 5.52 mmol) in ethanol (25 mL) under a stream of nitrogen was added palladium on carbon (587 mg, 10%, 0.55 mmol). The mixture was placed under a hydrogen atmosphere (balloon) and stirred at ambient temperature for 16 hours. The reaction vessel was charged with nitrogen and the mixture filtered (ethanol wash). The filtrate was concentrated and purified by chromatography (silica gel, 20% EtOAc/hexanes) to provide the title compound. MS (DCI/NH3) m/z 151 (M+NH4)+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[CH3:10][O:11][C:12](=[O:42])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:30]=[C:29]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:28]=[C:27](Br)[CH:26]=2)=[CH:17][C:16]=1[CH3:41]>CN(C=O)C.C(N(CC)CC)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.[Cu]I>[CH3:10][O:11][C:12](=[O:42])[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][C:25]2[CH:26]=[C:27]([C:3]#[C:2][CH2:1][N:4]3[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:28]=[C:29]([C:31]#[C:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[CH:30]=2)=[CH:17][C:16]=1[CH3:41]
Reactant: C#CCN1CCCCC1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCCCC3)c2)cc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCCCC3)cc(C#CCN3CCCCC3)c2)cc1C
Temperature: 60 °C

Procedure:
A mixture of 1-prop-2-ynyl-piperidine (322 mg, 2.62 mmol), (4-{3-[3-bromo-5-(3-piperidin-1-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (204 mg, 0.4 mmol, example 3), Pd(PPh3)4 (50 mg, 0.044 mmol), CuI (23 mg, 0.122 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 30 min at 60° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using ethyl acetate/methanol mixtures to give (4-{3-[3,5-bis-(3-piperidin-1-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester in 138 mg (57%) yield.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[C:7](=[O:16])[CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][N:8]([C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[C:7](=[O:16])[CH:6]=1
Reactant: [N-]=[N+]=NCc1ccn(-c2ccsc2)c(=O)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccn(-c2ccsc2)c(=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
To a solution of crude 4-azidomethyl-1-thiophen-3-yl-1H-pyridin-2-one in tetrahydrofuran (2 mL) is added triphenylphosphine (0.19 g). The mixture is stirred for 10 minutes before the addition of water (200 μL). After stirring for 16 hours at room temperature, the mixture is purified by reverse-phase high performance liquid chromatography (5% acetonitrile/95% water to 75% acetonitrile/25% water over 45 minutes) to provide 4-aminomethyl-1-thiophen-3-yl-1H-pyridin-2-one (60 mg, 34% over 2 steps).